Malabsorption
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Malabsorption is characterized by defective absorption of nutrients including fats, vitamins, proteins, carbohydrates, electrolytes, and water from the small intestine. The most common presentations are chronic diarrhea and excessive fat in stool. Malabsorption can result from defects in intraluminal digestion, terminal digestion, transepithelial transport, or lymphatic transport of nutrients. Common causes discussed in the document include cystic fibrosis, celiac disease, tropical sprue, Whipple's disease, and abetalipoproteinemia.
Malabsorption
- 2. Malabsorption is characterized by defective absorption of fats, fat-soluble and other vitamins, proteins, carbohydrates, electrolytes and minerals, and water. • The most common clinical presentation is chronic diarrhea. • The hallmark of malabsorption is steatorrhea (excessive fecal fat content).
- 3. DISTURBANCE IN FOUR PHASES OF NUTRIENT ABSORPTION (1) intraluminal digestion, in which proteins, carbohydrates, and fats are broken down into forms suitable for absorption (2) terminal digestion, which involves the hydrolysis of carbohydrates and peptides by disaccharidases and peptidases, respectively, in the brush border of the small intestinal mucosa (3) transepithelial transport, in which nutrients, fluid, and electrolytes are transported across and processed within the small intestinal epithelium (4) lymphatic transport of absorbed lipids.
- 5. Defective Intraluminal Digestion • Digestion of fats and proteins – Pancreatic insufficiency, owing to pancreatitis or cystic fibrosis – Zollinger-Ellison syndrome, with inactivation of pancreatic enzymes by excess gastric acid secretion • Solubilization of fat, owing to defective bile secretion – Ileal dysfunction or resection, with decreased bile salt uptake – Cessation of bile flow from obstruction, hepatic dysfunction • Nutrient preabsorption or modification by bacterial overgrowth
- 6. Primary Mucosal Cell Abnormalities • Defective terminal digestion – Disaccharidase deficiency (lactose intolerance) – Bacterial overgrowth, with brush border damage • Defective epithelial transport – Abetalipoproteinemia – Primary bile acid malabsorption owing to mutations in the ileal bile acid transporter • Reduced Small Intestinal Surface Area – Gluten-sensitive enteropathy (celiac disease) – Crohn disease
- 7. Lymphatic Obstruction • Lymphoma • Tuberculosis and tuberculous lymphadenitis
- 8. Others • Infection – Acute infectious enteritis – Parasitic infestation – Tropical sprue – Whipple disease (Tropheryma whippelii) • Iatrogenic – Subtotal or total gastrectomy – Short-gut syndrome, following extensive surgical resection – Distal ileal resection or bypass
- 9. CONSEQUENCES • Alimentary tract: diarrhea, both from nutrient malabsorption and excessive intestinal secretions, flatus, abdominal pain, weight loss, and mucositis resulting from vitamin deficiencies • Hematopoietic system: anemia from iron, pyridoxine, folate, and/or vitamin B12 deficiency and bleeding from vitamin K deficiency • Musculoskeletal system: osteopenia and tetany from calcium, magnesium, and vitamin D deficiency • Endocrine system: amenorrhea, impotence, and infertility from generalized malnutrition; hyperparathyroidism from protracted calcium and vitamin D deficiency • Epidermis: purpura and petechiae from vitamin K deficiency, edema from protein deficiency, dermatitis and hyperkeratosis from deficiencies of vitamin A, zinc, essential fatty acids and niacin • Nervous system: peripheral neuropathy from vitamin A and B12 deficiencies.
- 11. CYSTIC FIBROSIS • Low-grade chronic auto- digestion of the pancreas … EXOCRINE PANCREATIC INSUFFICIENCY in more than 80% of patients. • Effectively treated in most patients with oral enzyme supplementation
- 13. CELIAC DISEASE • Synonyms: Celiac sprue, Gluten-sensitive enteropathy, Non-tropical sprue • It is an immune-mediated enteropathy triggered by the ingestion of gluten-containing cereals, such as wheat, rye, or barley, in genetically predisposed individuals. • It improves on withdrawal of wheat gliadins and related grain proteins from the diet. • Celiac disease occurs largely in Caucasians.
