Parakkal Deepak, MD and Eli D. Ehrenpreis, MD
What are the common signs and symptoms of malabsorptive disorders?
Patients usually describe diarrhea (typically large volume) and weight loss. Other symptoms may include fatigue due to anemia, gas-related symptoms like bloating and flatulence, bruising from vitamin K deficiency, skin rash from deficiencies of vitamin A, K, niacin, pyridoxine and vitamin C, muscle wasting, and paresthesias.
What are the sites of carbohydrate digestion?
Intestinal lumen (salivary and pancreatic amylase) and brush border of the enterocyte (sucrose-isomaltase, lactase, maltase (glucoamylase), trehalase, and α-limit dextrinase).
What enzymes are involved in fat digestion?
Acid lipases (lingual lipase, gastric lipase) and the pancreatic lipases. Pancreatic carboxyl ester lipase hydrolyzes triglycerides, cholesterol, vitamin esters, and other substrates. Pancreatic phospholipase A2 hydrolyzes phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and cardiolipin.
How is steatorrhea defined?
The measurement of fat in the stools collected for 72 hours in a subject ingesting a diet adequate in fat intake (100 g/day) is required to diagnose steatorrhea. Steatorrhea is defined as a daily fecal fat output > 7 g/day (7% of dietary fat intake). However, diarrhea with increased fecal output can cause secondary fat malabsorption with levels up to 14 g fecal fat/day considered as the upper limit of normal in chronic diarrhea.
At what sites does protein digestion take place?
Lumen of the stomach and small intestine (pepsin, pancreatic proteases), brush border of the enterocyte (peptidases), and cytoplasm of the enterocyte (peptidases).
What tests are useful for determining enteric protein loss?
A 24-hour stool collection for determination of chromium51-albumin clearance is considered the gold standard but is mainly reserved for research use. The most widely available test used clinically is measurement of the clearance of α1-antitrypsin (AT) from the plasma during a 24-hour stool collection.
Formula: α1-AT plasma clearance = (daily stool volum × stool α1-AT)/serum α1-AT. α1-AT clearance in excess of 24 mL/day in patients without diarrhea and exceeding 56 mL/day in patients with diarrhea is considered abnormal.
What clinical tests are available to test exocrine pancreatic function?
The invasive pancreatic function tests require duodenal intubation and measurement of pancreatic enzyme secretion, volume, and bicarbonate output after pancreatic stimulation (secretin test, cholecystokinin test, and Lundh [liquid test meal]). These tests are uncomfortable, time consuming, and not widely available. “Tubeless” tests are noninvasive and include measurement of fecal chymotrypsin or elastase concentration, the fluorescein dilaurate test, the N-benzoyl-L-tyrosyl-para-aminobenzoic acid (also known as bentiromide) test, and the Stage III Schilling test. The latter three tests are either not available for use in the United States or of historical interest only.
How is the stool pH a useful test in suspected malabsoprtion?
A pH of less than 5.6 in the stool of a patient with diarrhea serves as a qualitative indicator of carbohydrate malabsorption.
Name some causes of lactase deficiency.
Acquired deficiency in adulthood, small intestinal disease or resection, and autosomal recessive congenital deficiency.
What is the role of genetic testing in lactose intolerance?
In Caucasians, a single-nucleotide polymorphism (SNP) –13910 T/C upstream of the gene coding for the enzyme lactase-phlorizin hydrolase (LPH gene) has been found to be involved in the regulation of LPH. The CC genotype of the SNP –13910 T/C upstream of the LPH gene is associated with adult-type hypolactasia. The sensitivity and specificity are 93% and 100%, respectively, which is comparable to the accuracy of both the lactose tolerance test and breath hydrogen test. However, the test is expensive and may not be useful for patients of African origin.
How are breath tests for lactose intolerance performed?
Lactose malabsorption is diagnosed if an increase in breath hydrogen concentration of greater than 20 parts per million (ppm) over baseline occurs after ingestion of 25 g of lactose. Exhaled breath measurements are performed every 30 minute after ingestion for up to 4 hours. Up to 20% of patients are hydrogen nonexcretors; a lactose tolerance test needs to be carried out in this group unless the breath is simultaneously monitored for methane.
How is the lactose tolerance test performed?
This test involves oral administration of a 50-g test dose in adults (or 2 g/kg in children), followed by blood glucose levels drawn at 0, 60, and 120 minutes. An increase in blood glucose of less than 20 mg/dL (1.1 mmol/L) and the development of symptoms such as abdominal pain, bloating, flatulence, diarrhea, and/or vomiting are diagnostic of lactose malabsorption/intolerance.
What clinical features suggest a functional cause in chronic diarrhea?
