Claire Meyer, Amit Patel, and Mauricio Lisker-Melman
VIRAL HEPATITIS
Hepatitis A
GENERAL PRINCIPLES
· Hepatitis A is caused by an RNA virus (picornavirus) and is acquired and spread via the fecal-oral route.
· The hepatitis A virus (HAV) causes acute hepatitis, defined as the sudden onset of significant aminotransferase elevation as a consequence of diffuse necroinflammatory liver injury, which can vary from mild illness to acute liver failure. There is no chronic form of hepatitis A.
· Although the annual reported incidence of hepatitis A is around 1.5 million, the actual incidence may be as much as 10-fold higher.1 The morbidity and mortality of this infection increase with increased age of onset.
· Most cases of hepatitis A resolve in 4 to 8 weeks. Prolonged cholestatic disease, characterized by persistent jaundice and waxing and waning liver enzymes, is more frequently seen in adults.
· Prophylaxis
o Preexposure prophylaxis: Vaccination is recommended for high-risk populations, including men who have sex with men, residents and staff of institutions that serve the mentally disabled, restaurant workers, and residents of and travelers to endemic areas.
o Postexposure prophylaxis: For nonimmune patients who are exposed to hepatitis A, immunoprophylaxis is available in the form of hepatitis A immune globulin (0.2 mL/kg). The hepatitis A vaccine has also been shown to be effective as postexposure prophylaxis. The immune globulin or the vaccine should be given within 2 weeks of exposure.2
DIAGNOSIS
· Hepatitis A can be asymptomatic, particularly in children and young adults.
· Common but nonspecific clinical manifestations of hepatitis A include malaise, fatigue, pruritus, headache, abdominal pain, myalgias, arthralgias, nausea, vomiting, anorexia, and fever.
· The diagnosis of acute hepatitis A is based on identification of IgM antibodies to HAV. Presence of IgG antibodies to HAV, in the absence of an acute hepatitis, suggests the recovery phase after acute hepatitis A or immunity to HAV.
TREATMENT
Patients can usually be treated supportively on an outpatient basis, but hospitalization may be required for those who are unable to maintain hydration. Emergent liver transplant evaluation should be considered for patients in whom acute liver failure develops.
Hepatitis B
GENERAL PRINCIPLES
· The hepatitis B virus (HBV) is a DNA virus of the hepadnavirus family. Eight genotypes (A through H) have been identified.
· In the US, the virus is most commonly transmitted through horizontal transmission via injection drug use and sexual contact. In Asia, vertical transmission (mother to child) continues to be a major public health problem.3
· HBV can cause both acute and chronic hepatitis.
· Two billion people worldwide have serologic evidence of past or present infection, with approximately 400 million being chronic carriers.
· Progression from acute to chronic disease occurs in about 90% of children infected before age 6 but in only 5% to 10% of those who acquire the virus as adults.
· Patients with acute hepatitis B have an excellent prognosis if they do not progress to chronic state.
· Prognosis in chronic hepatitis B is related to the level of activity (biochemical and histologic) and persistence of viral replication. For chronic hepatitis B patients, the cumulative 5-year incidence of progression to cirrhosis ranges from 8% to 20%. Hepatocellular carcinoma (HCC) is detected in 5% to 10% of patients with chronic hepatitis B with or without cirrhosis.
· Prophylaxis
o Preexposure prophylaxis: HBV vaccination should be considered for everyone, but particularly individuals who belong to high-risk groups, including patients on hemodialysis, injection drug users, individuals with multiple sexual partners, men having sex with men, household and heterosexual contacts of HBV carriers, residents and employees of residential care facilities, travelers to endemic regions, and individuals born in areas of high or intermediate prevalence (e.g., Alaska, Southern Asia, Africa, South Pacific Islands, and the Amazon).
o Postexposure prophylaxis: Infants born to hepatitis B surface antigen–positive mothers should receive the hepatitis B vaccine and hepatitis B immunoglobulin (HBIG) within 12 hours of birth. Susceptible sexual partners of individuals with HBV and those with needlestick injuries should receive HBIG and the first dose of the hepatitis B vaccine within 48 hours of exposure. A second dose of HBIG should be administered 30 days after exposure and the vaccination schedule completed.
DIAGNOSIS
· Acute hepatitis B can be asymptomatic, particularly in children and young adults. Common but nonspecific clinical manifestations include malaise, fatigue, pruritus, headache, abdominal pain, myalgias, arthralgias, nausea, vomiting, anorexia, and fever.
· Extrahepatic, unusual presentations include polyarteritis nodosa, glomerulonephritis, cryoglobulinemia, serum sickness-like illness, papular acrodermatitis (predominantly in children), and aplastic anemia.
· Chronic hepatitis B is defined as persistent viral activity (serologic or molecular studies) for at least six months from diagnosis. As in acute hepatitis, symptoms may vary. Chronic hepatitis B can progress to cirrhosis and HCC.
· Based on biochemical, serologic, molecular, and histologic criteria, chronic hepatitis B infection is a dynamic process that occurs in different phases (see Table 30-1).
TABLE 30-1 Use of HBV Markers in Clinical Practice
ALT, alanine transaminase; AST, aspartate transaminase; HBc, hepatitis B core antigen; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus.
TREATMENT
· Acute hepatitis B: Patients can usually be treated supportively on an outpatient basis.
· Chronic hepatitis B
o Current indications for treatment include patients with chronic hepatitis B (e antigen positive and negative) with HBV DNA >2,000 IU/mL and/or elevated ALT with necroinflammation and fibrosis on liver biopsy. Patients with cirrhosis, both compensated and decompensated, should be treated even with normal ALT levels or HBV DNA <2,000 IU/mL.4
o Entecavir, tenofovir, and pIFN-α are first-line treatment agents.5 The goal of treatment is viral suppression or eradication to prevent progression to cirrhosis and HCC. Treatment end points include clearance of HBV DNA, hepatitis B e antigen and hepatitis B surface antigen seroconversion (loss of antigen and production of antibody), and normalization of liver enzymes and histology.
Hepatitis C
GENERAL PRINCIPLES
· The hepatitis C virus (HCV) is an RNA virus of the Flavivirus family. There are six genotypes (1 to 6) and multiple subtypes (a, b, c, etc.). Genotype 1 is the most common in the United States (75%).
· HCV is a common blood-borne infection that is often transmitted by intravenous and intranasal drug use.
· HCV can cause both acute and chronic hepatitis.
· There are approximately 180 million HCV carriers worldwide. In the United States, about 4 million people are infected with HCV and 50% to 75% are unaware of their infection.6
· In industrialized countries, HCV accounts for 20% of cases of acute hepatitis, 70% of chronic hepatitis, 40% of cirrhosis, 60% of HCC, and 40% to 50% of liver transplantations.
· Male gender, older age at the time of infection, duration of infection, hepatic steatosis, heavy alcohol consumption, daily marijuana use, and coinfection with HIV have been identified as risk factors for fibrosis progression.