- 14. PATHOGENESIS
- 15. HOST FACTORS • Almost all people with celiac disease carry the class II HLA- DQ2 or HLA-DQ8 allele (50%) • Polymorphisms of immune-regulatory genes, such as those encoding IL-2, IL-21, CCR3, and SH2B3. • Other immune diseases including type 1 diabetes, thyroiditis, and Sjögren syndrome, as well as ataxia, autism, depression, some forms of epilepsy, IgA nephropathy, Down syndrome, and Turner syndrome • Polymorphism of genes that determine epithelial polarity.
- 16. MORPHOLOGY • Biopsy specimens from the second portion of the duodenum or proximal jejunum, which are exposed to the highest concentrations of dietary gluten, are generally diagnostic. • Histopathology is characterized by: – increased numbers of intraepithelial CD8+ T lymphocytes (intraepithelial lymphocytosis) – crypt hyperplasia – villous atrophy – increased numbers of plasma cells, mast cells, and eosinophils, especially within the upper part of the lamina propria.
- 18. Which one is more advanced?
- 19. SEROLOGY • Noninvasive serologic tests are generally performed prior to biopsy. • The most sensitive tests are the presence of IgA antibodies to tissue transglutaminase or IgA or IgG antibodies to deamidated gliadin. • Anti-endomysial antibodies are highly specific but less sensitive than other antibodies. • The absence of HLA-DQ2 or HLA-DQ8 is useful for its high negative predictive value, but the presence of these alleles is not helpful in confirming the diagnosis.
- 20. CLINICAL • In adults – presents most commonly between the ages of 30 and 60 – Silent celiac disease, defined as positive serology and villous atrophy without symptoms – Latent celiac disease, in which positive serology is not accompanied by villous atrophy. – Symptomatic adult celiac disease is often associated with anemia, chronic diarrhea, bloating, or chronic fatigue. – Detected two- to threefold more commonly in women, perhaps because monthly menstrual bleeding increases the demand for iron and vitamins and accentuates the effects of impaired absorption.
- 21. • In children, – Affects males and females equally – Classic symptoms include irritability, abdominal distention, anorexia, chronic diarrhea, failure to thrive, weight loss, or muscle wasting; disease typically begins between ages of 6 and 24 months – Nonclassic symptoms include abdominal pain, nausea, vomiting, bloating, or constipation; extra-intestinal complaints; tend to present at older ages
- 22. ALARM… • dermatitis herpetiformis • lymphocytic gastritis and lymphocytic colitis • higher than normal rate of malignancy (enteropathy-associated T-cell lymphoma & small intestinal adenocarcinoma)
- 23. TROPICAL SPRUE • It is a celiac-like disease that occurs almost exclusively in people living in or visiting the tropics. • It is postinfectious* and broad-spectrum antibiotics usually effect rapid recovery. • No definite causal organism has been identified … Cyclospora or enterotoxigenic bacteria have been suggested. • Histologic changes of tropical sprue are similar to celiac disease, but: – total villous atrophy is uncommon … only PARTIAL – tends to involve the distal small bowel – enlarged (megaloblastic) nuclei within epithelial cells.
- 25. WHIPPLE’S DISEASE • Whipple disease is a rare, multivisceral chronic disease.
- 29. AUTOIMMUNE ENTEROPATHY • An X-linked disorder due to mutation in the FOXP3 gene • Familial form is termed IPEX, an acronym denoting immune dysregulation, polyendocrinopathy, enteropathy, and X- linkage • FOXP3 mutations have defective T-regulatory function. • Autoantibodies: enterocytes and goblet cells (common); and parietal or islet cells (occasional) • Intraepithelial lymphocytes may be increased, but not to the extent seen in celiac disease, and neutrophils are often present. • Therapy includes immunosuppressive drugs such as cyclosporine and, in rare cases, bone marrow transplantation.
