Health Questions and Answers

Celiac Disease, Tropical Sprue, Whipple’s Disease, Lymphangiectasia, Immunoproliferative Small Intestinal Disease, and Nonsteroidal Anti-Inflammatory Drugs

What is the best screening test for fat malabsorption?
Microscopic examination of stool using Sudan stain to detect fat is the best screening test for fat malabsorption. This test has a 100% sensitivity and 96% specificity. A stool sample is smeared on a microscope slide and mixed with ethanolic Sudan III and glacial acetic acid. The slide is covered, heated just until boiling, and then examined for the presence of fatty acid globules. The presence of more than 100 globules >6 μm in diameter per high-powered field (×430) indicates a definite increase in fecal fat excretion. The number of globules correlates well with the quantitative amount of fecal fat present.

What is the best quantitative test for fat malabsorption?
The 72-hour stool fat collection. The patient is given a diet consisting of 100 gm of fat per day. Stool is collected, usually for 72 hours. The normal coefficient for absorption is approximately 93% of ingested fat. Consequently, if 100 gm of fat is digested, 7 gm or less of fat should appear in stool over a 24-hour period. If >7 gm of fecal fat is present, steatorrhea secondary to malabsorption is confirmed.

Under what physiologic conditions is fecal fat excretion increased?

  1. Diet high in fiber (>100 gm/day)
  2. Ingestion of solid-form dietary fat (e.g., whole peanuts)
  3. In the neonatal period, when intraluminal levels of pancreatic lipase and bile salts are low
  4. When olestra is consumed

What is the best test to differentiate malabsorption caused by small bowel enteropathy versus pancreatic insufficiency?
d-Xylose is one of the best tests to differentiate mucosal disease from pancreatic insufficiency as the cause of malabsorption. Normally, d-xylose is absorbed completely in the small bowel and excreted unchanged in the urine.

How is the d-xylose test performed?
A 25-gm dose of d-xylose is given orally after an overnight fast, and urine is collected for 5 hours. Normal urine excretion should be >5 gm of d-xylose. One-hour serum collection is also helpful but not as sensitive as urine collection. Normal serum levels 1 hour after ingestion are >20 mg/dL.

What conditions may cause a false-positive d-xylose test?

  1. Delayed gastric emptying
  2. Myxedema
  3. Vomiting
  4. Ascites
  5. Renal insufficiency

What is tissue transglutaminase?
Recently, tissue transglutaminase has been touted as the most sensitive and specific marker for celiac disease. Tissue transglutaminase is believed to be the autoantigen to which the endomysial antibodies react. Studies have shown that specificity for antitransglutaminase is comparable to that for antiendomysial antibodies; however, some investigators have observed that the antibody to transglutaminase is a more sensitive test, detecting 98-100% of patients with celiac sprue.

Name the conditions to consider in previously responsive patients with celiac sprue who begin to deteriorate.

  1. Noncompliance with gluten-free diet is the most common cause of deterioration in a previously responsive patient.
  2. Lymphoma is the most common malignancy complicating celiac disease, especially that of mucosal T-cell origin. Diagnosis of lymphoma requires a high index of suspicion because onset can be insidious or abrupt, and the histologic appearance can be indistinguishable from that of celiac sprue. A careful search for lymphoma is needed in patients with celiac sprue who do not respond to gluten withdrawal and patients with recurrent weight loss and malabsorption, despite strict adherence to a gluten-free diet. Computed tomography (CT) scan and exploratory laparotomy may be necessary to establish the diagnosis.
  3. Refractory sprue has clinical features and mucosal lesions indistinguishable from celiac sprue, but patients do not respond to a gluten-free diet, either at the onset of diagnosis or after becoming refractory to dietary therapy. Some patients may respond to corticosteroids or other immunosuppressive drugs, such as azathioprine, cyclophosphamide, or cyclosporine. Other patients do not respond to any treatment and face a dismal prognosis. The absence of Paneth cells on small bowel biopsy is a poor prognostic sign.
  4. Collagenous sprue is a subset of refractory sprue characterized by the progressive development of a thick band of collagen-like material beneath the basement membrane of epithelial cells. It is usually refractory to all forms of treatment other than parenteral alimentation.

