Yeong Kwok, MD
CASE 1
A. The four types of osteogenesis imperfecta are type I (mild), type II (perinatal, lethal), type III (progressive, deforming), and type IV (deforming with normal scleras). All forms of osteogenesis imperfecta are characterized by increased susceptibility to fractures (“brittle bones”), but there is considerable phenotypic heterogeneity, even within individual subtypes. Approximately one fourth of the cases of type I or type IV osteogenesis imperfecta represent new mutations; in the remainder, the history and examination of other family members reveal findings consistent with autosomal dominant inheritance. Type III is also transmitted as an autosomal dominant trait, although type III can occasionally be transmitted in an autosomal recessive manner. Type II, the most severe form, generally occurs as a result of a sporadic dominant mutation.
B. Type II osteogenesis imperfecta presents at birth (or even in utero) with multiple fractures and bony deformities, resulting in death in infancy and, therefore, not likely to be seen in a child 4 years of age. Type III presents at birth or in early infancy with multiple fractures—often prenatal—and progressive bony deformities. The absence of prenatal fractures and early deformities in this patient’s history is most suggestive of type I or type IV osteogenesis imperfecta. These individuals generally present in early childhood with one or a few fractures of long bones in response to minimal or no trauma, as seen in this case. Type I and type IV osteogenesis imperfecta are differentiated by their clinical severity and scleral hue. Type I tends to be less severe, with 10–20 fractures during childhood plus short stature but few or no deformities. These patients tend to have blue scleras. Patients with type IV osteogenesis imperfecta tend to have more fractures, resulting in significant short stature and mild to moderate deformities. Their scleras are normal or gray.
C. In patients with type I osteogenesis imperfecta, the fracture incidence decreases after puberty and the main features in adult life are mild short stature, conductive hearing loss, and occasionally dentinogenesis imperfecta (defective dentin formation in tooth development).
D. Advances in the last two decades demonstrate two genetically different groups: the “classical” group, in which more than 90% of cases are caused by a mutation of the COL1A1 or COL1A2 genes, which encode the subunits of type I collagen, proα1(I) and proα2(I), respectively, and a newer group, caused by loss-of-function mutations in proteins required for proper folding, processing, and secretion of collagen. The fundamental defect in most individuals with type I osteogenesis imperfecta is reduced synthesis of type I collagen resulting from loss-of-function mutations in COL1A1. Several potential molecular defects are responsible for COL1A1 mutations in type I osteogenesis imperfecta, including alterations in a regulatory region leading to reduced transcription, splicing abnormalities leading to reduced steady-state levels of RNA, and deletion of the entire COL1A1 gene. However, in many cases, the underlying defect is a single base pair change that creates a premature stop codon (also known as a “nonsense mutation”) in an internal exon. In a process referred to as “nonsense-mediated decay,” partially synthesized mRNA precursors that carry the nonsense codon are recognized and degraded by the cell. Each of these mutations gives rise to greatly reduced (partial loss-of-function) or no (complete loss-of-function) mRNA. Because the nonmutant COL1A1 allele continues to produce mRNA at a normal rate (ie, there is no dosage compensation), heterozygosity for a complete loss-of-function mutation results in a 50% reduction in the total rate of proα1(I) mRNA synthesis, whereas heterozygosity for a partial loss-of-function mutation results in a less severe reduction. A reduced concentration of pro1(I) chains limits the production of type I procollagen, leading to both a reduced amount of structurally normal type I collagen and an excess of unassembled proα2(I) chains, which are degraded inside the cell. This ultimately results in fragile bones.
CASE 2
A. The primary metabolic defect in phenylketonuria (PKU) is the inability to hydroxylate phenylalanine, an essential step in the conversion of phenylalanine to tyrosine and the synthesis of protein. This condition is most commonly due to a defect in phenylalanine hydroxylase, the responsible enzyme, or less commonly, to a defect in the metabolism of tetrahydrobiopterin (BH4), an essential co-factor in the hydroxylation of phenylalanine. This leads to the accumulation of phenylalanine and its metabolites.
B. The accumulation of phenylalanine and its metabolites, especially phenylpyruvate, directly reduces energy production and protein synthesis, and affects neurotransmitter homeostasis in the developing brain, since many neurotransmitters are derived from amino acids. Elevated levels of phenylalanine also inhibit amino acid transport across the blood-brain barrier, causing an amino acid deficit in the cerebrospinal fluid. All these effects combine to cause mental retardation, developmental delay, and seizures. Affected individuals also suffer from eczema, the mechanism of which is not well understood, and have hypopigmentation due to inhibition of melanocytes from the excess phenylalanine. Most, if not all, of the above consequences of PKU can be prevented by strict dietary management to ensure that excessive serum phenylalanine concentrations do not occur.
C. PKU is inherited as an autosomal recessive trait. The reproductive fitness of affected untreated individuals is poor, meaning that they are unlikely to produce offspring. Theories have been proposed about why the trait has persisted at a relatively high rate in the population. It is known that the rate of spontaneous PKU mutation is low. Two potential explanations for the high rate of the defective gene are the founder effect and heterozygote advantage. The founder effect occurs when a population founded by a small number of ancestors has by chance a high frequency of a deleterious gene. Heterozygote advantage refers to the fact that certain genes may actually confer a benefit in the heterozygote state even though the homozygote state is disadvantageous. This is the case for the genetic defect in sickle cell disease, in which heterozygote carriers have a relative resistance to malaria.
CASE 3
A. Fragile X–associated mental retardation is a syndrome caused by a genetic mutation of the X chromosome. The mutation leads to failure of the region between bands Xq27 and Xq28 to condense at metaphase, thereby increasing the “fragility” of the region. The mutation appears as an amplification of a (CGG)n repeat within the untranslated region of a gene named FMR1. The FMR1 gene encodes an RNA-binding protein named FMR1. However, in affected individuals, amplification of the gene results in methylation of an area known as the CpG island, located at Xq27.3. This methylation prevents expression of the FMR1 protein.
The FMR1 protein is normally expressed in brain and testes. This protein resembles a group of proteins named hnRNPs (heterogeneous nuclear RNA-binding proteins) that function in the processing or transport of nuclear mRNA precursors. It is believed that the FMR1 protein plays a general role in the cellular metabolism of nuclear RNA but only in the tissues in which it is primarily expressed (ie, the CNS and testes). This would explain in part the symptoms of mental retardation and enlarged testes. It is not known why the absence of FMR1 expression leads to joint laxity and hyperextensibility and facial abnormalities.
B. Fragile X–associated mental retardation is an X-linked disease. Given that a male child inherits his X chromosome from his mother, she is clearly the carrier of the mutation.
The boy’s mother and grandparents do not demonstrate the phenotype of fragile X–associated mental retardation because of the processes of premutation and parental imprinting. As mentioned, the mutation in fragile X is associated with amplification of a segment of DNA containing the sequence (CGG)n. This segment is highly variable in length. In individuals who are neither carriers nor affected, the number of repeats is generally less than 50. In transmitting males and unaffected carrier females, the number of repeats is usually between 70 and 100. Alleles with 55 or more repeats are unstable and often exhibit expansion after maternal transmission; these individuals are generally considered to carry the premutation. They are unaffected phenotypically, but the regions are unstable, and when transmitted from generation to generation, the regions tend to undergo amplification into a full mutation. Although premutation carriers do not develop a typical FMR syndrome, recent studies indicate that female premutation carriers exhibit a 20% incidence of premature ovarian failure, whereas male premutation carriers are at increased risk for a tremor-ataxia syndrome. In both cases, the mechanism is likely to be explained by somatic expansion of the premutation. Full mutations, observed in all affected individuals, always have more than 200 amplifications.
The most important determinant of whether a premutation allele is subject to amplification is the sex of the parent who transmits the premutation allele. A premutation allele transmitted by a female expands to a full mutation with a likelihood proportionate to the length of the premutation. In contrast, a premutation allele transmitted by a male rarely expands to a full mutation regardless of the length of the premutation. This process is called parental imprinting. Thus, it is likely that the boy’s mother and grandfather are carriers of a premutation allele and are, therefore, unaffected and that this gene amplified to a full mutation on transmission to the boy.
C. The chance that her unborn child will be affected depends on its gender. If it is a boy, the chance that it will be affected is approximately 80%, whereas if it is a girl the chance is only 32%.
CASE 4
A. Leber hereditary optic neuropathy (LHON) arises from a mutation in mitochondrial DNA (mtDNA). The mtDNA encodes protein components of the electron transport chain involved in the generation of adenosine triphosphate (ATP). Mutations in the mtDNA can result in the inability to generate ATP. This defect especially affects tissues with intensive ATP use such as the skeletal muscle and the central nervous system. It is not understood why the defect in LHON is largely confined to the optic nerve and the retina. Other mitochondrial disorders do affect skeletal muscle, most notably, mitochondrial encephalomyopathy with ragged red fibers (MERRF).
B. LHON is inherited through mtDNA mutations. All the mtDNA in our bodies comes exclusively from the egg. The sperm makes no contribution of mtDNA. Therefore, LHON is inherited only from the mother. In addition, a typical cell carries 10–100 separate mtDNA molecules, only a fraction of which carry the mutation. This is known as heteroplasmy. Within any one affected woman, the level of mutant DNA in different eggs may vary from 10% to 90%. Thus, some offspring may be severely affected, while others may not show any signs. Furthermore, within any given offspring, the level of mutant mtDNA will vary from tissue to tissue and from cell to cell.
C. LHON affects males 4 to 5 times more often than females. This difference is thought to be due to a factor on the X chromosome that modifies the severity of a mitochondrial mutation. Even though mtDNA encodes essential components of the electron transport chain, there are copies for most mitochondrial components also encoded on the nuclear genome.
CASE 5
A. Down syndrome occurs approximately once in every 700 live births. Common features include developmental delay, growth retardation, congenital heart disease (50%), immunodeficiency, and characteristic major and minor facial and dysmorphic features, including upslanting palpebral fissures (82%), excess skin on the back of the neck (81%), brachycephaly (75%), hyperextensible joints (75%), flat nasal bridge (68%), epicanthal folds (59%), small ears (50%), and transverse palmar creases (53%).
B. There are two major genetic abnormalities associated with Down syndrome. The most common abnormality occurs in children born to parents with normal karyotypes. It is caused by nondisjunction of chromosome 21 during meiotic segregation, resulting in one extra chromosome 21 or in trisomy 21 with 47 chromosomes on karyotyping. Alternatively, Down syndrome can be caused by DNA rearrangement resulting in fusion of chromosome 21 to another acrocentric chromosome via its centromere. This abnormal chromosome is called a robertsonian translocation chromosome. Unlike those with trisomy 21, these individuals have 46 chromosomes on karyotyping. This type of translocation can sometimes be inherited from a carrier parent.
Both of these genetic abnormalities result in a 50% increase in gene dosage for nearly all genes on chromosome 21. In other words, the amount of protein produced by all or nearly all genes on chromosome 21 is approximately 150% of normal in Down syndrome. The genes that have been shown to contribute to the Down syndrome phenotype include the gene that encodes the amyloid protein found in the senile plaques of Alzheimer disease and the one that encodes the cytoplasmic form of superoxide dismutase, which plays an important role in free radical metabolism.
C. It is not known why advanced maternal age is associated with an increased risk of Down syndrome. One theory suggests that biochemical abnormalities affect the ability of paired chromosomes to disjoin and that these abnormalities accumulate over time. Because germ cell development is completed in females before birth, these biochemical abnormalities are able to accumulate within the egg cells as the mother ages, thereby increasing the risk of nondisjunction. Another hypothesis is that structural, hormonal, and immunologic changes occur in the uterus as the woman ages, producing an environment less able to reject a developmentally abnormal embryo. Therefore, an older uterus would be more likely to support a trisomy 21 conceptus to term. Alternatively, it is possible that a combination of these and other genetic factors may contribute to the relationship between advanced maternal age and an increased incidence of Down syndrome.
CASE 6
A. Cross-linking of surface-bound IgE by antigen activates tissue mast cells and basophils, inducing the immediate release of preformed mediators and the synthesis of newly generated mediators. Mast cells and basophils also have the ability to synthesize and release proinflammatory cytokines, which are growth and regulatory factors that interact in complex networks. The interaction of mediators with various target organs and cells of the airway can induce a biphasic allergic response: an early phase mediated chiefly by release of histamine and other stored mediators (tryptase, chymase, heparin, chondroitin sulfate, and tumor necrosis factor [TNF]), whereas late-phase events are induced after generation of arachidonic acid metabolites (leukotrienes and prostaglandins), platelet-activating factor, and de novocytokine synthesis.
Histologically, the early response is characterized by vascular permeability, vasodilatation, tissue edema, and a mild cellular infiltrate of mostly granulocytes. The late-phase response is characterized by erythema, induration, heat, burning, and itching and microscopically by a significant cellular influx of mainly eosinophils and mononuclear cells. Changes consistent with airway remodeling and tissue hyper-reactivity may also occur.
B. Patients with allergic rhinitis develop chronic or episodic paroxysmal sneezing; nasal, ocular, or palatal pruritus; and watery rhinorrhea triggered by exposure to a specific allergen. Patients may demonstrate signs of chronic pruritus of the upper airway, including a horizontal nasal crease from frequent nose rubbing (“allergic salute”) and palatal “clicking” from rubbing the itching palate with the tongue. Symptoms of nasal obstruction may become chronic as a result of persistent late-phase allergic mechanisms. Nasal mucous membranes may appear pale blue and boggy. Children frequently show signs of obligate mouth breathing, including long facies, narrow maxillae, flattened malar eminences, marked overbite, and high-arched palates (so-called adenoid facies).
C. Serous otitis media and sinusitis are major comorbidities in patients with allergic rhinitis. Both conditions occur secondarily to the obstructed nasal passages and sinus ostia in patients with chronic allergic or nonallergic rhinitis. Complications of chronic rhinitis should be considered in patients with protracted rhinitis unresponsive to therapy, refractory asthma, or persistent bronchitis. Serous otitis results from auditory tube obstruction by mucosal edema and hypersecretion. Children with serous otitis media can present with conductive hearing loss, delayed speech, and recurrent otitis media associated with chronic nasal obstruction.
Sinusitis may be acute, subacute, or chronic depending on the duration of symptoms. Obstruction of osteomeatal drainage in patients with chronic rhinitis predisposes to bacterial infection in the sinus cavities. Patients manifest symptoms of persistent nasal discharge, cough, sinus discomfort, and nasal obstruction. Examination may reveal chronic otitis media, infraorbital edema, inflamed nasal mucosa, and purulent nasal discharge. Radiographic diagnosis by x-ray film or computed tomographic (CT) scan reveals sinus opacification, membrane thickening, or the presence of an air-fluid level.
CASE 7
A. The most likely cause of this child’s recurrent infections is severe combined immunodeficiency disease (SCID). These patients have complete or near-complete failure of development of both cellular and humoral components of the immune system. Placental transfer of maternal immunoglobulin is insufficient to protect these children from infection, and for that reason they present at a very early age with severe infections.
B. SCID is a heterogeneous group of genetic and cellular disorders characterized by a failure in the cellular maturation of lymphoid stem cells, resulting in reduced numbers and function of both B and T lymphocytes and hypogammaglobulinemia. The genetic and cellular defects can occur at many different levels, starting with surface membrane receptors, but also including deficiencies in signal transduction or metabolic biochemical pathways. Although the different molecular defects may cause clinically indistinguishable phenotypes, identification of specific mutations allows for improved genetic counseling, prenatal diagnosis, and carrier detection.
The most common genetic defect is an X-linked form of SCID (XSCID) in which the maturation defect is mainly in the T-lymphocyte lineage and is due to a point mutation in the γ chain of the IL-2 receptor. This defective γ chain is shared by the receptors for IL-4, IL-7, IL-9, and IL-15, leading to dysfunction of all of these cytokine receptors. Defective signaling through the IL-7 receptor appears to block normal maturation of T lymphocytes. Circulating B-cell numbers may be preserved, but defective IL-2 responses inhibit proliferation of T, B, and NK cells, explaining the combined immune defects seen in XSCID patients.
Several autosomally inherited defects have also been identified. A defect in the α chain of the IL-7 receptor can lead to an autosomal recessive form of SCID through mechanisms similar to XSCID but with intact NK cells.
About 20% of SCID cases are caused by a deficiency of adenosine deaminase (ADA), which is an enzyme in the purine salvage pathway, responsible for the metabolism of adenosine. Absence of the ADA enzyme results in an accumulation of toxic adenosine metabolites within the cells. These metabolites inhibit normal lymphocyte proliferation and lead to extreme cytopenia of both B and T lymphocytes. The combined immunologic deficiency and clinical presentation of this disorder, known as SCID-ADA, are identical to those of the other forms of SCID. Skeletal abnormalities and neurologic abnormalities may be associated with this disease.
An alternate autosomally recessive form of SCID is a deficiency of ZAP-70, a tyrosine kinase important in normal T-lymphocyte function. Deficiency of this tyrosine kinase results in total absence of CD8 T lymphocytes and functionally defective CD4 T lymphocytes, but normal B-lymphocyte and NK activity. Mutations of CD3δ, CD3γ, and CD3ε subunits may lead to partially arrested development of TCR expression and severe T-cell deficiency.
Deficiencies of both p56kk and Jak3 (Janus kinase 3) can also lead to SCID through defective signal transduction; p56kk is a T-cell receptor–associated tyrosine kinase that is essential for T-cell differentiation, activation, and proliferation. Jak3 is a cytokine receptor–associated signaling molecule. Finally, patients have been identified with defective recombination activating gene (RAG-1 and RAG-2) products. RAG-1 and RAG-2 initiate recombination of antigen-binding proteins, immunoglobulins and T-cell receptors. The defect leads to both quantitative and qualitative (functional) deficiencies of T and B lymphocytes.
C. Without treatment, most patients with SCID die within the first 1–2 years.
CASE 8
A. This child has X-linked agammaglobinemia, formerly called Bruton agammaglobinemia. The history of multiple infections occurring after the age of 6 months, the family history of a maternal uncle with lethal infection, the severe current infection with Streptococcus pneumoniae, and the absence of circulating B lymphocytes are characteristic of this disorder.
B. The main defect is a mutation in the BTK (Bruton tyrosine kinase) gene, which is located on the X chromosome. This gene’s product is a B-cell–specific signaling protein necessary for normal B-cell maturation. The mutation affects the catalytic domain of the protein, halting B-cell maturation. This, in turn, leads to absence or greatly reduced levels of the immunoglobulins IgA, IgG, and IgM. Their absence or reduction is a particular problem with fighting infections from encapsulated bacteria because these bacteria require antibody binding for efficient opsonization. Therefore, patients are particularly susceptible to infections with bacteria such as Haemophilus influenzae and S pneumoniae. Because they cannot mount an antibody response, they also develop very little immunity to these infections and are thus susceptible to repeated infections with the same organism.
C. The affected child is relatively protected by circulating maternal antibodies until 4–6 months of age. The child’s immune system is otherwise unaffected, but as the levels of maternal antibodies decrease, the child becomes increasingly susceptible to infection, particularly from encapsulated bacteria.
CASE 9
A. Individuals with common variable immunodeficiency (CVI) commonly develop recurrent sinopulmonary infections such as sinusitis, otitis media, bronchitis, and pneumonia. Common pathogens are encapsulated bacteria such as S pneumoniae, H influenzae, and Moraxella catarrhalis. Bronchiectasis may develop as a result of these recurrent infections. They may also develop GI malabsorption from bacterial overgrowth or chronic Giardia infection in the small bowel.
B. CVI is a heterogeneous disorder in which the primary immunologic abnormality is a marked reduction in antibody production, with normal or reduced numbers of circulating B cells. This is most commonly caused by a defect in the terminal differentiation of B lymphocytes in response to T-lymphocyte–dependent and T-lymphocyte–independent stimuli. However, defects in B-lymphocyte development have been shown to occur at any stage of the maturation pathway.
In many patients, the defect is intrinsic to the B-lymphocyte population. Approximately 15% of patients with CVI demonstrate defective B-cell surface expression of TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor), a member of the TNF receptor family. Lacking a functional TACI, the affected B cells will not respond to B-cell–activating factors, resulting in deficient immunoglobulin production. Another defect, which may lead to CVI, involves deficient expression of the B-cell surface marker, CD19. When complexed with CD21 and CD81, CD19 facilitates cellular activation through B-cell receptors. B-cell development is not affected but humoral function is deficient. A variety of T-cell abnormalities may also lead to immune defects with subsequent impairment of B-cell differentiation. A mutation of inducible T-cell costimulator gene (ICOS), expressed by activated T cells and responsible for B-cell activation and antibody production, may be the molecular defect in some cases of CVI. T-lymphocyte dysfunction can be manifested as increased suppressor T-lymphocyte activity, decreased cytokine production, defective synthesis of B-lymphocyte growth factors, defective cytokine gene expression in T cells, decreased T-cell mitogenesis, and deficient lymphokine-activated killer cell function.
C. Individuals with CVI are at increased risk of autoimmune disorders and malignancies. The autoimmune disorders most commonly seen in association with CVI include immune thrombocytopenic purpura, hemolytic anemia, and symmetric seronegative arthritis. The malignancies associated with CVI include lymphomas, gastric carcinoma, and skin cancers.
D. Treatment is mainly symptomatic along with replacement of immune globulin with monthly infusions of IVIG.
CASE 10
A. Pneumocystis pneumonia is commonly seen in AIDS. An HIV-1 antibody test should be obtained whenever the diagnosis of Pneumocystis jirovecii is suspected.
B. AIDS is the consequence of infection with HIV-1, a retrovirus that infects multiple cell lines, including lymphocytes, monocytes, macrophages, and dendritic cells. With HIV infection, there is an absolute reduction of CD4 T lymphocytes, an accompanying deficit in CD4 T-lymphocyte function, and an associated increase in CD8 cytotoxic T lymphocytes (CTLs). In addition to the cell-mediated immune defects, B-lymphocyte function is altered such that many infected individuals have marked hypergammaglobulinemia but impaired specific antibody responses. The resultant immunosuppression predisposes patients to the constellation of opportunistic infections that characterizes AIDS.
The loss of CD4 cells seen in HIV infection is the result of multiple mechanisms, including (1) autoimmune destruction, (2) direct viral infection and destruction, (3) fusion and formation into multinucleated giant cells, (4) toxicity of viral proteins to CD4 T lymphocytes and hematopoietic precursors, and (5) apoptosis (programmed cell death).
C. The clinical manifestations of HIV infection and AIDS are the direct consequence of progressive and severe immunosuppression and can be correlated with the degree of CD4 T-lymphocyte destruction. HIV infection may present as an acute, self-limited febrile syndrome. This is often followed by a long, clinically silent period, sometimes associated with generalized lymphadenopathy. The time course of disease progression may vary; the majority of individuals remain asymptomatic for 5–10 years. Approximately 70% of HIV-infected individuals will develop AIDS after a decade of infection. Approximately 10% of those infected manifest rapid progression to AIDS within 5 years after infection. A minority of individuals are “long-term nonprogressors.” Genetic factors, host cytotoxic immune responses, and viral load and virulence all appear to have an impact on susceptibility to infection and the rate of disease progression. Multidrug antiretroviral therapy has dramatically changed this natural history and markedly prolonged survival.
As the CD4 count declines, the incidence of infection increases. At CD4 counts between 200/μL and 500/μL, patients are at an increased risk for bacterial infections, including pneumonia and sinusitis. As CD4 counts continue to drop—generally below 250/μL—they are at high risk for opportunistic infections such as pneumocystic pneumonia, candidiasis, toxoplasmosis, cryptococcal meningitis, cytomegalovirus (CMV) retinitis, and Mycobacterium aviumcomplex infection. HIV-infected individuals are also at increased risk for certain malignancies, including Kaposi sarcoma, non-Hodgkin lymphoma, primary CNS lymphoma, invasive cervical carcinoma, and anal squamous cell carcinoma. Other manifestations of AIDS include AIDS dementia complex, peripheral neuropathy, monoarticular and polyarticular arthritides, unexplained fevers, and weight loss. Since patients are living longer due to potent antiretroviral therapies (ART), cardiovascular complications are more prominent. ART has been associated with dyslipidemia and metabolic abnormalities including insulin resistance. HIV infection may be atherogenic as well, through effects on lipids and proinflammatory mechanisms.
CASE 11
A. This patient’s presentation is characteristic of untreated infective endocarditis, an infection of the cardiac valves. The most common predisposing factor is the presence of structurally abnormal cardiac valves related to rheumatic heart disease, congenital heart disease, prosthetic valve, or prior endocarditis. Injection drug use is also an important risk factor for this disease. The patient’s history of significant illness as a child after a sore throat suggests the possibility of rheumatic heart disease.
B. The most common infectious agents causing native valve endocarditis are gram-positive bacteria, including viridans group streptococci, S aureus, and enterococci. Given the history of recent dental work, the most likely pathogen in this patient would be viridans group streptococci, which are normal mouth flora that can become transiently bloodborne after dental work.
C. The hemodynamic factors that predispose patients to the development of endocarditis include (1) a high-velocity jet stream causing turbulent flow, (2) flow from a high- to a low-pressure chamber, and (3) a comparatively narrow orifice separating two chambers that creates a pressure gradient. The lesions of endocarditis tend to form on the surface of the valve in the lower pressure cardiac chamber. The predisposed, damaged endothelium of an abnormal valve—or jet stream–damaged endothelium—promotes the deposition of fibrin and platelets, forming sterile vegetations. When bacteremia occurs, such as after dental work, microorganisms can be deposited on these sterile vegetations. Once infected, the lesions continue to grow through further deposition of platelets and fibrin. These vegetations act as a sanctuary from host defense mechanisms such as phagocytosis and complement-mediated lysis. It is for this reason that prolonged administration of bactericidal antibiotics and possible operative intervention are required for cure.
D. The painful papules found on the pads of this man’s fingers and toes are Osler nodes. They are thought to be caused by deposition of immune complexes in the skin. The painless hemorrhagic macules (Janeway lesions) and splinter hemorrhages are thought to result from microembolization of the cardiac vegetations.
E. In addition to the symptoms described in this man (fever, chills, night sweats, malaise, Roth spots, Janeway lesions, splinter hemorrhages, and Osler nodes), patients with infective endocarditis can develop multisystem complaints, including headaches, back pain, focal neurologic symptoms, shortness of breath, pulmonary edema, chest pain, cough, decreased urine output, hematuria, flank pain, abdominal pain, and others. These symptoms and signs reflect (1) hemodynamic changes from valvular damage, (2) end-organ damage by septic emboli (right-sided endocarditis causes emboli to the lungs; left-sided endocarditis causes emboli to the brain, spleen, kidney, GI tract, and extremities), (3) immune complex deposition causing acute glomerulonephritis, and (4) persistent bacteremia and distal seeding of infection, resulting in abscess formation.
Death is usually caused by hemodynamic collapse after rupture of the aortic or mitral valves or by septic emboli to the CNS, resulting in brain abscesses or mycotic aneurysms with resultant intracranial hemorrhage. Risk factors for a fatal outcome include left-sided cardiac involvement, bacterial causes other than viridans group streptococci, medical comorbidities, complications from endocarditis (heart failure, valve ring abscess, or embolic disease), and, for those with large vegetations and significant valvular destruction, delayed valvular surgery.
CASE 12
A. The most likely diagnosis in this patient is meningitis. The acuity and severity of presentation are most consistent with a pyogenic bacterial cause, although viral, mycobacterial, and fungal causes should be considered as well. In adults, the most likely bacterial pathogens are Neisseria meningitidis and S pneumoniae. In newborns younger than 3 months, the most common pathogens are those to which the infant is exposed in the maternal genitourinary canal, including E coli and other gram-negative bacilli, group B and other streptococci, and Listeria monocytogenes. Between the ages of 3 months and 15 years, N meningitidis and S pneumoniae are the most common pathogens. H influenzae, previously the most common cause of meningitis in this age group, is now primarily a concern in the unimmunized child.
