GI 2.2 Final

what is the process of heme anabolism (production)?

glucose → G-6P → 3P glycerate → serine → glycine → heme

how is glycine processed into heme?

glycine → ALA → porphobilinogen → hydroxymethylbilane → uroporphyrinogen III → coproporphyrinogen III → protoporphyrinogen III → protoporphyrin → heme

what is the rate limiting step of heme anabolism? what regulates it? products?

• glycine (+succinyl coa) → ALA

  • first step, translationally regulated

• via ALAS1 + cofactor (B6)

• also produces CoA-SH, CO2

how does iron effect RDS of heme anabolism? low iron?

• Fe translate AL to allow heme production

• low Fe =mRNA initiation site blocked + NO ALA translated (BAD)

what causes acute intermittent porphyria (AIP)? symptoms? treatments?

• def. HMBS (hydroxymethylbilane synthetase) via high liver demand (infection, fast, alcohol, steroid)

• symptoms: abdominal pain, psych. issues, peripheral neuropathy, precipitated, pink urine (5Ps)

  • ALA + porphobilinogen inc. in urine → pink

• hemin (panhematin) → block ALA synthase (interfere w/ porphyrins + heme synth.)

what causes porphyria cutanea tarda (PCT)? symptoms?

• UROD (uroporphyrinogen decarboxylase) def. or inhibitors

• uroporphyrinogen III accumulate + coproporphyrinogen III def.

• symptoms: photosensitivity, blistered skin, red urine (via uroporphyrin)

what causes variegate porphyria (VP)? symptoms?

• acute hepatic

• mut. PPOX (protoporphyrinogen) → PPIX excess in urine

  • dx: inc. plasma porphyrins

• symptoms: photosensitive + blister, neurovisceral attack, inc. ALA synthase

what causes hereditary coproporphyria (HCP)? symptoms?

• acute hepatic

• mut. CPOX (coproporphyrinogen) → CPIII excess in urine

  • dx: fecal coproporphyrins

• symptoms: same as VP (less severe cutaneous)

what type of medications do VP and CP precipitate with?

• CYP450 inducers

  • phenytoin + rifampin

what does lead poisoning cause? what does it do to Ca? symptoms? prevention?

• inhibition of enzymes w/ Cys (ie ALA DH + ferrochelatase) → elevated ALA + Fe

• replaces Ca in proteins → block NT firing→ dec. neuronal connection

• symptoms: cognitive issues, fatigue, blueness, bone/muscle dev. issue, hydrochromic microcytic anemia (w/ basophilic stippling)

• lead pipe w/ HPO4 = lead solidify → not in drinking water

what is the process of heme catabolism?

MO engulf heme → biliverdin (via heme oxygenase) → bilirubin (via biliverdin reductase) → stercobilin + urobilin

what is the difference between direct and indirect bilirubin?

• direct → conjugated

  • via UGT-1 (UDP GT) adding glucuronic acid = inc. solubility

  • also blue light (biliverdin photosensitive)

• indirect → unconjugated

  • insoluble (more toxic), bound to albumin (to liver)

what are the OA transporting peptides holding bilirubin in hepatocytes?

SLCO1B1 + 3

what are phases of a bruise?

• 1 → pink + red (via hemoglobin)

• 2-6 → blue + purple (via hemoglobin)

• 7 → pale green (via biliverdin)

• 8-14 → yellow + brown (via bilirubin)

what are symptoms of hyperbilirubinemia? types?

• jaundice + scleral icterus

• types:

  • unconjugated → UGT-1A def.

  • conjugated → overactive UGT-1A

what is crigler-najjar T1? T2?

• unconjugated hyperbilirubinemia

• T1 → absent UGT-1A

  • unconjugated bilirubin → BBB → encephalopathy → kernicterus (fetus, fatal)

• T2 → reduced UGT-1A

  • treat w/ phenobarbital (makes more UGT-1A)

what is gilbert syndrome? neonatal jaundice?

• unconjugated hyperbilirubinemia

• gilbert → mild dec. UGT-1A (benign)

• neonatal → 2-5 days post birth via low UGT-1A

  • light therapy conjugates bilirubin (H2O soluble photo isomers) = dec. bilirubin + prevents kernicterus

what causes dubin-johnson syndrome?

• conjugated hyperbilirubinemia

• ABCC2 mut. → dec. MRP2 transporter → prevent conjugated bilirubin sec. (hepatocyte → bile duct)

  • or pigment gallstone (block bile duct)

  • black liver

• MOST BENIGN

what causes rotor syndrome? symptoms?

• conjugated hyperbilirubinemia

• SLCO1B1 + 3 mut. → dec. OA transport polypeptide act.

• = less conjugated bilirubin in hepatocyte + more in circ. → high mixed

• red urine via coproporphyrin I

what is the first barrier of the immuno system?

