Pathology and mechanisms of malabsorption Dr. Mamlook Elmagraby

Objectives of the lecture: Upon completion of this lecture, students should be able to: Understand that the malabsorption is caused by either abnormal digestion or small intestinal mucosa Know that malabsorption can affect many organ systems ( alimentary tract, hematopoietic system, musculoskeletal system, endocrine system, epidermis, nervous system) Concentrate on celiac disease and lactose intolerance as two examples of malabsoption syndrome

Malabsorption Malabsorption is characterized by defective absorption of fats, fat- soluble and other vitamins, proteins, carbohydrates, electrolytes and minerals, and water The most common presentation is chronic diarrhea The hallmark of malabsorption syndromes is steatorrhea Malabsorption can result from impairment in any of the absorption process phases which include: Luminal Phase Mucosal Phase Transport Phase

Luminal Phase Reduced nutrient availability Cofactor deficiency (pernicious anemia; gastric surgery) Nutrient consumption (bacterial overgrowth) Impaired fat solubilization Reduced bile salt synthesis (hepatocellular disease) Impaired bile salt secretion (chronic cholestasis) Bile salt inactivation (bacterial overgrowth) Impaired cholecystokinin release (mucosal disease) Increased bile salt losses (terminal ileal disease or resection) Defective nutrient hydrolysis Lipase inactivation (Zollinger-Ellison syndrome) Enzyme deficiency (pancreatic insufficiency or cancer) Improper mixing or rapid transit (resection; hyperthyroidism) PATHOPHYSIOLOGIC MECHANISMS IN MALABSORPTION The time taken for food to transit عبورthrough the gastrointestinal tract varies depending on many factors, but roughly, it takes less than an hour after a meal for 50% of stomach contents to empty into the intestines while total emptying takes around 2 hours. Subsequently, 50% emptying of the small intestine takes between 1 and 2 hours. Finally, transit through the colon takes 12 to 50 hours

Extensive mucosal loss (resection or infarction) Mucosal Phase Extensive mucosal loss (resection or infarction) Diffuse mucosal disease (celiac disease) Crohn's disease; irradiation; infection; infiltrations; drugs: alcohol, colchicine, neomycin, iron salts Brush border hydrolase deficiency (lactase deficiency) Transport defects (vitamin B 12 and folate uptake) Epithelial processing (abetalipoproteinemia) PATHOPHYSIOLOGIC MECHANISMS IN MALABSORPTION TRANSPORT PHASE Vascular conditions (vasculitis; atheroma) Lymphatic conditions (lymphangiectasia; irradiation; nodal tumor, cavitation, or infiltrations)

Symptoms and signs of malabsorption and relevant pathophysiology

Symptoms and signs of malabsorption and relevant pathophysiology

Symptoms and signs of malabsorption and relevant pathophysiology

Celiac Disease Overview Celiac disease is an immune-mediated enteropathy triggered by the ingestion of gluten-containing cereals, in genetically predisposed individuals   Gluten-containing cereals include wheat, rye, barley In whites European populations, celiac disease is a common disorder, with an prevalence of 0.5% to 1% The primary treatment for celiac disease is a gluten-free diet, which results in symptomatic improvement for most patients

The left panel illustrates the morphologic alterations that may be present celiac disease, including villous atrophy, increased numbers of intraepithelial lymphocytes (IELs), and epithelial proliferation with crypt elongation. The right panel depicts a model for the pathogenesis of celiac disease. Note that both innate (CD8+ intraepithelial T cells, activated by IL 15) and adaptive (CD4+ T cells, and B cells sensitization to gliadin) immune mechanisms are involved in the tissue responses to gliadin.