B. Most cases of bacterial meningitis begin with colonization of the host’s nasopharynx. This is followed by local invasion of the mucosal epithelium and subsequent bacteremia. Cerebral endothelial cell injury follows and results in increased blood-brain barrier permeability, facilitating meningeal invasion. The resultant inflammatory response in the subarachnoid space causes cerebral edema, vasculitis, and infarction, ultimately leading to decreased cerebrospinal fluid flow, hydrocephalus, worsening cerebral edema, increased intracranial pressure, and decreased cerebral blood flow.
Bacterial pathogens responsible for meningitis possess several characteristics that facilitate the steps just listed. Nasal colonization is facilitated by pili on the bacterial surface of N meningitidis that assist in mucosal attachment. N meningitidis, H influenzae, and S pneumoniae also produce IgA proteases that cleave IgA, the antibody commonly responsible for inhibiting adherence of pathogens to the mucosal surface. By cleaving the antibody, the bacteria are able to evade this important host defense mechanism. In addition, N meningitidis, H influenzae, and S pneumoniae are often encapsulated, which can assist in nasopharyngeal colonization as well as systemic invasion. The capsule inhibits neutrophil phagocytosis and resists classic complement-mediated bactericidal activity, enhancing bacterial survival and replication.
It remains unclear how bacterial pathogens gain access to the CNS. It is thought that cells of the choroid plexus may contain receptors for them, facilitating movement into the subarachnoid space. Once the bacterial pathogen is in the subarachnoid space, host defense mechanisms are inadequate to control the infection. Subcapsular surface components of the bacteria, such as the cell wall and lipopolysaccharide, induce a marked inflammatory response mediated by IL-1, IL-6, matrix metalloproteinases, and TNF. Despite the induction of a marked inflammatory response and leukocytosis, there is a relative lack of opsonization and bactericidal activity such that the bacteria are poorly cleared from the cerebrospinal fluid. The host inflammatory response, with cytokine and proteolytic enzyme release, leads to loss of membrane integrity, with resultant cellular swelling and cerebral edema, contributing to many of the pathophysiologic consequences of this disease.
C. Cerebral edema may be vasogenic, cytotoxic, or interstitial in origin. Vasogenic cerebral edema is principally caused by the increase in the blood-brain barrier permeability that occurs when the bacteria invade the cerebrospinal fluid. Cytotoxic cerebral edema results from swelling of the cellular elements of the brain. This occurs because of toxic factors released by the bacteria and neutrophils. Interstitial edema is due to obstruction of cerebrospinal fluid flow.
D. Any patient suspected of having bacterial meningitis should have emergent lumbar puncture with Gram stain and culture of the cerebrospinal fluid. If there is concern about a focal neurologic problem—such as may occur with abscess—CT or MRI of the brain may be performed before lumbar puncture.
Antibiotics should be started immediately, without waiting for imaging study or lumbar puncture if delay is anticipated in these procedures. Corticosteroids should also be given if pneumococcal meningitis is suspected. The importance of the immune response in triggering cerebral edema has led researchers to study the role of adjuvant anti-inflammatory medications for bacterial meningitis. The use of corticosteroids has been shown to decrease the risk of sensorineural hearing loss among children with H influenzae meningitis and mortality among adults with pneumococcal meningitis. The benefit of adjuvant corticosteroids for other types of meningitis is unproven.
CASE 13
A. The patient described in this case has a moderately severe infection and an underlying diagnosis of COPD, requiring hospitalization but not ICU admission. The most likely pathogens are S pneumoniae, H influenzae, and M catarrhalis. Other potential pathogens include Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella pneumophila, and respiratory viruses. Tuberculosis and fungi should also be considered, although these are less likely in this patient with such an acute presentation. Anaerobes are also unlikely without a history of substance abuse or recent depressed mental status. If this patient required ICU admission, the atypical pathogens, M pneumoniae and C pneumoniae, are much less likely, and S aureus and Pseudomonas aeruginosa should be added to the differential diagnosis, particularly if the patient had been recently hospitalized.
B. Pulmonary pathogens reach the lungs by one of four routes: (1) inhalation of infectious droplets into the lower airways, (2) aspiration of oropharyngeal contents, (3) spread along the mucosal membrane surface, and (4) hematogenous spread.
C. Normal pulmonary antimicrobial defense mechanisms include the following: (1) aerodynamic filtration by subjection of incoming air to turbulence in the nasal passages and then abrupt changes in the direction of the airstream as it moves through the pharynx and tracheobronchial tree; (2) the cough reflex to remove aspirated material, excess secretions, and foreign bodies; (3) the mucociliary transport system, moving the mucous layer upward to the larynx; (4) phagocytic cells, including alveolar macrophages and PMNs, as well as humoral and cellular immune responses, which help to eliminate the pathogens; and (5) pulmonary secretions containing surfactant, lysozyme, and iron-binding proteins, which further aid in bacterial killing.
D. Common host risk factors include the following: (1) an immunocompromised state, resulting in immune dysfunction and increased risk of infection; (2) chronic lung disease, resulting in decreased mucociliary clearance; (3) alcoholism or other reduction of the level of consciousness, which increases the risk of aspiration; (4) injection drug abuse, which increases the risk of hematogenous spread of pathogens; (5) environmental or animal exposure, resulting in inhalation of specific pathogens; (6) residence in an institution, with its associated risk of microaspirations, and exposure via instrumentation (catheters and intubation); and (7) recent influenza infection, leading to disruption of respiratory epithelium, ciliary dysfunction, and inhibition of PMNs. This patient has a history of chronic lung disease, increasing his risk of pneumonia, and he is immunocompromised by the use of corticosteroids for his COPD.
CASE 14
A. There are three primary modes of transmission of pathogens causing infectious diarrhea. Pathogens such as Vibrio cholerae are water-borne and transmitted via a contaminated water supply. Several pathogens, including S aureusand Bacillus cereus, are transmitted by contaminated food. Finally, some pathogens, such as Shigella and Rotavirus, are transmitted by person-to-person spread and are, therefore, commonly seen in institutional settings such as child care centers.
B. The description of this patient’s diarrhea as profuse and watery suggests a small bowel site of infection. The small bowel is the site of significant electrolyte and fluid transportation. Disruption of this process leads to the production of profuse watery diarrhea, as seen in this patient.
C. The most likely cause of diarrhea in this patient, who has recently returned from Mexico, is enterotoxigenic E coli (ETEC), which is the most common cause of traveler’s diarrhea. Diarrhea results from the production of two enterotoxins that “poison” the cells of the small intestine, causing watery diarrhea. ETEC produces both a heat-labile and a heat-stable enterotoxin. The heat-labile enterotoxin activates adenylyl cyclase and formation of cAMP, which stimulates water and electrolyte secretion by intestinal endothelial cells. The heat-stable toxin produced by ETEC results in guanylyl cyclase activation, also causing watery diarrhea.
CASE 15
A. Factors that contribute to hospital-related sepsis are invasive monitoring devices, indwelling catheters, extensive surgical procedures, and the increased numbers of immunocompromised patients.
B. Sepsis generally starts with a localized infection. Bacteria may then invade the bloodstream directly (leading to bacteremia and positive blood cultures) or may proliferate locally and release toxins into the bloodstream. Gram-negative bacteria contain an endotoxin, the lipid A component of the lipopolysaccharide-phospholipid-protein complex present in the outer cell membrane. Endotoxin activates the coagulation cascade, the complement system, and the kinin system as well as the release of several host mediators such as cytokines, platelet-activating factor, endorphins, endothelium-derived relaxing factor, arachidonic acid metabolites, myocardial depressant factors, nitric oxide, and others. As sepsis persists, host immunosuppression plays a critical role. Specific stimuli such as organism, inoculum, and site of infection stimulate CD4 T cells to secrete cytokines with either inflammatory (type 1 helper T cell) or anti-inflammatory (type 2 helper T cell) properties (Figure 4-11). Among patients who die of sepsis, there is significant loss of cells essential for the adaptive immune response (B lymphocytes, CD4 T cells, dendritic cells). Apoptosis is thought to play a key role in the decrease in these cell lines and downregulates the surviving immune cells.
C. A hyperdynamic circulatory state, described as distributive shock to emphasize the maldistribution of blood flow to various tissues, is the common hemodynamic finding in sepsis. The release of vasoactive substances (including nitric oxide) results in loss of normal mechanisms of vascular autoregulation, producing imbalances in blood flow with regional shunting and relative hypoperfusion of some organs. Myocardial depression also occurs, with reduction in both the left and the right ventricular ejection fractions and increases in end-diastolic and end-systolic volumes. This myocardial depression has been attributed to direct toxic effects of nitric oxide, TNF, and IL-1. Refractory hypotension can ensue, resulting in end-organ hypoperfusion and injury.
D. Organ failure results from a combination of decreased perfusion and microvascular injury induced by local and systemic inflammatory responses to infection. Maldistribution of blood flow is accentuated by impaired erythrocyte deformability, with microvascular obstruction. Aggregation of neutrophils and platelets may also reduce blood flow. Demargination of neutrophils from vascular endothelium results in further release of inflammatory mediators and subsequent migration of neutrophils into tissues. Components of the complement system are activated, attracting more neutrophils and releasing locally active substances such as prostaglandins and leukotrienes. The net result of all of these changes is microvascular collapse and, ultimately, organ failure.
E. The outcome in sepsis depends on the number of organs that fail, with a mortality rate of 70% in patients who develop failure of three or more organ systems.
CASE 16
A. Carcinoid tumors arise from neuroendocrine tissue, specifically the enterochromaffin cells. These cells migrate during embryogenesis to the submucosal layer of the intestines and the pulmonary bronchi. Therefore, carcinoid tumors are most commonly found in the intestines and lungs.
B. Since carcinoid tumors are derived from neuroendocrine tissue, they can secrete many peptides that have systemic effects. This secretion is due to the inappropriate activation of latent synthetic ability that all neuroendocrine cells possess. Many of the peptides are vasoactive and can cause vasodilation, resulting in flushing. They can also cause wheezing, diarrhea, excessive salivation, or fibrosis of the heart valves or other tissues.
C. Serotonin production is characteristic of gut carcinoid tumors. Serotonin is metabolized to 5-HIAA. Therefore, finding high levels of 5-HIAA in a 24-hour urine collection in a patient with flushing or other symptoms is highly suggestive of the diagnosis. Bronchial carcinoids rarely produce 5-HIAA and, therefore, rarely present with carcinoid syndrome; instead, they often produce ectopic ACTH, resulting in the Cushing syndrome.
CASE 17
A. Adenomas are thought to be related to colorectal carcinoma by means of stepwise genetic alterations (or hits), with adenomas representing a precancerous lesion that may ultimately progress to cancer. It is believed that stepwise genetic alterations, including both oncogene activation and tumor suppressor gene inactivation, result in phenotypic changes that progress to neoplasia.
B. Two principal lines of evidence support the model of stepwise genetic alterations in colon cancer: (1) Familial colon cancer syndromes are known to result from germline mutations, implicating a genomic cause. Familial adenomatous polyposis is the result of a mutation in the APC gene, whereas hereditary nonpolyposis colorectal carcinoma is associated with mutations in the DNA repair genes hMSH2 and hMLH1. (2) Several factors linked to an increased risk of colon cancer are known to be carcinogenic. Substances derived from bacterial colonic flora, foods, or endogenous metabolites are known to be mutagenic. Levels of these substances can be decreased by taking a low-fat, high-fiber diet. Epidemiologic studies suggest that such a change in diet might reduce the risk of colon cancer.
C. The earliest molecular defect in the pathogenesis of colon cancer is the acquisition of somatic mutations in the APC gene in the normal colonic mucosa. This defect causes abnormal regulation of β-catenin, which leads to abnormal cell proliferation and the initial steps in tumor formation. Subsequent defects in the TGF-β signaling pathway inactivate this important growth inhibitory pathway and lead to further tumor mucosal proliferation and the development of small adenomas. Mutational activation of the K-ras gene leads to constitutive activation of an important proliferative signaling pathway and is common at these stages. It further increases the proliferative potential of the adenomatous tumor cells. Deletion or loss of expression of the DCC gene is common in the progression to invasive colon cancers. The DCC protein is a transmembrane protein of the immunoglobulin superfamily and may be a receptor for certain extracellular molecules that guide cell growth or apoptosis. Mutational inactivation of p53 is also a commonly observed step in the development of invasive colon cancer, seen in late adenomas and early invasive cancers, and leads to loss of an important cell cycle checkpoint and inability to activate the p53-dependent apoptotic pathways. In parallel to these sequential abnormalities in the regulation of cell proliferation, colon cancers also acquire defects in mechanisms that protect genomic stability. These generally involve mutations in mismatch repair genes or genes that prevent chromosomal instability, including MSH2, MLH1, PMS1, and PMS2. Germline mutations in these genes cause the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. Nonhereditary colon cancers develop genomic instability through defects in the chromosomal instability (CIN) genes. Defects in these genes lead to the gain or loss of large segments or entire chromosomes during replication, leading to aneuploidy.
D. Early in the progression of dysplasia, disrupted architecture results in the formation of fragile new blood vessels and destruction of existing blood vessels. These changes often occur before invasion of the basement membrane and, therefore, before progression to true cancer formation. These friable vessels can cause microscopic bleeding. This can be tested for by fecal occult blood testing, an important tool in the early detection of precancerous and cancerous colonic lesions.
CASE 18
A. Linkage analysis has identified genetic markers that are known to confer a high risk of developing breast cancer. Two such genes in particular have been found, BRCA1 and BRCA2. Both are involved in repair of DNA. Inherited mutations of BRCA1 or BRCA2 are associated with a lifetime risk of developing breast cancer of up to 80%. Mutations in these genes are also associated with a high incidence of ovarian cancer and can lead to increased incidences of prostate cancer, melanoma, and breast cancer in males.
B. There are two major subtypes of breast cancer. Ductal carcinomas arise from the collecting ducts in the breast glandular tissue. Lobular carcinomas arise from the terminal lobules of the glands.
C. While it is still contained by the basement membrane, the tumor is called carcinoma in situ. Invasive carcinoma occurs when tumor cells breach the basement membrane. Both ductal and lobular carcinomas may be either in situ or invasive. By definition, an in situ tumor does not carry a risk of spreading to the lymph nodes or of creating distant metastases. Finding an in situ tumor raises the affected individual’s risk of developing a subsequent breast cancer, in either breast, and of either subtype. Therefore, carcinoma in situ is a marker of heightened susceptibility to developing invasive breast cancer.
D. There are specific therapies that target receptors present in breast cancer. The amount of estrogen exposure is correlated with breast cancer risk. Antiestrogen therapy has long been used with success in patients with estrogen receptor–positive breast cancer, although half of patients diagnosed with breast cancer are estrogen receptor–negative. More recently, antibodies that target the HER2 receptor, a tyrosine kinase growth factor receptor, are used in tumors with an overexpression of the HER2 receptor.
CASE 19
A. Testicular cancer arises from germinal elements within the testes. Germ cells give rise to spermatozoa and thus can theoretically retain the ability to differentiate into any cell type. The pluripotent nature of these cells is witnessed in the production of mature teratomas. These benign tumors often contain mature elements of all three germ cell layers, including hair and teeth.
B. During early embryogenesis, germline epithelium migrates along the midline of the embryo. This migration is followed by formation of the urogenital ridge and ultimately the aggregation of germline cells to form the testes and ovaries. The pattern of migration of the germline epithelium predicts the location of extragonadal testicular neoplasms. These neoplasms are found in the midline axis of the lower cranium, mediastinum, and retroperitoneum.
C. One can monitor the serum concentrations of proteins expressed during embryonic or trophoblastic development to monitor tumor progression and response to therapy. These proteins include alpha-fetoprotein and human chorionic gonadotropin.
CASE 20
A. Sarcomas arise from mesenchymal tissue. These include myocytes, adipocytes, osteoblasts, chondrocytes, fibroblasts, endothelial cells, and synovial cells.
B. Many sarcomas are more common in younger people. This is thought to be because the cells of origin such as chondrocytes or osteoblasts are dividing more rapidly in childhood and adolescence than in adulthood.
C. Because osteosarcomas arise from osteoblasts, they retain their ability to produce a bone matrix of calcium and phosphorus within the tumor.
CASE 21
A. The theory that chronic immune stimulation or modulation may play an early role in the formation of lymphoma is supported by several observations. Iatrogenic immunosuppression, as seen in this patient and in other transplant patients, can increase the risk of B-cell lymphoma, possibly associated with Epstein-Barr virus infection. An increased risk of lymphoma is also seen in other immunosuppressed patients, such as those with AIDS and autoimmune diseases.
B. This patient has been diagnosed with a follicular cleaved cell lymphoma, a well-differentiated or low-grade lymphoma. Low-grade lymphomas retain the morphology and patterns of gene expression of mature lymphocytes, including cell surface markers such as immunoglobulin in the case of B lymphocytes. Their clinical course is generally more favorable, being characterized by a slow growth rate. Paradoxically, however, these lymphomas tend to present at a more advanced stage, as in this case.
C. Follicular lymphomas arise from lymphoblasts of the B-cell lineage. Common chromosomal abnormalities include translocations of chromosome 14, including t(14;18), t(11;14), and t(14;19). The t(14;18) translocation results in a fusion gene known as IgH;bcl-2, which juxtaposes the immunoglobulin heavy chain enhancer on chromosome 14 in front of the bcl-2 gene on chromosome 18. This results in enhanced expression of an inner mitochondrial protein encoded by bcl-2, which has been found to inhibit the natural process of cell death, or apoptosis. Apoptosis is required to remove certain lymphoid clones whose function is not needed. Inhibition of this process probably contributes to proliferation of lymphoma cells.
D. This patient’s symptoms of fever and weight loss are known as B symptoms. They are thought to be mediated by a variety of cytokines produced by lymphoma cells or may occur as a reaction of normal immune cells to the lymphoma. Two commonly implicated cytokines are IL-1 and TNF.
CASE 22
A. Like all neoplasms, leukemias are classified by their cell of origin. The first branch point is whether the malignant cell is of myeloid or lymphoid lineage, resulting in either a myeloid or lymphocytic leukemia. All types can be acute, presenting with more than 20% blasts on bone marrow biopsy, or chronic, presenting in a more indolent fashion with a usually slowly progressive course of many years. Lymphocytic leukemias are further divided into T-cell or B-cell leukemias depending on the type of lymphoid cell of origin. This type can be distinguished by the cluster of differentiation (CD) antigens found on the surface of the tumor cells. Myeloid leukemias are also divided into subtypes depending on the type of myeloid cell from which the leukemia arises. AML types M1–M3 arise from myeloblasts. Types M4 and M5 arise from monocytes. Type M6 arises from erythrocyte precursors, called normoblasts. Type M7 arises from platelet precursors, called megakaryoblasts.
B. Acute leukemias typically present with pancytopenia, or a decrease in the counts of all of the normal blood cells, including the normal white cells (the leukemic cells accounting for almost all of the high total WBCs), red blood cells, and platelets. This is caused by the crowding out of normal precursors in the bone marrow by the abnormally dividing blast cells, and by the inhibition of normal hematopoiesis due to secretion of cytokines and inhibitory substances. The patient’s presenting symptoms are directly related to the blood abnormalities. The fatigue and pallor are due to the anemia (lack of red blood cells) and the resulting reduced oxygen-carrying capacity. The petechiae and bleeding are from the lack of platelets, inhibiting the ability of the blood to clot. Patients with leukemia are susceptible to serious infections due to the lack of normal WBCs. Finally, the markedly elevated numbers of leukemic cells can clog small blood vessels and result in strokes, retinal vein occlusion, and pulmonary infarction.
C. Chromosomal deletions, duplications, and translocations have been identified in leukemias. One such genetic abnormality is the so-called Philadelphia chromosome, a balanced translocation of chromosomes 9 and 22, that is commonly found in chronic myelogenous leukemia (CML). This translocation results in a fusion gene, bcr-abl, which encodes a kinase that phosphorylates key proteins involved in cell growth. Targeted therapies that inhibit the enzymatic function of the bcr-abl kinase by competing with the ATP-binding site, induce remissions in most patients in chronic phases of CML.
CASE 23
A. The most likely cause of anemia in this patient is iron deficiency. Iron deficiency anemia is the most common form of anemia. In developed nations, it is primarily the result of iron loss, almost always through blood loss. In men and in postmenopausal women, blood is most commonly lost from the GI tract, as in this case. In premenopausal women, menstrual blood loss is the major cause of iron deficiency.
In this man, there are no symptoms of significant bleeding from the gut as would be manifested by gross blood (hematochezia) or metabolized blood in the stool (melena, usually described as black-colored stool), and he has no GI complaints. This makes some of the benign GI disorders such as peptic ulcer, arteriovenous malformations, and angiodysplasias less likely. He has no symptoms of inflammatory bowel disease such as diarrhea or abdominal pain. Concern is thus aroused about possible malignancy, particularly colon cancer.
When no source of bleeding is uncovered, GI malabsorption should be considered as a possible cause of iron deficiency anemia. Such malabsorption occurs in patients with celiac disease, H pylori infection, partial gastrectomy, or gastric bypass surgery. Other mechanisms of iron deficiency anemia include intravascular hemolysis (paroxysmal nocturnal hemoglobinuria or cardiac valvular disease) and response to erythropoietin treatment.
B. Blood loss results in anemia via a reduction in heme synthesis. With loss of blood comes loss of iron, the central ion in the oxygen-carrying molecule, heme. When there is iron deficiency, the final step in heme synthesis, during which ferrous iron is inserted into protoporphyrin IX, is interrupted, resulting in inadequate heme synthesis. Globin biosynthesis is inhibited by heme deficiency through a heme-regulated translational inhibitor (HRI). Elevated HRI activity (a result of heme deficiency) inhibits a key transcription initiation factor for heme synthesis, eIF2. Thus, there are both less heme and fewer globin chains available in each red cell precursor. This directly causes anemia, a decrease in the hemoglobin concentration of the blood.
C. In this symptomatic man, the peripheral blood smear is likely to be significantly abnormal. As the hemoglobin concentration of individual red blood cells falls, the cells take on the classic picture of microcytic (small), hypochromic (pale) erythrocytes. There is also apt to be anisocytosis (variation in size) and poikilocytosis (variation in shape), with target cells. The target cells occur because of the relative excess of red cell membrane compared with the amount of hemoglobin within the cell, leading to “bunching up” of the membrane in the center.
D. Laboratory tests may be ordered to confirm the diagnosis. The most commonly ordered test is serum ferritin, which, if low, is diagnostic of iron deficiency. Results may be misleading, however, in acute or chronic inflammation and severe illness. Because ferritin is an acute-phase reactant, it can rise in these conditions, resulting in a normal ferritin level. Serum iron and transferrin levels can also be misleading because these levels can fall not only in anemia but also in many other illnesses. Typically in iron deficiency, however, serum iron levels are low, whereas total iron-binding capacity (TIBC) is elevated. The ratio of serum iron to TIBC is less than 20% in uncomplicated iron deficiency. Serum (soluble) transferrin receptor (TfR), released by erythroid precursors, is elevated in iron deficiency. A high ratio of TfR to ferritin may predict iron deficiency when ferritin is not diagnostically low. Though helpful, this test has seen limited use in clinical practice.
Occasionally, when blood tests are misleading, a bone marrow biopsy is performed to examine for iron stores. Iron is normally stored as ferritin in the macrophages of the bone marrow and is stained blue by Prussian blue stain. A decrease in the amount of iron stores on bone marrow biopsy is diagnostic of iron deficiency. More commonly, however, the response to an empiric trial of iron supplementation is used to determine the presence of iron deficiency in complicated cases.
E. Fatigue, weakness, and shortness of breath are the direct results of decreased oxygen-carrying capacity, which leads to decreased oxygen delivery to metabolically active tissues, causing this patient’s symptoms. He is pale because there is less oxygenated hemoglobin per unit of blood, and oxygenated hemoglobin is red, giving color to the skin. Pallor results also from a compensatory mechanism whereby superficial blood vessels constrict, diverting blood to more vital structures.
CASE 24
A. The probable cause of this woman’s anemia is vitamin B12 (cobalamin) deficiency, which is characterized by anemia, glossitis, and neurologic impairment. Vitamin B12 deficiency results in anemia via effects on DNA synthesis. Cobalamin is a crucial cofactor in the synthesis of deoxythymidine from deoxyuridine. Cobalamin accepts a methyl group from methyltetrahydrofolate, leading to the formation of methylcobalamin and reduced tetrahydrofolate. Methylcobalamin is required for the production of the amino acid methionine from homocysteine. Reduced tetrahydrofolate is required as the single-carbon donor in purine synthesis. Thus, cobalamin deficiency depletes stores of tetrahydrofolate, lowering purine production and impairing DNA synthesis. Impaired DNA synthesis results in decreased production of red blood cells. It also causes megaloblastic changes in the blood cells in the bone marrow. These cells are subsequently destroyed in large numbers by intramedullary hemolysis. Both processes result in anemia.
B. The peripheral blood smear varies depending on the duration of cobalamin deficiency. In this patient, because she is profoundly symptomatic, we would expect a full-blown megaloblastic anemia. The peripheral smear would have significant anisocytosis and poikilocytosis of the red cells as well as hypersegmentation of the neutrophils. In severe cases, morphologic changes in peripheral blood cells may be difficult to differentiate from those seen in leukemia.
Other laboratory tests that may be ordered include a lactate dehydrogenase (LDH) level and indirect bilirubin determination. Both should be elevated in cobalamin deficiency, reflecting the intramedullary hemolysis that occurs in vitamin B12 deficiency. Serum vitamin B12 would be expected to be low. Yet there remain high rates of both false-positive and false-negative tests due to the fact that only 20% of total measured serum B12 is bound to the cellular delivery protein, transcobalamin; the rest is bound to haptocorrin, which is not available for cells to utilize. Antibodies to intrinsic factor are usually detectable. Concurrent elevations of both serum methylmalonic acid and serum homocysteine are highly predictive of B12 deficiency.
The various causes of megaloblastic anemia can often be differentiated by a Schilling test. This test measures the oral absorption of radioactively labeled vitamin B12 with and without added intrinsic factor, thereby directly evaluating the mechanism of the vitamin deficiency. It must be performed after cobalamin stores have been replenished.
C. Pernicious anemia is caused by autoimmune destruction of the gastric parietal cells, which are responsible for production of stomach acid and intrinsic factor. Autoimmune destruction of these cells leads to achlorhydria (loss of stomach acid), which is required for release of cobalamin from foodstuffs. The production of intrinsic factor decreases. Intrinsic factor is required for the effective absorption of cobalamin by the terminal ileum. Together these mechanisms result in vitamin B12 deficiency.
The evidence that parietal cell destruction is autoimmune in nature is strong. Pathologically, patients with pernicious anemia demonstrate gastric mucosal atrophy with infiltrating lymphocytes, predominantly antibody-producing B cells. Furthermore, more than 90% of patients with this disease demonstrate antibodies to parietal cell membrane proteins, primarily to the proton pump. More than half of patients also have antibodies to intrinsic factor or to the intrinsic factor–cobalamin complex. These patients also have an increased risk of other autoimmune diseases.
D. The patient’s tachycardia is probably a reflection of profound anemia. Unlike many other causes of anemia, pernicious anemia often leads to very severe decreases in the hemoglobin concentration. This results in a marked decrease in the oxygen-carrying capacity of the blood. The only way to increase oxygenation to metabolically active tissues is to increase cardiac output. This is accomplished by raising the heart rate. Over time, the stresses this puts on the heart can result in high-output heart failure.
The neurologic manifestations—paresthesias and impaired proprioception—seen in this patient are caused by demyelination of the peripheral nerves and posterolateral spinal columns, respectively. The lack of methionine caused by vitamin B12 deficiency appears to be at least partly responsible for this demyelination, but the exact mechanism is unknown. Demyelination eventually results in neuronal cell death. Therefore, neurologic symptoms may not be improved by treatment of the vitamin B12 deficiency.