• simple squamous → stomach, intestine, biliary tract

• pseudostratified columnar → trachea, bronchi, bronchioles

• NK strat. squam. → nasal sinus, tonsil, pharynx, larynx, oral cavity, esophagus, rectum

what are the cells within the mucosa?

• goblet cells → sec. mucus

• paneth cells → AMPs (defensin), lysozyme, lactoferrin, phospholipase A2

• brunner glands → sec. HCO3

what are the paneth cells defensins composed of?

• a → neutrophils, NK cells, paneth cells located in crypts of SI

• B → epithelial cells of skin + mucosa, immune cells

  • expression upregulated by infection, cytokine, IBD

what are MALTs? MALT lymphoma? cause? symptoms?

• adaptive immune response against pathogen @ mucosal sites

• lymphoma → chronic antigenic stim. of marginal B cells

  • cause: chronic infection (H. pylori) or autoimmune (sjorgren)

  • symptom: upper gastric pain, weight loss, fatigue, erythematous mass on funds (endoscopy)

what are GALTs?

• peyers patch (ileum)

• mesenteric LN

• large + small lymphoid aggregates (L: appendix, colon) (S: esophagus)

• lymphoid cells in LP

what type of cells do GALTs consist of? function?

• B + T cell, MO, DC, mast cells

• fxn: sample luminal antigens via

  • M cells: peyers patch, transcytosis → lymphoid → FDC/DC uptake

  • DC: LP, extend processes

  • sIgA: w/in binding antigen, transcytosis thru M cell → GALT → FDC/DC uptake

  • IgG: binds antigen + inwards transport via FcRn

what are the innate immune factors?

• gut microbiota

• AMP → defensins, lysozyme, lactoferrin, phospholipase A2

• PRR (TLR + NLR) → limit unnecessary inflammation

• tolerogenic MO → T reg attenuate inflammation via IG10 + TF

  • IL10 def. → diffuse inflammation via no attenuation

• ILC → interleukins

what are the types of ILCs?

• ILC1 → IFNy + TFNa → MO act. + elim. of IC infection (bacteria/virus), epithelial damage

• ILC2 → IL4, IL5, IL9, IL13 → eosinophilic act. + mucus prod., helminth infection

• ILC3 → IL17 + IL22 → defensin/AMP → enhance mucosa fxn + immune response, EC pathogen

what is the humeral adaptive immune response?

• IgA + IgM bind pIgR

• IgG binds FcRn

• homing of IgA producing B cells: TSLP → RALDH → retinoic acid → CCR9 → CCL25 → a4B7 → MAdCAM

what are the cellular (IEL) adaptive immune factors?

• natural IEL → CD4-CD8-TCRaB+ T cells, CD4-CD8-TCRyo+ T cells

• induced IEL → CD8+ T cells, CD4+ T cells, TCRaB+ T cells

what are the cellular (T cell) adaptive immune factors?

• Treg → TGF-B + IL10 (attenuate)

• Th2 → IL4, IL5, IL9, IL13 (eosinophil act. + mucus for helminth)

• Th17 → IL17, IL22 (defensin/AMP + EC pathogen response)

what are the lymphatic adaptive immune factors?

• a4B7 (LPAM-1) → MAdCAM-1 (mucosal HEV endothelium)

• CD62L (L selectin) → GlyCAM-1 + CD34 (all HEV endothelium, weak)

• LFA-1 → ICAM-1 (all HEV endothelium, strong)

• CCR7 → CCL19, CCL21 (all HEV endothelium, chemotaxis)

what causes celiac disease? symptoms? what does it causes risk of?

• HLA-DQ2/8 mut. → tissue-transglutaminase (TTG) antibody response against gluten + villous atrophy

• symptom: growth delay, diarrhea, belly pain, irritability, muscle pain, anemia, dermatitis, herpetiformis

• @ risk for vit. D, B, Fe, Ca def.

what causes whipple? symptoms? histological examination?

• HLA-B27 haplotype w/ gram (+) tropheryma whipplei infection → GI malabsorption

• symptoms: weight loss, abdominal pain, diarrhea, arthritis (WADA) → can involve CV, CNS, joint

• histological → foamy MO in intestine

what is IBD? symptoms?

• failure of oral/gut mucosal tolerance, ass. w/ gut dysbiosis + genetic predisposition

• symptoms → intermittent diarrhea, abdominal pain, rectal bleed/bloody stool, weight loss, malnutrition

what is the difference between UC and CD?

• UC → cont. inflammation of colon to rectum (some cecum)

• CD → scattered transmural inflammation on term ileum + colon (cobblestone)

  • fissures, fistulas, obstruction, abscess, perforation, sinus, stricture (FOAPS)

  • skip lesion, ileum + colon, perianal, spare rectum (SKIPS)

  • dense lymphocyte collection, defect in B defensin production

what causes type 0 GSD? symptoms

• def. glycogen synthase

• symptoms: severe fasting hypoglycemia (glycogen synthase is RLS of glycogenolysis)

what causes type 1 GSD (von Gierke)? symptoms?