Duration of symptoms greater than 1 year, lack of significant weight loss or nutritional deficiencies, absence of nocturnal diarrhea, and normal laboratory testing.
Name some diseases associated with chronic diarrhea that may be diagnosed by small intestinal biopsy and the characteristic findings on histology.
• Diffuse alteration of small bowel mucosa:
Abetalipoproteinemia (lipid accumulation and vacuolization of enterocytes)
Collagenous sprue (collagenous band below atrophic epithelium)
Mycobacterium-avium complex infection (acid-fast bacilli, foamy macrophages)
Whipple’s disease (foamy macrophages with period acid-Schiff [PAS]-positive inclusion bodies)
• Patchy distribution in small bowel mucosa: These diseases may therefore be missed on endoscopic small bowel biopsy.
Amyloidosis (congo red–stained deposits with apple-green birefringence in polarized light)
Crohn’s disease (epithelioid granulomas and characteristic focal inflammation)
Eosinophilic gastroenteritis (eosinophilic infiltration)
Lymphangiectasia (ectatic lymph vessels)
Lymphoma (clonal expansion of lymphocytes)
Mastocytosis (diffuse infiltration with mast cells)
Parasites (Giardia lamblia, Strongyloides stercoralis)
HIV enteropathy (focal enterocyte vacuolization)
Celiac disease (villous atrophy, intraepithelial lymphocytes (IELs), may be diffuse, diagnosis requires serologic confirmation)
How is the fecal osmotic gap calculated and how is it used?
Measurement of the fecal osmotic gap is performed on a randomly collected stool specimens analyzed for sodium and potassium concentrations. The following formula is used: Fecal osmotic gap = 290 – 2 ([Na + ] + [K + ]). The normal osmolality of stool is estimated to be 290 mOsm/kg. Measured stool osmolality in collected specimens is inaccurate because bacterial fermentation of unabsorbed carbohydrates produces osmotically active organic acids that raise the measured stool osmolality. An osmotic gap > 125 mOsm/kg is suggestive of pure osmotic diarrhea, whereas an osmotic gap < 50 mOsm/kg suggests a pure secretory diarrhea.
A 44-year-old man with chronic diarrhea has a fecal osmotic gap < 50 and fecal sodium >90. What form of diarrhea is this? If the diarrhea ceases with fasting, name a possible cause.
The fecal osmotic gap and sodium concentration are consistent with a secretory diarrhea. However, the cessation of diarrhea with fasting argues against secretory diarrhea. Ingestion of sodium sulfate or sodium phosphate (such as can occur with a factitious cause) would cause an osmotic diarrhea that mimics a secretory diarrhea because of the high sodium content.
Describe a bedside test for laxative use/abuse.
Alkalinization of 3 ml of stool supernatant or urine with one drop of concentrated (1 N) sodium hydroxide will result in a pink or red color if phenolphthalein is present and turns purple blue in the presence of bisacodyl. More sophisticated stool and urine tests are available for the detection of other laxatives. Stool sulfate, phosphate, and magnesium analysis detects factitious diarrheas caused by osmotic cathartics. Urine laxative screens detect common laxatives such as diphenolic laxatives (bisacodyl), anthraquinones (senna, cascara), magnesium, and phosphate. Stool laxative screens detect these and in addition, castor oil and mineral oil. Polyethylene glycol-containing laxatives require a separate stool or urine specimen.
What is pancreatic cholera?
Pancreatic cholera is a rare type of secretory diarrhea caused by the release of vasoactive intestinal peptide (VIP) into the circulation by a neuroendocrine tumor (ie, VIPoma). It should be suspected in diarrhea lasting longer than 4 weeks with the clinical features of secretory diarrhea, a stool volume always greater than 1 L/day, marked hypokalemia, hypochlorhydria, and severe dehydration.
Describe some extra-intestinal manifestations of celiac sprue.
In addition to the signs and symptoms common to all malabsorptive disorders, the following may also be seen:
• Cutaneous
Dermatitis herpetiformis (DH)
Ecchymoses and petechiae (vitamin K deficiency; rarely, thrombocytopenia)
Edema (hypoproteinemia)
Follicular hyperkeratosis and dermatitis (vitamin A and B complex malabsorption)
• Endocrinologic
Amenorrhea, infertility, and impotence (malnutrition and hypothalamic-pituitary dysfunction)
Secondary hyperparathyroidism (calcium/vitamin D malabsorption)
Thyroid disorders
• Hematologic
Anemia (iron, folate, vitamin B12, or pyridoxine deficiency)
Hemorrhage (vitamin K deficiency; rarely, thrombocytopenia due to folate deficiency)
Thrombocytosis, Howell–Jolly bodies (hyposplenism)
• Hepatic
Elevated liver biochemical test levels
• Muscular
Atrophy
Tetany
Weakness
• Neurologic
Peripheral neuropathy (deficiencies of vitamin B12 and thiamine)
Ataxia (cerebellar and posterior column damage)
Demyelinating central nervous system lesions
Seizures
• Skeletal
Osteopenia (calcium/vitamin D malabsorption)
Osteoarthropathy
Pathologic fractures
What serologic tests are available for the diagnosis of celiac sprue?