CASE 25
A. Classic, childhood-onset cyclic neutropenia results from mutations in the gene for a single enzyme, neutrophil elastase. Most cases reflect an autosomal dominant inheritance; however, sporadic adult cases also occur, and these are associated with neutrophil elastase mutations as well.
Studies of neutrophil kinetics in affected patients reveal that the gene defect results in abnormal production—rather than abnormal disposition—of neutrophils. In cyclic neutropenia, it is hypothesized that the mutant neutrophil elastase may have an overly inhibitory effect, causing prolonged trough periods and inadequate storage pools to maintain a normal peripheral neutrophil count. This production defect affects other cell lines as well, resulting in cyclic depletion of all storage pools. Because development of neutrophils from progenitor stage to maturity takes 2 weeks and the life span is only 12 days, depletion of the neutrophil cell line becomes clinically apparent. The other cell lines have longer life spans, and although they too undergo cyclic decreases in production, these decreases do not become clinically apparent.
The exact cause of the relationship between the cyclic waves of maturation and the neutrophil elastase mutation is not known. Because multiple cell lines are seen to cycle, it is believed that neutrophil elastase mutations accelerate the process of apoptosis (programmed cell death) in early progenitor cells unless they are “rescued” by granulocyte colony-stimulating factor (G-CSF). Some evidence suggests that neutrophil elastase can antagonize G-CSF action, but the relationship of mutated neutrophil elastase to G-CSF action in cyclic neutropenia is not well understood.
Clinically, administration of pharmacologic doses of G-CSF (filgrastim) to affected individuals has three interesting effects that partially overcome the condition. First, although cycling continues, mean neutrophil counts increase at each point in the cycle, such that patients are rarely neutropenic. Second, cycling periodicity decreases immediately from 21 days to 14 days. Third, other cell line fluctuations change in parallel; their cycle periodicity also decreases to 14 days, suggesting that an early progenitor cell is indeed at the center of this illness. However, the fact that cycling does not disappear demonstrates that there are other abnormalities yet to be discovered. It also suggests that there may be an inherent cycling of all stem cells in normal individuals, which is modulated by multiple cytokines in the marrow.
B. The periodic neutropenia with spontaneous remission seen in this patient is characteristic of cyclic neutropenia. In this disease, patients develop a drop in neutrophil count approximately every 3 weeks (19–22 days), with nadirs (low neutrophil counts) lasting 3–5 days. Patients are generally well during periods when the neutrophil cell count is normal and become symptomatic as the counts drop below 250/μL. Neutrophils are responsible for a significant portion of the immune system’s response to both bacterial and fungal infections. Thus, the primary clinical manifestation of cyclic neutropenia is recurrent infection. Each nadir is usually characterized by symptoms of fever and malaise. Cervical lymphadenopathy and oral ulcers, as seen in this patient, are also common. Life-threatening bacterial and fungal infections are uncommon but can occur, particularly as a result of infection from endogenous gut flora. More commonly, however, patients develop skin infections and chronic gingivitis.
C. The peripheral blood smear should be normal except for a paucity of neutrophils. Those neutrophils present would be normal in appearance. The bone marrow, however, would be expected to show increased numbers of myeloid precursors such as promyelocytes and myelocytes. Mature neutrophils would be rare. If marrow examination were repeated in 2 weeks—after neutrophil counts have improved—the results would be normal.
CASE 26
A. The most likely diagnosis in this patient is drug-associated immune thrombocytopenia. Many drugs—but most commonly heparin—have been associated with this phenomenon. There is a 10-fold increased risk for heparin-induced thrombocytopenia (HIT) in patients receiving unfractionated heparin (UFH) compared with those receiving low-molecular-weight heparin (LMWH). Cardiac or orthopedic surgery patients have a higher risk for clinical HIT (1–5%) than medical or obstetric patients (0.1–1%) when receiving UFH. Women have twice the risk for HIT as men.
B. Heparin leads to thrombocytopenia via two distinct mechanisms, both involving antibodies. It appears that heparin can bind to a platelet-produced protein, platelet factor 4 (PF4), which is released by platelets in response to activation. The heparin-PF4 complex acts as an antigenic stimulus, provoking the production of IgG. IgG can then bind to the complex, forming IgG-heparin-PF4. The new complex can bind to platelets via the Fc receptor of the IgG molecule or via the PF4 receptor. This binding can lead to two distinct phenomena. The first is platelet destruction by the spleen. Antibody adherence to the platelets changes their shape, causing the spleen to recognize them as abnormal and destroy them. This leads to simple thrombocytopenia, with few sequelae.
The second phenomenon is platelet activation, which can lead to more significant sequelae. After formation of an IgG-heparin-PF4 complex, both IgG and PF4 can bind to platelets. The platelets can become cross-linked, leading to platelet aggregation. This decreases the number of circulating platelets, leading to thrombocytopenia. However, it may also lead to the formation of thrombus, or “white clot.”
C. Even though the platelet count in drug-associated immune thrombocytopenia may be very low, significant bleeding is unusual. Most commonly, the primary manifestation is easy bruising, and, at platelet counts less than 5000/μL, petechiae may be seen on the skin or mucous membranes. When actual bleeding does occur, it is generally mucosal in origin, such as nosebleed, gingival bleeding, or GI blood loss.
As noted, when thrombocytopenia is due to heparin, paradoxical clotting may occur instead of bleeding. Thrombus formation often occurs at the site of previous vascular injury or abnormality and can present as either arterial or venous thrombosis.
CASE 27
A. The Virchow triad consists of three possible contributors to the formation of a clot: decreased blood flow, blood vessel injury or inflammation, and changes in the intrinsic properties of the blood. This patient has no history of immobility or other cause of decreased blood flow. She does, however, have a history of blood vessel injury (ie, deep vein thrombosis). Despite the absence of symptoms of a lower extremity thrombus, this is still the most likely site of origin of the pulmonary embolus. Finally, the recurrence now of thrombus formation along with the family history of clots is suggestive of a change in the intrinsic properties of the blood, as seen in the inherited hypercoagulable states.
B. The most common hypercoagulable states include activated protein C resistance (factor V Leiden), protein C deficiency, protein S deficiency, antithrombin III deficiency, and hyperprothrombinemia (prothrombin gene mutation). Except for hyperprothrombinemia, each of these results in clot formation because of a lack of adequate anticoagulation rather than overproduction of procoagulant activity; hyperprothrombinemia is caused by excess thrombin generation.
The most common site of the problem in the coagulation cascade is at factor Va, which is required for the formation of the prothrombinase complex with factor Xa, which leads to the thrombin burst and fibrin generation during hemostasis. Protein C is the major inhibitor of factor Va. It acts by cleaving factor V into an inactive form, thereby slowing the activation of factor X. The negative effect of protein C is enhanced by protein S. Quantitative or qualitative reduction in either of these two proteins thus results in the unregulated procoagulant action of factor Xa.
Activated protein C resistance is the most common inherited hypercoagulable state. It results from a mutation in the factor V gene. This mutation alters the three-dimensional conformation of the cleavage site within factor Va, where protein C usually binds. Protein C is then unable to bind to factor Va and is, therefore, unable to inactivate it. Coagulation is not inhibited.
Antithrombin inhibits the coagulation cascade at an alternative site. It inhibits the serine proteases: factors II, IX, X, XI, and XII. Deficiency of antithrombin results in an inability to inactivate these factors, allowing the coagulation cascade to proceed unrestrained at multiple coagulation steps.
Hyperprothrombinemia is the second most common hereditary hypercoagulable state and the only one so far recognized as being due to overproduction of procoagulant factors. It is caused by a mutation of the prothrombin gene that leads to elevated prothrombin levels. The increased risk of thrombosis is thought to be due to excess thrombin generation when the Xa-Va-Ca2+-PL complex is activated.
C. This patient may be evaluated by various laboratory tests for the presence of an inherited hypercoagulable state. Quantitative evaluation of the relative amounts of protein C, protein S, and antithrombin can be performed. Qualitative tests that assess the ability of these proteins to inhibit the coagulation cascade can be measured via clotting assays. The presence of the specific mutation in factor V Leiden can be assessed via polymerase chain reaction testing.
CASE 28
A. The most common form of motor neuron disease in adults is amyotrophic lateral sclerosis (ALS), in which mixed upper and lower motor neuron deficits are found in limb and bulbar muscles. In 80% of patients, the initial symptoms are due to weakness of limb muscles. Complaints are often bilateral but asymmetric. Involvement of bulbar muscles causes difficulty with swallowing, chewing, speaking, breathing, and coughing. Neurologic examination reveals a mixture of upper and lower motor neuron signs. There is usually no involvement of extraocular muscles or sphincters. The disease is progressive and generally fatal within 3–5 years, with death usually resulting from pulmonary infection and respiratory failure.
B. In ALS, there is selective degeneration of motor neurons in the primary motor cortex and the anterolateral horns of the spinal cord. Many affected neurons show cytoskeletal disease with accumulations of intermediate filaments in the cell body and in axons. There is only a subtle glial cell response and little evidence of inflammation.
C. There are several theories concerning the molecular pathogenesis of ALS. Glutamate is the most abundant excitatory neurotransmitter in the CNS and functions to generate an excitatory postsynaptic potential and raise the concentration of free intracellular Ca2+ in the cytosol of the postsynaptic neuron. This Ca2+ signal activates calcium-sensitive enzymes and is quickly terminated by removal of glutamate from the synapse and by mechanisms for calcium sequestration and extrusion in the postsynaptic cell. In 60% of patients with sporadic ALS, there is a large decrease in glutamate transport activity in the motor cortex and spinal cord, but not in other regions of the CNS. This has been associated with a loss of the astrocytic glutamate transporter protein excitatory amino acid transporter 2 (EAAT2), perhaps resulting from a defect in splicing of its messenger RNA. In cultured spinal cord slices, pharmacologic inhibition of glutamate transport induces motor neuron degeneration.
About 10% of ALS cases are familial and 20% of these familial cases are due to missense mutations in the cytosolic copper-zinc superoxide dismutase (SOD1) gene on the long arm of chromosome 21. SOD1catalyzes the formation of hydrogen peroxide from superoxide anion. Hydrogen peroxide is then detoxified by catalase or glutathione peroxidase to form water. Not all mutations reduce SOD1 activity, and the disorder is typically inherited as an autosomal dominant trait, suggesting that familial ALS results from a gain of function rather than a loss of function of the SOD1 gene product. One hypothesis suggests that the mutant enzyme has an altered substrate specificity catalyzing the reduction of hydrogen peroxide to yield hydroxyl radicals and utilizing peroxynitrite to produce nitration of tyrosine residues in proteins.
A role for neurofilament dysfunction in ALS is supported by the finding that neurofilamentous inclusions in cell bodies and proximal axons are an early feature of ALS pathology. In addition, mutations in the heavy chain neurofilament subunit (NF-H) have been detected in some patients with sporadic ALS, suggesting that NF-H variants may be a risk factor for ALS.
An exciting discovery of the protein transactive response DNA-binding protein 43 (TDP 43) may offer new clues to the etiology of this disorder. This newly discovered protein is the major component of the ubiquitinated, tau-negative inclusions that are the pathological hallmark of sporadic and familial ALS and frontotemporal dementia (FTD). It is also found in some cases of Alzheimer disease and Parkinson disease. Mutations in this gene, which is located on chromosome 1, co-segregate with disease in familial forms of ALS and FTD and are not found in SOD1 familial ALS. FTD and ALS overlap in approximately 15–25% of cases, and these disorders are starting to be referred to as “TDP-43 proteinopathies.” Several other genes and gene regions have been identified to cause both FTD and ALS such as TARDBP on chromosome 1p36.2, MAPT on chromosome 7q21, and DCTN1 on chromosome 2p13.
The major genetic cause of ALS and/or FTD was recently discovered. Two independent groups identified hexanucleotide repeats in an intron of C9ORF72 on chromosome 9 in 34% of familial ALS cases, 6% of sporadic ALS cases, 26% of familial FTD cases, and 5% of sporadic FTD cases. The protein is of unknown function. These mutations likely induce a gain-of-function mutation similar to other noncoding repeat-expansion disorders. This discovery of another disorder caused by nucleotide repeats provides an additional rationale for the development of one or more new drugs focused on decreasing expression of these toxic repeats.
CASE 29
A. This patient has parkinsonism. The resting tremor (which improves with activity), “cog-wheeling” rigidity, and difficulty with gait (especially with initiation of walking and with changing direction) are all characteristic of parkinsonism. While there are many causes of parkinsonism, including toxins, head trauma, drugs, encephalitis, and other degenerative diseases, the most common cause is Parkinson disease, an idiopathic degenerative neurological disorder.
B. Parkinson disease results from selective degeneration of the monoamine-containing neurons in the basal ganglia and brainstem, particularly the pigmented dopaminergic neurons of the substantia nigra. This region is involved in regulation of movement, particularly in initiating and stopping actions. In addition to the degeneration of the dopaminergic neurons, scattered neurons elsewhere contain eosinophilic cytoplasmic inclusion bodies, called Lewy bodies.
C. Through studies of familial cases of Parkinson disease as well as parkinsonism produced by toxins, some of the molecular processes involved have been discovered. One cause of parkinsonism is 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that was once a contaminant in illicit opioid drugs. It caused parkinsonism by being metabolized to N-methyl-4-phenylpyridinium (MPP+), which was taken up through dopamine uptake sites on dopamine nerve terminals and concentrated in mitochondria. This led to disturbed mitochondrial function and ultimately to cell death.
In familial cases of Parkinson disease, there have been several mutations identified involving genes encoding several proteins: parkin, alpha-synuclein, DJ-1, ubiquitin, and PTEN-induced kinase. Mutations in the glucocerebrosidase (GCase) enzyme account for 3% of sporadic Parkinson disease cases and 25% of juvenile-onset Parkinson disease cases. This enzyme is involved in lysosomal processing. The enzyme activity is reduced by 58% in the substantia nigra of heterozygous patients and 33% lower in sporadic Parkinson disease patients. Inhibiting this enzyme leads to accumulation of α-synuclein, which leads to further inhibition of this enzyme. These mutations are being studied to find clues about the molecular mechanisms involved in the pathogenesis of Parkinson disease.
CASE 30
A. The most likely diagnosis in this patient is myasthenia gravis, a disease characterized by fluctuating fatigue and weakness of muscles with small motor units, particularly the ocular muscles. Myasthenia gravis is an autoimmune disorder resulting in simplification of the postsynaptic region of the neuromuscular end plate.
Patients with this disease have lymphocytic infiltration at the end plate plus antibody and complement deposition along the postsynaptic membrane. Circulating antibodies to the receptor are present in 90% of patients, blocking acetylcholine binding and activation. The antibodies can cross-link the receptor molecules, leading to receptor internalization and degradation. They also activate complement-mediated destruction of the postsynaptic region, resulting in simplification of the end plate.
Many patients who lack antibodies to the acetylcholine receptor instead have autoantibodies against the muscle-specific receptor tyrosine kinase, which is an important mediator of acetylcholine receptor clustering at the end plate. These antibodies inhibit clustering of receptors in muscle cell culture. Thus, patients with myasthenia gravis have impaired ability to respond to acetylcholine release from the presynaptic membrane.
Referred to as double-sero-negative patients, some myasthenia gravis patients have no antibodies for either acetylcholine receptor antibodies or MuSK. Recently, a new antibody has been found in 50% of these patients. Antibodies to lipoprotein-related protein 4 (LRP4), which is the agrin-binding receptor of the MuSK complex, disrupt agrin-induced acetylcholine receptor clustering, causing the disease symptoms. The clinical presentation of these patients is similar to that of patients with acetylcholine receptor myasthenia gravis without thymoma.
B. Muscles with small motor units are most affected in myasthenia gravis. The ocular muscles are most frequently affected; oropharyngeal muscles, flexors and extensors of the neck and proximal limbs, and erector spinae muscles are next most commonly involved. In severe cases and without treatment, the disease can progress to involve all muscles, including the diaphragm and intercostal muscles, resulting in respiratory failure.
C. Normally, the number of quanta of acetylcholine released from the nerve terminal decreases with repetitive stimuli. There are usually no clinical consequences of this decrease because a sufficient number of acetylcholine receptor channels are opened despite the reduced amount of neurotransmitter. In myasthenia gravis, however, there is a deficiency in the number of acetylcholine receptors. Therefore, as the number of quanta released decreases, there is a decremental decline in neurotransmission at the neuromuscular junction. This is manifested clinically as muscle fatigue with sustained or repeated activity.
D. Myasthenia gravis is associated both with a family history of autoimmune disease and with the presence of coexisting autoimmune diseases. Hyperthyroidism, rheumatoid arthritis, systemic lupus erythematosus, and polymyositis are all seen with increased frequency in these patients. These patients also have a high incidence of thymic disease; most demonstrate thymic hyperplasia and 10–15% have thymomas.
E. There are two basic strategies for treating this disease: decreasing the immune-mediated destruction of the acetylcholine receptors and increasing the amount of acetylcholine available at the neuromuscular junction. As noted previously, many patients with myasthenia gravis demonstrate disease of the thymus gland. The thymus is thought to play a role in the pathogenesis of myasthenia gravis by supplying helper T cells that are sensitized to thymic nicotinic receptors. Removal of the thymus in patients with generalized myasthenia gravis can improve symptoms and even induce remission. Plasmapheresis, corticosteroids, and immunosuppressant drugs can all be used to reduce the levels of antibody to acetylcholine receptors, thereby suppressing disease. Increasing the amount of acetylcholine available at the neuromuscular junction is accomplished by the use of cholinesterase inhibitors. Cholinesterase is responsible for the breakdown of acetylcholine at the neuromuscular junction. By inhibiting the breakdown of acetylcholine, cholinesterase inhibitors can compensate for the normal decline in released neurotransmitter during repeated stimulation and thus decrease symptoms.
CASE 31
A. The characteristic pathologic finding in Alzheimer disease (AD) is the finding of neuritic plaques, made of a dense amyloid core surrounded by dystrophic neuritis, reactive astrocytes, and microglia. There are also neurofibrillary tangles, synaptic loss, and neuronal loss. Interestingly, the severity of disease does not correlate with plaque number.
B. In neurological disorders, the location of the lesion predicts what function will be affected. In AD, the neuritic plaques are most prominent in the hippocampus, entorhinal cortex, association cortex, and basal forebrain. These are areas involved in memory and higher order cortical functions such as judgment and insight. This explains why memory loss, poor judgment, and denial are such common presenting symptoms. In contrast, the motor and sensory cortexes are not prominently affected, and thus loss of motor and sensory function is not present until much later in the course of the disease.
C. The major protein in neuritic plaques is amyloid beta-peptide. This is a protein derived from beta-amyloid precursor protein (APP) that is encoded by a gene on chromosome 21. Increased production of APP results in increased amyloid beta-peptide, which is known to be toxic to cultured neurons. Individuals who produce excess APP, such as people with trisomy 21 or families with inherited mutations of the APP gene, develop early onset AD.
D. Currently, there is no role for genetic testing for AD. Only about 10% of the cases of AD are familial, and in these cases, several different mutations have been identified in affected families. It has also been recognized that individuals with a subtype 4 of apolipoprotein E have an increased risk of developing AD. However, 15% of the population carries this subtype, and most cases of AD develop in people who do not carry this subtype. Even among carriers, many never develop AD. Therefore, testing for it is not recommended.
CASE 32
A. Generalized tonic-clonic seizures are characterized by sudden loss of consciousness followed rapidly by tonic contraction of the muscles, causing extension of the limbs and arching of the back. This phase lasts approximately 10–30 seconds and is followed by a clonic phase of limb jerking. The jerking builds in frequency, peaking after 15–30 seconds, and then gradually slows over another 15–30 seconds. The patient may remain unconscious for several minutes after the seizure. This is generally followed by a period of confusion lasting minutes to hours.
B. Recurrent seizures are in many cases idiopathic, particularly those seen in children. Seizures may also be due to brain injury from trauma, stroke, mass lesion, or infection. Finally, one must consider metabolic causes such as hypoglycemia, electrolyte abnormalities, and alcohol withdrawal. The cause of this patient’s seizure is unknown because of the lack of an available history. However, because he has focal neurologic findings, with decreased movement of his left side, one must suspect an underlying brain lesion in the right cerebral hemisphere.
C. Seizures occur when neurons are activated synchronously. The kind of seizure depends on the location of the abnormal activity and the pattern of spread to different parts of the brain. The formation of a seizure focus in the brain may result from disruption of normal inhibitory circuits. This disruption may occur because of alterations in ion channels or from injury to inhibitory neurons and synapses. Alternatively, a seizure focus may be formed when groups of neurons become synchronized by reorganization of neural networks after brain injury. After formation of a seizure focus, local discharge may then spread. This spread occurs by a combination of mechanisms. After synchronous depolarization of abnormally excitable neurons—known as the paroxysmal depolarizing shift—extracellular potassium accumulates, depolarizing nearby neurons. Increased frequency of depolarization then leads to increased calcium influx into nerve terminals. This increases neurotransmitter release at excitatory synapses by a process known as posttetanic potentiation, whereby normally quiescent voltage-gated and N-methyl-D-aspartate (NMDA) receptor-gated excitatory synaptic neurotransmission is increased and inhibitory synaptic neurotransmission is decreased. The net effect of these changes is recruitment of neighboring neurons into a synchronous discharge, causing a seizure.
CASE 33
A. The diagnosis in this patient is stroke, characterized by the sudden onset of focal neurologic deficits that persist for at least 24 hours. The focal symptoms and signs that result from stroke correlate with the area of the brain supplied by the affected blood vessel. In this case, the patient has weakness and sensory loss on the right side. These symptoms suggest involvement of the left middle cerebral artery or at least its associated vascular territory. The vascular territory supplied by the middle cerebral artery includes the lateral frontal, parietal, lateral occipital, and anterior and superior temporal cortex and adjacent white matter as well as the caudate, putamen, and internal capsule.
B. Risk factors for stroke include age, male sex, hypertension, hypercholesterolemia, diabetes, smoking, heavy alcohol consumption, and oral contraceptives.
C. Stroke is classified as either ischemic or hemorrhagic in origin. Ischemic stroke may result from thrombotic or embolic occlusion of the vessel. Hemorrhagic stroke may result from intraparenchymal hemorrhage, subarachnoid hemorrhage, subdural hemorrhage, epidural hemorrhage, or hemorrhage within an ischemic infarction. Given the CT scan result, it is likely that this man has sustained an ischemic rather than a hemorrhagic stroke. Hemorrhagic and ischemic strokes can be difficult to differentiate on clinical grounds, but the former often produce a less predictable pattern of neurologic deficits. This is because the neurologic deficits in hemorrhagic stroke depend both on the location of the bleed and on factors that affect brain function at a distance from the hemorrhage, including increased intracranial pressure, edema, compression of neighboring brain tissue, and rupture of blood into the ventricles or subarachnoid space.
D. The most likely underlying cause of stroke in this patient is atherosclerosis. Atherosclerosis arises from vascular endothelial cell injury, often caused by chronic hypertension or hypercholesterolemia, both present in this man. Endothelial injury stimulates attachment of circulating monocytes and lymphocytes that migrate into the vessel wall and stimulate proliferation of smooth muscle cells and fibroblasts. This results in plaque formation. Damaged endothelium also serves as a nidus of platelet aggregation that further stimulates proliferation of smooth muscle and fibroblasts. The plaques formed may enlarge and occlude the vessel, leading to thrombotic stroke, or may rupture, releasing emboli and causing embolic stroke.
CASE 34
A. The lesions described are characteristic of psoriasis vulgaris. Psoriasis is both a genetic and an environmental disorder. A genetic origin is supported by several lines of evidence. There is a high rate of concordance for psoriasis in monozygotic twins and an increased incidence of psoriasis in the relatives of affected individuals. Furthermore, overexpression of gene products of class I alleles of the major histocompatibility complex (MHC) is seen in patients with psoriasis. However, psoriasis is not likely to be completely genetic in nature. Individuals with a genetic predisposition to the disorder appear to require environmental triggers, at least in some cases, such as trauma, cold weather, infections, stress, and drugs.
B. In psoriasis, there is shortening of the usual duration of the keratinocyte cell cycle and doubling of the proliferative cell population. This excessive epidermatopoiesis results in skin thickening and plaque formation. In addition to skin thickening, truncation of the cell cycle leads to an accumulation of cells within the cornified layer with retained nuclei. This pattern is known as parakeratosis and results in neutrophil migration into the cornified layer. Together these form the silvery scale characteristic of psoriasis. Finally, psoriasis induces endothelial cell proliferation, resulting in pronounced dilation, tortuosity, and increased permeability of the capillaries in the superficial dermis and causing erythema.
C. A large number of immunologic abnormalities that involve both innate and adaptive immunity have been documented in psoriatic skin. Antigenic stimuli are thought to activate the innate immune response, leading to the production of cytokines, such as interferon, TNF, IL-23, and IL-12, by macrophages, dendritic cells, and neutrophils. This leads to attraction, activation, and differentiation of T cells. These T cells, most importantly TH1 and TH17 cells, produce cytokines that lead to epidermal hyperplasia, recruitment of inflammatory cells, and ultimately a positive feedback loop that perpetuates the pathologic process.
CASE 35
A. The lesions described are characteristic of the “pruritic polygonal purple papules” of lichen planus. Although the triggers of lichen planus are often obscure, several drugs have been implicated. Antimalarial agents (eg, chloroquine) and therapeutic gold are the drugs most closely linked to this phenomenon. It is believed that these agents and other unknown triggers result in a cell-mediated autoimmune reaction leading to damage of the basal keratinocytes of the epidermis.
B. As mentioned, the triggers leading to lichen planus formation are often idiopathic. However, it appears that some form of antigenic stimulation leads to infiltration and activation of CD4 T lymphocytes. These stimulated CD4 cells elaborate cytokines, leading to the recruitment of cytotoxic T lymphocytes. Cell-mediated cytotoxicity, cytokines, interferon-γ, and TNF combine to injure keratinocytes and contribute to vacuolization and necrosis of these cells. Injured, enucleated keratinocytes coalesce to form colloid bodies. Melanocytes are destroyed as “innocent bystanders,” and melanin is phagocytosed by macrophages.
C. The appearance of the lichen planus papules is a direct reflection of the underlying histopathologic features. The dense array of lymphocytes in the superficial dermis yields the elevated, flat-topped appearance of the papule. The whitish coloration—Wickham striae—results from chronic inflammation and hyperkeratosis of the cornified layer of the epidermis. The purple hue of the lesions is caused by the macrophage phagocytosis of the released melanin to form melanocytes. Although the melanin is brown-black, the melanophages are embedded in a colloid matrix. This causes extensive scattering of light by an effect known as the Tyndall effect, resulting in interpretation of the lesion as dusky or violaceous by the human eye.
CASE 36
A. The lesions described are characteristic of erythema multiforme. The lack of mucosal involvement suggests erythema multiforme minor.
B. Erythema multiforme is similar to lichen planus in that both are interface dermatitides and both are caused by some inciting agent that results in lymphocyte migration to the epidermis and papillary dermis. Cytotoxic T cells then combine with elaborated cytokines, interferon-γ, and TNF to kill keratinocytes, resulting in enucleation, vacuolization, and coalescence to form colloid bodies.
Unlike lichen planus, with its dense dermal inflammatory infiltrate, the dermal infiltrate of lymphocytes in erythema multiforme is sparse. Thus, the vacuolated keratinocytes widely distributed in the epidermal basal layer are more conspicuous.
C. Many cases of erythema multiforme minor are triggered by herpes simplex virus (HSV), as seen in this patient. The evidence to support this association derives from both clinical and molecular data. Clinically, it has long been documented that erythema multiforme is often preceded by herpes simplex infection. Furthermore, antiherpetic agents such as acyclovir can suppress the development of erythema multiforme in some individuals. Molecular studies have confirmed the presence of herpes simplex DNA within skin from erythema multiforme lesions. HSV DNA is also present in the peripheral blood lymphocytes and lesional skin after resolution of the rash but is not found in nonlesional skin. Other known causes include Mycoplasma infection, contact dermatitis, drugs, and radiation.
