Lower GI Tract & Celiac Disease

Lower GI Tract Functions

• The small intestine facilitates the reabsorption of substrates like electrolytes, vitamins, lipids, and proteins/carbohydrates
• The large intestine is responsible for water reabsorption
• The rectum/anus is responsible for defecation

Celiac Disease and Gluten Interaction

• Gluten, found in wheat, barley, and rye, breaks down into gliadin, containing glutamine residues
• Gliadin is usually indigestible by the human small intestine and is lost in the stool
• Gliadin abnormally enters intestinal epithelial cells and interacts with Tissue Transglutaminase (TTG)
• TTG converts glutamine residues to glutamate via deamination and renders gliadin more immunogenic
• Innate immune cells induce local inflammation on the small intestine's brush border, which contains villi for substrate reabsorption
• Adaptive immune cells produce recognition proteins that recognize gliadin-based peptides with glutamate
• This process induces immune-based destruction of small intestinal cells and villi

Tissue Transglutaminase (TTG) in Celiac Disease

• TTG is an enzyme that catalyzes the deamination reaction, converting glutamine to glutamate on gliadin molecules

Anti-TTG Antibodies

• Anti-TTG antibodies stimulate TTG, unlike other antibodies
• Higher concentrations of anti-TTG antibodies result in more activation and more deamination of glutamine to glutamate
• This process leads to increased immunogenicity

Clinical Phenotypes of Celiac Disease

• Generalized weakness and fatigue can occur due to iron deficiency anemia
• Peripheral neuropathy is linked to B6 deficiency
• Seizures may occur due to B1 deficiency and hyponatremia
• Steatorrhea involves the presence of lipids in the stool, which appears yellowish and has a foul odor
• Individuals may experience severe abdominal pain in response to gluten exposure
• Dermatitis Herpetiformis, characterized by intensely itchy papular and vesicular rashes on elbows, forearms, knees, scalp, and back/buttocks, is a common association

Concurrent Diseases with Celiac Disease

• Autoimmune Type I Diabetes Mellitus
• Autoimmune Thyroiditis, most commonly Hashimoto’s Thyroiditis
• Autoimmune pancreatitis

Inflammatory Bowel Disease (IBD) Forms

• Ulcerative Colitis
• Crohn’s Disease

Histopathologic Differences in IBD

• Ulcerative Colitis involves a mucosa that appears engorged with blood, nodular, and coarse
• It may contain polyps/pseudopolyps and inflammation, and is sequestered to the mucosa without protruding into the submucosa/wall of intestines
• Crohn’s Disease involves a "cobblestone" mucosa, inflammation extends past the submucosa and wall of the intestine, and can lead to bowel perforation

GI Tract Regions Affected by IBD

• Ulcerative Colitis usually affects the rectum/anus and colon/large intestine in a continuous lesional pattern
• Crohn’s Disease can affect the rectum/anus, large intestine, and small intestine (ileum) in "skip" lesions spread throughout the lower GI tract

Pathophysiologic Abnormalities from Crohn's Disease

• Fistulas are abnormal connections between GI tract compartments/structures, which can send fecal products to inappropriate locations (rectovaginal, enterocutaneous, ureteroenteric)
• Strictures are abnormal fibrosis in the lower GI tract that can result in acute bowel obstruction

ASCA Testing in IBD

• 60-65% of patients with Crohn’s Disease test positive for ASCA, +ASCA indicates a higher likelihood of Crohn's Disease
• ASCA testing demonstrates high specificity and low sensitivity

Etiological Factors Predisposing to IBD

• Disruption in gut microflora/microbiota destroys beneficial colonizers in the GI tract, increasing inflammation
• Hyper-inflammation: Extra-gastrointestinal diseases can increase IFN gamma and TNF-alpha expression, inducing inflammation in the lower GI tract
• Epigenetic Factors: Diets with saturated fats and copious dairy/unpasteurized products increases IBD risk Smoking increases the risk of CD but can be protective in UC Chronic Alcoholism increases the risk of both UC and CD

Presentation of IBD

• Fever, tachycardia, and generalized fatigue occur due to volume loss or macrocytic anemia secondary to B12 deficiency, especially in CD
• Macrocytic Anemia: MCV > 100 occurs due to B12 deficiency and is more common in CD since it affects the terminal ileum
• Moderate to severe abdominal pain is characterized by tenderness to palpation, LLQ indicating UC, and RLQ indicating CD
• Crohn's Disease can result in stool/rectal products in abnormal locations due to fistulas, causing abdominal pain, constipation, vomiting, and food intolerance
• Hematochezia, which is blood in the stool, can range from mild to severe, and is often accompanied by mucus, and painful defecation