The anti-endomysial (EMA) IgA antibody, detected by indirect immunofluorescence, is the gold standard serological test for reliability with sensitivity of 90%, specificity of 99%, and reproducibility of 93%. Human antitype 2 tissue transglutaminase (tTG) ELISA is the other recommended serological test with sensitivity of 93%, specificity of 95%, and reproducibility of 83%. ELISA antigliadin IgA and IgG antibodies are inexpensive but less sensitive and specific and are no longer recommended for routine screening. Importantly, the prevalence of IgA deficiency is increased approximately 10-fold among patients with celiac sprue and testing for total IgA levels should be considered during the first step of serological testing if using an IgA-based test. Once IgA deficiency is established; testing for IgG anti-tTG antibodies or IgG anti-EMA is the next step.
What is the auto-antigen recognized by the anti-endomysial antibody?
The antigen is tTG, a calcium-dependent enzyme that catalyzes cross links between glutamine and lysine residues in substrate proteins. tTG is believed to cross-link gliadin, rendering it immunogenic.
True/False: The prevalence of IgA deficiency is increased approximately 100-fold among patients with celiac sprue compared to the general population.
False. The prevalence of IgA deficiency is increased approximately 10-fold.
What is the relationship between celiac sprue and DH?
More than 90% of patients with DH with a granular pattern of IgA deposition at the derma-epidermal junction, and at least 10% of patients with a linear pattern of IgA deposition at the derma-epidermal junction have coexisting celiac sprue. Many lack significant symptoms of the disease because the lesion is often mild and limited to the proximal intestine. Conversely, fewer than 10% of patients with celiac sprue have DH.
True/False: Gluten-free diet (GFD) is a major component of the treatment of DH.
True.
Describe the classic endoscopic appearance of the small intestine in celiac sprue.
Scalloping, multiple fissures or a mosaic-like appearance where the fissures circumscribe areas of mucosal nodularity, and/or absence of the small intestinal plicae (circular folds). However, the mucosa most commonly looks normal on endoscopy recognizing the need for biopsy and histologic examination if suspicion is high based on positive serology or clinical presentation.
Name other diseases where scalloping of the mucosa is seen?
Scalloping is not specific for celiac disease, and may be seen in:
• Eosinophilic enteritis
• Giardiasis
• Amyloidosis
• Tropical disease
• Human immunodeficiency virus enteropathy
What are the classic findings suggestive of celiac disease on histological examination?
Intraepithelial lymphocytosis, crypt hyperplasia, and villous atrophy.
True/False: The mucosal lesions seen in celiac sprue are specific for that disorder.
False. However, a completely flat mucosa is most suggestive of celiac sprue.
Intraepithelial lymphocytosis is also seen in:
• Giardiasis
• Tropical sprue
• Autoimmune diseases
• H. pylori gastritis
• Crohn’s disease
• Bacterial overgrowth
• NSAID use
Villous atrophy is also seen in:
• Cow’s milk protein intolerance (children)
• Postgastroenteritis syndrome
• Giardiasis
• Peptic duodenitis (including Zollinger–Ellison syndrome)
• Crohn’s disease
• Small intestinal bacterial overgrowth (SIBO)
• Eosinophilic gastroenteritis
• Radiation or cytotoxic chemotherapy
• Tropical sprue
• Severe malnutrition
• Diffuse small intestinal lymphoma
• Graft versus host disease
• Hypogammaglobulinemia
• Alpha chain disease
Name some diseases associated with celiac sprue.
• Clear-cut association
Bird-fancier’s lung
DH
Diabetes mellitus type 1
Down’s syndrome
Epilepsy with cerebral calcification
Fibrosing alveolitis
Hypothyroidism or hyperthyroidism
Idiopathic pulmonary hemosiderosis
Immunoglobulin A deficiency
Immunoglobulin A mesangial nephropathy
Inflammatory bowel disease
Microscopic colitis
Recurrent pericarditis
Rheumatoid arthritis
Sarcoidosis
• Possible association
Addison’s disease
Autoimmune hemolytic anemia
Autoimmune liver diseases
Cavitary lung disease
Congenital heart disease
Cystic fibrosis
Immune thrombocytopenic purpura
Iridocyclitis or choroiditis
Macroamylasemia
Myasthenia gravis
Polymyositis
Schizophrenia
Sjögren’s syndrome
Systemic and cutaneous vasculitides
Systemic lupus erythematosus
What is the role of genetic testing in the diagnosis of celiac disease?