D. The target-like lesions seen in erythema multiforme reflect zonal differences in the inflammatory response and its deleterious effects. At the periphery of the lesion, inflammation and vacuolization are sparse, resulting in the erythematous halo. The dusky bull’s eye in the center, on the other hand, is an area of dense epidermal vacuolization and necrosis.
CASE 37
A. The major alternative diagnoses to consider are bullous pemphigoid and pemphigus, although other blistering diseases such as erythema multiforme and dermatitis herpetiformis should be considered as well. Bullous pemphigoid is characterized by subepidermal and pemphigus by intraepidermal vesiculation. The distinction is important because bullous pemphigoid has a more favorable prognosis.
B. Microscopically, bullous pemphigoid lesions show a subepidermal cleft containing lymphocytes, eosinophils, neutrophils, and eosinophilic material, representing extravasated macromolecules such as fibrin. An inflammatory infiltrate of eosinophils, neutrophils, and lymphocytes is also present in the dermis beneath the cleft.
C. Direct immunofluorescence microscopy demonstrates IgG and C3 bound in a linear distribution along the epidermal-dermal junction. These autoantibodies are bound to a 230-kDa protein within the lamina lucida, known as the “bullous pemphigoid antigen.” This antigen has been localized to the hemidesmosomal complex of the epidermal basal cell. Its role is not established.
D. Blister formation is believed to begin with the binding of IgG to the bullous pemphigoid antigen, activating the complement cascade. Complement fragments then induce mast cell degranulation and attract neutrophils and eosinophils. The granulocytes and mast cells release multiple enzymes, resulting in enzymatic digestion of the epidermal-dermal junction and separation of the layers. It is also possible that the bullous pemphigoid antigen plays a vital structural role that is compromised when the autoantibodies bind, leading to cleavage of the epidermal-dermal junction.
CASE 38
A. Palpable purpura over the distal lower extremities or other dependent areas—recurring over a period of months—and histologic study revealing fibrinoid necrosis are most consistent with leukocytoclastic vasculitis. Common precipitants include infections and medications. Bacterial, mycobacterial, and viral infections can all trigger leukocytoclastic vasculitis; Streptococcus and Staphylococcus are the most common infectious precipitants. S pneumoniaeis the most common cause of pneumonia in this age group and may have been the precipitant in this man. Hepatitis C is also associated with leukocytoclastic vasculitis. Many drugs have been associated with this disorder, including antibiotics, thiazides, and nonsteroidal anti-inflammatory drugs (NSAIDs). Of the antibiotics, penicillins, such as the amoxicillin given to this man, are the most common offenders.
B. Eliciting factors such as microbial antigens or medications trigger the formation of immune complexes, consisting of antibodies bound to the exogenous antigen. For reasons not yet clear, these complexes are preferentially deposited in the small cutaneous vessels (venules). After becoming trapped in the tissue of the venules, the immune complexes activate the complement cascade, and localized production of chemotactic fragments and vasoactive molecules ensues. This attracts neutrophils, which release enzymes, resulting in destruction of the immune complexes, neutrophils, and vessels. Ultimately, erythrocytes and fibrin are able to exude through the vessel wall and enter the surrounding dermis, resulting in the classic finding of palpable purpura.
C. Leukocytoclastic vasculitis lesions are raised and papular because lesional skin is altered and expanded by an intense vasocentric infiltrate containing numerous neutrophils. The lesions are purpuric or erythematous because of the extravasated red blood cells that accumulate in the dermis.
D. Leukocytoclastic vasculitis may also involve small vessels in other portions of the body, including the joint capsules, soft tissues, kidneys, liver, and GI tract. The most common systemic symptoms include arthralgias, myalgias, and abdominal pain. It would be important to evaluate for these symptoms and order laboratory tests to assess liver or renal involvement.
CASE 39
A. The diagnosis is likely to be Rhus dermatitis (poison ivy and oak), a form of allergic contact dermatitis. The history of hiking in a heavily wooded area 2 days before onset of the rash is a helpful clue. However, the finding on physical examination of blisters arranged in straight lines helps make the diagnosis. Straight lines and angles suggest an exogenous cause for a skin eruption. In this case, poison ivy leaves traced a line across the skin as the patient walked through the brush, and she developed an allergic contact dermatitis in the pattern of the exposure.
B. A common misconception regarding Rhus dermatitis is that blister fluid from broken blisters (or even touching the blistered area) causes the eruption to spread. In fact, once the eruption has developed, the allergen has been irreversibly bound to other proteins or has been so degraded that it cannot be transferred to other sites. In this case, the patient developed large blisters or bullae in response to the contactant at the original sites of contact, the legs. This means that she had a severe reaction to the allergen. Intense inflammation such as this can result in the autosensitization phenomenon, which in this case explains the development of ill-defined erythematous plaques with small papules and vesicles within the plaques seen on this patient’s arms and trunk. Alternatively, inadvertent contact with contaminated clothes or other surfaces can induce new areas of dermatitis. The Rhus allergen is tremendously stable and can persist on unwashed clothing and remain capable of inducing allergic contact dermatitis for up to 1 year.
C. If the allergen exposure is transient, the first exposure to a Rhus antigen often does not result in a reaction at the exposure site. However, a contingent of “armed and ready” memory T cells is now policing the skin, waiting for the allergen to reappear. The individual is said to be sensitized. When the person is exposed to the antigen again, the elicitation phase begins. Langerhans cells process antigen and migrate to lymph nodes, but presentation and T-cell proliferation also occur at the site of contact with the allergen. Nonspecific T cells in the vicinity are recruited and stimulated by the inflammatory cytokines released by the specifically reactive T cells, and an amplification loop ensues, eventuating in clinically recognizable dermatitis. This complex series of events takes time to develop, resulting in the 24- to 48-hour delay between reexposure and rash eruption.
CASE 40
A. The probable diagnosis is erythema nodosum (EN), given their appearance as tender ill-defined nodules. The anterior lower legs are the most common locations for such lesions to develop. The patient probably has subclinical streptococcal pharyngitis. The fact that the patient herself had symptoms of pharyngitis, which were alleviated with antibiotics, is helpful. However, because the antibiotics course was much shorter than required (2 days vs. the standard 10), she must be suspected of having a partially treated (subclinical) infection. Until the infection is adequately treated, the patient will continue to manifest EN as a hypersensitivity response. Once the infection has been eradicated, the skin lesions should subside within several weeks. Persistent EN should prompt a thorough search for an alternate cause.
B. Common causes of EN include streptococcal pharyngitis, many different medications (including sulfa drugs), estrogen-containing oral contraceptives or pregnancy, and inflammatory bowel disease. There are numerous other possible causes.
C. Erythema nodosum is thought to represent a systemic delayed-type hypersensitivity reaction that localizes to the subcutis for unknown reasons.
D. In erythema nodosum, the inflammatory response consists of lymphocytes, histiocytes, neutrophils, and eosinophils scattered throughout the septal compartment of the subcutis with frequent multinucleated histiocytes. The septa are thickened and may become fibrotic, depending on the density of the infiltrate and the duration of the reaction. Even though the infiltrate is largely confined to subcutaneous septa, there is commonly an element of fat necrosis at the edges of the subcutaneous lobules in erythema nodosum. Evidence of fat necrosis may be seen in the form of an infiltrate of “foamy” (lipid-laden) macrophages at the periphery of subcutaneous lobules or in the form of small stellate clefts within multinucleate macrophages, indicating an element of lipomembranous fat necrosis.
CASE 41
A. The likely diagnosis is sarcoidosis. Because sarcoidosis is a diagnosis of exclusion, a thorough workup for specific causes is warranted. A skin biopsy should demonstrate changes typical for sarcoidosis with negative histochemical stains for mycobacterial and fungal organisms. Additionally, tissue culture performed on affected skin should be negative. Chest x-ray film is helpful to rule out tuberculosis and to investigate the presence of hilar adenopathy. Bone films may demonstrate characteristic findings as well.
B. This patient has sarcoidal papules around the edges of the nostrils, a finding known as lupus pernio or nasal rim sarcoidosis. This finding indicates that this patient is at high risk for significant involvement of the tracheobronchial tree or lung parenchyma. The complaint of chronic cough should also suggest lung involvement. Regardless of symptoms and dermatologic presentation, the possibility of pulmonary involvement should always be investigated in all cases of sarcoidosis because it is quite common and sometimes asymptomatic.
C. Sarcoidosis is a nodular dermatitis with histiocytic granulomas situated within the dermis. There are few lymphocytes present in and around the granulomas. Multinucleated histiocytes are frequently present.
D. Sarcoidosis is seen clinically as an elevation (papule, plaque, or nodule) caused by the expansion of the dermis by the infiltrate. There is no scale overlying the lesions because the epidermis is not affected.
CASE 42
A. Contrary to popular perception, acne is not caused by dirt clogging the pores. In fact, “blackheads” (open comedones) are black because of oxidation of the keratinaceous debris within the dilated follicles, not because of “dirt” at all. However, some exogenous substances such as oily cosmetics or petrolatum-based hair care products may promote comedone formation and thus exacerbate acne. Cleansing does not affect any of the four steps essential to the development of acne, because all of these steps occur within the follicles. Cleansing merely removes surface debris and oil. The patient should be advised to use a gentle soap or nonsoap cleanser designed for the face and to avoid scrubbing the skin with rough cloths, towels, or scrubbing pads, which is not helpful in ameliorating acne and may cause secondary irritation, making topical treatments less tolerable. She should also be advised to use nongreasy cosmetics, usually those labeled as “noncomedogenic,” as well as hair care products without petrolatum.
B. Keratinocytes fail to slough from the follicles as they should. As a result, the follicle becomes plugged (a comedo). The buildup of sebum behind the plug expands the follicle. Propionibacterium acnesovergrowth in the follicle breaks down sebum. Bacterial factors and sebum breakdown products attract neutrophils to the follicle, thus forming a pustule. Follicular rupture induces an intense inflammatory response in the dermis seen clinically as an inflammatory papule or pustule. Scarring may be the end result.
C. Follicular plugging may be corrected with retinoids (vitamin A analogues) either topically or, if the condition is severe enough, orally. Retinoids promote the proper desquamation of keratinocytes. Bacteria are controlled with topical or oral antibiotics. Some common topical antibiotic agents include benzoyl peroxide and clindamycin. Oral antibiotics such as erythromycin or tetracycline are frequently used in addition to topical antibiotics. These agents are not merely antibacterial but are known to have anti-inflammatory properties independent of their antibacterial action. Last, sebum production may be decreased through the use of retinoids, again topically or orally, although oral therapy is much more effective for this purpose, or with antiandrogen medications such as spironolactone and oral contraceptives.
CASE 43
A. The fundamental abnormality in asthma is increased reactivity of airways to stimuli. Asthma can be induced by many provocative agents. These can be broadly categorized as (1) physiologic or pharmacologic mediators of asthmatic airway responses, (2) allergens that can induce airway inflammation and reactivity in sensitized individuals, and (3) exogenous physicochemical agents or stimuli that produce airway hyperreactivity. This patient’s history (seasonal predilection) is most consistent with allergen-induced asthma. The worsening symptoms in the last few months may be due to an allergic reaction to the roommate’s cat.
B. The earliest events in asthma are the activation of local inflammatory cells, primarily mast cells and eosinophils, by the provocative agents described previously. This can occur by specific IgE-dependent mechanisms or indirectly by chemical irritant exposure or osmotic stimuli. Acute-acting mediators, including leukotrienes, prostaglandins, and histamine, induce smooth muscle contraction, mucus hypersecretion, and vasodilation with endothelial leakage and local edema formation. Epithelial cells also participate, releasing leukotrienes, prostaglandins, and inflammatory cytokines. Additional inflammatory cells, including neutrophils and eosinophils, are recruited to the airway mucosa. In addition, the cell cytokines released promote growth of mast cells and eosinophils, the influx and proliferation of T cells, and the differentiation of B lymphocytes into IgE- and IgA-producing plasma cells. Ultimately, this ongoing inflammation results in injury to epithelial cells, denudation of the airway, greater exposure of afferent sensory nerves, and subsequent smooth muscle hyperresponsiveness, chronic inflammation, submucosal gland hypersecretion, and increased mucus volume.
C. Wheezing is caused by a combination of smooth muscle contraction and mucus hypersecretion and retention, resulting in airway caliber reduction and prolonged turbulent airflow. The sensations of shortness of breath and chest tightness are also the result of a number of concerted changes. These include the detection by spindle cell stretch receptors of the greater muscular effort required to overcome the increased airway resistance as well as detection of thoracic distention resulting from chest hyperinflation, decreased lung compliance, and increased work of breathing. These are sensed by the chest wall nerves and manifested as chest tightness and shortness of breath. As obstruction worsens, hypoxemia and CO2 retention occur, further stimulating respiratory drive through peripheral and central chemoreceptors. This stimulus in the setting of respiratory muscle fatigue produces progressive dyspnea.
D. This patient’s symptoms are relatively mild, occurring only intermittently. In between exacerbations, her pulmonary function tests may be normal. During an attack, all indices of expiratory airflow may be reduced, including FEV1, FEV1/FVC, and peak expiratory flow rate. FVC may also be reduced as a result of premature airway closure. Total lung capacity, functional residual capacity, and residual volume may be increased as a consequence of airflow obstruction and incomplete emptying of lung units. DlCO may be increased because of increased lung and capillary blood volume.
CASE 44
A. Chronic obstructive pulmonary disease (COPD) is an intentionally imprecise term used to denote a process characterized by the presence of chronic bronchitis or emphysema that may lead to the development of fixed airway obstruction. Chronic bronchitis and emphysema are frequently encountered together in the same patient.
Chronic bronchitis is defined by a clinical history of productive cough for 3 months of the year for 2 consecutive years. Dyspnea and airway obstruction, often with an element of reversibility, are intermittently to continuously present. Cigarette smoking is by far the leading cause of this disease, although other inhaled irritants may induce the same process. While the predominant pathologic events are inflammation in larger airways, accompanied by mucosal thickening and mucus hypersecretion, it is the inflammation in smaller bronchioles that is the principal site of increased airflow obstruction.
Pulmonary emphysema is a condition marked by irreversible enlargement of the airspaces distal to the terminal bronchioles, accompanied by destruction of their walls, most often without obvious fibrosis. In contrast to chronic bronchitis, the primary pathologic defect in emphysema is not in the airways but rather in the respiratory unit walls, where the loss of elastic tissue results in a loss of appropriate recoil tension to support distal airways during expiration. Progressive dyspnea and nonreversible obstruction accompany the airspace destruction without mucus hypersecretion and productive cough. Furthermore, the loss of alveolar surface area and the accompanying capillary bed for gas exchange contribute to the progressive hypoxia and dyspnea.
B. The chronic productive cough and thick sputum production present in this patient are characteristic of chronic bronchitis. Cigarette smoking remains the principal cause of disease in up to 90% of patients with chronic bronchitis and emphysema. COPD is probably significantly underdiagnosed; although only 15–20% of smokers develop severe airflow obstruction, there is a dose-dependent relationship between tobacco smoke exposure and loss of lung function. Population-based studies suggest that chronic dust (including silica and cotton) or chemical fume exposure is a significant contributing risk factor for COPD. In the developing world, indoor exposure to smoke from burning biofuels is a major cause of COPD. The most important identified genetic risk factor for the evolution of COPD is deficiency of α1-protease (α1-antitrypsin) inhibitor. Reduced circulating and tissue levels can lead to early onset of severe emphysema, not chronic bronchitis.
C. Diffuse airway obstruction is demonstrated on pulmonary function testing as a global reduction in expiratory flows and volumes. FEV1, FVC, and the FEV1/FVC (FEV1%) ratio are all reduced. The expiratory flow-volume curve shows substantial limitation of flow. Some patients may respond to bronchodilators. Measurement of lung volumes reveals an increase in the RV and FRC, reflecting air trapped in the lung as a result of diffuse airway obstruction and early airway closure at higher lung volumes. This is characterized by flattened diaphragm on chest x-ray. DlCO is typically normal, reflecting a preserved alveolar capillary bed.
D. Ventilation/perfusion mismatching is common in chronic bronchitis. The A-a ΔPO2 is increased and hypoxemia is common mainly because of significant areas of low ratios (physiologic shunt); hypoxemia at rest tends to be more profound than in emphysema. There is also mismatch in emphysema, but typically, patients with emphysema adapt to high ratios by increasing their minute ventilation. They may maintain nearly normal PO2 and PCO2 levels despite advanced disease. However, with greater disease severity and further loss of capillary perfusion, the DlCO falls, leading to exercise-related and, ultimately, resting arterial hemoglobin desaturation. In both conditions, increasing PCO2 (hypercapnia) and respiratory acidosis, with compensatory metabolic alkalosis, are seen in severe disease.
CASE 45
A. Diffuse parenchymal lung disease encompasses many disorders with different precipitating events and possibly different cellular and molecular mechanisms. A common series of cellular events mediate and regulate lung inflammatory processes and fibrotic responses (Table 9-5). These events include (1) initial tissue injury; (2) vascular injury and endothelial cell activation, with increased permeability, exudation of plasma proteins into the extravascular space, and variable thrombosis and thrombolysis; (3) alveolar epithelial cell injury and activation, with loss of barrier integrity and release of proinflammatory mediators; (4) increased leukocyte adherence to activated endothelium, with transit of activated leukocytes into the interstitium; and (5) continued injury and repair processes characterized by alterations in cell populations and increased matrix production.
B. An intermittent, irritating, non-productive cough is often the first symptom of idiopathic pulmonary fibrosis (IPF). It may be refractory to antitussive therapy. The mechanism is likely multifactorial with fibrotic damage to terminal respiratory units causing bronchial and bronchiolar distortion, leading to alterations in both stimulatory and inhibitory nerve fibers involved in cough reflexes.
Multiple factors contribute to dyspnea in patients with IPF. Fibrosis of lung parenchyma decreases lung compliance; in combination with alterations in surfactant turnover, the distending pressure required to inflate the lungs increases, as does the work of breathing. Increased stimuli from C fibers in fibrotic alveolar walls or stretch receptors in the chest wall may sense the increased force necessary to inflate less compliant lungs.
Tachypnea results from increased lung sensory receptor stimuli and the attempt to maintain a normal alveolar minute ventilation (and hence normal PaCO2) as lung volumes decrease. A rapid, shallow breathing pattern also reduces ventilatory work in the face of increased lung elastic recoil. The diminished capillary bed and thickened alveolar-capillary membrane contribute to hypoxemia with exercise. In advanced disease, altered gas exchange with severe mismatching can produce hypoxemia at rest.
The diffuse inspiratory crackles reflect the successive opening on inspiration of respiratory units that are collapsed owing to the fibrosis and the loss of normal surfactant. The cause of digital clubbing is not known.
C. Characteristic chest radiograph findings include reduced lung volumes with increased reticular opacities that are prominent in the lung periphery and cause loss of definition of vascular structures, diaphragms, and cardiac border. Fibrosis surrounding expanded small airspaces is seen as honeycombing. With pulmonary hypertension, central pulmonary arteries may be enlarged. Pulmonary fibrosis produces a restrictive pattern on pulmonary function tests. This is manifested as reductions in TLC, FEV1, and FVC, with preservation of or increases in FEV1/FVC and expiratory flow rates. DlCO decreases progressively as fibrosis continues and lung capillaries are obliterated.
CASE 46
A. The four factors that account for almost all cases of pulmonary edema are (1) an increase in the hydrostatic pressure gradient (cardiogenic pulmonary edema); (2) an increase in vascular endothelial cell and/or alveolar epithelial cell permeability (noncardiogenic pulmonary edema); (3) a decrease in the oncotic pressure gradient (usually due to low protein content of the plasma); and (4) impaired lymphatic drainage either from physical lymphatic obstruction or from lymphatic obliteration that can occur in the setting of radiation treatment. This patient’s history of prior myocardial infarction, long-standing history of hypertension, and possible recent ischemia make it likely that he has cardiogenic pulmonary edema.
B. Cardiogenic or hydrostatic pulmonary edema classically results from elevated pulmonary venous and left atrial pressures due to left ventricular systolic or diastolic failure, mitral stenosis, or mitral regurgitation. This is primarily a mechanical process resulting in an ultrafiltrate of plasma. Edema fluid in this setting has a relatively low protein content, generally less than 60% of a patient’s plasma protein content. In normal individuals, pulmonary capillary pressure (ie, pulmonary capillary wedge pressure) must exceed approximately 20 mm Hg before the fluid leaving the vascular space exceeds the rate of resorption, leading to accumulation of interstitial (Figure 9-26) and ultimately alveolar fluid that we describe as pulmonary edema.
CASE 47
A. Thromboemboli almost never originate in the pulmonary circulation. More than 95% of pulmonary thromboemboli arise from the deep veins of the lower extremity: the popliteal, femoral, and iliac veins. The findings of right lower extremity warmth, erythema, and swelling in this patient support the view that this is very likely the site of origin of thromboembolism. It is important to note, however, that the absence of such lower extremity findings does not exclude the diagnosis of thrombus from the lower extremity, because findings are insensitive.
B. This patient has multiple risk factors for pulmonary embolism, and he was at high risk for such an event. He is older than 40 years, was anesthetized for more than 30 minutes for his total knee replacement, and underwent orthopedic surgery (risk imposed by immobilization). His risk for calf vein thrombosis is as high as 84%, and the risk of fatal pulmonary embolism is approximately 5%. All such patients should receive prophylactic therapy with anticoagulants postoperatively.
C. All patients with pulmonary emboli have some degree of mechanical obstruction. The effect depends on the proportion of the pulmonary circulation obstructed (how large the pulmonary embolus is), neurohumoral reflexes stimulated by the thrombus, and the severity of preexisting cardiopulmonary disease. As the degree of obstruction of pulmonary circulation increases, pulmonary artery pressures rise, ultimately leading to right ventricular strain. In severe pulmonary embolism, occlusion of the pulmonary outflow tract may occur, severely reducing cardiac output and causing cardiovascular collapse and death.
D. Pulmonary embolism decreases or eliminates perfusion distal to the site of the occlusion. The immediate effect is increased mismatching, with a shift in the proportion of lung segments with high ratios (alveolar dead space or wasted ventilation). A shift toward high ratios impairs the excretion of carbon dioxide with minimal effect on oxygenation. The patient compensates for this increase in wasted ventilation by increasing total minute ventilation. After several hours, local hypoperfusion reduces production of surfactant by type II alveolar cells, resulting in edema, alveolar collapse, and atelectasis, creating lung units with little or no ventilation. Depending on the level of perfusion to these segments, there will be an increase in lung units with low ratios including some areas of true shunting, both of which contribute to an increased A-a ΔPO2 and arterial hypoxemia.
CASE 48
A. The pathophysiology of increased permeability pulmonary edema (ARDS) is complex and may result from multiple different insults. Alveolar fluid accumulates as a result of loss of integrity of the alveolar epithelial barrier, allowing solutes and large molecules such as albumin to enter the alveolar space. This loss of integrity may result from direct injury to the alveolar epithelium by inhaled toxins or pulmonary infection, or they may occur after primary injury to the pulmonary capillary endothelium by circulating toxins as in sepsis or pancreatitis, followed by secondary inflammatory injury to the alveolar epithelial barrier. The presence of high-protein fluid in the alveolus, particularly the presence of fibrinogen and fibrin-degradation products, inactivates pulmonary surfactant, causing large increases in surface tension. This results in a fall in pulmonary compliance and alveolar instability, leading to areas of atelectasis. Increased surface tension decreases the interstitial hydrostatic pressure and favors further fluid movement into the alveolus. A damaged surfactant monolayer may increase susceptibility to infection as well.
B. ARDS is the final common pathway of a number of different serious medical conditions, all of which lead to increased pulmonary capillary leak. The range of clinical presentations includes all of the diagnoses in the adult ICU, including sepsis, pneumonia, pancreatitis, aspiration of gastric contents, shock, lung contusion, nonthoracic trauma, toxic inhalation, near-drowning, and multiple blood transfusions. About one third of ARDS patients initially have sepsis syndrome.
C. The severe hypoxia found in ARDS is due to several factors. Damage to endothelial and epithelial cells causes increased vascular permeability and reduced surfactant production and activity. These abnormalities lead to interstitial and alveolar pulmonary edema, alveolar collapse, a significant increase in surface forces, markedly reduced pulmonary compliance, and hypoxemia. As the process worsens, there may be a further fall in compliance and disruption of pulmonary capillaries, leading to areas of true shunting and refractory hypoxemia. The combination of increased work of breathing and progressive hypoxemia usually requires mechanical ventilation. Since the underlying process is heterogeneous, with normal-appearing lung adjacent to atelectatic or consolidated lung, ventilating patients at typical tidal volumes may overdistend normal alveoli, reduce blood flow to areas of adequate ventilation, and precipitate further lung injury (“volu-trauma”). Hypoxemia can be profound, typically followed days later by hypercapnia due to increasing dead space ventilation.
CASE 49
A. The atrioventricular (AV) node normally forms the only electrical connection between the atria and the ventricles. However, an accessory AV connection is found in approximately 1 in 1000 persons. This accessory pathway is usually composed of normal atrial or ventricular tissue. Because part of the ventricle is “pre-excited” over the accessory pathway rather than via the AV node, the surface ECG shows a short PR interval and a relatively wide QRS with a slurred upstroke, termed a delta wave.
B. Because the atria and ventricles are linked by two parallel connections, reentrant tachycardias are readily initiated. For example, a premature atrial contraction could be blocked in the accessory pathway but still conduct to the ventricles via the AV node. If enough time has elapsed so that the accessory pathway has recovered excitability, the cardiac impulse can travel in retrograde fashion to the atria over the accessory pathway and initiate a reentrant tachycardia.
C. First, increased automaticity resulting from more rapid phase 4 depolarizations can cause rapid heart rate. Second, if repolarization is delayed (longer plateau period), spontaneous depolarizations (caused by reactivation of sodium or calcium channels) can sometimes occur in phase 3 or phase 4 of the action potential. These depolarizations are called “triggered activity” because they are dependent on the existence of a preceding action potential. If these depolarizations reach threshold, tachycardia can occur in certain pathologic conditions.
CASE 50
A. Heart failure can be caused by (1) inappropriate workloads placed on the heart, such as volume overload or pressure overload; (2) restricted filling of the heart; (3) myocyte loss; or (4) decreased myocyte contractility. The patient has myocyte loss and decreased myocyte contractility from the myocardial infarction. She may also have restricted filling due to impaired relaxation of the myocytes if she has ongoing ischemia.
B. In systolic dysfunction, the isovolumic systolic pressure curve of the pressure-volume relationship is shifted downward. This reduces the stroke volume of the heart with a concomitant decrease in cardiac output. To maintain cardiac output, the heart can respond with three compensatory mechanisms: First, increased return of blood to the heart (preload) can lead to increased contraction of sarcomeres (Frank-Starling relationship). Second, increased release of catecholamines can increase cardiac output by both increasing the heart rate and shifting the systolic isovolumetric curve to the left. Finally, cardiac muscle can hypertrophy and ventricular volume can increase, which shifts the diastolic curve to the right. Although each of these compensatory mechanisms can temporarily maintain cardiac output, each is limited in its ability to do so, and if the underlying reason for systolic dysfunction remains untreated, the heart ultimately fails.
In diastolic dysfunction, the position of the systolic isovolumic curve remains unchanged (contractility of the myocytes is preserved). However, the diastolic pressure-volume curve is shifted to the left, with an accompanying increase in left ventricular end-diastolic pressure and symptoms of heart failure (Figure 10-17). Diastolic dysfunction can be present in any disease that causes decreased relaxation, decreased elastic recoil, or increased stiffness of the ventricle. Hypertension, which often leads to compensatory increases in left ventricular wall thickness, can cause diastolic dysfunction by changing all three parameters. Lack of sufficient blood to myocytes (ischemia) can also cause diastolic dysfunction by decreasing relaxation. If ischemia is severe, as in myocardial infarction, irreversible damage to the myocytes can occur, with replacement of contractile cells by fibrosis, which will lead to systolic dysfunction. In most patients, a combination of systolic and diastolic dysfunction is responsible for the symptoms of heart failure.