• inc. G-6P in liver cells (muscles spared) → hypoglycemia (early death, seizures), lactic acidosis, liver enzymes normal

• type IA (G-6Pase def.)

  • hepato/renomegaly, doll like face

  • need NGT tube for glucose

• type IB (G-6P transporter def.)

  • diarrhea, bruising, neutropenia

what causes type II GSD (pompe)? symptoms?

• def. a-glucosidase (GAA) or acid maltase → dec. glycogen breakdown in lysosome (muscle)

• symptoms: cardiomegaly, floppy infant syndrome (hypotonia, low CK), macroglossia, resp. issues

  • high CPK, AST, LDH, glycogen filled vacuoles

what causes type III GSD (cori/forbes)? symptoms? how does it differ from type I GSD (von Gierke)?

• def. a-1,6-glucosidase (debrancher) (liver + some muscle)

• mild von Gierke BUT: less severe hypoglycemia, NO lactic acidosis

• weak bones, skeletal/cardiac muscle weakness, fasting ketosis (ketones in urine), inc. AST/ALT

what causes type IV GSD (andersen)? symptoms?

• def. glycosyl 4,6 transferase branching enzyme (GBE1)

• symptoms: neuro impact, elevated bilirubin, prolonged PT/INR

what causes type V GSD (McArdle)? symptoms?

• def. muscle glycogen phosphorylase (myophosphorylase) → removes glucose form outer branch (muscle)

• symptoms: burgundy urine, exercise intolerance (cramps), “2nd wind” after VD

  • inc. CK

what causes type VI GSD (hers)? symptoms?

• mut. liver glycogen phosphorylase

• symptoms: hepatomegaly, hypoglycemia, fasting hyperlipidemia+ ketosis

• better after eating

what is the exocrine and endocrine function of the pancreas?

• exocrine → pancreatic juice w/ enzymes digesting carbs (amylase), proteins (trypsin), fats (lipase)

  • endocrine → islet cell

    • a → glucagon

    • B → insulin, amylin

    • D → somatostatin

what causes acute pancreatitis? how does necrosis occur?

• trypsinogen + chymotrypsin early act. w/in pancreas → autodigestion inflammation + hemorrhage (severe= necrosis)

• damage = lipase release from acinar cell → saponification necrosis

what is the difference between interstitial/edematous pancreatitis and acute hemorrhagic pancreatitis?

• interstitial/edematous → mild inflammation w/ edema + wide interstitial space (85%)

  • no necrosis, not Tx, spontaneous heal

• acute hemorrhagic → severe, prominent enzyme mediated tissue destruction (15%)

what are the etiologies of acute pancreatitis? diagnosis? imaging?

• idiopathic, gallstone, EtOH, trauma, steroids, mumps, autoimmune, scorpion bite, hypertriglyceridemia/hypercalcemia, ECRP, drugs (valproic acid azathioprine + diuretics)

• Dx: severe epigastric pain radiating to back, nausea/vomit, inc. amylase/lipase/trypsin

  • US w/ enlarged hypoechoic pancreas or CT w/ contrast showing pancreatic necrosis, inflammation, retroperitoneal fluid

what is chronic pancreatitis? labs? US? etiologies?

• persistent pancreas inflammation → impair endocrine fxn

• labs: inc. serum lipase, amylase (sometimes bilirubin + ALP if bile duct compress)

• US → calcification, ductal dilation, pancreatic enlargement, peripancreatic fluid accumulation

• etiologies → gallstone, alcohol, hypertriglyceridemia/hypercalcemia, tumors blocking cyst, cystic fibrosis

pancreatic cancer symptoms? risk factors?

• courvoisier sign (distended GB), trousseau sign, sister mary-joseph node

• risk: hereditary pancreatitis, BRCA2, peutz-jeghers, ataxia telangiectasia, ABO blood, chronic pancreatitis, smoking, obesity, NSAIDs, H. pylori, infection HepB

pancreatic cancer symptoms? imaging?

• symptom: epigastric pain radiating to back, weight loss, obstructive jaundice, steatorrhea, new onset diabetes (asymptotic until invasion)

• imaging: endoscopic US, percutaneous pancreatic biopsy (FNA), CT, ERCP, MRCP, MRI

cholelithiasis? cholecystitis? choledocholithiasis? cholangitis? cancer?

• cholelithiasis (gallbladder stones) → light stool/dark urine

• cholecystitis (inflammation) → + murphy sign

  • US, MRCP (dilation), ERCP, Tx: cholecystectomy

• choledocholithiasis (bile duct stone) → cut. jaundice + scleral icterus, hyperbilirubinemia

  • ERCP

• cholangitis (bile system inflammation) → charcot triad (RUQ, fever, jaundice)

• cancer → calcification/fibrosis (porcelain GB)