MalabsorptionVIKRAM GILL #1491

PATH II

What is Malabsorption?oMalabsorption is defined as defective absorption of fats, fat- and water-soluble vitamins, proteins, carbohydrates, electrolytes and minerals, and or water

oMalabsorption most commonly presents as chronic diarrhea, and a hallmark feature of malabsorption is steatorrhea- which is a bulky, greasy, foul smelling stool with high fat content

o The chronic malabsorptive disorders most commonly encountered in the United States are pancreatic insufficiency, celiac disease, and Crohn’s disease

oMalabsorption results from disturbance in at least one of the four phases of nutrient absorption:

1)Intraluminal digestion2)Terminal digestion3)Transepithelial transport of absorbed lipids4)Lymphatic transport of absorbed lipids

Four phases of nutrient absorption

1. Intraluminal digestion- the process where proteins, carbohydrates, and fats are broken down into forms suitable for absorption

2. Terminal digestion- involves the hydrolysis of carbohydrates and peptides by enzymes in the mucosa of the intestinal brush border

3. Transepithelial transport- where nutrients, fluid, and electrolytes are transported across and processed within the small intestinal epithelium

4. Lymphatic transport of absorbed lipids

Defects in malabsorptive and diarrheal disease

Cystic FibrosisoCystic Fibrosis is due to a defect in the CFTR protein channel, which is vital for proper bicarbonate, sodium, and water secretion, ultimately resulting in defective luminal hydration

oThis insufficient luminal hydration can cause intestinal obstruction, but more commonly in these patients it causes the formation of intraductal concretions within the pancreas

oThese concretions result in duct obstruction, low-grade chronic autodigestion of the pancreas, and eventual exocrine pancreatic insufficiency in more than 80% of patients

oThe result is failure of the intraluminal phase of nutrient absorption, which can be effectively treated in most patients with oral enzyme supplementation.

Celiac DiseaseoCeliac Sprue is an immune-mediated (allergic) enteropathy triggered by the ingestion of gluten-containing foods, such as wheat, rye, or barley, in genetically predisposed individuals

oPathogenesis:

1) Gluten is digested by luminal and brush-border enzymes into amino acids and peptides, including a 33-amino acid a-gliadin peptide that is resistant to degradation by gastric, pancreatic, and small intestinal proteases

2) Some gliadin peptides may induce epithelial cells to express IL-15, which in turn triggers activation and proliferation of CD8+ intraepithelial lymphocytes

3) The resulting epithelial damage may enhance passage of other gliadin peptides into the lamina propria; These gliadin peptides interact with HLA-DQ2 or HLA-DQ8 on antigen-presenting cells and, in turn, can stimulate CD4+ T cells to produce cytokines that contribute to tissue damage

Celiac Disease cont’doThe genetic variables that control the development of Celiac disease may also contribute associations between celiac disease and other immune diseases, including type 1 diabetes, thyroiditis, and Sjogren syndrome, IgA nephropathy, as well as certain neurologic disorders

oClinical features:1) In adults, celiac disease presents most commonly between the ages of 30 and 60; detected twice as often in females2) Pediatric celiac disease, which affects males and females equally, may present with

malabsorption or atypical symptoms affecting almost any organ; manifests as irritability, abdominal distention, anorexia, chronic diarrhea, failure to thrive, weight loss, or muscle wasting

3) A characteristic itchy, blistering skin lesion, dermatitis herpetiformis can be present in as many as 10% of patients

4) Individuals with celiac disease have a higher than normal rate of malignancy; enteropathy associated T-cell lymphoma is the most commonly associated malignancy followed by

adenocarcinomao Unfortunately the only treatment available right now is a gluten free diet

Celiac Disease

Tropical SprueoIs a malabsorption syndrome occurring almost exclusively in people living in or visiting the tropics, including Peurto Rico, the Caribbean, northern South America, West Africa, India, and Southeast Asia. However it is inexplicably UNCOMMON in Jamaica

oMalabsorption becomes apparent from days to weeks of an acute diarrheal infection in visitors, and though no causative organism has been isolated overgrowth of aerobic enteric bacteria has been documented in patients. Also, most patients rapidly recover with broad spectrum antibiotics• Cyclospora and ETEC are suspected etiologic factors

oHistologic changes seen in tropical sprue is nearly identical to celiac sprue except that in tropical sprue it is uncommon to see total villous atrophy, and that tropical sprue tends to involve the terminal small bowel• Ileum (terminal small bowel) is where vitamin B12 is absorbed, so tropical sprue is often associated

with megaloblastic anemia

Tropical Sprue cont’d

Autoimmune EnteropathyoIs an X-linked autoimmune disease that occurs most often in young children and is characterized by severe persistent diarrhea

oA particularly severe form of autoimmune enteropathy termed IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, and X-linkage) is due to a germ line mutation of the transcription factor FOXP3 which is expressed in CD4+ regulatory T-cells; Results in defective regulation of T-Cells

oProduction of autoantibodies to enterocytes, goblet cells, parietal, and sometimes even islet cells cause discomfort associated with condition

oIntraepithelial lymphocytes within the small intestine may be increased but not nearly to the extent seen in celiac disease, and neutrophils are often present

oThe treatment regiment includes immunosuppressive drugs (cyclosporine) and in rare cases, even bone marrow transplantation

Lactase Deficiency oThe disaccharidases, lactase included, are located in the apical brush-border membrane of the villus absorptive epithelial cells

oBecause the defect is biochemical biopsy histology is usually unremarkable

oThere are two types of lactase deficiency: Congenital and Acquired.• Congenital lactase deficiency is an autosomal recessive disorder caused by a mutation in a gene

encoding lactase. Disease is rare, and presents from birth as explosive diarrhea with watery, frothy stools and abdominal distention on milk ingestion. Symptoms abate when diet is lactose free

• Acquired lactase deficiency is caused by down-regulation of lactase gene expression and is particularly common among Native Americans, African, and Chinese populations. Onset of acquired lactase deficiency is sometimes precipitated by an enteric viral or bacterial infection

AbetalipoproteinemiaoIs a rare autosomal recessive disease characterized by an inability to secrete triglyceride-rich lipoproteins

oCaused by a mutation to the microsomal triglyceride transport protein (MTP) that catalyze the transport of triglycerides, cholesterol esters, and phospholipids

oWithout MTP, enterocytes cannot assemble or export lipoproteins. This results in intracellular lipid accumulation; Because of the triglyceride accumulation, vacuolization of small intestinal epithelial cells is evident and can be highlighted by special stains, such as oil red-O, particularly after a fatty meal

oAbetalipoproteinemia presents in infancy and the clinical picture is characterized by failure to thrive, diarrhea, and steatorrhea

o Patients also have a complete absence of all plasma lipoproteins containing apolipoprotein B, though the gene that codes apolipoprotein B is not affected

oPresence of acanthocytic red blood cells (Burr cells) can be seen in peripheral blood smears because of membrane defects in the RBC’s due to deficiency of essential fatty acids and fat soluble vitamins

Sources Robbins and Cotran: Pathologic Basis of Disease

8th Edition

Chpt 17 pages 793-797

Thank You