C. Shortness of breath is likely due to the rise in pulmonary capillary pressure relative to plasma oncotic pressure, which causes fluid to move into the interstitial spaces of the lung (pulmonary edema). Interstitial edema probably stimulates juxtacapillary J receptors, which in turn causes reflex shallow and rapid breathing. Replacement of air in the lungs by blood or interstitial fluid can cause a reduction of vital capacity, restrictive physiology, and air trapping as a result of closure of small airways. The work of breathing increases as the patient tries to distend stifflungs, which can lead to respiratory muscle fatigue and the sensation of dyspnea. Alterations in the distribution of ventilation and perfusion result in relative ventilation-perfusion mismatch, with consequent widening of the alveolar-arterial O2 gradient, hypoxemia, and increased dead space.
Sudden onset of severe respiratory distress at night—paroxysmal nocturnal dyspnea—probably occurs because of the reduced adrenergic support of ventricular function that occurs with sleep, the increase in blood return as described previously, and normal nocturnal depression of the respiratory center.
Shortness of breath occurs in the recumbent position (orthopnea) because of reduced blood pooling in the extremities and abdomen, and because the patient is operating on the steep portion of the diastolic pressure-volume curve, any increase in blood return leads to marked elevations in ventricular pressures. Patients usually learn to minimize orthopnea by sleeping with the upper body propped up by two or more pillows.
CASE 51
A. The three most common causes of aortic stenosis are congenital abnormalities (unicuspid, bicuspid, or fused leaflets), rheumatic heart disease, and degenerative valve disease resulting from calcium deposition. The most likely cause in this patient is rheumatic heart disease. Congenital aortic stenosis generally presents before age 30 years, whereas degenerative aortic stenosis is the most common cause in persons older than 70 years. Furthermore, this patient has a history of recurrent streptococcal sore throat, suggesting the possibility of rheumatic heart disease.
B. Syncope in aortic stenosis is usually due to decreased cerebral perfusion from the fixed obstruction, but it may also occur because of transient atrial arrhythmias with loss of effective atrial contribution to ventricular filling. Arrhythmias arising from ventricular tissue are also more common in patients with aortic stenosis and can result in syncope.
C. Angina can be caused by a number of different mechanisms. Approximately half of all patients have comorbid significant coronary artery disease, which can lead to angina. Even without coronary artery disease, aortic stenosis causes compensatory ventricular hypertrophy. Ventricular hypertrophy causes an increase in oxygen demand as well as compression of the vessels traversing the cardiac muscle, resulting in decreased oxygen supply. The result is relative ischemia of the myocytes. Finally, in the case of calcified aortic valves, calcium emboli can cause coronary artery obstruction, although this is rare.
D. Carotid upstroke is decreased (pulsus parvus) and late (pulsus tardus) because of the fixed obstruction to flow. Left ventricular hypertrophy causes the apical impulse to be displaced laterally and to become sustained. The increased dependence on atrial contraction is responsible for the prominent S4. Flow through the restricted aortic orifice results in the midsystolic murmur, whereas regurgitant flow causes the diastolic murmur.
E. Once symptoms occur in aortic stenosis, without treatment the prognosis is poor. Life expectancy is 2 years if aortic stenosis causes angina and 3 years if aortic stenosis causes syncope.
CASE 52
A. The fundamental problem in aortic regurgitation is volume overload of the left ventricle during diastole. In aortic regurgitation, blood enters the left ventricle both from the pulmonary veins and from the aorta (through the leaky aortic valve). The left ventricular stroke volume can increase dramatically, although the effective stroke volume may be minimally changed since much of the increase in stroke volume leaks back into the left ventricle. If the regurgitation develops slowly, the heart responds to the increased diastolic volume by elongation of the sarcomeres (dilation) and thickening of the wall (hypertrophy). This can result in an enlarged heart that is displaced to the left. All of these changes are characteristic of slowly progressive aortic regurgitation. However, if the condition develops quickly, over a few days, such as during destruction of the aortic valve from infective endocarditis, these compensatory mechanisms do not have a chance to develop.
B. In aortic regurgitation, the pulse pressure is widened both because of an increase in systolic pressure and a falling diastolic pressure. The systolic pressure is increased due to the increased stroke volume. The diastolic pressure is decreased due to the regurgitant flow back into the left ventricle and the increased compliance of the great vessels. This large difference between systolic and diastolic pressures is readily felt in the peripheral pulse as a sudden rise, then drop, in pressure. There are many physical signs resulting from this phenomenon, including the so-called water-hammer pulse (Corrigan pulse), head bobbing (de Musset sign), pulsation of the uvula (Müller sign), and arterial pulsations of the nailbeds (Quincke pulse).
C. The high-pitched diastolic murmur at the left lower sternal border is from the regurgitant flow through the leaky aortic valve. The diastolic rumbling at the apex, also known as the Austin Flint murmur, is from the regurgitant flow impinging on the anterior leaflet of the mitral valve, causing a functional mitral stenosis. The systolic murmur at the left upper sternal border is from the increased stroke volume flowing across the aortic valve during systole.
D. Early in aortic regurgitation, there is no heart failure because the left ventricle adapts to the increased volume by enlarging and thickening. However, at some point the compensatory mechanisms fail, and the end-diastolic pressure in the left ventricle rises. This rise in end-diastolic pressure is transmitted through the pulmonary veins to the lungs where it results in pulmonary edema due to increases in hydrostatic pressure. This buildup of fluid in the alveoli causes impaired oxygenation, leading to shortness of breath. In milder cases, the shortness of breath may only become evident when there is increased demand or, in severe cases, may manifest at rest. For example, increased demand can occur during exertion. It may also occur during sleep, when the supine position allows the interstitial fluid from dependent tissues to reenter the circulation, causing an increased intravascular volume.
CASE 53
A. The likely diagnosis in this patient is mitral stenosis. The history of a long illness following a sore throat in childhood is suggestive of acute rheumatic fever, the most common cause of mitral stenosis. The diastolic murmur results from the impaired blood flow across the narrowed mitral valve. The irregularly irregular rhythm is due to atrial fibrillation, and the shortness of breath and rales are due to the heart failure of advanced mitral stenosis.
B. The normal mitral valve area is 5–6 cm2. When it becomes narrowed to less than 1 cm2, the flow of blood from the left atrium to the left ventricle is compromised enough to result elevated left atrial pressure and volume. These elevations cause the left atrium to dilate, disrupting the orderly initiation of each heartbeat. Chaotic electrical activity replaces the usual control of the heart rhythm by the sinoatrial node, and atrial fibrillation ensues. The elevated left atrial pressure is also transmitted to the pulmonary veins and capillaries resulting in heart failure, pulmonary edema, and hemoptysis from leakage of engorged pulmonary veins.
C. The blood in the dilated left atrium is relatively static, and clots can form there in approximately 20% of patients with mitral stenosis. If these thrombi enter the left ventricle, they can be pumped out to the systemic circulation causing a sudden arterial blockage, such as a stroke.
CASE 54
A. The patient’s decompensation was likely triggered by the development of acute mitral regurgitation. The leaflets of the mitral valve are tethered by chordae tendineae, which are in turn attached to the ventricular wall by papillary muscles. The papillary muscles derive their blood supply from the left circumflex coronary artery and can become ischemic and even rupture if the blood supply is interrupted. When this happens, the leaflet is no longer tethered, and the valve no longer closes with systole, resulting in the sudden development of acute mitral regurgitation.
B. In mitral regurgitation, blood regurgitates into the left atrium from the left ventricle during systole. This leads to both volume and pressure overload of the left atrium, which in turn is transmitted to the pulmonary vasculature. It can also lead to dilation of the atrium and disruption of the heart’s electrical system, causing arrhythmias such as atrial fibrillation. The increased pulmonary pressures can lead to heart failure. Also, in contrast to mitral stenosis, there is also an element of volume overload on the left ventricle, as the regurgitant blood from the left atrium goes back into the left ventricle during diastole.
C. If mitral regurgitation develops more slowly, the heart has a chance to adapt to the increased volume. The left ventricle, in particular, can dilate and hypertrophy in response to the increased stroke volume (though usually not to the extent that this left ventricular dilation and hypertrophy happen in aortic regurgitation). As a result, the apical impulse becomes displaced to the left.
CASE 55
A. The most likely diagnosis in this patient is coronary artery disease, specifically angina pectoris. Because the symptoms are exertional only and have been stable for several months, this patient would be classified as having stable angina. If the pain occurred at rest, with less and less activity, or more frequently or for a longer duration despite similar activity levels, he would be classified as having unstable angina.
B. By far the most common cause of coronary artery disease is atherosclerosis of the large epicardial arteries, and this is the most likely cause in this patient. A less common cause is coronary artery vasospasm, found more commonly in Japanese individuals. Vasospastic angina is most often nonexertional. Rare causes include emboli and congenital abnormalities.
C. This patient has several cardiac risk factors, including male gender, a family history of coronary artery disease, hyperlipidemia, smoking, and hypertension.
D. The mechanism by which atherosclerotic plaques form remains unclear and is the subject of much debate. It appears that atherosclerosis starts early in life, when the endothelial linings of the blood vessels are exposed to shear stress. The injury that results causes the endothelial cells to release vascular cell adhesion molecules to which monocytes become attached and enter the subendothelium, where they engulf oxidized low-density lipoprotein (LDL), forming foam cells. The injured endothelium, in combination with the foam cells, forms the fatty streak characteristic of atherosclerosis. Oxidized LDL causes the release of cytokines and inhibition of NO. Vascular smooth muscle moves from the media to the intima, where they proliferate, laying down collagen and matrix and taking up oxidized LDL to form more foam cells. T cells also accumulate in the growing plaque. T cells, smooth muscle cells, and endothelial cells produce various cytokines and growth factors responsible for further cell migration and proliferation. Ultimately, the thickened and distorted artery wall takes up calcium, creating a brittle plaque.
E. Chest pain is due to myocardial ischemia, which occurs when cardiac oxygen demand exceeds supply. In the case of stable angina, fixed narrowing of one or more coronary arteries by atherosclerotic plaque occurs. When the patient exercises, cardiac oxygen demand increases. However, because of the decreased diameter of the coronary arteries, insufficient blood flow, and, therefore, insufficient oxygen, is supplied to the heart. Chest pain has been attributed to this ischemia; however, it has been shown that up to 80% of all ischemic episodes are asymptomatic. When present, chest pain is thought to be triggered by adenosine release, causing stimulation of the sympathetic afferent fibers that innervate the atrium and ventricle. These fibers then traverse the sympathetic ganglia and five upper thoracic dorsal roots of the spinal cord. These fibers converge with fibers from other structures in the spinal cord, which accounts for the frequent sensation of pain in the chest wall, back, and arm.
CASE 56
A. The probable diagnosis in this patient is pericarditis.
B. The most common cause of pericarditis is infection. Although bacteria, protozoa, and fungi can all cause pericarditis, viruses are most common offender, in particular the coxsackieviruses. Coxsackievirus infection is the most likely cause in this patient given his young age, absence of underlying diseases, and viral prodrome. Pericarditis also occurs after injury (eg, myocardial infarction, thoracotomy, chest trauma, or radiation therapy). Less common causes include collagen-vascular diseases (lupus erythematosus, scleroderma, rheumatoid arthritis), neoplasms, and renal failure.
C. Chest pain is probably due to pericardial inflammation. The pleuritic nature of the chest pain may be due to inflammation of the adjacent pleura.
D. The sound heard on cardiac examination is characteristic of a pericardial friction rub, which is pathognomonic for pericarditis. It is believed to be caused by friction between the visceral and parietal pericardial surfaces. The three components are attributable to the rapid movements of the cardiac chambers. The systolic component is related to ventricular contraction and is the one most commonly heard. There are two diastolic components: one in early diastole resulting from rapid ventricular filling and one late in diastole caused by atrial contraction. The two diastolic components frequently merge, so a two-component rub is most often heard.
E. One complication of pericarditis is pericardial effusion. Sudden onset of pericardial effusion may lead to tamponade. This sudden addition of fluid increases pericardial pressure to the level of right atrial and ventricular pressures, causing chamber collapse and inadequate filling. Physical findings consistent with tamponade include elevated jugular venous pressure, hypotension, paradoxical pulse, and muffled heart sounds.
A second complication of pericarditis is fibrosis resulting in constrictive pericarditis. In constrictive pericarditis, early diastolic filling is normal, but the filling is suddenly stopped by the nonelastic fibrotic pericardium. This cessation of filling is probably responsible for the diastolic knock classically heard in this disease. In addition, because of the limited flow into the heart, systemic and, therefore, jugular venous pressures are elevated. The Kussmaul sign may also be present (ie, inappropriate increase in jugular venous pressure with inspiration). Finally, elevated systemic venous pressures can lead to accumulation of fluid in the liver and intraperitoneal space, resulting in hepatomegaly and ascites.
CASE 57
A. The three classic signs of pericardial tamponade are called the Beck triad, after the surgeon who described them in 1935: (1) hypotension, (2) elevated jugular venous pressure, and (3) muffled heart sounds. In addition, the patient may have a decrease in systemic pressure with inspiration (paradoxic pulse).
B. The pericardium is normally filled with a small amount of fluid (30–50 mL) with an intrapericardial pressure that is usually about the same as the intrapleural pressure. With the sudden addition of fluid, the pericardial pressure can increase, at times to the level of the right atrial and right ventricular pressures. The transmural distending pressure of the ventricle decreases and the chamber collapses, preventing appropriate filling of the heart from systemic venous return. The four chambers of the heart occupy a relatively fixed volume in the pericardial sac, and hemodynamic evaluation reveals equilibration of ventricular and pulmonary artery diastolic pressures with right atrial and left atrial pressures, all at approximately intrapericardial pressure.
C. Arterial systolic blood pressure normally drops 10–12 mm Hg with inspiration. A marked inspiratory decrease in systolic blood pressure (>20 mm Hg) is an important physical finding in the diagnosis of cardiac tamponade but can also be seen in severe pulmonary disease and, less commonly, in constrictive pericarditis. Marked inspiratory decline in left ventricular stroke volume occurs because of decreased left ventricular end-diastolic volume. With inspiration, increased blood return augments filling of the right ventricle, which causes the interventricular septum to bow to the left and reduce left ventricular end-diastolic volume (reverse Bernheim effect). Also during inspiration, flow into the left atrium from the pulmonary veins is reduced, further reducing left ventricular preload.
CASE 58
A. This patient likely has angina pectoris and intermittent claudication due to underlying atherosclerosis.
B. The initial event in atherosclerosis is infiltration of low-density lipoproteins (LDLs) into the subendothelial region. The endothelium is subject to shear stress, the tendency to be pulled along or deformed by flowing blood. This is most marked at points where the arteries branch, and this is where the lipids accumulate to the greatest degree. The LDLs are oxidized or altered in other ways and activate various components of innate immune system including macrophages, natural antibodies, and innate effector proteins such as C-reactive protein and complement. The oxidized LDL is taken up into macrophages, forming foam cells. The foam cells form fatty streaks. Vascular smooth muscle cells in the vicinity of foam cells are stimulated and move from the media to the intima, where they proliferate, lay down collagen and other matrix molecules, and contribute to the bulk of the lesion. Smooth muscle cells also take up oxidized LDL and become foam cells. Lipids accumulate both intracellularly and extracellularly. The intercellular “soup” in the plaques contains a variety of cell-damaging substances, including ozone. In addition, the “loading” of macrophages with cholesterol can be lipotoxic to the endoplasmic reticulum, resulting in macrophage apoptosis and plaque necrosis. Cholesterol crystals associated with necrotized macrophages further stimulate inflammation and lead to the recruitment of neutrophils. As the atherosclerotic lesions age, T cells of the immune system and monocytes are attracted to them, creating a vicious cycle of necrosis and inflammation. As plaques mature, a fibrous cap forms over them. The plaques with defective or broken caps are most prone to rupture. The lesions alone may distort vessels to the point that they are occluded, but it is usually rupture or ulceration of plaques that triggers thrombosis, blocking blood flow.
C. This patient is postmenopausal and a smoker, has high blood pressure, and is diabetic. Estrogen increases cholesterol removal by the liver, and the progression of atherosclerosis is less rapid in premenopausal women that in men. On the other hand, large estrogen doses increase the incidence of blood clots, and even small doses produce a slight increase in clotting. In addition, in several studies, estrogen treatment of postmenopausal women failed to prevent second heart attacks. The reason for the discrepancies between the epidemiologic and experimental data is currently unsettled. The deleterious effects of smoking include endothelial damage caused by carbon monoxide–induced hypoxia. Other factors may also be involved. Thus, stopping smoking is a major way to slow the progress of atherosclerosis. Because of the increased shear stress imposed on the endothelium by an elevated blood pressure, hypertension is another important modifiable risk factor for atherosclerosis. Lowering blood pressure has its greatest effect in reducing the incidence of stroke, but there are beneficial effects on ischemic heart disease as well. In diabetics, there are both microvascular and macrovascular complications. The latter are primarily related to atherosclerosis. There is a 2-fold increase in the incidence of myocardial infarction compared with nondiabetics; severe circulatory deficiency in the legs with gangrene is relatively common; there are more thrombotic strokes; and chronic kidney disease is a serious problem.
CASE 59
A. Hypertension is generally defined as a blood pressure greater than 140/90 mm Hg on three consecutive doctor’s office visits, and prehypertension as blood pressures of 120–139/80–89 mm Hg. Although this patient would certainly be considered to have high blood pressure on this visit, he would not yet be diagnosed with hypertension.
B. In long-standing severe hypertension, one may note hypertensive retinopathy, including narrowed arterioles or even retinal hemorrhages and exudates. Cardiac enlargement resulting from hypertrophy may be noted as a displaced and prominent point of maximal impulse on cardiac palpation. An S4 may be heard on cardiac auscultation.
C. Complications of hypertension include accelerated atherosclerosis resulting in ischemic heart disease, thrombotic strokes, cerebral hemorrhages, and renal failure. In severe hypertension, encephalopathy may occur.
D. By far the most common cause of hypertension is essential hypertension, and that is probably the cause in this patient. Because the patient is black, salt sensitivity may be a contributory factor. Other relatively common causes are diffuse renal disease, medications, renal arterial disease, and neurologic disorders. Less commonly, coarctation of the aorta, mineralocorticoid excess, glucocorticoid excess, and catecholamine excess can cause hypertension.
CASE 60
A. The four major pathophysiologic types of shock are hypovolemic, distributive, cardiogenic, and obstructive. Given the patient’s age, history of severe trauma, and physical findings, the most likely type in this case is hypovolemic shock.
B. In hypovolemic shock, decreased blood volume leads to inadequate perfusion of the tissues. This results in increased anaerobic glycolysis and production of lactic acid. Lactic acidosis depresses the myocardium, decreases peripheral vascular responsiveness to catecholamines, and may cause coma. Decreased mean arterial blood pressure decreases arterial baroreceptor firing, resulting in increased vasomotor discharge. This causes generalized vasoconstriction. Vasoconstriction in the skin causes coolness and pallor.
C. There are five causes of hypovolemic shock: hemorrhage, trauma, surgery, burns, and fluid loss resulting from vomiting or diarrhea. This patient was in a motor vehicle accident, resulting in traumatic shock. This was caused by blood loss into the abdomen, as suggested by the physical examination.
CASE 61
A. Other historical features to be elicited include chest pain (12%), flushing (14%), excessive sweating (50%), fainting (40%), and GI symptoms such as nausea or vomiting (19%), abdominal pain (14%), and diarrhea (6%). In addition, a medical history or family history of genetic diseases increasing the risk of pheochromocytoma should be elicited, as should a family history of pheochromocytoma independent of other genetic syndromes. Approximately 20–30% of pheochromocytomas are familial. Most familial cases are caused by one of four syndromes: neurofibromatosis type 1, von Hippel–Lindau syndrome, multiple endocrine neoplasia type 2 (MEN-2), and familial paraganglioma syndrome. Germline mutations in RET, VHL, SDHx, and others account for at least 20–30% of cases of isolated pheochromocytomas and paragangliomas.
B. Pheochromocytoma is usually diagnosed by demonstrating abnormally high concentrations of catecholamines or their breakdown products in the urine or plasma. Increases in plasma metanephrine and normetanephrine concentrations are greater and more consistent than increases in plasma catecholamines or urinary metanephrines. Administration of clonidine, 0.3 mg orally, can also be used to differentiate patients with pheochromocytoma from those with essential hypertension. Clonidine normally suppresses sympathetic nervous system activity and substantially lowers plasma norepinephrine levels, reducing blood pressure. However, in patients with pheochromocytoma, clonidine has little or no effect on the blood pressure or plasma catecholamine level because these tumors behave autonomously.
C. As a tumor of adrenal medullary tissue, pheochromocytoma produces symptoms of catecholamine excess. Anxiety, headache, and palpitations are direct effects of catecholamine discharge; the weight loss is secondary to one of the metabolic effects of excessive circulating catecholamines. These include an increase in basal metabolic rate and an increase in glycolysis and glycogenolysis, leading to hyperglycemia and glycosuria.
CASE 62
A. This patient likely has achalasia, a condition where the lower esophageal sphincter fails to relax properly. Under normal circumstances, the lower esophageal sphincter is a 3–4 cm ring of smooth muscle that is contracted, under stimulation by vagal cholinergic inputs. When a swallow is initiated, vagal inhibitory fibers allow the sphincter to relax so that the bolus of food can pass into the stomach. In achalasia, there is degeneration of the myenteric plexus and loss of the inhibitory neurons that allow this relaxation. Therefore, the sphincter remains tightly closed. The neural dysfunction can also extend further up the esophagus as well, and effective esophageal peristalsis is also often lost.
B. Injection of botulinum toxin into the lower esophageal sphincter in patients with achalasia diminishes the excitatory pathways responsible for the tonic contraction of the sphincter and allows its partial relaxation.
C. The tight closure of the lower esophageal sphincter in achalasia can result in a dilation of the lower portion of the esophagus and storage of up to 1 L of material there. This material can become infected and aspirated into the lungs. It can also cause esophageal mucosal ulceration and even perforation or rupture.
CASE 63
A. This patient appears to suffer from reflux esophagitis. Normally, the tonically contracted lower esophageal sphincter provides an effective barrier to reflux of acid from the stomach back into the esophagus. This is reinforced by secondary esophageal peristaltic waves in response to transient lower esophageal sphincter relaxation. Effectiveness of that barrier can be altered by loss of lower esophageal sphincter tone, increased frequency of transient relaxations, loss of secondary peristalsis after a transient relaxation, increased stomach volume or pressure, or increased production of acid, all of which can make more likely reflux of acidic stomach contents sufficient to cause pain or erosion. Recurrent reflux can damage the mucosa, resulting in inflammation, hence the term “reflux esophagitis.” Recurrent reflux itself predisposes to further reflux because the scarring that occurs with healing of the inflamed epithelium renders the lower esophageal sphincter progressively less competent as a barrier.
B. Many factors such as her food choices (eg, chocolate), medications such as benzodiazepines, and smoking decrease lower esophageal sphincter tone, resulting in reflux of acid-rich gastric contents into the esophageal lumen. This process is exacerbated at night when she lies down to sleep.
C. The most common complication is the development of stricture in the distal esophagus. Progressive obstruction, initially to solid food and later to liquid, presents as dysphagia. Other complications of recurrent reflux include hemorrhage or perforation; hoarseness, coughing, or wheezing; and pneumonia as a result of aspiration of gastric contents into the lungs, particularly during sleep. Epidemiologic studies suggest that cigarette smoking and alcohol abuse associated with recurrent reflux result in a change in the esophageal epithelium from squamous to columnar histology, termed Barrett esophagus. In 2–5% of cases, Barrett esophagus leads to the development of esophageal adenocarcinoma.
CASE 64
A. Excessive acid secretion or diminished mucosal defenses predispose to the development of acid-peptic disease, specifically gastric ulcer. Most gastric ulcers are believed to be related to impaired mucosal defenses, because the acid and pepsin secretory capacity of some affected patients is normal or even below normal. Motility defects have been proposed to contribute to development of gastric ulcer in at least three ways: (1) by a tendency of duodenal contents to reflux back through an incompetent pyloric sphincter (bile acids in the duodenal reflux material act as an irritant and may be an important contributor to a diminished mucosal barrier against acid and pepsin); (2) by delayed emptying of gastric contents, including reflux material, into the duodenum; and (3) by delayed gastric emptying and hence food retention, resulting in increased gastrin secretion and gastric acid production. It is not known whether these motility defects are a cause or a consequence of gastric ulcer formation. Mucosal ischemia may also play a role in the development of a gastric ulcer (see Answer B following). Subsets of gastric ulcer patients with each of these defects have been identified. Thus, the risk factors (NSAID ingestion, smoking, psychologic stress, H pylori infection) that have been associated with gastric ulcer probably act by diminishing one or more mucosal defense mechanisms.
B. Prostaglandins are known to increase mucosal blood flow as well as bicarbonate and mucus secretion and to stimulate mucosal cell repair and renewal. Thus, their deficiency, resulting from NSAID ingestion or other insults, may predispose to gastritis and gastric ulcer, as might diminished bicarbonate or mucus secretion due to other causes.
C. H pylori can cause acid-peptic disease by multiple mechanisms, including altered signal transduction, resulting in increased inflammation, increased acid secretion, and diminished mucosal defenses. It may also affect apoptosis in the GI tract. Despite the high rate of association of inflammation with H pylori infection, the important role of other factors is indicated by the fact that only about 15% of H pylori–infected individuals ever develop a clinically significant ulcer. These other factors (both genetic and environmental, such as cigarette smoking) must account for the individual variations and are pathophysiologically important. Nevertheless, the role of H pylori is of particular clinical importance because, of patients who do develop acid-peptic disease, almost all have H pylori infection. Furthermore, treatment that does not eradicate H pylori is associated with rapid recurrence of acid-peptic disease in most patients. Recent studies have also associated different strains of H pylori with different forms and degrees of acid-peptic disease and implicated H pylori infection in the development of GI tract cancers. Cornerstones of therapy for this patient include discontinuation of ibuprofen, proton pump inhibitors to decrease acid production, and antibiotics to treat the H pylori infection.
CASE 65
A. Normal gastric emptying is influenced in part by the intrinsic enteric nervous system and its autonomic control. These systems are compromised by long-standing diabetes mellitus and its associated autonomic neuropathy.
It is likely that this patient’s elevated fingerstick glucose is due to poor adherence to the medical regimen. This is supported by 6 months of worsening peripheral neuropathy. The newly diagnosed gastroparesis may, however, complicate attempts at improved glucose control.
B. His diarrhea may be multifactorial. Poorly coordinated pyloric contractions may result in entry into the duodenum of too large a bolus of chyme, which is ineffectively handled by the small intestine. Malabsorption results, leading to diarrhea. This malabsorption also predisposes to bacterial overgrowth, which may further exacerbate his diarrhea.
CASE 66
A. Many factors are involved in gallstone formation, but they can be divided into factors affecting bile composition and factors affecting gallbladder motility. Factors affecting the lithogenicity of bile include the cholesterol content, the presence of nucleating factors, prostaglandins, and estrogen, the rate of bile formation, and the rate of water and electrolyte absorption. Gallbladder motility also plays a major factor. Usually, bile does not stay in the gallbladder long enough to form a gallstone, but it may happen if stasis occurs.
B. In premenopausal women, high levels of serum estrogens promote gallstone formation in two ways: Estrogens both increase cholesterol concentration of bile and decrease gallbladder motility. Bile stasis and elevation of its cholesterol concentration enable gallstone formation.