Celiac Disease Morphology Biopsy specimens from the second portion of the duodenum or proximal jejunum, are generally diagnostic in celiac disease   The histopathology is characterized by: Increased numbers of T lymphocytes (intraepithelial lymphocytosis) Crypt hyperplasia Villous atrophy This loss of mucosal and brush-border surface area due to villous atrophy probably accounts for the malabsorption

Duodenum, normal villus In this duodenal biopsy specimen from a healthy person, note the appearance of the normal villi that can be best seen in areas where the specimen is optimally oriented. Although the lamina propria normally contains numerous lymphocytes, as seen here, only a few scattered lymphocytes are present within normal epithelium Duodenum, celiac sprue Note the flattening of the duodenal villi. In this specimen, they are almost absent Note the numerous intraepithelial lymphocytes

Celiac Disease Increased rates of epithelial turnover may limit the ability of absorptive enterocytes to fully differentiate and express proteins necessary for terminal digestion and transepithelial transport Other histologic features of celiac disease can include increased numbers of plasma cells, mast cells, and eosinophils   It should be noted that intraepithelial lymphocytosis and villous atrophy can be present in other disorders, including viral enteritis The combination of histologic and serologic findings is, therefore, most specific for diagnosis of celiac disease

Celiac Disease Clinical Features Pediatric celiac disease. Pediatric celiac disease affects male and female children equally   Baby may manifest with classic symptoms, typically between 6 and 24 months of age (after introduction of gluten to the diet). Classic manifestations include irritability, abdominal distention, anorexia, diarrhea, failure to thrive, weight loss, or muscle wasting. Children with nonclassic symptoms tend to present at older ages with complaints of abdominal pain, nausea, vomiting, bloating, constipation

Celiac Disease In adults. Celiac disease manifests most commonly between 30 and 60 years of age   Some patients have silent celiac disease, defined as positive serology and villous atrophy without symptoms Some patients have latent celiac disease, in which positive serology is accompanied neither by villous atrophy nor symptoms Symptomatic adult celiac disease is often associated with anemia, diarrhea, bloating, fatigue Dermatitis herpetiformis, is present in as many as 10% of patients

Celiac Disease The most sensitive tests are: The presence of IgA antibodies to tissue transglutaminase IgA or IgG antibodies to deamidated gliadin   Anti-endomysial antibodies are highly specific but less sensitive than other antibodies Patients with celiac disease exhibit a higher than normal rate of malignancy. Enteropathy-associated T cell lymphoma Small-intestinal adenocarcinoma Most individuals with celiac disease do well with dietary restrictions and die of unrelated causes

Lactase (Disaccharidase) Deficiency Normally, lactase turns milk sugar into two simple sugars which are absorbed into the bloodstream through the intestinal lining The disaccharidases, including lactase, are located in the apical brush-border membrane of the villus absorptive epithelial cells Lactose intolerance occurs when the small intestine doesn't produce enough of an enzyme (lactase) to digest milk sugar (lactose) Because the defect is biochemical, biopsy histology is unremarkable If there is lactase deficiency, lactose in the food moves into the colon instead of being processed and absorbed

Lactase (Disaccharidase) Deficiency In the colon, normal bacteria interact with undigested lactose, causing the signs and symptoms of lactose intolerance Intolerance to dairy products is associated with osmotic diarrhea and malabsorption Symptoms, including abdominal fullness, diarrhea, and flatulence

Lactase (Disaccharidase) Deficiency Causes of lactose intolerance. There are three types of lactose intolerance. Different factors cause the lactase deficiency underlying each type Primary lactose intolerance This is the most common type of lactose intolerance   People who develop primary lactose intolerance start life producing plenty of lactase (necessity for infants) As children replace milk with other foods, their lactase production normally decreases, but remains high enough to digest the amount of dairy in a typical adult diet

Lactase (Disaccharidase) Deficiency In primary lactose intolerance, lactase production falls off sharply, making milk products difficult to digest by adulthood Primary lactose intolerance is genetically determined, occurring in a large proportion of people with African, Asian or Hispanic ancestry   The condition is also common among those of Mediterranean or Southern European descent

Lactase (Disaccharidase) Deficiency Secondary lactose intolerance This form occurs when the small intestine decreases lactase production after an illness, injury or surgery involving the small intestine   Among the diseases associated with secondary lactose intolerance are: Celiac disease Bacterial overgrowth Crohn's disease Treatment of the underlying disorder may restore lactase levels and improve signs and symptoms

Lactase (Disaccharidase) Deficiency Congenital or developmental lactose intolerance Rarely, babies can be born with lactose intolerance caused by a complete absence of lactase activity   This disorder is passed from generation to generation in a autosomal recessive pattern of inheritance Premature infants may also have lactose intolerance because of an insufficient lactase level