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Ulcerative colitis
- Location: Mucosal inflammation starting at the distal rectum and extends into colon
- Symptoms: bloody diarrhea, rectal urgency, feeling of incomplete defecation, weight loss
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Crohn's Disease
- Location: Transmural inflammation of any part of GIT but often near ileocecal valve (often discontinuous) Can lead to fibrosis, strictures, or fistula formation
- Symptoms: Watery diarrhea (sometimes blood), RLQ abdominal pain, low grade fever, malabsorption, weight loss
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Pathophysiology for Ulcerative Colitis & Crohn's Disease
- Antigen exposure: Impairment of epithelial barrier allows access of bacterial antigens to APCs (dendritic cells)
- T cell activation: APCs present antigen and secrete cytokines = TH1 differentiation (CD) or TH2 differentiation (UC)
- Inflammation: IFNγ and TNFα activate macrophages; Recruit leukocytes (Integrin adhesion)
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Tx Ulcerative Colitis & Crohn's Disease
- Aminosalicylates: Sulfasalazine and mesalamine
- Corticosteroids
- Immunosuppresants: Azathiopurine and mercaptopurine
- Biologics: Infliximab, adalimumab, certolizumab, natalizumab
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Aminosalicylates: Examples, MoA, Location, Tx
- Sulfasalazine, mesalamine, olsalazine, balsalazide
- MoA: 5-aminosalicylate (5-ASA) is responsible for anti-inflammation; Inhibit IL-1, TNFα, lipoxygenases, NFκB and scavenge free radicals
- Location: Act at varying sites in the GIT; 5-ASA routes = Rowasa (suppository), Canasa (enema), Asacol (delayed release), Pentasa (pH coating)
- UC: Mild-to-moderate disease has 60-80% response rate
- CD: Modest benefit, not great for maintaining remission
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Aminosalicylates: PK, ADEs
- PK: Sulfasalazine is metabolized to 5-ASA and sulfapyridine
- Sulfapyridine portion: highly lipid soluble, hepatic metabolism (acetylation, hydroxylation, glucuronidation)
- Acetylation phenotype of patient determines side effects (rapid acetylators have fewer ADEs)
- ADEs: related to sulfa moiety = headache, nausea, fatigue, rash, fever, Stevens-Johnson syndrome, hepatitis, hemolytic anemia; Inhibits folate absorption (need supplementation)
- 5-ASA may cause interstitial nephritis (rare)
- Newer forms = less frequent/severe, i.e. diarrhea
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Corticosteroids
- Tx: acute attacks in moderate to severe disease
- Responsiveness varies: 40% responsive, 30-40% partial response or become glucocorticoid dependent, and 15-20% don't respond.
- ADEs: hyperglycemia, hypertension, hypothyroidism, osteoporosis, insulin resistance
- Dosing: PO prednisolone, budesonide; Rectal cortifoam; IV hydrocortisone, methylprenisolone (sever)
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Immunosuppressants
- Tx: steroid resistant or dependent IBD
- 6-mercaptopurine & azathiopurine: impair purine biosynth and inhibit cell proliferation; beware polymorphisms in thiopurine methyltransferase; ADEs: pancreatitis, arthralgia, bone marrow suppression
- Methotrexate (Tx Crohn's only): Inhibit dihydrofolate reductase which blocks DNA synthesis and causes cell death; IM or SC
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Biologics: TNFα Inhibitors
- Tx Crohn's
- Infliximab: Chimeric mAb against TNFα (IV)
- Adalimumab: Human mAb against TNFα (SC)
- Certolizumab pegol: Humanized pegylated Fab fragment against TNFα (SC)
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Biologics: A4 Integrin Inhibitor
Natalizumab: Inhibits leukocyte adhesion and migration by targeting α4 integrin
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What is Short Bowel Syndrome?
- Poor absorption of nutrients due to small intestine removal
- Some causes: Necrotizing enterocolitis, congenital defects, meconium ileus (CF patients), Crohn’s disease, trauma
- Main symptom is diarrhea
- Intestinal adaptation begins 24-48 h post-surgery and continues up to 2 y
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Tx Short Bowel Syndrome
- NonRx: Eat small meals, supplements, antidiarrheals, enteral/parenteral nutrition in severe cases
- Somatropin (Zorbitive) – recombinant growth hormone to stimulate bowel adaptation
- Glutamine (Nutrestore) – amino acid that contributes to intestinal structure
- Teduglutide (Gattex) – analog of glucagon-like peptide 2 (SC) for patients on parenteral nutrition (ADEs:intestinal cancer, pancreas/gall bladder/biliary tract disease)
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Ursodeoxycholic acid (Ursodiol, Actigall)
- Dried extract from Himalayan bear bile (Only 1 to 3% of human bile supply)
- Increases bile formation
- Solubilize cholesterol monohydrate stones (30-50% efficacy)
- Counter the effects of the hydrophobic bile acids on cell membranes
- Decrease biliary lipid secretion
- Reduce cholesterol content of bile
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Cholestyramine (Questran), Colestipol (Colestid)
- Bile Acid Sequesterants
- MoA: bind bile acids and prevents reabsorption by acting as an anion exchange resin
- Tx: bile-salt induced diarrhea; C.diff GI infxn; pruritis associated with biliary obstruction (i.e. primary biliary cirrhosis)
- ADEs: constipation
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What is/causes cirrhosis?