What are the hepatic manifestations of celiac sprue, and how are they managed?
Asymptomatic elevation of liver function tests, predominantly aminotransferases, can be seen in up to 42% of celiac patients. Strict adherence to a gluten-free diet will lead to a reduction in aminotransferase levels in the majority of individuals. Failure of liver function test improvement, despite treatment with a gluten-free diet, should prompt consideration of coexistent forms of autoimmune liver disease, such as autoimmune hepatitis, primary biliary cirrhosis, or primary sclerosing cholangitis.

Describe the manifestations of Whipple’s disease.
Whipple’s disease is a chronic systemic illness with various potential manifestations. The most common presentation includes weight loss (90%), diarrhea (>70%), and arthralgia (>70%). Arthralgia may exist for many years before the diagnosis of Whipple’s disease. Cardiac involvement includes congestive heart failure, pericarditis, and valvular heart disease (30%). Lymphadenopathy and hyperpigmentation are frequent findings on physical examination. Hematochezia is rare, but occult bleeding has been detected in up to 80% of patients with Whipple’s disease. The most common central nervous system manifestations (5%) are dementia, ocular disturbances, meningoencephalitis, and cerebellar symptoms, including ataxia and mild clonus.

What is the differential diagnosis of a macrophage infiltrate of the small bowel lamina propria?

  1. Whipple’s disease: inclusions are rounded or sickle-shaped.
  2. Mycobacterium avium-intracellulare: inclusions contain acid-fast bacilli. This condition is seen commonly in AIDS patients with small bowel involvement.
  3. Histoplasmosis or cryptococcosis: inclusions contain large, round, encapsulated organisms.
  4. Macroglobulinemia: no inclusions are seen, and there are only faintly staining, homogeneously periodic acid-Schiff (PAS)-positive macrophages.
  5. Miscellaneous disease: PAS-positive macrophages are frequently present in the normal gastric and rectal mucosa and may contain lipids or mucin, respectively.

What causes Whipple’s disease?
Tropheryma whippelii causes the disease in humans but has been cultured only recently. The organism was identified by direct amplification of a 16S-rRNA sequence from a microbial pathogen in tissue. According to phylogenetic analysis, this bacterium is a gram-positive actinomycete that is not closely related to any known genus. Prolonged treatment with antibiotics (up to 6 months) is often required to eradicate the organism. Measurements of T. whippelii DNA concentration in tissue by polymerase chain reaction is the most sensitive marker of patient response to antibiotic therapy. Of interest, T. whippelii DNA has been found in the small intestine of asymptomatic patients, suggesting that host factors play a role in disease penetration, just as in Helicobacter pylori infection.

What are the complications of the enteropathy induced by nonsteroidal anti-inflammatory drugs (NSAIDs)?
NSAID-induced enteropathy is associated with intestinal bleeding, protein loss, ileal dysfunction, and malabsorption. There is no close relationship between upper endoscopic findings and evidence of intestinal bleeding among NSAID-treated patients, even when blood loss has led to iron-deficiency anemia. Chronic blood loss and protein loss seem to occur from the inflammatory site. Protein loss can result in significant hypoalbuminemia. Ileal dysfunction can lead to bile acid malabsorption and, in rare cases, mild vitamin B12 malabsorption. Mefenamic acid (Postel) and sulindac (Clinoril) have been implicated as causes of severe malabsorption with subtotal villus atrophy that resembles celiac disease

Does scleroderma produce any manifestations in the small bowel?
Patients with scleroderma may have small bowel dysfunction caused by absent cycling of the normal contractile pattern, known as the migrating motor complex. Small bowel motility studies reveal markedly diminished amplitude in all phasic pressure waves. This finding may manifest clinically as intestinal pseudo-obstruction and bacterial overgrowth. Patients may suffer from nausea, vomiting, abdominal pain, diarrhea, and malabsorption. Small bowel radiographic series may show megaduodenum and dilated loops of jejunum.

