patoloji-ders-notlari

Title

Serdar Balcı

Malabsorption and Diarrhea

Serdar BALCI, MD

Diarrhea

• Increase in stool mass, frequency, or fluidity
• Volumes greater than 200 mL per day
  • In severe cases exceed 14 L per day and lethal
• Dysentery
  • painful, bloody, small-volume diarrhea
• Secretory diarrhea
  • isotonic stool and persists during fasting
• Osmotic diarrhea
  • lactase deficiency
  • osmotic forces by unabsorbed luminal solutes
  • diarrheal fluid is more than 50 mOsm
  • more concentrated than plasma
  • Relives with fasting
• Malabsorptive diarrhea
  • inadequate nutrient absorption
  • associated with steatorrhea
  • relieved by fasting
• Exudative diarrhea
  • inflammatory disease
  • purulent, bloody stools
  • continue during fasting

Malabsorptive Diarrhea

• Chronic diarrhea
• Defective absorption of
  • Fats
  • Fat- and water-soluble vitamins
  • Proteins
  • Carbohydrates
  • Electrolytes and minerals
  • Water

Chronic malabsorption

• Weight loss
• Anorexia
• Abdominal distention
• Stomach rumble (gas movement)
• Muscle wasting
• Steatorrhea
  • excessive fecal fat
  • bulky, greasy, yellow or clay-colored stools

Chronic malabsorptive disorders

Pancreatic insufficiency

Celiac disease

Crohn disease

Intestinal graft-versus-host disease

Environmental enteropathy (tropical sprue)

Localizations of Malabsorption

• Intraluminal digestion
  • proteins, carbohydrates, and fats are broken down into absorbable forms
• Terminal digestion
  • hydrolysis of carbohydrates and peptides by disaccharidases and peptidases
  • in the brush border of the small intestinal mucosa
• Transepithelial transport
  • nutrients, fluid, and electrolytes are transported across and processed within the small intestinal epithelium
• Lymphatic transport of absorbed lipids

Robbins Basic Pathology

CYSTIC FIBROSIS

Cystic Fibrosis

• Defects in intestinal and pancreatic ductal chloride ion secretion
• Problems in bicarbonate, sodium, and water secretion
• Defective luminal hydration
• Result in meconium ileus
  • 10% of newborns with cystic fibrosis
• Pancreas
  • intraductal concretions
  • begin to form in uterine life
  • obstruction, low-grade chronic autodigestion of the pancreas
  • exocrine pancreatic insufficiency
    • 80% of patients
• Failure of the intraluminal phase of nutrient absorption
• Oral enzyme supplementation

CELIAC DISEASE

Celiac Disease

• Celiac sprue

• Gluten-sensitive enteropathy

• Immune-mediated enteropathy

• Triggered by the ingestion of gluten-containing cereals (tahıl)

  • Wheat (buğday), rye (çavdar), barley (arpa)

• Occur in genetically predisposed persons

• White people of European ancestry

  • common disorder, estimated prevalence of 0.5% to 1%

• Primary treatment is a gluten-free diet

• Intestinal immune reaction to gluten
• Gluten is digested by luminal and brush border enzymes into amino acids and peptides
• 33–amino acid gliadin peptide
  • **resistant to degradation by gastric, pancreatic, and small intestinal proteases **

Robbins Basic Pathology

Gliadin is deamidated by tissue transglutaminase

Interact with HLA-DQ2 or HLA-DQ8 on antigen-presenting cells

Presented to CD4+ T cells

T cells produce cytokines

Tissue damage and characteristic mucosal histopathology

Robbins Basic Pathology

• B cell response
• Production of antibodies
  • Anti-tissue transglutaminase
  • Anti-deamidated gliadin
  • Anti-endomysial antibodies
    • Produced as a result of cross-reactive epitopes
    • used for diagnosis
    • Contribution to celiac disease pathogenesis is controversial