· Patients with cirrhosis due to hepatitis C develop HCC at a rate of approximately 1% to 4% per year.7
DIAGNOSIS
· Acute hepatitis can be asymptomatic, especially in children and young adults. Symptoms vary from mild illness to acute liver failure. Malaise, fatigue, pruritus, headache, abdominal pain, myalgias, arthralgias, nausea, vomiting, anorexia, and fever are common but nonspecific presentations.
· Chronic hepatitis C runs an indolent course, sometimes for decades, and its diagnosis requires a high index of suspicion. Fatigue is a common symptom. The disease may only become clinically apparent late in the natural course, when advanced liver disease develops. Patients with risk factors for HCV infection should be tested. In addition, the CDC recommends one-time screening for hepatitis C for all those born in the decades from 1945 through 1965.8
· Extrahepatic, unusual presentations include mixed cryoglobulinemia (10% to 25% of patients with HCV), glomerulonephritis, porphyria cutanea tarda, vasculitis, lymphoma, diabetes mellitus, and lichen planus.9
· The diagnosis of hepatitis C is based on a combination of liver chemistries, serologies, molecular studies, and histology.
· Antibodies against HCV (anti-HCV) may be undetectable for the first 8 weeks after infection. Antibodies do not confer immunity. The test has a sensitivity of 95% to 99% and a lower specificity. A false-positive test (anti-HCV positive with HCV RNA negative) may occur in the setting of autoimmune hepatitis (AIH) or hypergammaglobulinemia. A false-negative test (anti-HCV negative with HCV RNA positive) may be seen in immunosuppressed individuals and in patients on hemodialysis.
· HCV RNA can be detected by PCR in serum as early as 1 to 2 weeks after infection (qualitative and quantitative assays). HCV RNA determination is useful for both diagnosis and treatment purposes.
· HCV genotype influences the duration, dosage, and response to treatment.
· Liver biopsy is useful to score the degree of inflammation (grade) and fibrosis (stage) in the liver of chronically infected patients. It also allows for assessment of the amount of liver steatosis and guides treatment decisions.
TREATMENT
· Acute hepatitis C: IFN-α (standard or pegylated) for 6 months has been associated with a high rate (98%) of sustained HCV RNA clearance.10
· Chronic hepatitis C: Treatment varies according to genotype. In patients with genotype 1, the standard of care is to use triple therapy including pegylated interferon (pIFN-α), ribavirin, and a protease inhibitor (PI). Boceprevir and telaprevir are the only two currently approved PIs (only for genotype 1 patients). In patients with genotype 2 or 3, a combination of pIFN-α and ribavirin is administered for 6 to 12 months.
· Multiple side effects are associated with these regimens. pIFN-α is associated with flu-like symptoms, neuropsychiatric disorders, and bone marrow suppression. Ribavirin is associated with hemolytic anemia and pulmonary symptoms. PIs are associated with anemia, rash, dysgeusia, diarrhea, and anal discomfort.
· pIFN-α should not be used in patients with decompensated cirrhosis or in patients with autoimmune conditions. Ribavirin is teratogenic and should not be used in pregnancy, in women of childbearing age who are not using birth control, in patients with chronic renal insufficiency, or in those who cannot tolerate anemia. PIs inhibit the hepatic cytochrome P450 enzymes and have extensive drug-drug interactions.
IMMUNE-MEDIATED LIVER DISEASE
Autoimmune Hepatitis
GENERAL PRINCIPLES
· AIH is a chronic disorder characterized by inflammation of the liver associated with circulating autoantibodies and hypergammaglobulinemia.
· There are two types of AIH. Type 1 is the most common form (80%). It is associated with ANA (antinuclear antibodies) and/or ASMA (anti–smooth muscle antibodies). Type 2, predominately seen in children and young adults, is associated with antibodies to liver/kidney/microsome type 1 (ALKM-1) and/or antibodies to cytosol type 1 (ALC-1).
· AIH affects all ethnic groups and occurs worldwide. In Norway and Sweden, for example, its prevalence is 11 to 17 per 100,000.11
· Women are affected more than men (gender ratio 3.6:1).
DIAGNOSIS
· An acute presentation, clinically similar to acute viral hepatitis, is observed in 30% to 40% of patients.
· Extrahepatic manifestations may be found in 30% to 50% and include synovitis, celiac disease, Coombs-positive hemolytic anemia, autoimmune thyroiditis, Graves disease, rheumatoid arthritis, ulcerative colitis, uveitis, and other autoimmune-mediated processes.
· The most common symptoms at presentation include fatigue, jaundice, myalgia, anorexia, diarrhea, acne, and right upper quadrant abdominal tenderness.
· Diagnostic criteria are based on autoantibodies, IgG levels, histologic changes, and the exclusion of viral hepatitis and other liver conditions.12
· Liver biopsy is essential for the diagnosis.
TREATMENT
· Goals of treatment include biochemical normalization and histologic remission.
· Treatment should be started in patients with elevated serum aminotransferase levels and hypergammaglobulinemia (aminotransferases >10 times upper limit of normal [ULN] or aminotransferases >5 times ULN and immunoglobulins ≥2 times ULN) or those with biopsy findings of interface hepatitis, bridging necrosis, or multiacinar necrosis.
· Therapy is initiated with either prednisone monotherapy (40 to 60 mg/day) or a combination of prednisone and azathioprine (30 mg/day and 1 to 2 mg/kg/day, respectively).11
· Prednisone is tapered with biochemical and clinical improvement. Some patients require lifelong low-dose therapy.
· Liver transplantation should be considered in patients with decompensated cirrhosis and those with AIH-mediated acute liver failure.
· Most adults (90%) have clinical and biochemical improvement within 2 weeks of beginning treatment. Remission is achieved in 80% of patients at 3 years.
· Relapses occur in at least 20% to 50% of patients after treatment discontinuation. Those patients require retreatment.
Primary Biliary Cirrhosis
GENERAL PRINCIPLES
· Primary biliary cirrhosis (PBC) is a cholestatic disorder with autoimmune features and unknown etiology.
· It is more commonly seen in women (90% to 95%) and in Caucasians.
· PBC is an indolent disease that progresses from laboratory abnormalities to increasing histologic damage, leading to fibrosis, cirrhosis, and liver failure.
DIAGNOSIS
· The clinical course is highly variable, with up to 50% to 60% of patients asymptomatic at the time of diagnosis. Fatigue, jaundice, and pruritus are often the most troublesome symptoms. While there are no exam findings that are specific for PBC, xanthomata and xanthelasma can be manifestations of underlying cholestasis.
· Extrahepatic manifestations include keratoconjunctivitis sicca (Sjögren syndrome), renal tubular acidosis, gallstones, thyroid disease, scleroderma, Raynaud phenomenon, CREST syndrome, and celiac disease.
· Antimitochondrial antibodies are present in >90% of patients with PBC. Typical biochemical features include elevated levels of alkaline phosphatase, total bilirubin, and cholesterol as well as elevations of IgM.
· Liver biopsy is helpful for both diagnosis and staging.
TREATMENT
· No curative therapy is available, but ursodeoxycholic acid (13 to 15 mg/kg/day) has been shown to improve laboratory abnormalities as well as survival.13
· Symptom-specific therapy for pruritus, steatorrhea, and malabsorption may be needed.