- 34. LACTASE (DISACCHARIDASE) DEFICIENCY • Congenital lactase deficiency: – an autosomal recessive disorder – presents as explosive diarrhea with watery, frothy stools and abdominal distention upon milk ingestion. – Symptoms abate when exposure to milk and milk products is terminated • Acquired lactase deficiency – caused by down-regulation of lactase gene expression – presents after childhood, • Because the defect is biochemical, biopsy histology is generally unremarkable.
- 35. ABETALIPOPROTEINEMIA • A rare autosomal recessive disease • Inability to secrete triglyceride-rich lipoproteins. • Mutation in the microsomal triglyceride transfer protein (MTP) … MTP-deficient enterocytes are unable to export lipoproteins and free fatty acids. • Presents in infancy • Clinical picture: failure to thrive, diarrhea, and steatorrhea
- 36. LABORATORY WORKUP • Lipid vacuolization of small intestinal epithelial cells is evident under the light microscope and can be highlighted by special stains, such as oil red-O, particularly after a fatty meal. • A complete absence of all plasma lipoproteins containing apolipoprotein B, although the gene that encodes apolipoprotein B itself is not affected. • Deficiencies of fat-soluble vitamins as well as lipid membrane defects … presence of acanthocytic red cells (burr cells) in peripheral blood smears.
- 39. A QUICK REVIEW Disease Intraluminal Digestion Terminal Digestion Transepithelial Transport Lymphatic Transport Whipple disease + Abetalipoproteinemia + Viral gastroenteritis + + Bacterial gastroenteritis + + Parasitic gastroenteritis + + IBD + + +
- 40. Disease Intraluminal Digestion Terminal Digestion Transepithelial Transport Lymphatic Transport Celiac disease + + Tropical sprue + + Chronic pancreatitis + Cystic fibrosis + Primary bile acid malabsorption + + Carcinoid syndrome + Autoimmune enteropathy + + Disaccharidase deficiency +
Editor's Notes
- #10: DON’T WORRY …
- #12: Due to absence of the epithelial cystic fibrosis transmembrane conductance regulator (CFTR), individuals with cystic fibrosis have defects in intestinal chloride ion secretion. This interferes with bicarbonate, sodium, and water secretion, ultimately resulting in defective luminal hydration. Formation of intraductal concretions can begin in utero, leading to duct obstruction…
- #13: Do you love these eatables … THANKS GOD
- #15: Gluten is the major storage protein of wheat and similar grains, and the alcohol-soluble fraction of gluten, gliadin, contains most of the disease-producing components. Gluten is digested by luminal and brush-border enzymes into amino acids and peptides, including a 33–amino acid α-gliadin peptide that is resistant to degradation by gastric, pancreatic, and small intestinal proteases ( Fig. 17-25 ). The network of immune reactions to gliadin that are thought to result in celiac disease is illustrated below. Some gliadin peptides induce epithelial cells to express IL-15, which in turn triggers activation and proliferation of CD8+ intraepithelial lymphocytes that are induced to express NKG2D, a natural killer cell marker. These lymphocytes become cytotoxic and kill enterocytes with surface MIC-A, an HLA class I–like protein expressed in response to stress. NKG2D is the receptor for MIC-A. Thus, unlike the CD4+ T cells, these NKG2D+ CD8+ T cells do not recognize gliadin. The resulting epithelial damage may contribute to the process by which other gliadin peptides cross the epithelium to be deamidated by tissue transglutaminase. Deamidated gliadin peptides are then able to interact with HLA-DQ2 or HLA-DQ8 on antigen-presenting cells and be presented to CD4+ T cells. These T cells produce cytokines that contribute to tissue damage and the characteristic mucosal pathology.