Almost all patients with celiac disease are positive for human leukocyte antigen (HLA) DQ2 or DQ8. However, 35% of the persons of European ancestry in the general population are also positive for one of these. Hence, testing is useful to exclude celiac disease in the absence of the specific loci in the following conditions:
• Patients started on a gluten-free diet empirically without confirmation with serology or characteristic intestinal histology before starting a gluten challenge.
• Patient with celiac-like intestinal histology but negative serologies in which case a negative result indicates the need for alternative diagnosis.
When is a gluten challenge reasonable to consider in clinical practice?
Gluten challenge may be useful in two scenarios:
1. Patients started on a gluten-free diet empirically without confirmation with serology or characteristic intestinal histology, if HLA DQ2/DQ8 positive.
2. Diagnosis of celiac disease made during childhood based on positive intestinal histology with negative serology.
Describe how to conduct a gluten challenge.
Baseline serologic studies, such as IgA anti-tTG, should be performed. HLA typing for DQ2 and DQ8 may be considered, because if negative, these exclude celiac disease. A small bowel biopsy may be obtained as a baseline. Initially, a small amount of gluten (cracker or one quarter of a slice of bread) is given, which if tolerated, is doubled every 3 days until ingesting the equivalent of at least four slices of bread daily (10 g gluten). This is continued for at least 6 weeks or until more severe symptoms redevelop, at which time both serologies and/or small bowel biopsies are performed.
What is nonresponsive celiac disease (NRCD)?
Persistence of symptoms, signs, or laboratory abnormalities typical of celiac disease despite adherence to a GFD for at least 6 months. At least 10% of celiac patients are unresponsive at diagnosis or following a period of initial response to GFD.
How should NRCD be evaluated?
The commonest cause for NRCD is continued gluten ingestion, suggested by a persistent elevation of anti-tTG antibodies. The next most common cause to be ruled out is intolerance to disaccharides (eg, lactose and fructose). After these are ruled out, small bowel biopsies should be performed.
• If normalization or near normalization of small bowel histology is seen on GFD, consider:
IBS
Microscopic colitis
SIBO
Eating disorders
Food intolerances
Peptic ulcer disease
Gastroparesis
Pancreatic insufficiency
• If persistence of small bowel histological abnormalities is seen on GFD, consider:
Refractory celiac disease (RCD)
SIBO
Peptic duodenitis
Common variable immunodeficiency
Crohn’s disease
Tropical sprue
Giardiasis
Post-gastroenteritis
Eosinophilic gastroenteritis
Autoimmune enteropathy
Name some gastrointestinal complications specific to celiac sprue?
Refractory sprue, collagenous sprue, ulcerative jejunoileitis, and development of malignancy (small bowel lymphoma [T and B cell], extra-intestinal lymphoma, small bowel adenocarcinoma, esophageal squamous cell carcinoma, oropharyngeal, and liver cancers).
What is RCD and what are its types?
Symptomatic, severe small intestinal villus atrophy that mimics celiac disease but does not respond to at least 6 months of a strict GFD and is not accounted for by other causes of villus atrophy or overt intestinal lymphoma.
• Type I RCD: Normal IELs and/or absence of T cell receptor (TCR) γ chain rearrangement.
• Type II RCD: Aberrant IELs and clonal TCRγ rearrangement.
Describe the treatment of RCD.
Glucocorticoids (budesonide) are the first line treatment for RCD, which generally improve the symptoms but may not reverse histology. Budesonide has also been used to treat RCD. Other medications include steroid-sparing agents (azathioprine and cyclosporine) and infliximab.
What is the risk of enteropathy-associated T cell lymphoma (EATL) with RCD and how is it diagnosed?
Type I RCD has an 80% 5-year survival with no risk of developing EATL, whereas Type II RCD has a 45% 5-year survival with 67% of the patients developing EATL. Poor prognostic factors include age ≥65, albumin ≤3.2, and hemoglobin ≤11.2.
EATL can be ruled out through molecular and immunohistochemical studies of small intestinal biopsies. Small intestinal radiology, enteroscopy with biopsy of the mucosa at multiple levels, capsule endoscopy, and CT or MR scanning may be helpful. As a last step, full-thickness biopsy of the small intestine can be done with lymph node biopsy at laparoscopy. Positron emission tomography (PET) scan as an addition to CT has recently been shown to increase the sensitivity of diagnosing such complications of celiac disease.