· Liver transplantation is an alternative in advanced liver disease.
Primary Sclerosing Cholangitis
GENERAL PRINCIPLES
· Primary sclerosing cholangitis (PSC) is a cholestatic liver disease characterized by inflammation, fibrosis, and progressive obliteration of the extrahepatic and intrahepatic biliary tree.
· PSC can be subdivided into those with small duct and large duct involvement. Small duct disease has typical histologic features of PSC with a normal cholangiogram. Large duct, or classic, PSC has characteristic strictures of the biliary ducts that can be detected by cholangiography.
· Most patients have involvement of both intrahepatic and extrahepatic ducts, with <25% having only intrahepatic involvement and <5% only extrahepatic disease.14
· Male to female ratio is 2:1, and peak incidence is approximately age 40.
· The clinical progression of PSC is unpredictable, but most patients have insidious progression to cirrhosis.
· Cholangiocarcinoma has a poor prognosis; however, perihilar cholangiocarcinoma may be an indication for liver transplantation in selected patients.
DIAGNOSIS
· Clinical manifestations include intermittent episodes of jaundice, hepatomegaly, pruritus, weight loss, and fatigue. Acute cholangitis is a frequent complication in patients with severe biliary strictures.
· Patients are at increased risk for cholangiocarcinoma, which develops in 10% to 30%.15
· In 70% of patients with PSC, ulcerative colitis is an associated condition. Crohn disease is less commonly associated with PSC.
· pANCA (perinuclear antineutrophil cytoplasmic antibody) is positive in 80% of cases. In contrast, ANA is only seen in 50% of patients.
· Imaging studies useful in the diagnosis of PSC include liver ultrasound, MRCP (magnetic resonance cholangiopancreatography), and ERCP (endoscopic retrograde cholangiopancreatography). Those studies typically show ductal dilation, strictures, or irregularities of the intrahepatic or extrahepatic bile ducts. ERCP is also useful to obtain brushings to evaluate for associated malignancy.
· While liver biopsy is not the gold standard for the diagnosis of PSC, it is helpful to exclude other diseases and for staging.
TREATMENT
· No specific drug treatments have been shown to alter disease progression. Ursodeoxycholic acid is not currently recommended for therapy.14
· Acute cholangitis should be managed with antibiotics and endoscopic therapy (dilation and stenting of dominant strictures).
· Symptom-specific therapy for pruritus, steatorrhea, and malabsorption may be needed.
· Liver transplantation is an alternative in advanced liver disease.
METABOLIC LIVER DISEASE
Nonalcoholic Fatty Liver Disease
· Nonalcoholic fatty liver disease (NAFLD) is an increasingly common metabolic disorder of the liver strongly associated with diabetes mellitus type 2, the metabolic syndrome, obesity, and dyslipidemia.16
· The disorder can range from the benign accumulation of triglyceride in hepatocytes (simple steatosis) to the nonalcoholic steatohepatitis (NASH) characterized by steatosis with hepatocellular ballooning plus lobular inflammation. The proportion of patients with NAFLD who will progress to NASH is unknown. For patients with NASH, progression to cirrhosis occurs in approximately 11% over a 15-year period.17
· NAFLD has an estimated prevalence of 6% to 14% in the general population in the US.18
· NAFLD should be considered in the differential diagnosis of patients with elevated liver enzymes, particularly those with the metabolic syndrome.
· Imaging studies, including ultrasound, CT, and MRI, may show steatosis, but the presence of inflammation can only be determined by liver biopsy.
· Weight loss improves liver histology, and bariatric surgery can be considered in morbidly obese patients.16 Discontinuation of medications associated with NAFLD (e.g., amiodarone, corticosteroids, and total parenteral nutrition) should also be considered.
Alpha-1 Antitrypsin Deficiency
· Alpha-1 antitrypsin (α1AT) is a PI. α1AT deficiency is an autosomal recessive disorder that damages the liver through the accumulation of misfolded α1AT in hepatocytes and damages the lungs through uninhibited proteolysis, resulting in cirrhosis and emphysema.
· Patients with low serum α1AT levels (<10% to 15% of normal) should undergo α1AT genotype testing. The M allele gives rise to the normal PI, while S and Z are the most common deficiency alleles. The genotypes associated with liver disease are SZ, ZZ, and possibly MZ.19 Patients who are homozygous for the Z allele may develop chronic hepatitis, cirrhosis, or HCC at a rate of 10% to 15% in the first 20 years of life.
· Diagnosis requires liver biopsy showing periportal hepatocytes with intracellular globules.
· No specific drug therapy exists for α1AT-associated liver disease.
· Liver transplantation in patients with decompensated cirrhosis normalizes α1AT production.
Hereditary Hemochromatosis
GENERAL PRINCIPLES
· Hereditary hemochromatosis is characterized by increased iron absorption and toxic deposition of iron into parenchymal cells of various tissues. It can be caused by mutations that affect any of the proteins that limit the entry of iron into the blood.
· Ninety percent of individuals with hereditary hemochromatosis are homozygous for the mutation C282Y in the HFE gene on chromosome 6. However, not all patients with the mutation develop iron overload.20 There are other conditions, not linked to the C282Y mutation, associated with iron overload or high ferritin, suggesting that other proteins in the iron metabolism process are defective.
· Patients with a family history of hemochromatosis in a first-degree relative due to an HFE gene mutation should be screened for hemochromatosis.21
· Noncirrhotic patients appropriately treated for hereditary hemochromatosis have an excellent prognosis. The survival rate in appropriately treated noncirrhotic patients is identical to that of the general population.
· Patients with cirrhosis or advanced fibrosis are at increased risk for the development of HCC despite therapy and should be routinely screened for HCC.
DIAGNOSIS
· Patients with hereditary hemochromatosis may be asymptomatic or may develop hepatic dysfunction (including cirrhosis), bronzing of the skin, diabetes, cardiomyopathy, arthritis, and hypogonadism.
· Transferrin saturation (serum iron divided by the total iron-binding capacity) ≥45% and/or elevated ferritin are suggestive of hemochromatosis and should be further investigated with HFE mutation analysis.21
· Indications for liver biopsy in patients with an HFE gene mutation include ferritin >1,000 μg/L and elevated transaminases.
· MRI is the modality of choice for noninvasive quantification of iron storage in the liver.
TREATMENT
· Treatment consists of phlebotomy (500 mL blood) every 1 to 2 weeks until the ferritin is 50 to100 μg/L. The need for maintenance phlebotomy varies.21
· For patients who cannot tolerate phlebotomy, iron chelation with deferoxamine may be an alternative. Side effects include gastrointestinal distress, visual and auditory impairments, and muscle cramps. Deferoxamine is only given IV, IM, or SC. Deferasirox is another alternative in the treatment of iron overload and is given orally.22
Wilson Disease
GENERAL PRINCIPLES
· Wilson disease is an autosomal recessive disorder (ATP7B gene on chromosome 13) leading to progressive copper overload. Incidence is 1 in 30,000 with a female to male ratio of 2:1 and an age at presentation ranging from 6 to 20 years.
· The gene mutation in Wilson disease results in accumulation of copper in the liver and ultimately liver injury. In addition, copper is also deposited in other organs, notably the brain, kidneys, and cornea.