Hematochezia

• Hematochezia is the technical term for blood in the stool
• Dark Hematochezia indicates upper GI bleeds because HCl interacts with iron in the heme of red blood cells
• Bright red hematochezia indicates lower GI bleeds

Pharmacologic Approaches to Managing IBD

• Aminosalicylates (5-ASA based drugs) include Mesalamine and Sulfasalazine and are the first-line treatment for mild/moderate cases
• Aminosalicylates inhibit leukotriene and prostaglandin synthesis, inhibit the expression of nuclear factors involved with IFN-gamma and TNF-alpha, and reduce free radicals and ROS formation
• Corticosteroids include Hydrocortisone, Prednisone, and Budesonide and are indicated for acute flare-ups to induce remission rates
• Long-term Corticosteroids should be avoided due to a risk of: Hyperglycemia, Hypertension, Cushingoid features, and Electrolyte Abnormalities

Immunosuppressant Therapy

• Azathioprine (6-MP) and Methotrexate
• Azathioprine: A prodrug converted to 6-MP, which interferes with purine synthesis in hyperactive immune cells, decreasing cellular proliferation of auto-reactive, hyperinflammatory immune cells affects purines
• Methotrexate: A DHFR inhibitor that interferes with purine and pyrimidine synthesis decreases cellular proliferation of auto-reactive, hyperinflammatory immune cells; affects pyrimidines

Biologics in IBD

• Targeted immunotherapy against immune components
• TNF-alpha inhibitors: Infliximab and Adalimumab downregulate TNF-α, decreasing cell-mediated hyperinflammation, and patients need tuberculosis screening before starting
• Anti-Integrin Inhibitor: Natalizumab inhibits integrin, decreasing chemotaxis and diapedesis of neutrophils and requires monitoring for PML due to JC virus reactivation
• Jak-Stat Inhibitor: Upadacitinib inhibits the Jak-Stat pathway, decreasing interferon signaling and macrophage activation, only indicated for UC and requires monitoring for thromboembolism/pulmonary embolism

Acid-Base Condition in Diarrhea

• Hyperchloremic, Hypokalemic Metabolic Acidosis

Viral Etiologies of Diarrhea

• Norovirus and Rotavirus: are extremely common in areas with large gatherings and causes mild to moderate abdominal cramping, nausea, and moderate to severe watery diarrhea, conservative management and volume status monitoring is needed
• Adenovirus: commonly affects children < 2 years and causes watery diarrhea, mild fever, and upper respiratory infection, improves with conservative management
• Cytomegalovirus (CMV) affects HIV-infected patients, causing retinitis

Bacterial Causes of Diarrhea

• E. Coli: Can be contracted from contaminated food or unprotected sexual encounters
  • ETEC causes non-bloody watery diarrhea and mild fever
  • EHEC produces a "shiga-like" toxin which induces bloody diarrhea often associates with Hemolytic Uremic Syndrome (HUS) in children, intestinal damage, and acute kidney injury, antibiotics should be avoided in patients with HUS
• Salmonella: from contaminated poultry, eggs, and unpasteurized dairy; causes watery diarrhea, mild fever, and abdominal cramps
• Campylobacter: from spoiled poultry, unclean water, and kittens/puppies, which can lead to bloody diarrhea and Guillain-Barre syndrome, an ascending demyelinating polyneuropathy
• Clostridium Difficile: from excessive antibiotic use, highly transmissible, causes foul-smelling, nonbloody diarrhea, and requires emergency surgery

Fungal Causes of Diarrhea

• Candida Albicans: Most common fungal etiology and leads to candidal infections elsewhere

Other Diagnoses Related to Diarrhea

• Histoplasmosis: may come with watery diarrhea, pulmonary disease, and enlargement of the liver and spleen
• Cryptosporidiosis: almost always seen in AIDS patients

Metabolic Causes of Diarrhea

• Hyperthyroidism increases intestinal motility and decreases water reabsorption time
• Diabetes Mellitus leads to an increased presence of glucose in stool resulting in osmotic diarrhea
• Hypercalcemia increases smooth muscle contractility, decreasing water reabsorption time
• Lactose Intolerance results in abdominal cramps non-bloody diarrhea and flatulence
• Malabsorption of Lipids occurs with Pancreatic insufficiency, Bile Acid Deficiency, and Celiac Disease

Pharmacologic Options for Managing Diarrhea

• Loperamide (Imodium): mu-opioid receptor agonist, reduces parasympathetic nervous system-mediated intestinal contractility, and rarely results in opioid-induced psychosis Loperamide rarely crosses the blood-brain barrier so P-glycoprotein pumps it back into circulation
• Diphenoxylate + Atropine (Lomotil): Two-headed mechanism for diarrhea treatment Diphenoxylate is a mu-opioid receptor agonist Atropine is anticholinergic to slow motility