C. A gallstone may become lodged in the cystic duct, obstructing the emptying of the gallbladder. This can lead to inflammation (cholecystitis) and infection of the static contents (empyema) of the gallbladder. If untreated, such inflammation and infection can lead to necrosis of the gallbladder and sepsis. If a gallstone becomes lodged in the common bile duct, it can cause obstructive jaundice with elevation in serum bilirubin levels. If it lodges further along the common bile duct and blocks the pancreatic duct near the sphincter of Oddi, it can cause acute pancreatitis, perhaps because the digestive enzymes of the pancreas are trapped in the pancreatic duct and cause inflammation of the pancreas.
CASE 67
A. Lactose intolerance is the most common problem of carbohydrate digestion. It results mainly from the reduction of intestinal brush border lactase activity in adults. Lactase is expressed normally at high levels in the jejunum of neonatal and infant humans. In many parts of the world, lactase levels are gradually reduced after weaning. However, lactase levels do not decrease significantly in populations where milk products are an important part of the adult diet. Lactase activity is rate-limiting for lactose digestion in most adults throughout other regions of the world.
B. Carbohydrates, which are mainly present in the diet as polysaccharides and disaccharides, must be digested to monosaccharides for absorption. If lactase is deficient, nondigested lactose is not absorbed. The nonabsorbed lactose retains water in the lumen to maintain the osmolality of chyme equivalent to that of plasma. This retention of fluid causes abdominal pain (cramps), nausea, and diarrhea. Bacterial fermentation of lactose in the distal small intestine and colon further exacerbates these symptoms.
CASE 68
A. Crohn disease is a regional enteritis that primarily affects the distal ileum and colon but may affect the GI tract from mouth to anus as evidenced by the significant oral aphthous ulcers seen in this patient.
B. The pathogenesis of Crohn disease remains unclear. Many factors have been speculated to contribute to the development of Crohn disease, including microorganisms (bacteria and viruses), dietary factors, genetic factors, defective immune responses, and psychosocial factors. The association of Crohn disease with other known hereditary disorders, such as cystic fibrosis and ankylosing spondylitis, is indirect evidence of a genetic component. The normal gut is able to modulate frank inflammatory responses to its constant bombardment with dietary and microbial antigens in the lumen. This modulation may be defective in Crohn disease, resulting in uncontrolled inflammation.
There has been considerable recent interest in the role of cytokines, such as interleukins and TNF, in Crohn disease. Cytokine profiles of the TH1 category have been implicated in Crohn disease. Mice lacking IL-10 have a TH1 cytokine profile and develop a Crohn disease–like inflammation of the intestine. Monoclonal antibodies to TNF reduce inflammation in affected animals and humans.
C. Acute and chronic inflammation causes a relapsing and remitting clinical course. Complications such as small bowel obstruction can occur as a result of active inflammation or, more commonly, from chronic fibrotic stricturing. Fistulization, abscesses, perianal disease, carcinoma, and malabsorption are other known complications of Crohn disease.
D. Extraintestinal manifestations include migratory arthritis, inflammatory disorders of the skin, eye, and mucous membranes, gallstones from malabsorption of bile salts from the terminal ileum, and nephrolithiasis from increased oxalate absorption. Amyloidosis is a serious complication of Crohn disease, as is thromboembolic disease.
CASE 69
A. Diverticular disease (diverticulosis) commonly affects older patients and is caused by herniation of mucosa and submucosa through the muscularis layer of the colon. There are both structural and functional abnormalities that contribute to its development. The structural integrity of the muscularis layer may be compromised by abnormal connective tissue. The functional abnormality may involve the development of a pressure gradient between the colonic lumen and the peritoneal space, which results from vigorous wall contractions needed to propel stool through the colon. Higher pressures are created to compensate for poor dietary fiber intake affecting normal stool bulk. Epidemiologic data support this assertion because the incidence of diverticular disease has increased with our society’s reliance on fiber-poor foods and consequent constipation.
B. Opioids for abdominal pain control should be avoided because they directly raise intraluminal pressure and may increase the risk of perforation.
C. There are two important complications of diverticulosis. Diverticular bleeding from intramural arteries that rupture into the diverticula is a common cause of lower GI tract bleeding in the elderly. Diverticulitis, as seen in this patient, is due to a focal area of inflammation in the wall of a diverticulum in response to irritation from retained fecal material. Fever, abdominal pain, and diarrhea or constipation are typically present. The local infection may progress to an abscess with or without perforation, requiring surgical intervention.
CASE 70
A. This patient likely has irritable bowel syndrome. She has the three classic symptoms of irritable bowel syndrome: crampy abdominal pain, alternating constipation and diarrhea, and bloating. She also has normal laboratory and colonoscopy results. The onset of irritable bowel syndrome after a bout of gastroenteritis is not unusual.
B. Irritable bowel syndrome is a complex and not well understood condition. Affected patients have decreased intestinal motility along with increased intestinal pain sensitivity, also known as visceral hyperalgesia. Both of these can result from alterations in the intrinsic and extrinsic nervous systems of the intestine. One hypothesis is that intestinal inflammation from an infection or other insult results in these intestinal nervous system changes, which in turn lead to altered intestinal motility, secretion, and sensation.
CASE 71
A. Acute hepatitis is an inflammatory process, causing liver cell death, which can be initiated by viral infection or, in this case, by toxic exposure. Prescription and nonprescription drugs are common inciters of acute hepatic injury and can be divided into predictable, dose-related toxicity (eg, acetaminophen) and unpredictable, idiosyncratic reactions such as with isoniazid. Isoniazid is an infrequent but important cause of acute hepatitis and may in susceptible individuals be due to a genetic predisposition to certain pathways of drug metabolism that create toxic intermediates. Synergistic reactions between drugs have also been implicated in acute liver failure. Recovery of normal hepatic function typically follows prompt discontinuation of the offending agent.
B. Histologic findings in acute hepatitis include focal liver cell degeneration and necrosis, portal inflammation with mononuclear cell infiltration, bile duct prominence, and cholestasis. Less commonly, acute hepatitis may result in bridging hepatic necrosis. Normal lobular architecture is largely restored in the recovery phase.
C. Jaundiced skin and icteric sclera on physical examination suggest hyperbilirubinemia from intrahepatic cholestasis caused by the acute hepatic injury. As a result, conjugated bilirubin is inadequately excreted into the bile, explaining the appearance of clay-colored stools. Conjugated bilirubin is also extruded from hepatocytes into the bloodstream, and its water-soluble metabolites are excreted by the kidneys, darkening the urine. These changes in stool and urine often precede clinically evident jaundice. Yellowing of the skin reflects the accumulation of water-insoluble metabolites of bilirubin and is usually not appreciated on examination until the serum bilirubin rises above 2.5 mg/dL.
CASE 72
A. This patient has chronic hepatitis B infection. The absence of recurrent acute episodes and extrahepatic involvement suggests chronic persistent infection. Further histologic, serologic, and autoimmune markers are helpful to determine more precisely whether hepatitis B infection is a chronic persistent or chronic active infection.
B. Approximately 5% of patients acutely infected with hepatitis B will mount an immune response that fails to clear the liver of virus, resulting in a chronic carrier state. Two thirds of these patients will develop chronic persistent infection characterized by a relatively benign course and rare progression to cirrhosis. One third will develop chronic active disease marked by histologic changes such as piecemeal necrosis, portal inflammation, distorted lobular architecture, and fibrosis. Chronic active hepatitis patients are at greater risk of progression to cirrhosis, and, independently of this risk, are predisposed to hepatocellular carcinoma.
C. Hepatitis D superinfection increases the likelihood of chronic active hepatitis beyond that which usually follows isolated hepatitis B infection. Coinfection is associated with a high incidence of fulminant hepatic failure.
D. Immune-mediated damage is supported by liver biopsy results demonstrating inflammation with lymphocytic infiltration. Viral DNA integrates itself into the genome of the infected cell, and viral antigens are expressed on the surface associated with class I HLA determinants, resulting in lymphocytic cytotoxicity. The degree of injury is largely related to viral replication and the host’s immune response.
CASE 73
A. The exact mechanism of alcohol-induced injury to the liver is unknown; however, it is thought that the marked distortion of hepatic architecture, fibrous tissue deposition and scarring, and regenerative nodule formation result from multiple processes. Chronic alcohol use has been associated with impaired protein synthesis, lipid peroxidation, and the formation of acetaldehyde, which may interfere with membrane lipid integrity and disrupt cellular functions. Local hypoxia, as well as cell-mediated and antibody-mediated cytotoxicity, has also been implicated.
B. Portal hypertension is in part responsible for many of the complications of cirrhosis, including clinically apparent ascites, a sign of liver disease associated with poor long-term survival. Although no single hypothesis can explain its pathogenesis, portal hypertension and inappropriate renal retention of sodium are important elements of any theory. Portal hypertension changes the hepatocellular architecture, resulting in increased intrahepatic vascular resistance. This elevates the sinusoidal pressures transmitted to the portal vein and other vascular beds. Splenomegaly and portal-to-systemic shunting result. Vasodilators such as nitric oxide are shunted away from the liver and not cleared from the circulation, resulting in peripheral arteriolar vasodilation. Decreased renal artery perfusion from this vasodilation is perceived as an intravascular volume deficit by the kidney, encouraging sodium and water resorption. By overwhelming oncotic pressure, increased hydrostatic pressure from fluid retention in the portal vein results in ascites formation. Exceeding lymphatic drainage capacity, ascites accumulates in the peritoneum.
C. Splenomegaly and hypersplenism are a direct consequence of elevated portal venous pressure. Thrombocytopenia and hemolytic anemia occur as a result of both sequestration of these formed elements by the spleen and the depressive effect of alcohol on the bone marrow. The frequent bruising and the elevated prothrombin time in this patient highlight the coagulopathy seen in cirrhosis and chronic liver disease. As a result of inadequate bile excretion, there is impaired absorption of the fat-soluble vitamin K, a vitamin necessary for the activation of specific clotting factors. In addition, inadequate hepatic synthesis of other clotting factors causes a coagulopathy.
CASE 74
A. Biliary tract disease is a common cause of acute pancreatitis. It is hypothesized that the inciting event is obstruction of the common bile and main pancreatic ducts by a gallstone lodged in the ampulla of Vater. Parenchymal injury may be caused by the local reflux of bile or duodenal contents. It has also been proposed that inflammation is caused by bacterial toxins or free bile acids transported from the gallbladder to the pancreas through lymphatics.
B. Although choledocholithiasis appears to be the most likely cause of this patient’s acute pancreatitis, other causes should be considered, for example, alcohol use, infection (viral, bacterial, and parasitic), concomitant drugs, recent surgeries, comorbid rheumatologic disease, and a family history of pancreatitis. Laboratory studies such as a serum calcium and lipid panel, including triglycerides, would be helpful in ruling out important metabolic causes of pancreatitis. Of note, however, the cause of the pancreatitis remains unclear despite workup in approximately 15–25% of cases. To help guide prognosis, Ranson criteria require an assessment of the white blood cell count, serum glucose, LDH, and AST.
C. Acute respiratory distress syndrome (ARDS) may be caused, in part, by activated pancreatic enzymes such as circulating phospholipases, which are released systemically and interfere with the normal function of pulmonary surfactant. In addition, the systemic release of both the CC and CXC families of cytokines and endotoxin, beginning shortly after pain onset and peaking 36–48 hours later, corresponds temporally with the profound clinical decline observed. In particular, substance P, neurokinin-1, and platelet activating factor (PAF) are involved in the proinflammatory responses seen in pancreatitis-associated acute lung injury. Elevated serum levels of IL-6 have been associated with the severity of lung injury in acute pancreatitis, an effect mediated by NFκB activation in pancreatic acinar cells. IL-6 and other inflammatory signaling pathways may prove to be appropriate therapeutic targets in severe acute pancreatitis, although to date no therapeutic agents have been found to be effective in clinical trials.
CASE 75
A. Alcoholism is the most common cause of chronic pancreatitis, accounting for 70–80% of cases. The risk is directly related to the duration and amount of alcohol consumed, but in fact, only 5–10% of heavy drinkers actually develop the disease. Recent epidemiologic evidence identifies cigarette smoking as a strong independent risk factor for the development of chronic pancreatitis. Moreover, tobacco exposure appears to have a dose-dependent relationship with its incidence. The number of daily cigarettes smoked as well as the duration of tobacco smoke exposure appear to be important risk factors. Last, the combination of significant alcohol and cigarette augments the risk of chronic pancreatitis.
B. It is thought that ethanol causes secretion of insoluble pancreatic proteins that calcify and occlude the pancreatic duct. This results in progressive fibrosis and subsequent destruction of glandular tissue. In addition, deficiencies of dietary antioxidants such as zinc and selenium may lead to the buildup of toxic free radicals. Unlike other forms of chronic pancreatitis, alcohol-related chronic disease may evolve from multiple episodes of severe acute pancreatitis.
C. Proton pump inhibitors may be helpful adjuvant therapy along with pancreatic enzyme replacement by decreasing postprandial gastric acid secretion, commonly seen in patients with severe pancreatic insufficiency.
CASE 76
A. Because pancreatic lipase is essential for fat digestion, its absence leads to steatorrhea (the occurrence of greasy, bulky, light-colored stools). On the other hand, although pancreatic amylase and trypsin are important for carbohydrate and protein digestion, other enzymes in gastric and intestinal juice can usually compensate for their loss. Thus, patients with pancreatic insufficiency seldom present with maldigestion of carbohydrate and protein (nitrogen loss).
B. In severe cases of fat malabsorption, deficiencies of the fat-soluble vitamins (vitamins A, D, E, and K) may occur and require parenteral supplementation. Diarrhea results from the cathartic action of hydroxylated fatty acids. These fatty acids inhibit the absorption of sodium and water by the colon. Hypocalcemia, hypophosphatemia, tetany, osteomalacia, osteopenia (low bone mineral density), and osteoporosis can occur both from deficiency of the fat-soluble vitamin D and from the binding of dietary calcium to unabsorbed fatty acids, forming insoluble calcium-fat complexes (soaps) in the gut. These soaps also prevent the normal binding of dietary oxalate to calcium. Dietary oxalate remains in solution and is absorbed from the colon, causing hyperoxaluria and predisposing to nephrolithiasis. About 40% of patients with pancreatic insufficiency demonstrate malabsorption of vitamin B12 (cobalamin), although clinical manifestations of vitamin B12 deficiency (anemia, subacute combined degeneration of the spinal cord, and dementia) are rare. The malabsorption of vitamin B12 appears to result from reduced degradation by pancreatic proteases of the normal complexes of vitamin B12 and its binding protein (R protein), resulting in less free vitamin B12 to bind to intrinsic factor in the small intestine. Finally, long-standing malabsorption leads to protein catabolism and consequent weight loss, muscle wasting, fatigue, and edema. At times, weight loss occurs in patients with chronic pancreatitis because eating exacerbates their abdominal pain or because narcotics used to control pain cause anorexia.
CASE 77
A. The Courvoisier law distinguishes the causes of the gallbladder findings on physical examination. A palpable gallbladder makes gallstones of the common bile duct less likely than carcinoma of the pancreas because gallstones typically result in inflammation and subsequent scarring, resulting in a shrunken, and not a distended, gallbladder.
B. Adenocarcinomas of the pancreas may present with anemia, migratory thromboembolic disease, or disseminated intravascular coagulation. The coagulopathies may be related to thromboplastins released within the mucinous secretions of the adenocarcinoma.
C. Clinical prognostic factors include tumor size, site, clinical stage, lymph node metastasis, type of surgery, anemia requiring blood transfusion, performance status, and adjuvant radiation therapy. The poor overall prognosis (5-year survival of <5%, and only 15–20% of patients undergoing curative tumor resections living >5 years) can be attributed primarily to the advanced stage of the disease by the time it presents clinically, the rapid rate of local tumor expansion, and the early systemic dissemination.
CASE 78
A. The clinical summary and the elevated creatine kinase suggest rhabdomyolysis-induced acute tubular necrosis (ATN). Crush injuries release myoglobin into the bloodstream that precipitates in the renal tubules, causing intrarenal toxicity and subsequent failure. With this underlying defect, antibiotic therapy may exacerbate the situation or may induce a separate inflammatory interstitial nephritis. The absence of documented hypotension makes ischemia-mediated ATN less likely. Thus, she has an intrarenal cause of acute kidney injury.
B. Besides the likely intrarenal mechanism of disease, she may also have a prerenal cause as a result of dehydration from being trapped or from poor oral intake. To distinguish between these two possibilities, one can calculate the fractional excretion of sodium. The fractional excretion of sodium, FENa+, derived from measurement of the urine and plasma sodium and creatinine, reflects the ability of the kidney to generate a concentrated urine. This function is essentially lost in the setting of acute tubular necrosis, and the patient’s urine osmolarity is probably less than 350 mOsm/L. More commonly in the setting of myoglobinuria-induced ATN, her FENa+ would be greater than 2%; however the FENa+ has been noted to be less than 1% in some cases of rhabdomyolysis.
C. Mainstays of treatment involve maintenance of a vigorous alkaline diuresis to prevent myoglobin precipitation in the tubules and adjusting renally cleared antibiotics to prevent further nephrotoxicity.
CASE 79
A. This patient probably suffers from osteoporosis, accelerated by her underlying renal failure. The pathogenesis of bone disease is multifactorial. Calcium is poorly absorbed from the gut because of decreased renally generated vitamin 1,25-(OH)2D3 levels. Hypocalcemia results and is further exacerbated by high serum phosphate levels from impaired phosphate excretion by the kidney. Low serum calcium and hyperphosphatemia trigger PTH secretion, which depletes bone calcium and contributes to osteomalacia and osteoporosis. Also implicated are the diminished responsiveness of bone to vitamin D3and chronic metabolic acidosis.
B. Easy fatigability is often attributable to a worsening normochromic, normocytic anemia seen in chronic kidney disease. This occurs primarily because of impaired synthesis of erythropoietin by the kidney and thus decreased erythropoiesis. To improve symptoms, exogenous erythropoietin is started to raise the hematocrit of 25–28% typically seen in chronic kidney disease patients.
C. A pericardial friction rub suggests uremia-related pericarditis. This is thought to occur from uremic toxins that irritate and inflame the pericardium. The absence of this finding, lack of asterixis, and clear mentation suggest that despite underlying chronic kidney disease, the patient does not exhibit evidence of uremia at this time.
CASE 80
A. Poststreptococcal glomerulonephritis results from a skin infection with a nephritogenic strain of group A (β-hemolytic) streptococci such as type 12. The abrupt onset of hematuria (“cola”-colored urine), edema, and variable degrees of hypertension most commonly occur 7–14 days after streptococcal pharyngitis or impetigo and can occur sporadically or in clusters. Significant glomerular damage can lead to rapid progression to oliguria and acute kidney injury.
B. Bacterial infections can cause glomerular damage through the deposition of antibody-antigen complexes. Vasculitis does not occur, however, in the setting of all infections. Rather, subendothelial deposition of immune complexes is required to damage highly vascularized nephrons by fixing complement (this explains the serum levels measured) and by activating myelomonocytic cells. Deposition of these complexes can only occur in the presence of excess antigens to make the complexes soluble, permitting them access to the subendothelial space and enabling them to cause injury.
C. This disorder is usually self-limited; 95% of individuals recover normal renal function within 2 months after onset. As antibody titers rise, immune complex formation decreases, and soluble complexes are eventually cleared provided that antigen administration is not sustained. Treatment of underlying infectious substrates may hasten resolution of the glomerulonephritis.
CASE 81
A. Patients with the nephrotic syndrome have hypoalbuminemia and profoundly decreased plasma oncotic pressures because of the loss of serum proteins in the urine. This leads to intravascular volume depletion and activation of the renin-angiotensin-aldosterone system and the sympathetic nervous system. Vasopressin secretion is also increased. Such patients also have altered renal responses to atrial natriuretic peptide. Despite signs of volume overload such as edema or anasarca, patients may develop signs of intravascular volume depletion, including syncope, shock, and acute kidney injury.
B. Minimal change disease, as the name suggests, is associated with few or no changes apparent on light microscopy, as opposed to other subtypes of glomerulonephritis associated with varying degrees of segmental sclerosis or basement membrane thickening. Immunofluorescence staining is generally unremarkable, whereas membranous glomerulonephritis is characterized by IgG and C3 deposited uniformly along capillary loops. However, the pathologic changes are most evident on electron microscopy, which reveals obliteration of epithelial foot processes and slit diaphragm disruption. Minimal change disease is typically seen in children, but when found in adults it can be idiopathic or can follow upper respiratory tract infection, be associated with tumors such as Hodgkin disease, or be related to hypersensitivity reactions.
C. Hypercoagulability is a clinically significant manifestation of the nephrotic syndrome and is caused by renal losses of proteins C and S and antithrombin, as well as elevated serum fibrinogen and lipid levels. Immobilization from a prolonged hospital stay puts this patient at additional risk for deep venous thrombosis.
CASE 82
A. This patient is presenting with his first episode of renal stone disease. Most commonly, stones are calcium containing and reflect idiopathic hypocalciuria. Hyperparathyroidism and hyperuricosuria are other important causes of calcium stones. If the patient is able to collect a passed stone, analysis of its composition would be helpful in diagnosis of the subtype and in tailoring treatment.
B. After effective pain control is achieved, the patient may return home, and adequate hydration with 2 L/day should be reinforced. Hydration may dilute unknown substances that predispose to stone formation and minimize the likelihood of Ca2+ precipitation in the nephron. High-protein diets in known stone formers predispose to recurrent calcium nephrolithiasis. This results from a transient increase in calcium resorption from bone and increased filtration through the nephron in response to a protein load that stimulates the GFR. A high-sodium diet should be avoided because Na+ predisposes to Ca2+excretion and increases the saturation of monosodium urate, which acts as a nidus for calcium oxalate stone formation. Finally, citrate supplementation may be considered because of its ability to chelate calcium in solution, forming soluble complexes as opposed to calcium oxalate or phosphate.
C. Fragments of renal pelvis stones that break off and travel down the ureter produce the pain syndrome known as colic. Distention at the level of the renal pelvis, ureter, or renal capsule can produce pain that can become quite significant in the setting of acute obstruction.
CASE 83
A. Primary hyperparathyroidism accounts for most cases of hypercalcemia in the outpatient setting. Given the chronic nature of this woman’s symptoms and the history of recurrent renal stones, this is the most likely diagnosis. However, particularly in older individuals, hypercalcemia of malignancy is another important cause to consider. Medications, particularly lithium and the thiazide diuretics, also cause hypercalcemia. Other causes include familial hypocalciuric hypercalcemia, thyrotoxicosis, granulomatous diseases, milk-alkali syndrome, and adrenal insufficiency.
B. In primary hyperparathyroidism there is excessive secretion of PTH in relation to the serum calcium. This is due both to an increase in parathyroid cell mass and to a reduced sensitivity to serum calcium levels, resulting in a qualitative regulatory defect in serum PTH secretion.
The PRAD1 gene, which produces D1 cyclin, has been implicated in the pathogenesis of primary hyperparathyroidism. Cyclins are cell cycle–regulatory proteins. PRAD1 and the gene encoding PTH are both located on the long arm of chromosome 11. An inversion event occurs leading to juxtaposition of the 5′-regulatory domain of the PTH gene upstream to the PRAD1 gene. This leads to abnormally regulated transcription of the PRAD1 gene in a parathyroid-specific manner. Overproduction of the PRAD1 gene product, D1 cyclin, increases cell proliferation.
The MEN1 gene, also on chromosome 11, has been implicated in both MEN-1 kindreds and in up to 25% of people with nonfamilial benign primary hyperparathyroidism. MEN1 appears to be a tumor suppressor gene. The hyperparathyroidism in MEN-2a and MEN-2b appears to be caused by mutations in the RET protein.
C. The diagnosis of primary hyperparathyroidism is confirmed by at least two simultaneous measurements of serum calcium and intact PTH. An elevated or normal PTH in the setting of hypercalcemia confirms the diagnosis.
CASE 84
A. The likely diagnosis in this patient is familial hypocalciuric hypercalcemia (FHH). The diagnosis is suggested by the findings of an elevated serum calcium level with normal levels of intact parathyroid hormone (PTH) and 1,25-OH vitamin D. It is also possible that the patient has mild primary hyperparathyroidism as well, but the low urinary calcium excretion strongly suggests FHH rather than hyperparathyroidism.
B. This condition results from a defect in the CaSR, a member of the G protein receptor family. CaSR is highly expressed in the kidney and parathyroid glands. In the kidney, CaSR detects the serum calcium concentration and adjusts the urinary calcium excretion accordingly. In the parathyroid glands, CaSR regulates the secretion of PTH. If CaSR is defective, it misreads the serum calcium concentration as inappropriately low and causes the kidneys to retain calcium and the parathyroid glands to secrete excess PTH. Fortunately, in FHH, the elevation in serum calcium tends to be mild, and most patients are clinically asymptomatic. A rare, severe form that manifests in infancy is called neonatal severe primary hyperparathyroidism. Although this is a genetic disorder with an autosomal dominant mode of inheritance, there is no genetic testing available for the condition because the various responsible mutations are dispersed over the large gene encoding the calcium receptor.
CASE 85
A. Hypercalcemia is most commonly seen in solid tumors, primarily squamous cell carcinomas, renal cell carcinoma, and breast carcinoma. It also occurs frequently in multiple myeloma. It occurs less commonly in lymphomas and leukemias. Given this patient’s long-standing smoking history and abnormal lung examination, the most likely diagnosis is squamous cell carcinoma of the lung.
B. Serum PTH should be undetectable, and PTHrP should be elevated. This is due to the fact that 70–80% of malignancy-induced hypercalcemia is caused by tumor secretion of PTHrP. This is true of squamous cell carcinoma–induced hypercalcemia.
C. PTHrP is homologous with PTH at its amino terminal and is recognized by the type 1 PTH receptor. Therefore, it has effects on bone and kidney similar to those of PTH, including increasing bone resorption, increasing phosphate excretion, and decreasing renal calcium excretion.
CASE 86
A. The parathyroid glands lie in close proximity to the thyroid gland and are, therefore, at risk of trauma, devascularization, or removal during thyroid surgery. Damage to the parathyroid glands results in decreased PTH release, with resultant inability to maintain serum calcium concentrations. Because PTH is required to stimulate the renal production of 1,25-(OH)2D, levels of 1,25-(OH)2D are low in patients with hypoparathyroidism. This leads to reduced intestinal calcium absorption. In the absence of adequate PTH and 1,25-(OH)2D, the mobilization of calcium from bone is abnormal. Furthermore, because less PTH is available to act in the distal nephron, urinary calcium excretion may be high. A combination of these mechanisms is responsible for the hypocalcemia seen in hypoparathyroidism.
There may be a prolonged latent period before symptomatic hypocalcemia develops. Hypoparathyroidism may vary in severity. In this case, it is likely that the patient has decreased parathyroid reserve only. The increased stress on her parathyroid glands because of her pregnancy has probably precipitated her symptomatic hypocalcemia.
B. The Chvostek sign is elicited by tapping on the facial nerve anterior to the ear. Twitching of the ipsilateral facial muscles is a positive test. A positive Trousseau sign is demonstrated by inflating the sphygmomanometer above the systolic blood pressure for 3 min. Painful carpal muscle contractions and spasms signify a positive test. Both signs indicate latent tetany secondary to hypocalcemia.
C. Serum phosphate is often but not invariably elevated in hypoparathyroidism. Hyperphosphatemia occurs because the proximal tubular effect of PTH to promote phosphate excretion is lost.
CASE 87
A. Medullary carcinoma of the thyroid is a C-cell neoplasm. Because C cells are neuroendocrine cells, they have the capacity to release several hormones. The secretion of serotonin, prostaglandins, or calcitonin probably causes the watery (secretory) diarrhea this patient has. Flushing is generally caused by tumor production either of substance P or of calcitonin gene–related peptide, both of which are vasodilators.