· First-degree relatives of patients diagnosed with Wilson disease should be screened for this condition.
DIAGNOSIS
· Presentation of liver disease in Wilson disease ranges from asymptomatic to acute liver failure.
· Extrahepatic manifestations include neuropsychiatric symptoms, gold-brown rings at the periphery of the cornea on slit-lamp examination (Kayser-Fleischer rings), Coombs-negative hemolytic anemia, renal tubular acidosis, arthritis, and osteopenia.
· Low serum ceruloplasmin of <20 mg/dL (seen in 85% of patients) and elevated 24-hour urine copper level of >100 mcg/24 hours suggest the diagnosis.23
· Liver biopsy with a copper level >250 mcg/g (dry weight) is consistent with Wilson disease.
TREATMENT
· Copper-chelating agents (including D-penicillamine, trientine, and zinc salts) block the intestinal absorption of copper and are used to treat Wilson disease.23 While zinc and trientine are well tolerated, D-penicillamine is associated with several side effects including hypersensitivity, bone marrow suppression, proteinuria, systemic lupus erythematosus, and Goodpasture syndrome.
· Patients presenting with fulminant liver failure should be considered for liver transplant.
· Liver transplant in patients with Wilson disease without neurologic symptoms carries an excellent prognosis.
ALCOHOLIC AND DRUG-INDUCED LIVER DISEASE
Alcohol-Induced Liver Disease
GENERAL PRINCIPLES
· Alcohol is, when used in excess, a hepatotoxin capable of inducing a spectrum of diseases including fatty liver, alcoholic hepatitis, and alcoholic cirrhosis. In the US, excessive alcohol consumption is the third leading preventable cause of death and 50% of all cases of cirrhosis are due to alcohol abuse.
· Patients with fatty liver are generally asymptomatic and may have hepatomegaly and mild transaminase elevations (typically with an AST:ALT ratio >2:1).
· Alcoholic hepatitis ranges from asymptomatic to quite severe, with fever, abdominal pain, jaundice, complications of portal hypertension and, in some cases, liver failure and death.
· Alcoholic cirrhosis is typically micronodular and results from chronic alcohol consumption. The sensitivity of the liver to damage from alcohol varies widely. Among patients with heavy alcohol consumption, only 6% to 41% progress to cirrhosis.24
DIAGNOSIS
· A thorough history is essential; self-reports of alcohol consumption may be underestimates.
· Patients with suspected alcoholic liver disease should be evaluated for coexisting causes of liver injury. Liver biopsy may be helpful if alternative diagnoses are being considered.
· Severity of alcoholic hepatitis can be estimated by using a discriminant function.25
(DF) = (4.6 × [measured PT − control PT]) + bilirubin (mg / dl)
· A DF of >32 defines a severe alcoholic hepatitis and is associated with a high 30-day mortality.
· In-hospital mortality of severe alcoholic hepatitis is approximately 50%.
TREATMENT
· The cornerstone of treatment is abstinence from alcohol. Abstinence from alcohol may reverse fatty liver and lead to biochemical improvement in patients with alcoholic cirrhosis.
· In alcoholic hepatitis, medical therapies include corticosteroids and pentoxifylline. Corticosteroids (prednisolone 40 mg daily for 4 weeks) should be considered in subjects with alcoholic hepatitis and a DF of ≥32 or encephalopathy. Potential contraindications to steroids include infection, gastrointestinal bleeding, and pancreatitis.26 Pentoxifylline (400 mg tid for 4 weeks) decreases cytokine production and is an alternative for patients in whom steroids are contraindicated.27 In addition, good nutrition is an essential component of treatment.
· Patients with decompensated alcoholic cirrhosis may be considered for transplant when they have demonstrated sustained abstinence from alcohol (>6 months) and enrollment in a rehabilitation program.
DRUG-INDUCED LIVER INJURY
GENERAL PRINCIPLES
· Drug-induced liver injury (DILI) may be intrinsic or idiosyncratic. Intrinsic hepatotoxicity is a direct, dose-dependent drug effect. Idiosyncratic hepatotoxicity includes hypersensitivity reactions and altered drug metabolism, which are variable and not predictable.
· Incidence of DILI is estimated to be between 1 in 10,000 and 1 in 100,000. A searchable database of medications and supplements associated with liver injury is available online (http://livertox.nih.gov, last accessed April 18, 2014). DILI accounts for up to 10% of all adverse drug reactions and represents 10% of hepatology consultations.
· DILI is a frequent cause of acute jaundice, and it is the most common cause of acute liver failure in the US. Jaundice in DILI is a poor prognostic indicator, with a case fatality rate of 10% to 50%.28
· Use of herbal and dietary supplements is common in the US. Like other pharmaceuticals, these supplements may exhibit hepatotoxicity, manifested as transient abnormalities of liver enzymes or acute or chronic hepatitis.
DIAGNOSIS
· Clinical presentation of DILI ranges from asymptomatic elevation of liver enzymes to fulminant hepatic failure.
· A high index of suspicion is essential to suspect DILI. A thorough interview with the patient and his/her relatives and a review of pharmacy records are essential to define the drugs, herbs, or dietary supplements involved in the liver injury.
· Diagnostic criteria include clinical suspicion, temporal relationship between drug exposure and liver injury, and resolution of injury after discontinuing the offending agent.
· Patterns of liver biochemistry abnormalities in DILI include hepatocellular (AST and ALT >2× ULN), cholestatic (alkaline phosphatase and conjugated bilirubin >2× ULN), and mixed (hepatocellular and cholestatic).
TREATMENT
Treatment involves stopping the offending agent, instituting supportive measures and, when applicable (e.g., acetaminophen), use of drug-specific therapy.28
Acetaminophen Hepatotoxicity
GENERAL PRINCIPLES
· Acetaminophen is a safe and effective analgesic and antipyretic if consumed at the recommended dose of <4 g/day. However, it is the most common cause of acute liver failure in the US (suicide attempts or therapeutic misadventures).29
· The toxicity of acetaminophen is dose dependent. Overdose is defined as >150 mg/kg in children and >10 to 15 g in adults. Toxicity can actually occur at doses <10 g.
· Toxicity is due to the metabolism of acetaminophen to toxic N-acetyl-p-benzoquinone imine (NAPQI). At usual doses, NAPQI is quickly detoxified by conjugation with glutathione.
· Hepatotoxicity is not increased in the setting of nonalcoholic chronic liver disease. In chronic ethanol abusers, the repetitive use of supratherapeutic doses of acetaminophen is linked to liver toxicity.
· Drugs that induce CYP2E1 enzymes (carbamazepine, phenytoin, phenobarbital, isoniazid, and rifampin) can produce liver injury in the absence of acetaminophen overdose.
DIAGNOSIS
· Patients may present asymptomatically; symptoms of toxicity may not develop until 1 to 2 days after ingestion. Initial symptoms are nonspecific and include anorexia, malaise, nausea, and vomiting, followed by right upper quadrant pain.
· Subsequently, hepatic failure develops, including jaundice, encephalopathy (cerebral edema), and coagulopathy. Renal failure can also develop at this point, due to drug-induced acute tubular necrosis and dehydration.