Robbins Basic Pathology

• T cells
• Accumulation of CD8+ cells
  • not specific for gliadin
• Cause tissue damage
• Deamidated gliadin peptides induce epithelial cells
• Epithelial cells produce IL-15
• IL-15 triggers activation and proliferation of CD8+ intraepithelial lymphocytes

Robbins Basic Pathology

Intraepithelial lymphocytes activated via IL-15 express NKG2D

NKG2D is a ligand for MIC-A receptor (HLA class I–like protein) found on enterocytes

some factors induce some enterocytes to express MIC-A

Lymphocytes become cytotoxic and kill enterocytes that express surface MIC-A

Robbins Basic Pathology

• Both innate and adaptive immune mechanisms are involved in the tissue responses to gliadin
• Host factors determine whether disease develops
  • HLA proteins are important in less than half of cases
  • Almost all people with celiac disease carry the class II HLA-DQ2 or HLA-DQ8 alleles
• Associated with other immune diseases
  • Type 1 diabetes, thyroiditis, and Sjögren syndrome

• Biopsy specimens
  • Taken from the second portion of the duodenum or proximal jejunum
  • These areas are exposed to the highest concentrations of dietary gluten
• Morphologic alterations present in celiac disease
  • Villous atrophy
  • Increased numbers of intraepithelial lymphocytes (IELs)
  • Epithelial proliferation with crypt elongation
• Morphologic features are not specific
  • Clinical and serological features are used together for diagnosis

Robbins Basic Pathology

Normal duodenal bulb

**transition zone that is normally subjected to physiologic peptic injury **

Normal second duodenum and proximal jejunum

The villus-to-crypt ratio 3:1-5:1

Two intraepithelial lymphocytes per 10 enterocytes

crypt hyperplasia

villous atrophy

Robbins Basic Pathology

increased numbers of intraepithelial CD8+ T lymphocytes

intraepithelial lymphocytosis

Robbins Basic Pathology

• Loss of mucosal and brush border surface area leads to malabsorption
• Increased rates of epithelial turnover limit the ability of absorptive enterocytes to fully differentiate
  • contribute to defects in terminal digestion and transepithelial transport
• Patients have a higher than normal rate of malignancy
• Enteropathy-associated T cell lymphoma
  • Aggressive tumor of intraepithelial T lymphocytes
• Small intestinal adenocarcinoma

TROPICAL ENTEROPATHY

Environmental (Tropical) Enteropathy

• Syndrome of stunted growth and impaired intestinal function
• Common in developing countries
  • Affect over 150 million children worldwide
• There is a malnutrition component of the disease
  • however supplementary feeding does not fully reverse the syndrome
• Repeated bouts of diarrhea
• Within the first 2 or 3 years of life
• Endemic pathogens??
• Intestinal biopsies on limited number of patients
  • similar to those of severe celiac disease, not to those of infectious enteritis
• Recurrent diarrhea cause a cycle of mucosal injury, malnutrition, infection, and inflammation

LACTASE DEFICIENCY

Lactase (Disaccharidase) Deficiency

Defect is biochemical

Biopsies are generally unremarkable

Congenital lactase deficiency

Autosomal recessive disorder

Mutation in the gene encoding lactase

Rare

Explosive diarrhea with watery stools and abdominal distention after milk ingestion

Symptoms abate when milk is removed from diet

Acquired lactase deficiency

Downregulation of lactase gene expression

Common among Native Americans, African Americans, and Chinese populations

Occurs in the gut after childhood

Onset is sometimes associated with enteric viral or bacterial infections

ABETALIPOPROTEINEMIA

Abetalipoproteinemia

• Autosomal recessive disease
• Inability to secrete triglyceride-rich lipoproteins
• Transepithelial transport defect that leads to malabsorption
• Enterocytes unable to export lipoproteins and free fatty acids
  • Monoglycerides and triglycerides accumulate within the epithelial cells
• Manifests in infancy
  • failure to thrive, diarrhea, and steatorrhea
• Deficiencies of fat-soluble vitamins, and lipid defects in plasma membranes often produce acanthocytic red cells (spur cells) in peripheral blood smears

acanthocytic red cells (spur cells) in peripheral blood smears

• Lipid vacuoles in small intestinal epithelial cells
• Seen by light microscopy
• Highlighted by special stains
  • oil red O