B. The diagnosis would be made most efficiently by fine-needle aspiration of the thyroid nodules. They should demonstrate the characteristic C-cell lesion with positive immunostaining for calcitonin. A serum calcitonin level would also be beneficial, because it is typically elevated in medullary carcinoma and correlates with extent of tumor burden. Calcitonin levels may be monitored during treatment to assess response.
C. As noted, serum calcitonin levels are a useful means of assessing tumor burden and for monitoring disease progression during and after treatment. Serum carcinoembryonic antigen (CEA) is also frequently elevated in patients with medullary carcinoma and present at all stages of the disease. Rapid increases in CEA predict a worse clinical course.
All patients with medullary carcinoma of the thyroid should be tested for the RET oncogene. Although this patient denies a family history of MEN, she is young (<40 years) and has bilateral tumors, both of which facts are concerning for hereditary forms of medullary carcinoma and the MEN syndromes. More than 95% of patients with MEN-2 harbor RET mutations. Even sporadic cases of medullary carcinoma should be tested for RET mutations, because new mutations in the RET gene are frequently present, and family members can then be screened for these mutations.
If MEN-2 syndrome is detected in this patient, she should be tested for pheochromocytoma as well as for hyperparathyroidism before undergoing thyroid surgery by testing plasma fractionated metanephrines together with serum calcium and PTH; additional biochemical testing or imaging is undertaken as indicated.
CASE 88
A. Genetics are very important in determining peak bone mass and loss. However, a number of hormonal and environmental factors can reduce the genetically determined peak bone mass or hasten the loss of bone mineral and thus present important risk factors for osteoporosis. The most important etiologic factor in osteoporosis is deficiency of gonadal sex steroids, either estrogen in the case of postmenopausal women or testosterone in hypogonadal men. Another important cause is excess cortisol either in the form of exogenous corticosteroid use or endogenous excess in Cushing syndrome. Other medications such as heparin, thyroid hormone, and anticonvulsants can also cause osteoporosis. Immobilization, alcohol abuse, and smoking are also important risk factors. Diet in the form of adequate calcium and vitamin D intake and weight-bearing exercise are also vital because they are necessary to build peak bone mass and minimize loss. Many additional disorders affecting the GI, hematologic, and connective tissue systems can contribute to the development of osteoporosis (Table 17-10).
B. This patient likely has a combination of post-menopausal and age-related osteoporosis. Postmenopausal osteoporosis is caused by accelerated bone resorption. Although bone formation is also increased, it is insufficient to fully counteract bone resorption and net bone loss occurs. The cellular basis for the activation of bone resorption in postmenopausal osteoporosis is somewhat unclear. Osteoclasts have estrogen receptors, and this may account at least in part for their activation during estrogen deficiency. There is also evidence that osteoclast-stimulating cytokines, such as IL-6, are released from other bone cells after menopause.
The pathogenesis of age-related or senile osteoporosis is even less clear. Again, there is an uncoupling of bone resorption and bone formation, such that bone formation does not keep pace with resorption. Deficiency of dietary calcium and 1,25-(OH)2D is one important pathogenic factor. As people age, intestinal calcium absorption is decreased while renal calcium loss is preserved, resulting in an increased need for dietary calcium. This occurs at a time when most people reduce their calcium intake.
In addition, some older individuals may be deficient in vitamin D, further impairing their ability to absorb calcium. Particularly in northern climates, where sunlight exposure is reduced in the winter months, borderline low levels of 1,25-(OH)2D and mild secondary hyperparathyroidism are evident by the end of winter.
Secondary hyperparathyroidism may also occur in the aged due to changes in multiple organ systems with aging, including decreased renal function. As renal function decreases, so may renal production of 1,25-(OH)2D, thereby increasing PTH secretion. Reduced 1,25-(OH)2D secretion also results in decreased calcium absorption, exacerbating the intrinsic inability of the aging intestine to absorb calcium. Because the responsiveness of the parathyroid gland to calcium seems to be reduced in aging, the hyperparathyroidism seen in aging seems to be the result of the combined effects of aging on the kidney, intestine, and parathyroid gland.
C. There are three major risk factors for fractures in osteoporosis: decreased bone density, poor bone quality, and falls. For every standard deviation below the mean bone density for age, there is a 2- to 3-fold increased risk for fracture. The microarchitecture of bone also determines its mechanical strength and its ability to withstand stress. Finally, fractures rarely occur unless people fall or otherwise sustain trauma. Muscle weakness, impaired vision, impaired balance, sedative use, and environmental factors (eg, stairs, carpeting) are all important risk factors for falls and, therefore, fractures.
D. The 6-month mortality rate for hip fracture is approximately 20%, much of it resulting from the complications of immobilizing a frail person in a hospital bed. The complications include pulmonary embolus and pneumonia. About half of elderly people with a hip fracture will never walk freely again.
E. Treatments for reduced bone mass include calcium and vitamin D supplementation, estrogen replacement therapy with hormone replacement therapy or raloxifene, antiresorptive agents, such as the bisphosphonates, calcitonin, denosumab (a monoclonal antibody to RANK ligand) and PTH. In contrast to the bone resorption that is caused by continuous elevations in PTH such as occur in hyperparathyroidism, a single daily injection of PTH stimulates bone formation and, to a lesser extent, bone resorption, resulting in net gains in bone density and decreased fracture risk.
CASE 89
A. Osteomalacia can result from vitamin D deficiency, phosphate deficiency, hypophosphatasia, and several toxic substances (fluoride, aluminum, and phosphate-binding agents) with effects on bone. Vitamin D deficiency is the likely cause in this patient. She is homebound and bed-bound in a basement apartment, preventing adequate sunlight exposure. She is a strict vegetarian, even refraining from eating dairy products, so she has limited to no exposure to dietary supplementation. Finally, the x-ray evidence of pseudofracture of the pubic rami is strongly indicative of vitamin D–deficient osteomalacia.
B. Vitamin D deficiency produces osteomalacia in two stages. Initially, decreased vitamin D leads to decreased intestinal calcium absorption and secondary hyperparathyroidism. Serum calcium is maintained at the expense of increased renal phosphate excretion and hypophosphatemia. Ultimately, however, hypocalcemia ensues. Poor delivery of calcium and phosphate to bone results in impaired mineralization of the matrix. Osteoid or unmineralized matrix, therefore, accumulates at the bone-forming surfaces.
C. If bone undergoes biopsy for quantitative histomorphometry, osteoid seams and a reduction in the mineralization rate are found.
CASE 90
A. Ketoacidosis is caused by a severe lack of insulin seen most commonly in patients with type 1 diabetes mellitus. It may be the initial presentation of this disorder. However, in this patient with a long-standing history of type 2 diabetes and resultant insulin resistance and true insulinopenia, ketosis was precipitated by acute infection. In this case, severe cellulitis induced counterregulatory hormone production, which inhibits insulin’s action. Thus, in the effective absence of insulin, lipolysis generates fatty acids that are preferentially converted to ketone bodies by the liver, resulting in ketoacidosis.
B. Altered mental status in diabetic ketoacidosis, as in hyperosmolar coma, most closely correlates with the degree of hyperosmolality induced by hyperglycemia and the associated osmotic diuresis. Profound intracellular dehydration is seen in the brain as fluid shifts in response to elevated plasma osmolality. The effective osmolality in this patient is calculated as follows: 2(132 + 3.7) + 488/18 = 298.5. Coma occurs when the effective plasma osmolality reaches 340 mOsm/L. Although alterations in mental status can occur as plasma osmolality rises above the upper limit of normal (295 mOsm/L), patients usually do not exhibit anything more than mild to moderate drowsiness at the level of osmolarity seen in this patient. Therefore, other possible causes of altered mental status should be considered, including stroke, infection, and drugs.
C. This patient exhibits Kussmaul breathing (hyperpnea that effectively drops the PCO2 to partially compensate for the underlying metabolic acidosis). This respiratory pattern is commonly seen with a blood pH less than 7.20. In addition, the fruity odor detected on his breath is due to the keto acid acetone produced in this disorder.
D. Mainstays of treatment for diabetic ketoacidosis include concomitant insulin therapy along with free water and electrolyte replacement. The osmotic diuresis results in significant free water loss and total body potassium depletion. However, the serum potassium appears normal because of the shift of K+ out of cells and into the extracellular space—induced by acidosis, hyperglycemia, and insulinopenia. Correction of the acidosis and hyperglycemia with insulin therapy shifts potassium back into cells. Unless carefully monitored and replete, serum K+ levels can drop dangerously low, leading to potentially fatal cardiac arrhythmias. Phosphate depletion can also be seen, but replacement is considered only in severe cases because of the risks of intravenous phosphate repletion.
CASE 91
A. The Whipple triad sets forth the diagnostic criteria for hypoglycemia: (1) symptoms and signs of hypoglycemia, (2) an associated low plasma glucose level, and (3) improvement in symptoms with the administration of glucose. This patient’s self-diagnosis of hypoglycemic attacks meets these criteria.
B. The patient’s age and the fasting hypoglycemia are suggestive of insulinoma, an insulin-secreting tumor of the B cells of the islets of Langerhans. Normally during exercise, insulin levels decline, allowing for significant glycogen uptake in the periphery. In addition, glucagon-stimulated hepatic glucose output increases so as to maintain adequate serum glucose levels, and counterregulatory hormones mobilize fatty acids for ketogenesis and fatty acid oxidation by muscle. However, during exercise, an elevated insulin level secreted by an insulinoma suppresses the glucagon-mediated glucose output while insulin-induced peripheral glucose uptake continues. Thus, the patient becomes hypoglycemic and his symptoms recur.
C. Hypoglycemia in the setting of an elevated serum insulin level essentially rules out examples of non–insulin-mediated causes of hypoglycemia such as Addison disease, sepsis, and severe hepatic injury. The differential diagnosis of insulin-mediated hypoglycemia includes surreptitious insulin injection, oral hypoglycemic use (stimulating endogenous insulin production), and the presence of insulin antibodies. In this patient, a C peptide measurement was elevated, suggesting that this was not due to surreptitious injections or to antibodies. A greater challenge is to distinguish insulinoma from oral hypoglycemic use, both of which show an elevated C peptide and, therefore, require the direct measurement of serum levels of oral hypoglycemic agents to confirm the latter diagnosis.
CASE 92
A. Necrolytic migratory erythema is typically a late manifestation of glucagonoma and may be the result of hypoaminoacidemia stemming from excessive glucagon-mediated hepatic uptake of amino acids. This nutritional deficiency, rather than a direct effect of glucagon itself, is linked to the dermatologic manifestations.
B. Diabetes or glucose intolerance is usually mild, seen in response to hyperstimulation of hepatic glucose output by supranormal glucagon levels. Subsequently, serum insulin is increased, which prevents lipolysis and an associated ketotic state.
C. Glucagonomas are usually malignant, and weight loss and liver metastasis are commonly seen at the time of diagnosis; surgical resection is rarely pursued. Once diagnosed, the median survival is typically less than 3 years.
CASE 93
A. Somatostatinomas are very rare tumors, typically associated with a triad of findings, including diabetes, steatorrhea, and cholelithiasis. The latter finding is thought to be due to somatostatin-induced gallbladder hypomotility.
B. Because somatostatin suppresses both insulin and glucagon secretion, the resulting hyperglycemic state is mild and not accompanied by glucagon-mediated hepatic ketogenesis.
CASE 94
A. Body weight is controlled by a complex interaction of hormones that act on the hypothalamus to maintain body weight over the short and the long term. A main mechanism by which short-term food intake and satiety are regulated is the communication via the “gut-brain axis.” The gut-brain crosstalk uses two main routes of communication, including neural components (ie, afferent vagal fibers) and hormonal components [cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1) and ghrelin]. In contrast to short-term control of body weight, long-term regulation is largely influenced by the degree of obesity. Fat cells secrete hormones including leptin in proportion to the amount of triglyceride they have stored. Leptin decreases appetite and increases metabolism through effects in the CNS.
B. Body mass index (BMI) is the most commonly used index of overweight and obesity. The BMI is calculated as the patient’s body weight (in kilograms) divided by the height (in meters squared). The normal range is defined as a BMI of 18.5–25, overweight is defined as a BMI of 25.1–30, and obesity is defined as a BMI of more than 30.
C. Obesity increases the risk of developing many medical conditions. Obesity increases insulin resistance and can lead to the development of type 2 diabetes. Obese people have increased vascular tone and sodium retention, leading to hypertension. These two risk factors, as well as decreases in high-density lipoprotein cholesterol and increases in low-density lipoprotein cholesterol, in obese persons can lead to coronary artery disease or stroke. The excess soft tissue in the head and neck can lead to obstructive sleep apnea. Increases in serum estrogen and cholesterol levels in obese individuals can lead to gallstones. The excess wear and tear on joints can lead to osteoarthritis. Uric acid levels can be elevated and lead to gout. Also, obese individuals have an increased risk of several cancers.
CASE 95
A. The likely diagnosis is pituitary adenoma.
B. The pituitary adenoma probably developed from a single cell with altered growth control and feedback regulation. At least four different syndromes caused by defined genetic mutations are known to significantly raise the incidence of pituitary tumor formation: multiple endocrine neoplasia type 1 (MEN-1), Carney complex (CNC), McCune-Albright syndrome, and AIP (aryl hydrocarbon receptor–interacting protein)-related predisposition to pituitary adenoma. In this patient, a multistep process of genetic alterations and local cell reactions likely led to the formation of the adenoma. There are several known or proposed factors that have been shown to be part of transformation of pituitary cells (eg, GNAS1, PTTG). Other factors promoting pituitary tumor formation include chromosomal instability, presumably because of an unknown gene mutation, which results in further gene mutations and aneuploidy, altered hypothalamic signaling, and other endocrine and paracrine factors (eg, estrogens, growth factors).
C. Both this patient’s bitemporal hemianopia and her headaches are symptoms of the mass effect of the pituitary adenoma. The bitemporal hemianopia occurs because the crossing fibers of the optic tract, which lie directly above the pituitary gland and innervate the part of the retina responsible for temporal vision, are compressed by the tumor. Her headaches are caused by stretching of the dura by the tumor.
D. Irregular menses and galactorrhea are symptoms of prolactin excess. Galactorrhea occurs because of the direct effect of prolactin, and irregular menses are due to the indirect effect of prolactin of suppressing gonadal function.
CASE 96
A. This patient probably suffers from amenorrhea resulting from hypopituitarism. Her history of pituitary radiation is strongly suggestive of this cause. Radiation therapy frequently results in progressive destruction of the pituitary gland. This results in LH and FSH deficiency, causing menstrual irregularity and ultimately amenorrhea.
B. The patient’s history of fatigue and weight gain, in conjunction with the physical examination findings of dry brittle hair and delayed relaxation phase of her deep tendon reflexes, suggests the diagnosis of hypothyroidism. Again, given her history of pituitary radiation, TSH deficiency is the probable cause.
C. One should be concerned about the diagnosis of panhypopituitarism in this patient. In addition to LH, FSH, and TSH deficiency, she may also have deficiencies of ACTH and vasopressin. Because mineralocorticoid secretion is only partially controlled by ACTH, sufficient glucocorticoid may be present even in the absence of ACTH. Adrenal insufficiency may go unnoticed until another unrelated medical emergency occurs and the patient is unable to mount a normal protective stress response. Vasopressin deficiency may go unnoticed so long as the patient is able to maintain adequate intake of fluids to compensate for the inability to concentrate urine.
CASE 97
A. Both central and nephrogenic diabetes insipidus result in the same symptoms: polyuria, polydipsia, hypotonic urine, and hypernatremia. The history of lithium use, however, is suggestive of nephrogenic diabetes insipidus. To confirm the diagnosis, one must assess responsiveness to injected vasopressin. In central diabetes insipidus, vasopressin causes a dramatic decrease in urine volume and an increase in urine osmolarity. This occurs because the basic defect in central diabetes insipidus is a lack of vasopressin. In nephrogenic diabetes insipidus, injected vasopressin has little or no effect because the kidneys are unable to respond to the circulating vasopressin.
B. Vasopressin receptors in the kidney appear to be sensitive to lithium and other salts, preventing vasopressin binding and, therefore, disabling the kidney’s ability to retain water.
C. Polyuria in nephrogenic diabetes insipidus results from inability to conserve water in the distal nephron because of a lack of vasopressin-dependent water channels. These channels are normally inserted into the apical plasma membrane in response to vasopressin stimulation, resulting in water conservation. In nephrogenic diabetes insipidus, the kidneys are resistant to circulating vasopressin and unable to respond to it. Thirst results from the hypertonicity brought on by the inability to concentrate the urine.
D. If the patient is unable to maintain sufficient water intake for any reason, dehydration and hypernatremia result. This can lead to progressive obtundation, myoclonus, seizures, and ultimately coma.
CASE 98
A. SIADH is caused by a variety of vasopressin-secreting tumors, CNS disorders, pulmonary disorders, and drugs. Small cell bronchial carcinoma is an important cause of SIADH and present in this patient. His lung examination and fever suggest the possibility of pneumonia, another cause of SIADH. Although this patient is not currently undergoing therapy for lung cancer, several chemotherapeutic agents can cause SIADH, including vincristine and vinblastine, and it would be important to determine whether the patient was given either of these drugs during his therapy.
B. SIADH is due to secretion of vasopressin in excess of what is appropriate for hyperosmolarity or intravascular volume depletion. The pathophysiologic mechanisms behind most cases of SIADH are poorly understood. However, in this patient, the most likely cause is small cell lung cancer, which is probably secreting vasopressin.
C. The patient’s neurologic symptoms are the result of osmotic fluid shifts causing brain edema and elevated intracranial pressures. These are the result of hyponatremia.
D. Hyponatremia resulting from SIADH is treated with simple water restriction. Treatment of the underlying disease can help as well.
CASE 99
A. Other historical features to be elicited include heat intolerance, excessive sweating, nervousness, irritability, emotional lability, restlessness, poor concentration, muscle weakness, palpitations, and increased frequency of bowel movements.
B. The examiner should evaluate the eyes for stare, lid lag, proptosis, and abnormal eye movements; the heart for irregular rhythm, flow murmur, and heart failure; the breasts for gynecomastia; the nails for onycholysis; the pretibial area for dermopathy; and the deep tendon reflexes for a rapid relaxation phase.
C. The free thyroxine (free T4) should be high; the TSH level should be low. Rarely, hyperthyroidism is caused by secondary or tertiary hyperthyroidism as a result of excessive TSH or TRH production, respectively. In these cases, TSH would be elevated.
D. Possible causes of this patient’s condition include thyroid hormone overproduction (in Graves disease, toxic multinodular goiter, autonomous hyperfunctioning follicular adenoma), thyroid gland destruction with release of stored hormone (in thyroiditis), or ingestion of excessive exogenous thyroid hormone.
E. Graves disease is the most common cause of hyperthyroidism. In Graves disease, TSH receptor autoantibodies, TSH-R [stim] Ab, also known as thyroid-stimulating antibodies (TSI), are present in the circulation. These are autoantibodies of the IgG class, directed against TSH receptors on the follicular cell membrane. When they bind to the cell membrane TSH receptors, they stimulate the thyroid follicular cells to produce excessive amounts of T4 and T3, causing hyperthyroidism. The precipitating cause of this antibody production is unknown, but an immune response against a viral antigen that shares homology with TSH-R may be responsible. Another theory of the pathogenesis of Graves disease is a defect of suppressor T lymphocytes, which allows helper T lymphocytes to stimulate B lymphocytes to secrete antibodies directed against follicular cell membrane antigens, including the TSH receptor.
F. Tachycardia is thought to be related to direct effects of excess thyroid hormone on the cardiac conducting system. Weight loss results from an increase in the basal metabolic rate. Autoantibodies have been identified that stimulate the growth of thyroid epithelial cells and produce the goiter of Graves disease. The muscle weakness is related to increased protein catabolism and muscle wasting, decreased muscle efficiency, and changes in myosin.
CASE 100
A. Other features to be elicited in the history include cold intolerance, mental slowing, forgetfulness, lethargy, muscle weakness or cramps, and hair loss. The examiner should also evaluate the body temperature, the musculature for weakness, the face and skin for puffiness and carotenemia, the extremities for edema, and the deep tendon reflexes for sluggishness and a slowed (“hung-up”) relaxation phase.
B. Weight gain is related to a decrease in the basal metabolic rate. Constipation is caused by decreased GI motility. Menorrhagia results from anovulatory menstrual cycles. Thyroid atrophy and fibrosis may result from lymphocytic infiltration and destruction of thyroid follicles, destruction of the thyroid by surgery or radiation, or atrophy as a result of diminished TSH secretion. The skin changes of hypothyroidism are the result of accumulation of polysaccharides in the dermis.
The quiet heart sounds may be related to development of pericardial effusion or of cardiomyopathy caused by deposition of mucopolysaccharides in the interstitium between myocardial fibers.
C. Serum TSH is the most sensitive test for detecting hypothyroidism. TSH is elevated in almost all cases of hypothyroidism, with the rare exceptions of pituitary and hypothalamic disease. Free thyroxine levels should be low.
D. In the adult, hypothyroidism may result from Hashimoto (autoimmune) thyroiditis, lymphocytic thyroiditis, thyroid ablation (via surgery or radiation), hypopituitarism or hypothalamic disease, and drugs. The most likely cause of this patient’s hypothyroidism is Hashimoto thyroiditis both because it is the most common cause and because of the atrophic thyroid gland on examination.
E. Other autoimmune disorders, including endocrine disorders such as diabetes mellitus and hypoadrenalism, and nonendocrine disorders such as pernicious anemia, systemic lupus erythematosus, and myasthenia gravis are all seen with increased frequency in patients with Hashimoto thyroiditis.
CASE 101
A. The physician should ask about causes of goiter such as increased intake of foods containing goitrogens (eg, rutabagas, cabbage, turnips, cassava), diminished intake of foods containing iodine (eg, fish), and use of medications associated with goiter (eg, propylthiouracil, methimazole, nitroprusside, sulfonylureas, lithium). Symptoms of thyroid encroachment on surrounding structures such as respiratory or swallowing difficulties should be elicited. Because of this patient’s fatigue and depression, the physician should also probe for other symptoms of hypothyroidism.
B. The most common cause of goiter in developing nations is dietary iodine deficiency. Because this patient is 40 years of age and recently emigrated from Afghanistan, iodine deficiency would be the most likely cause. A diet low in iodine (<10 μg/d) hinders the synthesis of thyroid hormone, resulting in decreased thyroid hormone secretions and an elevated TSH level. The elevation in serum TSH level results in diffuse thyroid hyperplasia. If TSH stimulation is prolonged, the diffuse hyperplasia is followed by focal hyperplasia with necrosis, hemorrhage, and formation of nodules.
C. The serum TSH should be determined to exclude hypothyroidism.
CASE 102
A. Primarily on the basis of the history consistent with hyperthyroidism and the presence of a single thyroid nodule palpable on examination, this patient most likely has hyperthyroidism resulting from an autonomous hyperfunctioning follicular adenoma.
B. A serum TSH should be ordered and possibly a free thyroxine index. The free thyroxine index will be elevated and the serum TSH suppressed if the patient is truly hyperthyroid.
C. A radioactive iodine scan could be performed to confirm the diagnosis. Radioactive iodine uptake will be elevated in the region of the nodule and suppressed elsewhere. Thyroid scan will show a “hot” nodule.
D. Biopsy of the nodule will show normal follicles of varying size. Excisional biopsy will show compression of surrounding normal thyroid and areas of hemorrhage, fibrosis, and calcification or cystic degeneration. Biopsy is important to rule out the diagnosis of thyroid cancer, although given the patient’s symptoms of hyperthyroidism, this is less likely.
CASE 103
A. Although this patient has an elevated total T4 level, she has no symptoms or signs of hyperthyroidism. An elevated total T4 level in clinically euthyroid individuals may be idiopathic or may be due to pregnancy, acute or chronic hepatitis, acute intermittent porphyria, estrogen-producing tumors, and hereditary disorders. Drugs that may cause elevated total T4 levels are estrogens (including oral contraceptives), methadone, heroin, perphenazine, and clofibrate.
B. The resin uptake of T4 or T3 (RT4U or RT3U) should be determined and the free thyroxine index calculated. The serum TSH level should be normal if the patient is euthyroid.
C. Elevated TBG levels in pregnancy lead to increased binding of free T4. When the free T4 falls, the pituitary secretes more TSH. This, in turn, leads to increased T4 production by the gland and equilibration at a new level at which the total T4 level is elevated but the free T4 level is again normal.
D. A syndrome of familial euthyroid hyperthyroxinemia is most likely. These inherited syndromes may be caused by several mechanisms, including abnormal binding of T4 (but not T3) to albumin, an increased serum level of transthyretin, altered affinity of transthyretin for T4, or pituitary and peripheral resistance to thyroid hormone.
CASE 104
A. Additional features of Cushing syndrome include hirsutism (82%), muscular weakness (58%) and muscular atrophy (70%), back pain (58%), acne (40%), psychologic symptoms (40%), edema (18%), headache (14%), polyuria and polydipsia (10%), and hyperpigmentation (6%).
B. The exact cause of hypertension in hypercortisolism remains unclear. It may be related to salt and water retention from the mineralocorticoid effects of the excess glucocorticoid, to increased secretion of angiotensinogen or deoxycorticosterone, or to a direct effect of glucocorticoids on blood vessels.
The cause of the obesity and redistribution of body fat seen in Cushing syndrome is also somewhat unclear. It may be explained by the increase in appetite or by the lipogenic effects of hyperinsulinemia caused by cortisol excess. The striae result from increased subcutaneous fat deposition, which stretches the thin skin and ruptures the subdermal tissues. These striae are depressed below the skin surface because of loss of underlying connective tissue.
C. Major causes of Cushing syndrome include Cushing disease (ACTH-secreting pituitary adenoma), ectopic ACTH syndrome, functioning adrenocortical adenoma or carcinoma, and long-term high-dose exogenous glucocorticoid intake (iatrogenic Cushing syndrome).
In Cushing disease and in ectopic ACTH syndrome, production of both ACTH and cortisol is excessive. Adrenocortical adenomas or carcinomas are characterized by autonomous secretion of cortisol and suppression of pituitary ACTH. The most likely cause in this patient, a 38-year-old woman with gradual onset of symptoms, is Cushing disease (ACTH-secreting pituitary adenoma).
D. Current recommendations involve a stepwise approach to diagnostic evaluation. The first step is to demonstrate pathologic hypercortisolemia and confirm the diagnosis of Cushing syndrome. Measurement of free cortisol in a 24-hour urine specimen collected on an outpatient basis demonstrates excessive excretion of cortisol (24-hour urinary free cortisol levels >150 μg/24 h) and is the most sensitive and specific screening test for Cushing syndrome. Urinary free cortisol values are rarely normal in Cushing syndrome. Performance of an overnight 1-mg dexamethasone suppression test will demonstrate lack of the normal suppression by exogenous corticosteroid (dexamethasone) of adrenal cortisol production. The overnight dexamethasone suppression test is accomplished by prescribing 1 mg of dexamethasone at 11:00 pm and then obtaining a plasma cortisol level the following morning at 8:00 am. In normal individuals, the dexamethasone suppresses the early morning surge in cortisol, resulting in plasma cortisol levels of less than 5 μg/dL (0.14 μmol/L); in Cushing syndrome, cortisol secretion is not suppressed to as great a degree, and values are more than 10 μg/dL (0.28 μmol/L). If the overnight dexamethasone suppression test result is normal, the diagnosis is very unlikely; if the urine free cortisol level is also normal, Cushing syndrome is excluded. If both test results are abnormal, hypercortisolism is present and the diagnosis of Cushing syndrome can be considered established provided that conditions causing false-positive results (pseudo-Cushing syndrome) are excluded (acute or chronic illness, obesity, high-estrogen states, drugs, alcoholism, and depression). The CRH test is a useful adjunct in patients with borderline elevated urinary cortisol levels resulting from probable pseudo-Cushing state. In patients with equivocal or borderline results, a 2-day low-dose dexamethasone suppression test is often performed (0.5 mg every 6 hours for eight doses). Normal responses to this test exclude the diagnosis of Cushing syndrome. Normal responses are an 8:00 am plasma cortisol less than 5 μg/dL (138 nmol/L); a 24-hour urinary free cortisol less than 10 μg/24 h (<28 μmol/24 h); and a 24-hour urinary 17-hydroxycorticosteroid level less than 2.5 mg/24 h (6.9 μmol/24 h) or 1 mg/g creatinine (0.3 mmol/mol creatinine).