What is collagenous sprue?
Collagenous sprue is a rare disorder that presents with symptoms identical to celiac sprue. However, small intestinal biopsies show excess collagen deposition in the lamina propria beneath the epithelial layer. Patients with this condition have a poor prognosis as they do not respond to a GFD.
Describe ulcerative jejunoileitis.
Clinical features include weight loss, abdominal pain, and diarrhea unresponsive to GFD. Patients typically experience recurrent episodes of intestinal ulceration and strictures resulting in obstruction with gradual weight loss despite surgery and strict adherence to GFD. Diagnosis is made by enteroscopy, contrast studies of the small intestine, abdominal CT, capsule endoscopy, or laparotomy. Surgical excision of the worst-affected segments of small intestine is the most effective treatment; glucocorticoids and azathioprine have also been used. Increased risk of transformation to diffuse or multifocal EATL is present; 5-year survival rate is less than 50%.
Which measurement used in the D-xylose test is preferable: the 1-hour serum test or the 5-hour urine test?
The 1-hour serum D-xylose test is preferable. The 5-hour urine test can be falsely abnormal in patients with renal insufficiency, incomplete urine specimen collection, and a variety of other conditions.
What is hypogammaglobulinemic sprue?
Common variable immunodeficiency presents with chronic diarrhea, recurrent sinopulmonary infection, and meningitis. Small bowel biopsy shows decreased plasma cells in lamina propria or nodular lymphoid hyperplasia. Common intestinal infections include Giardiasis, Isospora belli, Cryptosporidium, and Microsporidia. Treatment is with intravenous immunoglobulin.
A 25-year-old male recently migrated from the Middle East presents with a 3-month history of abdominal pain, weight loss, diarrhea, and digital clubbing on examination. What is the diagnosis?
Immunoproliferative small intestinal disease (IPSID). This is a disease caused by a clonal proliferation of cells that produce an abnormal alpha heavy chain immunoglobulin that can be detected in the serum. Infection with Campylobacter jejuni has been causally associated with IPSID. Mucosal small intestinal biopsy shows dense cellular lymphoplasmacytic infiltrate in lamina propria that effaces the crypts. Premalignant forms (stage A) can be treated with long-term tetracycline, whereas the advanced stages of lymphoplasmacytic and immunoblastic lymphoma require chemotherapy or total abdominal irradiation.
What is autoimmune enteropathy?
In this condition, patients present with severe high output diarrhea and malabsorption. Diagnosis is based on ruling out other conditions such as celiac disease and histologic changes on intestinal biopsy such as partial or complete villous blunting, deep crypt lymphocytosis, increased crypt apoptotic bodies, and minimal intraepithelial lymphocytosis. Serum antibodies to enterocytes and goblet cells may be seen. Treatments include glucocorticoids and immunosuppressive drugs along with appropriate nutrition support.
What is the suggested pathophysiology of “diabetic diarrhea”?
Since most patients with diabetic diarrhea also have autonomic neuropathy, this condition was classically thought to be due to disordered motility. More recently, sympathetic denervation with decreased enterocyte α-2 adrenergic receptors has been described and this is thought to result in decreased intestinal absorptive function. Steatorrhea and bile salt malabsorption may also occur in these patients. Other causes of diarrhea in diabetic patients include bacterial overgrowth, celiac sprue, microscopic colitis, pancreatic dysfunction, and, rarely, islet cell tumors (glucagonoma, VIPoma, and somatostatinoma).
Describe eosinophilic gastroenteritis.
Eosinophilic gastroenteritis may involve any layer of the gut wall, from the mucosa to the serosa. Manifestations of eosinophilic gastroenteritis include nausea, vomiting, diarrhea, weight loss, iron deficiency, malabsorption, protein-losing enteropathy, pyloric outlet or intestinal obstruction, and eosinophilic ascites. Immunologic evidence of underlying allergy is usually lacking unless a convincing history of symptoms triggered by food and presenting with immediate reactions (IgE mediated), or is accompanied by eczema or asthma. A trial of elemental diet can be used to rule out food hypersensitivity.
What conditions are associated with the occurrence of vitamin B12 malabsorption?
Inadequate dietary intake, pernicious anemia, small bowel bacterial overgrowth, old age (incomplete release of food-bound vitamin B12 due to gastric atrophy), gastric surgery (achlorhydria, decreased intrinsic factor), therapy with proton pump inhibitors and H2 receptor antagonists (incomplete release of food-bound vitamin B12), HIV infection (enteropathy, ileal disease, achlorhydria), Crohn’s disease (ileal disease or resection > 60 cm), helminthic infection (Diphyllobothrium latum), chronic pancreatitis and Zollinger–Ellison syndrome (both due to incomplete cleavage of the R protein–vitamin B12 complex), and congenital diseases with selective ileal malabsorption of vitamin B12 despite normal ileal histology due to abnormalities of the vitamin B12 receptor (Imerslund–Gräsbeck syndrome).