How does octreotide affect intestinal motility and bacterial overgrowth in scleroderma?
Octreotide evokes alternating phase-1 and phase-3 activities in normal people and patients with scleroderma. In patients with scleroderma, these complexes propagate at the same velocity and have two-thirds the amplitude of spontaneous complexes in normal people. This effect is independent of motilin because octreotide inhibits motilin release. Octreotide may retard gastric antral motility-unlike erythromycin, which markedly stimulates gastric antral motor activity.

What are the clinical manifestations of abetalipoproteinemia?
Abetalipoproteinemia is an autosomal recessive condition characterized by the inability to form chylomicrons and very low density lipoprotein particles by the enterocytes because of abnormal apoprotein B. Most patients suffer severe fat malabsorption and retardation and rarely survive the third decade. The largest series of patients has been studied at the National Institutes of Health.

What are the different clinical presentations of eosinophilic gastroenteritis?
Eosinophilic gastroenteritis is characterized by eosinophilic infiltration in the gastrointestinal tract. Clinical features and severity depend on the layer and location of involvement. Mucosal involvement leads to protein-losing enteropathy, fecal blood loss, and malabsorption. Involvement of the muscle layer often causes obstruction of gastric or small bowel. Subserosal involvement causes ascites, pleural effusion, or, on occasion, pericarditis.

How are patients with eosinophilic gastroenteritis treated?
The mainstay of treatment for eosinophilic gastroenteritis is corticosteroids, even though no controlled trials have been performed. The recommended dosage of prednisone is usually 20-40 mg/day for treatment of the initial episode and relapses, with 5-10 mg/day for maintenance. Some patients respond to a short course of treatment but may suffer relapse. Others may require long-term maintenance therapy. The course of disease may wax and wane in severity but is rarely life threatening. The therapeutic effect of oral sodium cromoglycate is controversial. Trial elimination diets have, occasionally, been successful, but relapse is common.

What are the common causes of diarrhea in a patient with Crohn’s disease and ileal resection?
Ileal resection <100 cm: bile salt diarrhea. Normally, conjugated bile acids are reabsorbed in the ileum. When <100 cm ileum is resected, bile acids pass into the colon, causing direct irritation of the colonic epithelium and net water secretion by the colon. Bile-salt diarrhea is typically watery, may not start until a normal diet is resumed after surgery, is precipitated by a meal (typically after breakfast when a large amount of bile is stored in the gallbladder), and does not lead to weight loss. Patients benefit from an empiric trial of cholestyramine, a bile acid-binding agent. Ileal resection >100 cm: steatorrhea. When >100 cm of ileum is lost to surgical resection or disease, the daily loss of bile acids exceeds the ability of the liver to synthesize new bile acids; hence, the total circulation bile acid pool is diminished. Bile acid deficiency leads to impaired intraluminal micellar fat absorption or steatorrhea. Patients benefit from a low-fat diet or supplement of medium-chain triglycerides. The diminished circulating pool of bile acids also promotes formation of cholesterol gallstones.

Where are the endemic areas for tropical sprue?
Tropical sprue is endemic in Puerto Rico, Cuba, the Dominican Republic, and Haiti but not in Jamaica or the other West Indies islands. It is found in Central America, Venezuela, and Columbia. Sprue is common in the Indian subcontinent and Far East, although little information is available from China. Sprue has been reported among several visitors to countries in the Middle East. It is rare in Africa, although the occurrence of sprue among populations living in the central and southern parts is now well established.

How is tropical sprue treated?
The most effective therapy for tropical sprue in returning travelers or expatriates is a combination of folic acid and tetracycline. Folic acid should be given in a dosage of 5 mg/day orally and tetracycline in a dosage of 250 mg four times/day. Vitamin B12 should be given parenterally, in addition to the previously mentioned combination, if a deficiency of this vitamin is discovered. Treatment should be continued for at least several months or until intestinal unction returns to normal. Treatment with folic acid alone may be effective in reversing small bowel abnormalities or even in curing the acute illness, but not in curing the chronic form. On the other hand, long-term treatment with tetracycline alone may result in cure of both acute and chronic forms of sprue.