· Differential diagnosis includes gastroenteritis, acute cholecystitis, pancreatitis, alcoholic hepatitis, viral hepatitis, Reye syndrome, shock liver, and other forms of drug/herb hepatotoxicity.
· The Rumack-Matthew nomogram is used to predict the likelihood of hepatotoxicity given the serum acetaminophen level obtained and the time since consumption.29
· Serum aminotransferases begin to rise sharply about 12 hours after ingestion. Peak levels occur at about 72 hours and are frequently >3,000 IU/L.
· Hepatic synthetic function declines as hepatotoxicity progresses (e.g., prolonged PT, hyperbilirubinemia, hypoalbuminemia, and hypoglycemia). Acidosis, azotemia, and electrolyte disturbances may occur.
TREATMENT
· Treatment involves the prompt administration of N-acetylcysteine (NAC) (a glutathione precursor) to protect the liver against the toxic metabolites of acetaminophen.29 If the patient presents with acute liver failure, treatment should be administered in intensive care units of hospitals with liver transplant programs.
· Treatment should begin ideally within 8 to 10 hours postingestion, but may be beneficial up to 24 hours.
· NAC is given orally or intravenously.
o Oral: Loading dose of 140 mg/kg followed by a maintenance dose of 70 mg/kg every 4 hours for a total of 17 doses over 72 hours.
o Intravenous: Loading dose of 150 mg/kg IV over 15 minutes followed by a maintenance dose of 50 mg/kg over 4 hours followed by 100 mg/kg over 16 hours. Other IV dosage regimens have also been suggested.
· Patients who present late (>10 hours after ingestion) may benefit from longer treatment durations than those described above.
· Prompt administration of N-acetylcysteine is associated with a good outcome. Unfortunately, many patients present for medical care late, once the toxic effects are established and the acute liver failure is too advanced to be reversed by simple administration of NAC.
· Careful attention should be paid to detecting cerebral edema and correcting fluid, electrolyte, and acid-base abnormalities.
· Liver transplantation should be considered in patients with liver failure that continues to progress despite adequate treatment.29
TUMORS OF THE LIVER
Adenoma
· Hepatic adenomas are rare, benign epithelial liver tumors commonly associated with a history of oral contraceptive (OC) use and androgen steroid therapy. Usually located in the right hepatic lobe, roughly three-fourths of adenomas are solitary.30
· The incidence of liver adenomas is estimated to be 0.1 per year per 100,000 and has grown to be 3 to 4 per 100,000 in long-term OC users.31
· Hepatic adenomas, especially those that are larger, may present with upper abdominal pain. Adenomas >5 cm in diameter have an increased risk of spontaneous bleeding. Hepatic adenomas have a risk of malignant transformation that has been calculated at 4% to 10%.32
· Diagnosis is usually based on the clinical setting with the assistance of imaging studies. In particular, contrast CT scans may show early-phase peripheral enhancement followed by centripetal flow during the portal venous phase.33
· OC cessation may lead to regression and even complete resolution of hepatic adenomas.34
· Because of the risk of hemorrhage, rupture, and malignant transformation, surgical resection is typically recommended for adenomas >5 cm in diameter.35
Hemangioma
· Hepatic hemangiomas, the most common benign liver tumors, are nonepithelial lesions usually discovered incidentally.36
· Approximately three-fourths are found in females. Female sex hormones (endogenous or exogenous) may exert influence over the growth of hemangiomas, but significant enlargement still only occurs in a minority of patients.37
· Although typically of minimal clinical concern, hemangiomas measuring >10 cm in diameter may be symptomatic (right upper quadrant abdominal pain, nausea, or early satiety).
· Giant hepatic hemangiomas may be associated with the Kasabach-Merritt syndrome, which is characterized by fibrinolysis, thrombocytopenia, coagulopathy, and a fatal outcome in up to 30% of patients and often represents an indication for liver transplantation.
· Diagnosis of liver hemangiomas is made on imaging.
· As most hemangiomas remain stable in size, surgical indications are typically limited to symptomatic patients with giant hemangiomas.38
Focal Nodular Hyperplasia
· Focal nodular hyperplasia (FNH) is a benign liver tumor that is usually solitary (but may be multiple in 20% of cases) and <5 cm in diameter. FNH is the second most common benign liver tumor after hemangiomas and is found predominantly in females in a roughly 10:1 ratio.39
· It is thought that FNH arises in response to arterial malformations as hyperplastic lesions. While controversial, current OC (low-dose estrogen) use is not associated with FNH lesions. Moreover, pregnancy does not affect the clinical behavior of FNH.40
· Diagnosis is made with imaging modalities; CT and MRI are particularly specific for FNH with typical features. However, imaging similarities have been described with liver adenomas and even HCCs. Therefore, when findings are atypical, invasive diagnostic measures (liver biopsy) should be considered.41
· FNH has no known malignant potential and only very rarely ruptures or bleeds. Most FNH lesions remain stable in size, and a minority may regress. Given the absence of malignant potential, stability of most lesions, possibility of lesion regression, and especially low risk of rupture, FNH is almost always managed conservatively.42
· Resection should be considered for patients with symptomatic FNH (large and subcapsular lesions), lesions with atypical radiologic characteristics, and lesions that increase in size.
Hepatocellular Carcinoma
GENERAL PRINCIPLES
· HCC represents an increasingly common complication of liver disease.
· Cirrhosis is present in 80% to 90% of patients with HCC.
· Over 500,000 individuals worldwide are diagnosed each year with HCC (fifth most common cancer in men and the seventh most common cancer in women). Roughly half occur in the setting of chronic HBV infection.43Nearly 85% of cases of HCC occur in developing countries.44
· In the US, up to half of all cases of HCC occur in the setting of HCV infection. Other associated conditions include alcoholic cirrhosis, α1AT deficiency, and hemochromatosis.45
· Early diagnosis is essential, as surgical resection and liver transplantation can improve long-term survival with 5-year disease-free survival exceeding 50%. Advanced HCC has a dismal prognosis with a 5-year survival of 0% to 10%.
DIAGNOSIS
· Clinical presentation is proportional to the stage of disease. HCC may present with right upper quadrant abdominal pain, weight loss, and hepatomegaly. HCC should be suspected in a cirrhotic patient who develops manifestations of liver decompensation.
· The diagnosis of HCC can often be made with imaging. In patients with suspicious imaging findings, an elevated serum α-fetoprotein >400 is highly predictive of HCC. Liver biopsy can be considered for patients at risk for HCC with suspicious liver lesions >1 cm with noncharacteristic imaging features.
· Since patients with cirrhosis are at the highest risk for developing HCC, surveillance ultrasonography or cross-sectional imaging is recommended for cirrhotics every 6 months to allow diagnosis at early stages. Serum α-fetoprotein should not be used as the only screening modality.46
TREATMENT
· Oral systemic chemotherapy with sorafenib may be used as palliative therapy for advanced-stage HCC. In patients with advanced HCC, median survival and radiologic progression were 3 months longer for patients treated with sorafenib compared to placebo.47
· Transarterial chemoembolization (TACE) or transarterial radioembolization (TARE) may be used for palliation in intermediate-stage or multifocal HCC or to downstage HCC to meet the Milan criteria.46
· Local radiofrequency or alcohol ablation therapy is best for very early-stage HCC or early-stage HCC not amenable to surgical resection or transplantation.48
· The best candidates for surgical resection are those with small solitary tumors in the absence of cirrhosis or in those with cirrhosis with well-preserved liver function.