How is the Schilling test performed?
Of note, this test is mainly of historical interest in the present day. An intramuscular dose of nonlabeled vitamin B12 (usually 1000 µg) is administered to saturate liver binding sites. Oral radiolabeled vitamin B12 is then administered and urine radioactivity is measured over 24 hours. Appearance of less than 10% of the radiolabeled vitamin B12 in the urine is considered diagnostic of vitamin B12 malabsorption. If vitamin B12 malabsorption is corrected by administration of intrinsic factor, it establishes intrinsic factor deficiency (Stage II Schilling test). If vitamin B12 malabsorption is corrected with pancreatic enzymes (Stage III) or with antibiotics (Stage IV), then the test establishes pancreatic insufficiency or bacterial overgrowth, respectively. If the test does not correct with any of these maneuvers, then the cause of malabsorption is ileal disease or resection.
A 72-year-old woman presents with memory loss and a borderline low vitamin B12 level (< 250 pg/mL) is found. How can a definitive diagnosis of vitamin B12 deficiency be made?
Elevated serum methylmalonic acid and/or homocysteine levels establish the presence of vitamin B12 deficiency at the tissue level. Elevated homocysteine levels may also indicate the presence of folic acid deficiency.
Name the clinical conditions associated with SIBO.
• Small intestinal stagnation due to anatomical derangements (Billroth II gastrectomy, duodenal or jejunal diverticulosis, surgical blind loop, and obstruction).
• Motor disorders (scleroderma, intestinal pseudo-obstruction, and diabetic gastroenteropathy).
• Abnormal connection from colon to proximal small bowel (intestinal fistulae or resected ileocecal valve).
• Achlorhydria (medications, atrophic gastritis, and vagotomy).
• Others (cirrhosis, celiac disease, chronic pancreatitis, chronic kidney disease, radiation enteritis, rheumatoid arthritis, and cystic fibrosis).
What is the most consistent laboratory abnormality that may occur in SIBO?
An elevated folate with or without vitamin B12 deficiency is the most common abnormality. Serum folate levels are frequently elevated because of bacterial production of folate, whereas B12 levels are reduced due to bacterial consumption.
What tests are available to diagnose SIBO?
The “gold” standard for the diagnosis of bacterial overgrowth is quantitative small bowel culture. Bacterial concentrations greater than 105 colony forming units/mL indicates bacterial overgrowth. Several different breath tests (C14-D-xylose, glucose-H2, and lactulose-H2) are also available; however, there is controversy regarding the sensitivity and specificity of these tests. Because of limited availability and known problems inherent in the above-mentioned tests, a therapeutic trial of antibiotics is often used as a “diagnostic” tool in clinical practice.
What are the mechanisms of malabsorption that can occur in patients with scleroderma?
Bacterial overgrowth often occurs secondary to small intestinal stasis, loss of the migrating motor complex, and the presence of small intestinal diverticula. Villous atrophy, enterocyte dysfunction, and submucosal collagen deposition may also be present. Pancreatic insufficiency may also occur.
True/False: Octreotide has a role in the management of SIBO.
True, at least in patients with scleroderma and associated intestinal dysmotility. Octreotide at a low dose of 50 mcg every evening for 3 weeks has been shown to induce migrating motor complexes, reduce bacterial overgrowth, and relieve abdominal symptoms in SIBO associated with systemic sclerosis.
How is tropical sprue treated?
Initial treatment includes correction of fluids, electrolytes, and deficient nutrients. Tetracycline (250 mg four times a day) or doxycycline (100 mg once daily) and folic acid are given as pharmacotherapy. The beneficial effect of treatment with folic acid on both macrocytic anemia and villous atrophy suggests that folate deficiency plays a role in perpetuating the intestinal lesion of tropical sprue. It is recommended that treatment be continued for 6 months. A GFD is not needed.
How does ileal resection lead to diarrhea and what is the treatment?
Resection of less than 100 cm leads to bile salt wasting. Bile salts are deconjugated in the colon where they cause a secretory diarrhea. Bile salt wasting is compensated by increased bile salt synthesis in the liver, leading to normal fat absorption. Treatment includes bile salt binders such as cholestyramine.