- Progressive destruction of liver cells and replacement with scar tissue (fibrosis)
- 1. Increase portal vein pressure and decrease plasma oncotic pressure ⇨ varices (dilated submucosal veins, rupture risk) and ascites (fluid in abdomen)
- 2. Increase ammonia levels ⇨ encephalopathy (reduced mental status)
- 3. Reduce ability to fight infection ⇨ bacterial peritonitis
- Major causes: chronic alcohol, chronic viral hepatitis, nonalcoholic steatohepatitis
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Portal Hypertension & Varices
- Prevention: Non-selective Beta blockers Propanolol and nadolol decrease portal blood pressure
- Treatment of active variceal bleeding: Vasopressin (Pitressin) and Terlipressin (Varipres) act as vasopressor and ADH; Octreotide (Sandostatin) is synthetic somatostatin analog that causes splanchnic vasoconstriction by blocking vasodilatory peptides
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Tx Cirrhosis
- Bacterial peritonitis: E. coli (g-) and Klebsiella (g+)
- - 3rd generation cephalosporin (cefotaxime), fluoroquinolones (norfloxacin, ciprofloxacin) and trimethoprim-sulfamethoxazole)
- Ascites: salt restriction, diuretics
- - Spironolactone (K+-sparing diuretic) and furosemide (loop diuretic)
- Encephalopathy: protein restriction, reduce ammonia
- - Lactulose (Cephulac) decreases GI pH, osmotic laxative
- -Neomycin (Mycifradin) and Rifaximin (Xifaxan) = aminoglycosides that target ammonia-producing gut bacteria
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Acute Pancreatitis
- Symptoms: Severe, persistent epigastric pain, N/V, abdominal tenderness
- Pathophysiology: “Autodigestion” Associated with gallstones, alcohol, viruses, trauma, drugs (Estrogens, metronidazole, ACEI, tetracycline, valproic acid, corticosteroids, 6-mercaptopurine, thiazide diuretics, azathioprine)
- Supportive treatment: pain management, nutrition, IV antibiotics against gram negative bacteria
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Chronic Pancreatitis
- Symptoms: Abdominal pain, steatorrhea, malabsorption, diabetes
- Pathophysiology: Inflammation with fibrosis and calcification; Associated with alcohol (1° cause), hyperlipidemia, pancreatic cancer; Increased release of cholecystokinin (CCK) = cause pain due to continuous stimulation of enzyme output and increased intraductal pressure
- Treatment: pain management, reduce fat consumption, pancreatic enzyme supplements to prevent malabsorption
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Pancrease, Pancreacarb, Zenpep, Viokace, Ultrase, Creon
- Pancreatic Enzyme Supplements
- Enteric-coated, delayed release to activate in duodenum
- Often derived from porcine pancreas (avoid if allergy)
- Take with meals and snacks
- ADEs: N/V/D/C, bloating
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Lactose Intolerance
- Pathology: Deficiency in digestive enzyme lactose galactosidases
- Symptoms: Diarrhea, abdominal cramping, pain, flatulence, and malabsorption
- Tx: Enzyme replacements are over the counter and can be added to meals. They are bacterial or yeast-derived β-galactosidases, with varying efficacy (LACTAID, LACTRASE, DAIRYEASE, others)
- Because of the essential requirements to maintain protein, calcium, and vitamin D intake, these must be supplemented if dairy products are limited.
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Children's Celiac Disease
- Symptoms: Fatigue, bloating, constipation, abdominal pain, chronic diarrhea, irritability, vomiting
- Signs: Muscle wasting, weight loss, short stature, delayed puberty, osteopenia, hepatitis, dental anomalies, anemia
- Cause: Genetic predisposition (HLA-DQ2 and HLA-DQ8) and exposure to gluten
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Adult's Celiac Disease
- Symptoms: Abdominal pain, chronic diarrhea, abdominal distension
- Signs: Weight loss, infertility, dermatitis herpetiformis, hepatitis, anemia, alopecia, malignancy, seizures, osteopenia, arthritis
- Cause: Genetic predisposition (HLA-DQ2 and HLA-DQ8) and exposure to gluten
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Tx Celiac Disease
- Treatments: Dietary changes (avoid gluten), vitamin and mineral supplements (calcium and vitamin D)
- May consider immunomodulators (corticosteroids, azathioprine, cyclosporine, tacrolimus, infliximab, alemtuzumab) for refractory cases
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Gluten-full foods
Wheat, barley, rye, bran, graham flour, spelt, wheat germ, oats
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