· Liver transplantation represents a curative treatment, but patients must meet the Milan criteria to be eligible for transplantation (solitary nodule ≤5 cm or three nodules each ≤3 cm).
Cholangiocarcinoma
· Cholangiocarcinoma is a malignancy affecting the intrahepatic and extrahepatic bile ducts. It represents the second most common primary hepatic cancer behind HCC.
· Men are more frequently affected, and it typically presents in the seventh decade of life. Risk factors include PSC, bile duct cysts, hepatolithiasis, toxins (e.g., thorotrast), and parasitic infections (e.g., hepatobiliary flukes).49
· Since tumors are often locally advanced at presentation, prognosis is poor with 5-year survival rates of 5% to 10%.
· When symptomatic (often late in the natural history), cholangiocarcinomas may present with symptoms of bile duct obstruction and right upper quadrant abdominal pain.50
· Serum CA 19-9 is often elevated, but has limited specificity for cholangiocarcinoma.51
· Imaging can identify ductal dilation or a dominant stricture, but may not always identify the primary tumor. Ideal imaging modalities include MRCP and ERCP, which afford the opportunity for visualization of the biliary tree as well as diagnosis (via brush cytology, biopsy, and/or fluorescence in situ hybridization [FISH]).
· Surgical resection represents a chance for cure, though postsurgical cancer recurrence remains a concern. Radiation and chemotherapy have not been shown to enhance survival for inoperable tumors. Liver transplantation in combination with neoadjuvant chemoradiotherapy can represent an option for selected perihilar cholangiocarcinomas. Palliation may involve biliary drainage via stents or photodynamic therapy.52
CIRRHOSIS
GENERAL PRINCIPLES
· Cirrhosis is characterized by the diffuse replacement of liver cells by fibrotic tissue, leading to nodular-appearing distortion of the normal liver architecture.
· Although chronic viral infection, alcoholic liver disease, and NASH account for the majority of cases of cirrhosis, other causes may include AIH, drug-induced hepatotoxicity, venoocclusive disease, Wilson disease, hemochromatosis, and α1AT deficiency. In some instances, no etiology for cirrhosis is identified; in which case, it is categorized as cryptogenic.
DIAGNOSIS
The diagnosis of cirrhosis typically lies in the recognition of its complications. The main complications of cirrhosis include portal hypertension (esophageal and gastric varices, portal hypertensive gastropathy and colopathy, gastric antral vascular ectasia, ascites and spontaneous bacterial peritonitis [SBP], hepatorenal syndrome [HRS]), hepatic encephalopathy, and HCC.
Complications
Portal Hypertension
· Portal hypertension represents the primary complication of cirrhosis and is characterized by increased resistance to portal flow and increased portal venous inflow. Portal hypertension is established by measuring the pressure gradient between the hepatic vein and the portal vein (normal approximately 3 mm Hg). Clinical consequences of portal hypertension typically appear when the portosystemic pressure gradient exceeds 10 mm Hg.53
· Ultrasonography, CT, and MRI showing cirrhosis, splenomegaly, collateral venous circulation, and ascites may indicate portal hypertension.
· Upper endoscopy can reveal varices (esophageal or gastric), portal hypertensive gastropathy, or gastric antrum vascular ectasia (GAVE).
Esophageal and Gastric Varices
· Esophageal and gastric varices are asymptomatic sequelae of portal hypertension until they rupture. Upper gastrointestinal bleeding secondary to variceal rupture is the most common lethal complication of cirrhosis.
· In 50% of patients with cirrhosis, varices are present. Predictors of bleeding risk include variceal size, red wale marks on varices, and severity of liver dysfunction. Variceal hemorrhage happens at a yearly rate of 5% to 15% and is associated with a mortality rate of 20% at 6 weeks.54
· Screening esophagogastroduodenoscopy (EGD) should be performed at the time of diagnosis of cirrhosis.
o In patients with compensated cirrhosis without varices, EGD should be repeated in 3 years. In patients with low-risk small varices that have not bled, EGD should be repeated in 2 years.55
o However, if small varices are present in the setting of increased risk for hemorrhage (decompensated cirrhosis or red wale marks) or medium or larger varices are present, indefinite treatment with nonselective β-blockers, such as propranolol or nadolol, decreases the risk of variceal bleeding. Endoscopic variceal ligation (EVL) may be equivalent to β-blockade for preventing the first variceal hemorrhage in high-risk varices and should be especially considered in patients with contraindications to or noncompliance with β-blockade.56
· After variceal hemorrhage, secondary prophylaxis with both nonselective β-blockade and EVL should be used.
· Transjugular intrahepatic portosystemic shunt (TIPS) can be considered for recurrent episodes of variceal hemorrhage. Surgical shunts are now rarely performed.
Ascites and Spontaneous Bacterial Peritonitis
· Ascites is the accumulation of fluid (>25 mL) within the peritoneal cavity. While commonly due to portal hypertension, other causes of ascites may include peritoneal carcinomatosis, heart failure, tuberculosis, myxedema, pancreatic disease, nephrotic syndrome, trauma to the lymphatic system or ureters, and serositis.
· Clinical presentation may range from ascites detected only by imaging to a distended, bulging, and sometimes tender abdomen. Physical exam can reveal shifting dullness, dullness to flank percussion, palpable fluid wave, and umbilical hernia.
· The initial laboratory investigation of ascitic fluid should include an ascitic fluid cell count and differential, ascitic fluid total protein, and serum-ascites albumin gradient (SAAG). An SAAG value of >1.1 g/dL is consistent with ascites secondary to portal hypertension.57
· First-line treatment of cirrhotic ascites includes sodium restriction (2 g/day) and combination diuretics (typically oral spironolactone starting at 100 mg PO qd and oral furosemide starting at 40 mg PO qd).58
· Patients should be observed closely for signs of dehydration, electrolyte disturbances, encephalopathy, muscle cramps, and renal insufficiency. NSAIDs may blunt the effects of diuretics and increase the risk of renal dysfunction. Care must also be taken to avoid salt substitutes rich in potassium.