Resection of greater than 100 cm of ileum leads to depletion of the bile salt pool resulting in impaired micelle formation, fat malabsorption, steatorrhea, and diarrhea. Treatment theoretically consists of exogenous conjugated bile acid supplements (eg, cholylsarcosine 2–4 g with meals or desiccated ox bile 500 mg capsule with meals); however, these are not readily available. Therefore, a fat-restricted diet with or without medium-chain triglyceride oil supplementation is the primary treatment. Bile salt binders should be avoided as they exacerbate the problem by further depletion of the bile salt pool.
What mechanisms may be responsible for diarrhea in Crohn’s disease?
Small bowel inflammation, small bowel bacterial overgrowth, surgical resection, fistulae, cholerrhetic diarrhea, and steatorrhea.
Explain the mechanism of calcium oxalate stone formation in Crohn’s disease.
This condition is termed enteric hyperoxaluria. Bile salt malabsorption due to ileal disease or resection may result in fat malabsorption. Intraluminal fatty acids bind calcium cations, which would otherwise bind to intestinal oxalate. Free oxalate thus enters the colon where it is absorbed and then renally excreted, causing calcium oxalate stones. Prevention of calcium oxalate stones in patients with Crohn’s disease involves limitation of fat and oxalate intake, as well as calcium supplementation. A patient who has undergone a colectomy cannot develop enteric hyperoxaluria.
What are some common ingredients of prescription and nonprescription medications that may cause malabsorption?
Polyols (sorbitol, mannitol, and xylitol), gluten, and lactose.
A 15-year-old boy presents with chronic diarrhea and steatorrhea. You elicit a history of recurrent upper respiratory infections. What laboratory test is recommended?
A sweat test to rule out cystic fibrosis. If this were negative, testing for common variable immunodeficiency (quantitative immunoglobulins) should be considered.
What medications may result in malabsorption of vitamins and other nutrients?
Antacids, H2 blockers, proton pump inhibitors, mineral oil, cholestyramine, methotrexate, chemotherapeutic agents, phenytoin, orlistat, sulfasalzine, and sucralfate.
Name some medications that can cause secretory diarrhea.
Laxatives, cholinergic agents, quinidine and quinine, colchicine, metoclopramide, misoprostol, olsalazine, theophylline, lubiprostone, tegaserod, and thyroid preparations.
What enteric infections may present with malabsoprtion?
• Protozoan infections
Giardiasis (Giardia lamblia)
Cryptosporidium parvum
Isospora belli
Cyclospora cayetanensis
Microsporidia (enterocytozoon bieneusi and encephalitozoon intestinalis)
Visceral leishmaniasis
• Helminthic infections
Strongyloides stercoralis
Capillaria philippinensis
What are the mechanisms causing diarrhea in Zollinger–Ellison (ZE) syndrome?
High volume of secreted hydrochloric acid, fat maldigestion due to inactivation of pancreatic lipase, and bile acid precipitation due to the low duodenal pH. Diarrhea occurs in up to one-third of patients with the ZE syndrome, may precede the other symptoms, and may be the major clinical manifestation of the disease.
What is the Cronkhite–Canada syndrome?
The Cronkhite–Canada syndrome is a noninherited polyposis syndrome characterized by hamartomatous polyps found throughout the gastrointestinal tract and by a severe protein-losing enteropathy due to a diffuse mucosal injury of obscure etiology. Clinical features also include cutaneous hyperpigmentation, alopecia, and nail atrophy.
Describe the clinical features and genetic defect of abetalipoproteinemia?
Abetalipoproteinemia is a rare autosomal recessive disorder of lipoprotein metabolism characterized by extremely low levels of serum cholesterol and triglycerides and the absence of apoB-containing lipoproteins. Clinical manifestations include intestinal malabsorption, neurological symptoms such as spinocerebellar dysfunction, and retinopathy that causes impairment of night and color vision. Mutations of the microsomal triglyceride transfer protein have been shown to cause abetalipoproteinemia. Peripheral blood smear shows the presence of acanthocytes and low plasma chylomicrons, and small bowel biopsy shows lipid accumulation with vacuolization of enterocytes.
What are the clinical features of intestinal lymphatic obstruction?
Findings of protein-losing enteropathy including hypoalbuminemia, hypoglobulinemia, lymphopenia, peripheral edema, ascites, and possibly anasarca. The differential diagnosis of intestinal lymphatic obstruction includes congenital intestinal lymphangiectasia, cardiac disease, Whipple’s disease, Crohn’s disease, mesenteric tuberculosis, mesenteric sarcoidosis, lymphoma, and lymphenteric fistula.
What are the causes of iron deficiency occurring after gastric surgery?