MICROSCOPIC COLITIS

Microscopic Colitis

• Idiopathic diseases
• Chronic, nonbloody, watery diarrhea without weight loss
• Collagenous colitis
  • middle-aged and older women
  • dense subepithelial collagen layer
  • increased numbers of intraepithelial lymphocytes
  • mixed inflammatory infiltrate within the lamina propria
• Lymphocytic colitis
  • subepithelial collagen layer is of normal thickness
  • increase in intraepithelial lymphocytes
  • >1 T lymphocyte per five colonocytes
  • associated with celiac and autoimmune diseases, including thyroiditis, arthritis, and autoimmune or lymphocytic gastritis

GRAFT-VERSUS-HOST DISEASE

Graft-Versus-Host Disease

Occurs after allogeneic hematopoietic stem cell transplantation

Lymphocytic infiltrate in the lamina propria is typically sparse

Epithelial apoptosis, particularly of crypt cells, is the most common histologic finding

Intestinal graft-versus-host disease often manifests as a watery diarrhea

IRRITABLE BOWEL SYNDROME

Irritable Bowel Syndrome

Chronic and relapsing abdominal pain, bloating, and changes in bowel habits including diarrhea and constipation

Psychologic stressors, diet, and abnormal gastrointestinal motility

No gross or microscopic abnormalities are found

Diagnosis depends on clinical symptoms

INFECTIOUS ENTEROCOLITIS

Infectious Enterocolitis

Robbins Basic Pathology

Bacterial infections induce acute self-limited colitis

Prominent lamina propria and intraepithelial neutrophil infiltrates

Robbins Basic Pathology

Cryptitis

-neutrophil infiltration of the crypts

Crypt abscesses

-crypts with accumulations of luminal neutrophils

Crypt architecture is preserved in most cases

Robbins Basic Pathology

Pseudomembranous colitis

Clostridium difficile

-Pseudomembranes composed of neutrophils, dead epithelial cells, and inflammatory debris

Robbins Basic Pathology

Pseudomembranes

Typical pattern of neutrophils emanating from a crypt is reminiscent of a volcanic eruption

Robbins Basic Pathology

Giardiasis

Decreases the expression of brush border enzymes, including lactase

Causes microvillous damage

Apoptosis of small intestinal epithelial cells

Noninvasive

Clinically characterized by acute or chronic diarrhea and can result in malabsorption

Whipple disease

Tropheryma whippelii

organism-laden macrophages accumulate within the small intestinal lamina propria and mesenteric lymph nodes

lymphatic obstruction

Malabsorptive diarrhea

Histologic features of viral enteritis include increased numbers of intraepithelial and lamina propria lymphocytes and crypt hypertrophy

**Diffuse eosinophilic infiltrates in parasitic infection. This case was caused by Ascaris (upper inset), but a similar tissue reaction could be caused by Strongyloides **

Schistosomiasis can induce an inflammatory reaction to eggs trapped within the lamina propria

Entamoeba histolytica in a colon biopsy specimen. Note some organisms ingesting red blood cells (arrow)

Cryptosporidia organisms are seen as small blue spheres that appear to lie on top of the brush border but are actually enveloped by a thin layer of host cell cytoplasm

The morphology of mycobacterial infection can be similar to Whipple disease, particularly in the immunocompromised host

Mycobacteria are positive with stains for for acid-fast bacteria

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• Yersinia
  • may cause granuloma and erosions
  • Ileum, appendix, right colon
  • ddx Tbc, Crohn
• Salmonella
  • affect Payer patches
  • Enlarge up to 8 cm
• **Shigella **
  • Common in left colon
  • Aphtous ulcers similar to Crohn