· Ascites is considered refractory when unresponsive to maximal doses of diuretics (spironolactone 400 mg/day and furosemide 160 mg/day) or if the patient is unable to tolerate diuretic therapy. Refractory ascites may require treatment with serial large-volume paracentesis or TIPS. Moreover, referral for liver transplantation should be expedited.59
· Spontaneous bacterial peritonitis (SBP) is an infectious complication of portal hypertension–related ascites defined as ascitic fluid containing >250 neutrophils/mm3. SBP may be asymptomatic. Cirrhotic patients with ascites and evidence of any clinical deterioration should undergo diagnostic paracentesis and be treated with empiric antibiotics. These patients typically require hospitalization. Regarding SBP prophylaxis, norfloxacin 400 mg PO qd is the treatment of choice and should be given indefinitely to any patient who has been diagnosed with SBP.60
Portosystemic Encephalopathy
· Portosystemic encephalopathy (PSE) is characterized by altered consciousness and disordered neuromuscular activity in patients with acute or chronic hepatic failure or portosystemic shunting. While its pathogenesis is controversial, PSE probably results from disordered clearance of neurotransmitters and gut-derived toxins. Excess ammonia, in particular, may lead to astrocyte swelling and cerebral edema.61
· Common precipitants of PSE may include noncompliance with medications, specifically lactulose; azotemia; opioids or sedative-hypnotic medications; acute liver failure; acute gastrointestinal bleeding; alkalosis (diuretics or diarrhea); constipation; infection; high-protein diet; progressive hepatocellular dysfunction; and portosystemic shunts (surgical or TIPS).
· PSE may be graded by the clinical West Haven criteria. The following grades may overlap and quickly change:
o Grade I: shortened attention span, trivial lack of awareness, mild confusion, tremor
o Grade II: lethargy, disorientation, inappropriate behavior, subtle personality change
o Grade III: somnolence to semistupor (responsive to verbal stimuli), severe confusion
o Grade IV: coma (unresponsive to stimuli)
· Physical examination findings may include altered mental status, asterixis (flapping tremor not specific to PSE), or hyperactive reflexes.62
· Management of PSE includes supportive care, identification of precipitating factors, elimination of sedative or hypnotic medications, and the reduction of gut-derived nitrogenous products.63 Medications include nonabsorbable disaccharides or antibiotics. Lactulose may be titrated to produce three to five soft bowel movements daily. Moreover, nonabsorbed oral antibiotics, such as rifaximin 550 mg PO bid, may also be used. Neomycin and metronidazole are used less often than rifaximin due to their attendant toxicities.64
Hepatopulmonary Syndrome
· Hepatopulmonary syndrome presents as dyspnea and hypoxemia due to pulmonary vasodilation as a result of liver disease.
· Physical exam findings may include platypnea (shortness of breath when upright) or orthodeoxia (decrease in arterial oxygenation when upright).
· Agitated saline contrast echocardiography (bubble study) may show the early appearance of intravenous microbubbles in the left atrium (within 2 to 3 heartbeats).
· Management of hepatopulmonary syndrome includes supplemental oxygen; resolution is typically seen with liver transplantation.65
Hepatorenal Syndrome
· HRS represents functional renal impairment in the setting of acute or chronic liver disease. Precipitants may include systemic infection, SBP, and therapeutic paracentesis (especially without volume expansion).66
· Type I HRS involves rapidly progressive oliguric renal failure with serum creatinine doubling to ≥2.5 mg/dL in less than 2 weeks, whereas type II HRS is a steady and relentless deterioration in renal function associated with refractory ascites and a median survival of 6 months.67
· HRS is characterized by major criteria: renal failure in the absence of other causes (shock, infection, nephrotoxins, renal outflow obstruction), failure to improve after intravenous volume expansion, and absence of proteinuria >500 mg/day. Additional criteria include low urine volume <500 mL/day, low urine sodium concentration <10 mEq/L, urine osmolality greater than plasma osmolality, urine red blood cells <50/hpf, and serum sodium concentration <130 mEq/L.68
· Upon the suspicion for or diagnosis of HRS, patients should be admitted for inpatient workup and treatment. Treatments for HRS may include systemic vasoconstrictors (terlipressin, octreotide, midodrine) with plasma expansion. TIPS placement and hemodialysis may represent treatment alternatives to be used in selected patients. Ultimately, liver transplantation is curative.
LIVER TRANSPLANTATION
GENERAL PRINCIPLES
· Liver transplantation represents an effective option for irreversible acute or chronic liver failure, especially when available therapies have failed. The explosive growth in the number of liver transplants in the US over the past several decades has had a favorable impact on chronic liver disease mortality. Survival rates in the US after liver transplantation at 1, 3, and 5 years are 88%, 80%, and 75%, respectively.69
· Allocation for liver transplantation is based on the Model for End-Stage Liver Disease (MELD) score, which aims to provide donor organs for listed patients with the greatest short-term (3-month) mortality. The MELD score calculation variables are serum bilirubin, international normalized ratio (INR), and serum creatinine. MELD score calculators are readily available online.70
INDICATIONS
· Patients should be evaluated for transplant when they reach a MELD score of ≥15.
· Liver transplantation evaluation includes multidisciplinary comprehensive physical, physiologic, and psychosocial assessments to address the following 3 concerns: (a) Will liver transplant offer the best chance for long-term survival? (b) Are there any comorbid medical or psychosocial conditions that may outweigh the benefits of transplantation? (c) What is the urgency of transplant (informed by the MELD score)?
· Contraindications to liver transplantation include extrahepatic malignancy, hepatic malignancy with macrovascular or diffuse tumor invasion, active extrahepatic infection, active substance abuse, severe comorbid conditions (especially cardiopulmonary), psychosocial factors likely to preclude recovery, technical and/or anatomical barriers, and brain death.71
IMMUNOSUPPRESSION
· Posttransplant immunosuppression aims to prevent the immune system from rejecting the allograft while preserving physiologic defenses against infection and neoplasia.72
· Classes of immunosuppressants with attendant concerns include the following:
o Corticosteroids are typically weaned off within 3 to 6 months posttransplant, though they are used as first-line therapy for acute cellular rejection. Side effects of steroids can include hypertension, glucose intolerance, dyslipidemia, central obesity, osteoporosis, avascular necrosis, adrenal suppression, and poor wound healing.
o Calcineurin inhibitors (CNI), such as cyclosporine and tacrolimus, represent the foundation of maintenance immunosuppression and are used in >95% of transplant centers on discharge. Classic adverse effects include nephrotoxicity, neurotoxicity (especially with tacrolimus), hypertension, and hyperlipidemia.
o Mycophenolate mofetil is notable for its lack of renal toxicity and can be used with low-dose CNI in renal-sparing protocols. Adverse effects can include diarrhea and bone marrow suppression.
o mTOR inhibitors, such as sirolimus (SRL) and everolimus (EVL), are rarely used as first-line therapy but may be used in patients with CNI-induced nephrotoxicity. Side effects can include proteinuria, increases in cholesterol and triglycerides, interstitial pneumonitis, and early posttransplant hepatic artery thrombosis.
POSTTRANSPLANT COMPLICATIONS
· Early posttransplant complications typically stem from issues of allograft function, surgical anatomy, or infection. Early complications include acute cellular rejection (often managed with steroids), biliary disease (such as anastomotic stricture), hepatic artery thrombosis (may require retransplantation), or infection.
· Posttransplant immunosuppression increases the risk for malignancy (skin and nonskin cancers), cardiometabolic conditions (such as the metabolic syndrome and its components), and infection.73Clinicians should, therefore, screen regularly for malignancy, hypertension, diabetes, dyslipidemia, cardiovascular disease, renal disease, and bone mineral density.74
· Chronic rejection is a late complication.