Gastric acid dissociates iron salts from food and dissolves them. The achlorhydric stomach cannot release food-bound iron. In addition, patients who have undergone antrectomy have defective meat digestion so that heme proteins (myoglobin and hemoglobin) cannot be digested properly by pancreatic proteases to liberate the heme–iron complexes. Finally, iron deficiency may result from decreased food intake and blood loss from gastritis.
Name some systemic diseases associated with malabsorption.
Thyrotoxicosis, hypothyroidism, Addison’s disease, hypoparathyroidism, diabetes mellitus, scleroderma, and HIV infection.
What are clinical and diagnostic features of Whipple’s disease?
Diarrhea with steatorrhea, fever, arthritis, lymphadenopathy, pericarditis, endocarditis, myocarditis, dementia, depression, choreoathetosis, and ophthalmoplegia. This condition, which typically affects older men, is caused by a Gram-positive bacillus called Tropheryma whippelii. Polymerase chain reaction (PCR) analysis of small intestinal biopsies is now the preferred test. Treatment usually consists of an induction phase (first 10–14 days) using penicillin G plus streptomycin or a third-generation cephalosporin (eg, Ceftriaxone) followed by treatment with double-strength trimethoprim-sulfamethoxazole twice daily for 1 year.
What are the causes of PAS-positive macrophages present in the lamina propria seen on intestinal biopsy?
In the past, the finding of lamina propria PAS-positive macrophages was diagnostic of Whipple’s disease. More recently, it has been recognized that PAS-positive macrophages are also seen with atypical mycobacterial infections. The acid-fast stain distinguishes between the two.
What are the most common causes of short bowel syndrome in children?
Congenital defects (eg, intestinal atresia) (75%) and necrotizing enterocolitis (25%).
What are the most common cause of short bowel syndrome in adults?
Crohn’s disease requiring multiple bowel resections and acute mesenteric ischemia.
Describe the pathophysiology and clinical features of D-lactic acidosis?
D-lactic acidosis is a rare complication of short bowel syndrome that occurs as a result of carbohydrate overfeeding and, possibly, small bowel bacterial overgrowth. Malabsorbed carbohydrate is metabolized by colonic bacteria to short-chain fatty acids and lactate, which, in turn, lower colonic pH. A lower colonic pH favors the growth of D-lactate-producing enteric flora. D-lactate is absorbed but is poorly metabolized due to a lack, in humans, of D-lactic acid dehydrogenase.
Patients present with anion gap metabolic acidosis with a normal L-lactate level, nystagmus, ophthalmoplegia, ataxia, confusion, and inappropriate behavior. The mediator of the neurologic symptoms is unknown. Initial treatment consists of bicarbonate administration and fasting. Prevention may be attempted with a low carbohydrate diet and, possibly, antibiotics and/or probiotics.
What pancreatic enzyme formulations are used for the treatment of the pain of chronic pancreatitis?
Although controversial, non-enteric-coated formulations are potentially beneficial in the treatment of chronic pain in some patients with chronic pancreatitis. Some data suggest that the protease components of these supplements reduce the pain of chronic pancreatitis. Enteric-coated formulations are used to treat pancreatic maldigestion. To prevent steatorrhea, the recommended dose is 30,000 IU (90,000 USP units) of lipase in the prandial and postprandial portions of each meal.
What are the mechanisms of diarrhea in patients with radiation enteritis?
Altered absorption of fluids and electrolytes, bile-salt malabsorption, bacterial overgrowth due to stasis, enteroenteric fistulae, and short bowel syndrome secondary to resection.
What is the rationale for using medium-chain triglycerides (MCTs) as nutritional supplements in patients with fat malabsorption syndromes?
Normal fat digestion and absorption require a multistep process including emulsification in the stomach, release of free fatty acids by gastric acids, breakdown of triglycerides by pancreatic lipases, formation of micelles with bile salts in the duodenum, and enterocyte absorption. MCTs are rapidly hydrolyzed and absorbed directly without requiring pancreatic lipase, bile salts, or micelle formation.
• • • SUGGESTED READINGS • • •
Hogenauer C, Hammer HF. Maldigestion and Malabsorption. In: Feldman F, Friedman LS, Brandt LJ, eds. Sleisinger and Fordtran’s gastrointestinal and liver disease: pathophysiology, diagnosis and management. 9th ed. Philadelphia, PA: Saunders-Elsevier; 2010: 1736-1767.
Farrell RJ, Kelly CP. Celiac Disease and Refractory Celiac Disease. In: Feldman F, Friedman LS, Brandt LJ, eds. Sleisinger and Fordtran’s gastrointestinal and liver disease: pathophysiology, diagnosis and management. 9th ed. Philadelphia, PA: Saunders-Elsevier; 2010: 1797-1819.