How is bacterial overgrowth diagnosed?
The gold standard for the diagnosis of bacterial overgrowth is demonstration of increased concentrations of bacteria (>105 colony-forming units/mL) in fluid obtained from the intestine during duodenal intubation. If quantitative culture of the small bowel aspirate is not possible, the diagnosis can be made with various breath tests. With the lactulose-hydrogen breath test, a rise in breath hydrogen level of 12 ppm from baseline values is taken as diagnostic of bacterial overgrowth. The 14C-glycocholate and 14C-d-xylose breath tests detect the release of the radiolabeled carbon dioxide as the result of bacterial deconjugation of bile acid and metabolism of xylose. Normalization of the Schilling’s test after treatment with antibiotics is highly suggestive of bacterial overgrowth.

What is the mechanism of hyperoxaluria in short bowel syndrome?
Normally, intraluminal calcium binds to oxalate and prevents intestinal absorption of oxalate. With short bowel syndrome, malabsorption of fat leads to excessive luminal free fatty acids, which bind to calcium, allowing oxalate to pass unbound and become available for absorption. Excessive luminal free fatty acids and bile acids appear to increase colonic permeability to oxalate, further increasing its absorption. Therefore, hyperoxaluria appears to depend on the presence of an intact colon. To prevent calcium oxalate nephrolithiasis in patients with bowel disease, a low-oxalate and low-fat diet should be recommended.

What is immunoproliferative small intestinal disease (IPSID)?
Also known as alpha heavy-chain disease, IPSID is a type of lymphoma composed of dense lymphoplasmacytic mucosal infiltrate that secretes an abnormal alpha-heavy chain protein. The disease usually affects the small intestine from the second part of the duodenum distally into the jejunum. It presents in young adults and is usually associated with poor socioeconomic conditions in the Mediterranean region and many developing nations.

What causes immunoproliferative small intestinal disease?
Although its exact etiology is unclear, early stage IPSID has been linked to a bacterial origin. Recently, investigators have established an association between IPSID and Campylobacter jejuni with use of polymerase chain reaction and DNA sequencing techniques.

What are the most common clinical manifestations of immunoproliferative small intestinal disease?

  1. Abdominal pain
  2. Diarrhea
  3. Malabsorption
  4. Weight loss
  5. Growth retardation
  6. Paraproteinemia with overproduction of heavy chain of IgA

How is immunoproliferative small intestinal disease treated?
Early stage disease responds frequently to tetracycline or to other broad-spectrum antibiotic treatment and may result in complete remission. IPSID that has progressed to high-grade lymphoma may respond to systemic combination chemotherapy.

References

WEBSITES

http://www.celiac.org/
http://www.consensus.nih.gov
(Search “celiac disease”)
http://www.vhjoe.com

BIBLIOGRAPHY

  1. Akbulut H, Soykan I, Yakaryilmaz F, et al: Five-year results of the treatment of 23 patients with immunoproliferative small intestinal disease: a Turkish experience. Cancer 80:8-14, 1997.
  2. Balasekaran R, Porter JL, Santa Ana CA, Fordtran JS: Positive results on tests for steatorrhea in persons consuming olestra potato chips. Ann Intern Med 132:279-282, 2000.
  3. Bardella MT, Fraquelli M, Quatrini M, et al: Prevalence of hypertransaminasemia in adult celiac patients and effect of gluten-free diet. Hepatology 22:833-836, 1995.
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  8. Lecuit M, Abachin E, Martin A, et al: Immunoproliferative small intestinal disease associated with Campylobacter jejuni. N Engl J Med 350:239-248, 2004.
  9. Ramzan NN, Loftus E Jr, Burgart LJ: Diagnosis and monitoring of Whipple disease by polymerase chain reaction. Ann Intern Med 126:520-527, 1997.
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  12. Roberts IM: Workup of the patient with malabsorption. Postgrad Med 81:32-42, 1987.
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  14. Seissler J, Boms S, Wohlrab U, et al: Antibodies to human recombinant tissue transglutaminase measured by radioligand assay: Evidence for high diagnostic sensitivity for celiac disease. Horm Metab Res 31:375-379, 1999.
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