OUTPATIENT BILIARY AND PANCREATIC DISEASES
Cholelithiasis
GENERAL PRINCIPLES
· Cholelithiasis is a common phenomenon, with an estimated prevalence of 10%.
· Gallstones are typically cholesterol stones, brown stones, or black stones.
o Cholesterol stones, which account for over three-fourths of biliary stones in Westernized societies, are associated with risk factors of female gender, obesity, Native American ethnicity, rapid weight loss, and estrogen therapy.
o Brown pigment stones form when bacteria in the biliary tree deconjugate bilirubin, forming insoluble calcium bilirubinate.
o Black pigment stones typically develop in cirrhosis or chronic hemolytic states, such as sickle cell disease, thalassemias, or hereditary spherocytosis.75
· Biliary sludge appears to be capable of producing biliary symptoms and should be managed in same fashion as gallstones.76
DIAGNOSIS
· Approximately 80% of gallstones are asymptomatic (with many found incidentally); however, complications from obstruction of the biliary tree may develop in a minority of patients.77
· Uncomplicated biliary colic is the most common manifestation and is characterized by several hours of right hypochondrium or epigastric pain often radiating to the right shoulder as well as intolerance to fried or fatty foods.78
· Complications include acute cholecystitis, choledocholithiasis, ascending cholangitis, gallstone pancreatitis, and gallstone ileus.
· Ultrasound is the most frequently used test for cholelithiasis, with greater sensitivity than CT.
TREATMENT
· Given that most gallstones are asymptomatic, laparoscopic cholecystectomy is only indicated to prevent recurrent symptoms and complications from symptomatic gallstones. Patients at high risk for gallbladder carcinoma, such as those with calcified or “porcelain” gallbladders and those of Native American descent, should be considered for cholecystectomy even in the absence of symptoms.
· Dissolution therapy with ursodeoxycholic acid may be an option for patients with symptomatic cholesterol gallstones who are not surgical candidates. Extracorporeal biliary shock wave lithotripsy is now rarely utilized.
Chronic Pancreatitis
GENERAL PRINCIPLES
· Chronic pancreatitis represents irreversible morphologic and functional damage to the pancreas from progressive inflammatory changes.
· Causes of chronic pancreatitis include the following:
o Alcohol is the most common cause in Westernized societies, though only 5% to 10% of alcoholics develop chronic pancreatitis.
o Genetic syndromes, such as cystic fibrosis or hereditary pancreatitis (autosomal dominant).
o Ductal obstruction from stones, trauma, neoplasia, or sphincter of Oddi dysfunction.
o Autoimmune conditions such as systemic lupus erythematosus, Sjögren syndrome, inflammatory bowel disease, and autoimmune pancreatitis.
o “Tropical” pancreatitis typically occurs in young people in impoverished areas of Africa and Asia, though its cause is unknown.
o Idiopathic pancreatitis accounts for 30% to 40% of chronic pancreatitis.79
DIAGNOSIS
· Clinical presentation is classically recurrent attacks of dull upper abdominal pain that may radiate to the midback or scapula and be associated with nausea and vomiting.
· The diagnosis of chronic pancreatitis is typically made clinically. Amylase and lipase may be normal or only mildly elevated, and laboratory testing for pancreatic exocrine function can be complex.
· Pancreatic calcifications may be seen on abdominal plain films in up to 30% of patients with pancreatitis. Their presence does not correlate with disease severity. While imaging with ultrasound or CT is relatively sensitive for chronic pancreatitis, MRCP, endoscopic ultrasound (EUS), and ERCP are the best imaging studies for diagnosis and management.
TREATMENT
· Alcohol cessation is paramount.
· Pain is the symptom that most frequently requires treatment.
o Analgesia with nonopioids and opioids is often needed.
o Pancreatic enzyme supplementation reduces pancreatic stimulation and may decrease pain but should be used with acid suppression to minimize acid degradation.
o Octreotide, a somatostatin analog, may aid with pain relief.
o Celiac plexus nerve block is a treatment alternative in refractory cases.
o Surgical drainage (pancreaticojejunostomy), surgical resection, lithotripsy, or endoscopic stent placement can be considered.80
· Pancreatic insufficiency occurs when >80% to 90% of pancreatic function is compromised, resulting in steatorrhea (fat malabsorption) and/or glucose intolerance (exocrine and endocrine pancreatic insufficiency, respectively). Malabsorption is typically managed with a low-fat diet and pancreatic enzyme replacement therapy (along with acid suppression).
· Pancreatic pseudocysts may be asymptomatic. They develop in 10% of chronic pancreatitis, may rupture or become infected, and require endoscopic, radiologic, or surgical drainage.
· Pancreatic ascites is notable for a high ascitic fluid amylase concentration, and treatment may be nonoperative (aspiration or diuretics) or operative.
· Bile duct or duodenal obstruction typically presents with pain and often requires endoscopic or surgical intervention.
· Splenic vein thrombosis may occur due to adjacent inflammation and should be suspected in patients with gastric varices. Splenectomy may be necessary in those with bleeding varices.
Pancreatic Cancer
GENERAL PRINCIPLES
· Pancreatic ductal adenocarcinoma ranks fourth among cancer-related deaths in the US. The overall 5-year survival rate for pancreatic cancer is <5%. Less than 10% of pancreatic cancers are localized at diagnosis. More than 80% of pancreatic cancers are diagnosed after the age of 60 years.81
· The causes of pancreatic cancer are not well known, but the risk of pancreatic cancer in smokers is approximately three times that in nonsmokers. Other risk factors may include male sex, age >45 years, African American ethnicity, chronic pancreatitis, heavy alcohol consumption, family history of pancreatic cancer, BRCA2 mutations, history of partial gastrectomy, obesity, and diabetes.82
· Universal screening is controversial and not currently recommended.
· About two-thirds of pancreatic cancers occur in the head of the pancreas (where they can cause obstructive cholestasis), with the remainder in the body or tail.
DIAGNOSIS
· The classic symptoms of pancreatic cancer are painless jaundice, pain (dull, deep epigastric or right upper quadrant) and weight loss (anorexia from pain, cachexia from proinflammatory cytokines, and malabsorption from pancreatic insufficiency). Other presentations may include dysglycemia, pancreatitis, gastrointestinal bleeding, emesis, or thrombophlebitis (Trousseau sign).
· Upon suspicion, imaging frequently establishes the diagnosis. CT predicts surgical resectability with 80% to 90% accuracy. ERCP allows for tissue diagnosis and/or stent placement for biliary obstruction. EUS may be used, especially if no mass is seen on CT or for fine needle aspiration (FNA).83 Diagnostic testing may include the CA 19-9 level (tumor marker with limited sensitivity and specificity for pancreatic cancer).
TREATMENT
· When surgical resection is possible, a Whipple procedure (cephalic pancreaticoduodenectomy) may be performed for tumors of the pancreatic head, whereas a distal pancreatectomy and splenectomy may be performed for tumors of the pancreatic body or tail.
· For nonresectable pancreatic cancer, palliative options include endoscopically placed stents to relieve biliary obstruction, chemoradiation (typically with 5-fluorouracil or gemcitabine), and derivative surgical procedures.
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