The second step is to distinguish ACTH-independent disease from ACTH-dependent disease (Figure 21-14) with assay of the plasma ACTH level. The high-dose dexamethasone suppression test is useful for differentiating pituitary from ectopic ACTH secretion.
The final step for patients with ACTH-dependent disease is to determine the anatomic localization of the ACTH source by MRI or thin-section CT (pituitary, adrenal, lung, or other) or, if equivocal, by inferior petrosal sinus sampling (IPSS) or cavernous sinus sampling (CSS).
CASE 105
A. An incidentally found adrenal mass is often referred to as an adrenal incidentaloma. The mass could be an adrenal adenoma or a non-adenoma, which could be a malignancy (primary adrenocortical carcinoma, pheochromocytoma, or a metastatic cancer from a different source), infiltrating process, hemorrhage, or cyst. The evaluation of an adrenal mass requires both a functional and an anatomic workup. The functional evaluation is to determine whether the mass is producing excess adrenal hormone by performing a dexamethasone suppression test (or 24-hour urine free cortisol) to exclude hypercortisolism, by measuring the plasma or urinary metanephrines to exclude pheochromocytoma, and by measuring the serum potassium and aldosterone-to-renin ratio to exclude hyperaldosteronism.
B. Anatomically, the lesion needs to be evaluated to determine level of concern for malignancy. Lesions like the one in this patient that are small (<3 cm) and homogenous and low in signal intensity (<10 HU) are likely benign, lipid-rich adenomas. Lesions that are large (>6 cm), heterogenous, and not low in signal intensity can be malignant. Lesions that are functional and those that do not fulfill the criteria for benignity are usually removed. A mass that is not removed is followed up with one surveillance CT scan 6–12 months later to ensure that it is not enlarging, which would suggest malignancy. Clinical and/or hormonal reevaluation can be repeated periodically if the patient develops symptoms consistent with a hyperfunctional adrenal tumor since nonfunctioning adenomas may (rarely) develop hormone overproduction at a later time.
CASE 106
A. Other symptoms of chronic adrenal insufficiency include anorexia, nausea, vomiting, hypoglycemia, and personality changes. The examiner should look also for orthostatic changes in blood pressure and pulse, hyperpigmentation of the mucous membranes and other areas, vitiligo, and loss of axillary and pubic hair.
B. The serum sodium is typically low and the serum potassium high. In Addison disease, the deficiency of cortisol is associated with a deficiency of aldosterone, resulting in unregulated renal loss of sodium and retention of potassium. Additional blood chemistry findings suggesting Addison disease include mild acidosis, azotemia, and hypoglycemia.
C. The diagnosis of hypoadrenocorticism can be established by performing an ACTH stimulation test. In Addison disease, there is a low 8:00 am plasma cortisol and virtually no increase in plasma cortisol 30 minutes and 60 minutes after administration of 250 μg of synthetic ACTH (cosyntropin) intravenously or intramuscularly. At a specificity of 95%, the sensitivity of the 250-μg cosyntropin stimulation test is 97% for primary adrenal insufficiency.
D. Hypotension, including recumbent hypotension, occurs in about 90% of patients with Addison disease and may cause orthostatic symptoms and syncope. These symptoms are related to the volume contraction resulting from unregulated renal losses of sodium.
Cortisol deficiency commonly results in loss of appetite and in GI disturbances, including nausea and vomiting. Weight loss is common and, in chronic cases, may be profound (≥15 kg).
In primary adrenal insufficiency, the persistently low or absent plasma cortisol level results in marked hypersecretion of ACTH by the pituitary. ACTH has intrinsic melanocyte-stimulating hormone activity, causing a variety of pigmentary changes in the skin, including generalized hyperpigmentation.
CASE 107
A. The major consequences of chronic aldosterone excess are sodium retention and potassium and hydrogen ion wasting by the kidney. Aldosterone binds to a mineralocorticoid receptor in the cytosol. The steroid-receptor complex then moves into the nucleus of the target cell and increases transcription of DNA, induction of mRNA, and stimulation of protein synthesis by ribosomes. The aldosterone-stimulated proteins have two effects: a rapid effect, to increase the activity of epithelial sodium channels (ENaCs) by increasing the insertion of ENaCs into the cell membrane from a cytosolic pool, and a slower effect to increase the synthesis of ENaCs. One of the genes activated by aldosterone is the gene for serum- and glucocorticoid-regulated kinase (sgk), a serine-threonine protein kinase. The sgk gene product increases ENaC activity (Figure 21-10). Aldosterone also increases the mRNAs for the three subunits that comprise the ENaCs. Aldosterone also binds directly to distinct membrane receptors with a high affinity for aldosterone and, by a rapid, nongenomic action, increases the activity of membrane Na+-K+ exchangers to increase intracellular Na+. In the distal renal tubules and collecting ducts, aldosterone acts to promote the exchange of Na+ for K+ and H+, causing Na+ retention, K+ diuresis, and increased urine acidity. Elsewhere, it acts to increase the reabsorption of Na+ from the colonic fluid, saliva, and sweat. Increased sodium is associated with fluid retention, blunting the hypernatremia. The net effect in primary aldosteronism is the mild hypernatremia, hypokalemia, and acidosis seen in this patient.
Hypertension results from this underlying sodium retention and subsequent expansion of plasma volume. The prolonged potassium diuresis produces symptoms of potassium depletion, including muscle weakness, muscle cramps, nocturia (frequent nighttime urination), and lassitude. Blunting of baroreceptor function, manifested by postural falls in blood pressure without reflex tachycardia, may develop.
B. Prolonged potassium depletion damages the kidney (hypokalemic nephropathy), causing resistance to antidiuretic hormone (vasopressin). Patients may be unable to concentrate urine (nephrogenic diabetes insipidus), resulting in symptoms of thirst and polyuria and the finding of a low urine specific gravity (<1.010). Urinary electrolytes show an inappropriately large amount of potassium in the urine.
C. The diagnosis of primary aldosteronism is already suggested by finding hypokalemia in an untreated patient with hypertension. Currently, the best screening test for primary aldosteronism involves determinations of plasma aldosterone concentration (normal: 1–16 ng/dL) and plasma renin activity (normal: 1–2.5 ng/mL/h), and calculation of the plasma aldosterone-renin ratio (normal: <25). Patients with aldosterone-renin ratios of 25 or more require further evaluation.
Subsequent workup entails measuring the 24-hour urinary aldosterone excretion and the plasma aldosterone level with the patient on a diet containing more than 120 mEq of Na+ per day. The urinary aldosterone excretion exceeds 14 μg/d, and the plasma aldosterone is usually more than 90 pg/mL in primary aldosteronism. High-resolution CT or MRI of the adrenal glands can also help to differentiate between adrenal adenoma and bilateral adrenal hyperplasia. The gold standard for diagnosis is bilateral adrenal venous sampling, which is more sensitive and specific than imaging, to identify a unilateral cause, namely, an adrenal adenoma causing the primary aldosteronism.
CASE 108
A. This patient probably has hyporeninemic hypoaldosteronism (type IV renal tubular acidosis), a disorder characterized by hyperkalemia and acidosis in association with (usually mild) chronic kidney disease. The syndrome is thought to be due to impairment of renin production by the juxtaglomerular apparatus, associated with underlying renal disease. Chronic kidney disease is usually not severe enough by itself to account for the hyperkalemia. Impaired secretion of both potassium and hydrogen ion in the renal tubule causes the observed hyperkalemia and metabolic acidosis.
B. Other causes of hypoaldosteronism include (1) bilateral adrenalectomy; (2) acute or chronic adrenocortical insufficiency; (3) ingestion of exogenous mineralocorticoids (fludrocortisone) or inhibitors of the 11β-hydroxysteroid dehydrogenase type 2 enzyme (licorice), leading to sodium retention, volume expansion, and suppression of renin production; (4) long-standing hypopituitarism, resulting in atrophy of the zona glomerulosa; (5) congenital adrenal hypoplasia, caused by one or more enzymatic abnormalities in mineralocorticoid biosynthesis; and (6) pseudohypoaldosteronism, in which there is renal tubular resistance to mineralocorticoid hormones, presumably because of a deficiency of mineralocorticoid hormone receptors.
C. Plasma and urinary aldosterone levels and plasma renin activity are consistently low and unresponsive to stimulation by ACTH administration, upright posture, dietary sodium restriction, or furosemide administration.
CASE 109
A. Congenital adrenal hyperplasia is a relatively common disease, occurring in 1 in 5000–1 in 15,000 births. By far, the most frequent cause of congenital adrenal hyperplasia is 21β-hydroxylase deficiency. During the newborn period, there are two classic presentations of congenital adrenal hyperplasia resulting from classic 21β-hydroxylase deficiency: salt wasting and non-salt wasting (also called “simple virilizing”). Neonates with the salt-wasting form have severe cortisol and aldosterone deficiencies and, if undiagnosed and untreated, will develop potentially lethal adrenal crisis and salt wasting at 2–3 weeks of age. Since this is a serious condition that is relatively common with a known treatment, it is sensible to screen newborns for this condition.
B. More than 90% of cases are due to deficiency of the enzyme steroid 21β-hydroxylase. The 21β-hydroxylase enzyme (cytochrome P450c21) is encoded by the gene CYP21A2. More than 50 different CYP21A2 mutations have been reported, perhaps accounting for a wide range of congenital adrenal hyperplasia phenotypes. The 15 most common mutations, which constitute 90–95% of alleles, derive from intergenic recombination of DNA sequences between the CYP21A2 gene and a neighboring pseudogene (an inactive gene that is transcribed but not translated). These intergenic CYP21A2 mutations are caused by conversion of a portion of the active CYP21A2 gene sequence into a pseudogene sequence, resulting in a less active or inactive gene (gene conversion).
C. Impaired CYP21A2 or CYP11B1 activity causes deficient production of both cortisol and aldosterone. The low serum cortisol stimulates ACTH production; adrenal hyperplasia occurs, and precursor steroids—in particular 17-hydroxyprogesterone—accumulate. The accumulated precursors cannot enter the cortisol synthesis pathway and thus spill over into the androgen synthesis pathway, forming androstenedione and DHEA/DHEAS. Prenatal exposure to excessive androgens results in masculinization of the female fetus, leading to ambiguous genitalia at birth. Newborn males have normal genitalia.
CASE 110
A. Dysmenorrhea may be a primary disorder in which no identifiable pelvic disease is present, or it may be secondary to an underlying pelvic disease. Among the most common causes are endometriosis, leiomyomas, chronic pelvic infections, and adhesions from prior infections or ectopic pregnancies. Finally, dysmenorrhea may occur as a part of premenstrual syndrome, in which it is associated with other symptoms, including bloating, weight gain, edema, irritability, mood swings, and acne. This patient’s constellation of symptoms in combination with her lack of prior medical problems and normal physical examination makes premenstrual syndrome the most likely diagnosis.
B. Dysmenorrhea in premenstrual syndrome and in primary dysmenorrhea is due to disordered or excessive prostaglandin production by the secretory endometrium of the uterus. Patients with dysmenorrhea have excessive production of prostaglandin F2α, which stimulates myometrial contractions of the uterus. Excessive contractions of the myometrium cause ischemia of the uterine muscle, thereby stimulating uterine pain fibers. Anxiety, fear, and stress may lower the pain threshold and thereby exaggerate the prominence of these symptoms from one patient to another and over time in a given patient.
C. The first step in treating patients with premenstrual syndrome is to encourage lifestyle changes such as more sleep, exercise, improved diet, and discontinuation or decreased use of tobacco, alcohol, and caffeine. Pharmacologic therapy with serotonin-reuptake inhibitors (SSRIs) has proven beneficial in addition to behavioral modification. Additionally, pain may be treated with monthly pharmacotherapy with prostaglandin synthesis inhibitors such as NSAIDs.
CASE 111
A. About 15% of couples are infertile. It is estimated that infertility is due to female factors about 30% of the time, and about 30% of cases are due to female factors combined with male factors. (About 30% of cases are due to male factors alone, and about 10% of cases are unexplained.) Forty percent of cases of female infertility are due to ovulatory failure, as occurs in hypothalamic, pituitary, and ovarian disorders. Another 40% of cases are due to endometrial or tubal disease, as occurs with pelvic infections and endometriosis. Ten percent are due to less common causes such as those that affect the production of GnRH by the hypothalamus or the hormone’s effect on the pituitary (thyroid disease, hyperprolactinemia) and those that affect ovarian feedback (hypergonadism, polycystic ovary disease). The final 10% of cases are of unknown cause.
B. The most likely cause of this patient’s infertility is endometrial and tubal scarring as a result of her prior sexually transmitted diseases. Infections such as gonorrhea and the often asymptomatic chlamydial infections can cause scarring and adhesions. This scarring may impede sperm or egg transport and implantation. Her history of regular menses and her normal examination argue against the other causes of female infertility (other than idiopathic). Finally, it is possible that the infertility results from her husband (male factor infertility) and not the patient herself.
CASE 112
A. The most likely diagnosis is preeclampsia-eclampsia. Although preeclampsia can be difficult to differentiate from essential hypertension developing during pregnancy, the fact that her hypertension developed after week 20 and was associated with edema and proteinuria strongly suggests a diagnosis of preeclampsia.
B. Predisposing factors for the development of preeclampsia include first pregnancy, multiple previous pregnancies, preexisting diabetes mellitus or hypertension, hydatidiform mole, malnutrition, and a family history of preeclampsia.
C. For unclear (perhaps immune-mediated) reasons, changes that normally occur in the blood vessels of the uterine wall early in implantation do not occur in patients with preeclampsia-eclampsia. A condition of relative placental ischemia is established. Undetermined factors are released that cause damage to vascular endothelium. This damage occurs first within the placenta and later throughout the body. Endothelial damage alters the balance between vasodilation and vasoconstriction, with increased vasoconstriction of small blood vessels and resultant hypoperfusion and ischemia of downstream tissues and systemic hypertension. The endothelial cell barrier between platelets and the collagen of basement membranes is breached. As a result of these changes, there is increased platelet aggregation, activation of the clotting cascade, and production of vasoactive substances causing capillary leak. Further tissue hypoperfusion, edema formation, and proteinuria result. These processes all cause further endothelial damage, thus establishing a vicious circle. Interesting recent speculation has centered on the potential of serotonin to modulate vasodilation or vasoconstriction, respectively, via the 5-HT1 or 5-HT2 serotonin receptors. New data also invoke a role for agonistic autoantibodies directed against the second extracellular loop of the angiotensin II AT1 receptor, resulting in the vasospasm associated with preeclampsia.
D. The risks to the fetus of preeclampsia-eclampsia are the consequence of placental deterioration and insufficiency and include intrauterine growth retardation and hypoxia.
E. Patients can develop multiple complications as a result of preeclampsia-eclampsia, including malignant hypertension, hepatic damage (periportal necrosis, congestion, and hemorrhage can lead to elevated liver function tests and ultimately rupture of the hepatic capsule), renal changes (glomerular endothelial cell swelling, mesangial proliferation, marked narrowing of glomerular capillary lumens, and cortical ischemia that may progress to frank necrosis and acute kidney injury), thrombocytopenia, disseminated intravascular coagulopathy, and cerebrovascular accidents. Eclampsia, or maternal seizures resulting from cerebral ischemia and petechial hemorrhage, can occur in this setting or can appear as the first manifestation of this disease. Delivery of the fetus is the only definitive cure for this syndrome, which carries a high mortality rate for mother and child.
CASE 113
A. It is estimated that infertility is due to male factors in about 30% of cases and combined male and female factors in another 30%. Overall, of the cases due to male factors, approximately 50% are potentially treatable. Identifiable causes of male infertility are classified into three major categories: (1) pretesticular causes, (2) testicular causes, and (3) post-testicular causes. Pretesticular causes are generally hormonal in nature and include hypothalamic-pituitary disorders, thyroid disorders, adrenal disorders, and drugs that can affect hormonal secretion or action. Testicular causes may be chromosomal (Klinefelter syndrome) or developmental (cryptorchidism) or may result from varicocele, trauma, infection (mumps), or drugs and toxins. Post-testicular causes include ductal obstruction and scarring, retrograde ejaculation, antibodies to sperm or seminal plasma, developmental abnormalities (penile anatomic defects), androgen insensitivity, poor coital technique, and sexual dysfunction. Despite evaluation, the majority of cases of male infertility are idiopathic in nature, without a currently identifiable cause.
B. Considering the history of sexually transmitted diseases and the physical examination findings of epididymal irregularity, the most likely diagnosis is bilateral obstruction to sperm outflow.
C. Semen analysis should reveal oligospermia (<15 million sperm/mL semen) or, more likely, azoospermia (absence of sperm). These abnormalities would be expected because the epididymal abnormalities on examination suggest bilateral obstruction to the outflow of sperm. LH, FSH, and testosterone should all be normal because no defects are present in the hypothalamic-pituitary axis or in the testes themselves.
D. Testing of fructose in the seminal fluid was once performed because fructose is produced in the seminal vesicles, and its absence in the semen implies obstruction of the ejaculatory ducts. This test is currently used sparingly, and more emphasis is placed on low semen volume as a screening test and transrectal ultrasound of the prostate as a confirmatory test. Obstruction of the ejaculatory ducts is strongly suggested by a seminal vesicle anteroposterior diameter of more than 1.5 cm on ultrasound. Testicular biopsy may also be helpful in distinguishing intrinsic testicular pathology from ductal obstruction.
CASE 114
A. The diagnosis of benign prostatic hyperplasia is suspected based on the history and physical examination. A symptom index questionnaire may be administered to the patient to objectively evaluate the severity and complexity of symptoms. Digital rectal examination reveals the enlarged prostate seen here. Prostatic enlargement may be focal or diffuse, and the degree of enlargement does not necessarily correlate with the degree of symptoms. Blood urea nitrogen and serum creatinine are measured to exclude renal failure, and urinalysis is performed to rule out infection. In most patients, this is enough to make the diagnosis of benign prostatic hyperplasia. A urodynamic evaluation with uroflowmetry and cystometry may be undertaken to assess the significance of the disorder. These pressure-flow studies can help in determining which patients are less likely to benefit from prostatic surgery by providing information on detrusor function. Renal ultrasonography or intravenous urography may be performed on patients with hematuria or suspected hydronephrosis. Ultrasonography of the prostate with possible biopsy may be necessary to exclude prostate cancer as the cause of symptoms.
B. Although the actual cause of benign prostatic hyperplasia is unclear, several factors have been identified as contributing factors. These include age-related growth of the prostate, the presence of a prostatic capsule, androgenic hormones and their receptors (especially dihydrotestosterone), stromal-epithelial interactions and growth factors (FGF, TGF), and detrusor responses.
C. This patient has both irritative symptoms and obstructive symptoms. His irritative symptoms include urinary frequency, nocturia, and urgency. These occur as the result of bladder hypertrophy and dysfunction. His obstructive symptoms include incomplete emptying and postvoid dribbling. These are caused by distortion and narrowing of the bladder neck and prostatic urethra, leading to incomplete emptying of the bladder.
CASE 115
A. Gout flares are typically precipitated by a combination of metabolic and physical stressors in the setting of either urate underexcretion, seen in the vast majority of cases, or urate overproduction. The mild renal insufficiency may be associated with a decreased glomerular filtration rate and thus poor urate excretion. The recent addition of a diuretic further exacerbated this underlying impairment.
B. Multiple inflammatory pathways are invoked by the negatively charged urate crystals. For example, they activate the classic complement pathway whose cleavage products serve as effective neutrophil chemoattractants. The kinin system is stimulated by crystals as well, contributing to the inflammatory signs seen on examination such as tenderness and erythema from local vasodilation. In addition, macrophages phagocytose urate crystals, initiating the release of proinflammatory cytokines (eg, IL-1 and TNF), which activate the vascular endothelium, encouraging neutrophil adhesion and migration. Neutrophils are able to simulate their own recruitment by releasing leukotriene B4 in response to urate crystal phagocytosis.
C. Therapy for an acute gouty attack should target the proinflammatory mediators described previously. NSAIDs such as ibuprofen reduce prostaglandin synthesis, colchicine impairs the migration of neutrophils into the joints, and corticosteroids deactivate myelomonocytic cells responsible for crystal phagocytosis and subsequent cytokine release. Because gouty flares are typically self-limited events, treatment is offered to alleviate symptoms and reduce the duration of the flare. On the other hand, uricosuric agents, such as probenecid, and xanthine oxidase inhibitors, such as allopurinol and febuxostat, and pegloticase, which converts uric acid to allantoin, an inactive and soluble metabolite that is readily excreted by the kidneys, are typically reserved for the prevention of future attacks.
CASE 116
A. This patient likely has an immune complex vasculitis. When it manifests itself in the skin, it is also called cutaneous small vessel or leukocytoclastic vasculitis.
B. Immune complexes are generated by the combination of an antigen and an antibody. In this case, the antigen is the penicillin that the person has been taking regularly for a week. The penicillin stimulated an antibody response, leading to antibody production against, and then binding to, the penicillin. The antigen-antibody complexes are soluble and they are deposited in the subendothelial space, in this case, in the small vessels of the skin. There, they trigger an inflammatory response, which causes a rash. If the supply of new antigen is cut off (eg, by stopping the medication), the immune complexes are cleared by the immune system and the process resolves.
C. The same process can also affect the joints and the kidneys, both areas rich in small blood vessels. The specific organ(s) affected depend on the solubility of the specific antigen-antibody complex.
CASE 117
A. This patient’s suspicion that her arthralgias may be explained by lupus is supported by a high prevalence of SLE among African American women—approximately 1 in 250—as well as her family history of this disorder. In fact, if a mother has SLE, her daughters’ risk of developing the disease is 1 in 40, considerably higher than the risk in the general population. However, to make the diagnosis with reasonable certainty, 4 of 11 diagnostic criteria should be met, supported by a strong clinical impression: (1) malar rash, (2) discoid rash, (3) photosensitivity, (4) oral ulcers, (5) arthritis, (6) serositis, (7) renal disease, (8) neurologic disease, (9) hematologic disorders (eg, hemolytic anemia and antibody-mediated thrombocytopenia), (10) immunologic abnormalities (eg, antibodies to native DNA), and (11) positive anti-nuclear antibody (ANA).
B. A number of drugs (eg, procainamide, hydralazine, isoniazid) have been implicated in provoking a lupus-like syndrome. A helpful clue in distinguishing the drug-induced form from SLE is that withdrawal of the offending drug typically results in improved clinical features and resolution of abnormal laboratory values.
C. These mechanisms include (1) subendothelial deposition of immune complexes, in which antigens are derived from damaged or dying cells; (2) autoantibody binding to extracellular molecules in the target organs (eg, skin, joints, kidneys, blood elements), which activates inflammatory effector functions and induces damage at that site; and (3) induction of cell death by autoantibodies.
D. The natural history of SLE is characterized by a relapsing, remitting course. Flares reflect immunologic memory, sparked by rechallenge of a primed immune system with antigen. Numerous stimuli such as viral infections, ultraviolet light exposure, and endometrial and breast epithelial involution may induce apoptosis, which resupplies immune inciting antigens. Despite this course, 10-year survival rates commonly exceed 85%.
CASE 118
A. This patient has Sjögren syndrome, which occurs in approximately 1–3% of the adult population. Sjögren syndrome is approximately 9 times more prevalent in women than in men. Affected individuals frequently manifest intense dryness of their eyes (xerophthalmia) and mouth (xerostomia), giving rise to the alternate name keratoconjunctivitis sicca.
B. Dryness in the respiratory tract may give rise to hoarseness and recurrent bronchitis. Moreover, when immune activation is severe, patients experience systemic symptoms, including fatigue, arthralgia, myalgia, and low-grade fever. Other potentially affected organ systems include the kidneys, lungs, joints, and liver (resulting in interstitial nephritis, interstitial pneumonitis, nonerosive polyarthritis, and intrahepatic bile duct inflammation, respectively). As many as half of affected individuals experience autoimmune thyroid disease. Those patients with particularly severe disease are at increased risk for cutaneous vasculitis (including palpable purpura and skin ulceration) and lymphoproliferative disorders (eg, mucosa-associated lymphoid tissue [MALT] lymphoma).
CASE 119
A. Polymyositis and dermatomyositis share several similar pathologic features but possess distinctive ones as well. These include patchy involvement, presence of inflammatory infiltrates, and areas of muscle damage and regeneration. In polymyositis, inflammation is located around individual muscle fibers (“perimyocyte”), and the infiltrate is T-cell (CD8+ > CD4+)- and macrophage-predominant. It has been suggested that the inflammation seen in polymyositis is driven by autoantigens expressed in the muscle environment, given the restricted T-cell repertoire in both circulating and muscle-infiltrating lymphocytes.
In dermatomyositis, the pathology looks quite different, although the outcome—profound muscle weakness—is the same. The major pathologic hallmarks of this condition include atrophy at the periphery of muscle bundles (“perifascicular atrophy”) and a predominantly B-cell and CD4+ T-cell infiltrate localized to the perifascicular space and surrounding capillaries (which are reduced in number). Activation of the complement cascade is seen as well. Major involvement of the capillaries has led many experts to suggest that the primary disorder in dermatomyositis is a small-vessel vasculitis, with myositis occurring later as a result of tissue ischemia and repair. The characteristic skin and nailfold capillary changes seen in patients with dermatomyositis lend support to this notion.
B. There are four characteristic criteria for the diagnosis of polymyositis: (1) weakness, (2) elevated laboratory parameters of muscle tissue (eg, creatine phosphokinase or aldolase), (3) an irritable electromyogram upon electrodiagnostic evaluation (producing sharp waves, spontaneous discharges), and (4) an inflammatory infiltrate upon histologic evaluation.
C. In adult patients, the new diagnosis of an inflammatory myopathy frequently heralds the co-occurrence or subsequent development (within 1–5 years) of a malignancy. The veracity of this observation has been confirmed in several population-based studies that link the diagnoses of dermatomyositis and polymyositis with various types of cancer in cancer registries. A diagnosis of dermatomyositis carries a 2-fold greater risk of incident malignancy, particularly stomach, lung, breast, colon, and ovarian cancers.
CASE 120
A. The pathophysiology of rheumatoid arthritis is centered around the synovial linings of joints. The normal synovium is one to three cell layers thick. In rheumatoid arthritis, the synovium is markedly thickened and contains inflammatory cells in the interstitium, including T cells, B cells, and macrophages. This inflammatory tissue can invade adjacent bone and cartilage, accounting for the bony erosions and joint destruction.
B. Rheumatoid arthritis is thought to arise when an environmental factor (such as an infection) triggers an autoimmune response to antigens present in the synovium and elsewhere in the body. However, the specifics have not been identified. No definite infectious agents have been identified as causal agents in rheumatoid arthritis. The autoimmune mechanisms involved in the triggering and maintenance of the rheumatoid inflammatory response have also not been definitively identified, although TNF plays a central role. Genetic factors have been found, arising from the observation that twins have a 15–35% concordance rate of developing rheumatoid arthritis. A specific subset of MHC class II alleles have been found that determine disease severity.
C. For many years, the mainstay of treatment for rheumatoid arthritis involved nonspecific immunosuppressant agents. With the recognition of the central role of TNF in the autoimmune response in rheumatoid arthritis, TNF inhibitors have found widespread use in its treatment. These inhibitors sequester TNF so that it cannot maintain the inflammatory response. They either are soluble TNF receptors or monoclonal antibodies that bind the free TNF and clear it from the body.