- #17: However, intraepithelial lymphocytosis and villous atrophy are not specific for celiac disease and can be present in other diseases, including viral enteritis. The combination of histology and serology is most specific for diagnosis of celiac disease.
- #18: Celiac disease. A, Advanced cases of celiac disease show complete loss of villi, or total villous atrophy. Note the dense plasma cell infiltrates in the lamina propria. B, Infiltration of the surface epithelium by T lymphocytes.
- #19: Mucosal (villous) flattening and chronic mucosal inflammation, Which one is more advanced? LEFT or RIGHT? Ans: The FLATTER one Mucosal histology usually reverts to normal or near-normal following a period of gluten exclusion from the diet.
- #20: In cases with negative IgA tests, IgA deficiency, which is more common in celiac patients, should be ruled out. If IgA deficiency is present, titers of IgG antibodies to tissue transglutaminase and deamidated gliadin should be measured.
- #22: NONCLASSIC: include arthritis or joint pain, seizure disorders, aphthous stomatitis, iron deficiency anemia, pubertal delay, and short stature.
- #24: Malabsorption usually becomes apparent within days or a few weeks of an acute diarrheal enteric infection in visitors. The latter probably explains the frequency of folate or vitamin B12 deficiencies with enlarged (megaloblastic) nuclei within epithelial cells that are reminiscent of those seen in pernicious anemia.
- #25: Tropical sprue. A variable degree of villous blunting is seen in tropical sprue. In this duodenal biopsy, only mild villous blunting is present. A marked increase in number of intraepithelial lymphocytes can be seen, which is more prevalent in the crypts than in the surface epithelium. The lamina propria is expanded with mononuclear cells. (Courtesy of Raymond Yesner.)
- #26: The lymphatic blockade is believed to be responsible for lipid deposition in the villi, thus the original impression of intestinal lipodystrophy.
- #27: The villous expansion caused by the dense macrophage infiltrate imparts a shaggy gross appearance to the mucosal surface. Lymphatic dilatation and mucosal lipid deposition account for the common endoscopic detection of white to yellow mucosal plaques.
- #28: The morphologic hallmark of Whipple disease is a dense accumulation of distended, foamy macrophages in the small intestinal lamina propria ( Fig. 17-30A ). The macrophages contain periodic acid–Schiff (PAS)-positive, diastase-resistant granules that represent lysosomes stuffed with partially digested bacteria ( Fig. 17-30B ). Intact rod-shaped bacilli can also be identified by electron microscopy ( Fig. 17-30C ). A similar infiltrate of foamy macrophages is present in intestinal tuberculosis ( Fig. 17-30D ), and in both diseases the organisms are PAS-positive. However, the acid-fast stain can be used to distinguish between these, since mycobacteria stain positively ( Fig. 17-30E ) while T. whippelii do not. The morphology of mycobacterial infection can be similar to Whipple disease, particularly in the immunocompromised host. Compare with A. E, Mycobacteria are positive with stains for acid-fast bacteria.
- #29: Whipple's disease is a rare, systemic infectious disease caused by the bacterium Tropheryma whipplei. DISTENDED MACROPHAGES in the LAMINA PROPRIA, PAS positive and ROD SHAPED BACILLI.
- #30: FOXP3 is a transcription factor expressed in CD4+ regulatory T cells.
- #32: (A) Duodenal biopsy demonstrates moderate villous blunting and absence of goblet cells; there is no abnormal surface lymphocytosis.
- #33: (C) Gastric biopsy taken from the fundus demonstrates features of autoimmune atrophic gastritis, with complete absence of oxyntic glands and partial replacement by pseudo-pyloric metaplasia (arrow).
- #36: assembled into chylomicrons and triglycerides accumulate within the epithelial cells. The malabsorption of abetalipoproteinemia is therefore a failure of transepithelial transport.
- #39: Micrograph showing enterocytes with a clearcytoplasm (due to lipid accumulation) characteristic of abetalipoproteinemia. Burr cells