Liver and Biliary Tract Flashcards
Hepatic Failure
- when 80-90% of hepatic function is lost.
- mortality is 80%.
- presentation: jaundice, hypoalbuminemia with systemic edema, hyperammonemia, fetor hepaticus (odor from mercaptan formation), hyperestrogenemia from impaired estrogen metabolism (have palmar erythema, spider angiomata, hypogonadism, gynecomastia).
- complications: coagulopathy, multiple organ failure, hepatic encephalopathy (from porto-systemic shunting and loss of hepatocellular function. excess ammonia ⇒ brain edema, disturbances in consciousness, limb rigidity, hyperreflexia, asterixis), hepatorenal syndrome (↓ renal perfusion pressure, renal vasoconstriction, sodium retention, impaired free-water excretion), hepatopulmonary syndrome (from intrapulmonary vascular dilation and functional shunting from pulmonary arteries to veins, have hypoxia, V/Q mismatch).
Acute Liver Failure
- liver illness associated with encephalopathy within 6 months of initial diagnosis.
- from hepatic necrosis from drug/toxin injury, viral hepatitis, autoimmune damage.
Chronic Liver Disease
- most common cause of failure.
- ends in cirrhosis
Hepatic Dysfunction without Overt Necrosis
- viable hepatocytes can’t perform normal metabolic functions.
Liver Cirrhosis
- from alcohol abuse, viral hepatitis, non-alcoholic steatohepatitis. biliary disease and hemochromatosis less common.
- 20% are cryptogenic cirrhosis = unknown cause.
- characteristics = bridging fibrosis (links portal tracts with central veins), parenchymal nodules (hepatocyte regeneration when encircled by fibrosis), disrupted hepatic parenchymal architecture.
-
pathogenesis: hepatocyte death, ECM deposition, vascular reorganization.
- types I and III collagen deposited in space of Disse. sinusoidal endothelium loses fenestration. new vascular channels link portal triads to central veins.
- fibrosis from proliferation and activation of stellate cells, promoted by PDGFreceptor beta. causes ↑ collagen synthesis and ↑ intrahepatic vascular resistance.
- stellate cells and fibroblasts activated by: TNFalpha and IL-1beta, TFG-beta, direct toxin stimulation, disruption of ECM.
-
presentation: silent until advanced. anorexia, weight loss, weakness, debilitation. precipitated by infection or GI hemorrhage.
- death from progressive liver failure, complication of portal HTN, hepatocellular carcinoma.
Portal Hypertension
- from ↑ flow into portal circulation and/or ↑ resistance to portal blood flow.
- prehepatic = from thrombosis, portal vein narrowing, ↑ splanchnic arterial circulation, massive splenomegal with ↑ splenic vein blood flow.
- intrahepatic = cirrhosis, schistosomiasis, massive fatty change, granulomatous disease, or nodular regenerative hyperplasia.
- posthepatic = right-sided heart failure, constrictive pericarditis, hepatic vein obstruction.
-
consequences: ascites, portosystemic shunts, splenomegaly
- ascites = have hypeatic sinusoidal hypertension from hypoalbuminemia, hepatic lymph in peritoneum, splanchnic vasodilation causes hypotension so retain sodium and water, have intestinal capillary transudation.
- portosystemic shunts = from ↑ portal pressure. flow reversed from portal into systemic circulation. usually at esophagogastric varices, can rupture and have massive hematemesis. also at rectum (hemorrhoids), and falciform ligament/umbilicus (caput medusa).
- splenomegaly = from long-standing congestion. can get thrombocytopenia from hypersplenism.
Bilirubin and Bile Formation
- heme degraded to biliverdin to bilirubin, then bound to albumin, delivered to liver, conjugated to glucuronic acid by **UGT1A1 **⇒ water soluble bilirubin glucuronides excreted in bile, deconjugated in gut, degraded to urobilinogen and fecally eliminated.
- 20% urobilinogen reabsorbed and go to liver.
Icterus
- yellow sclera discoloration.
Jaundice
- yellow skin discoloration.
- bilirubin production exceeds hepatic uptake, conjugation, and/or excretion.
- unconjugated hyperbilirubinemia = excess production or diminished uptake and/or conjugation.
- conjugated hyperbilirubinemia = defective excretion
Unconjugated Bilirubin
- water insoluble. usually bound to albumin.
- small amount circulates free and can diffuse into tissues (neonatal brain).
- unbound fraction increases with severe hemolysis or when drugs displace from albumin.
Conjugated Bilirubin
- water-soluble, non-toxic, loosely bound to albumin.
- excess is renally excreted.
Neonatal Jaundice
- transient, mild unconjugated hyperbilirubinemia until 2 weeks of age.
- hepatic metabolic machinery doesn’t develop until about 2 weeks.
- exacerbated by breast-feeding from bilirubin-deconjugating enzymes in breast milk.
Crigler-Najjar Syndrome Type 1
- autosomal recessive.
- total absence of UGT1A1 causes jaundice with high serum levels of unconjugated bilirubin, normal liver histology.
- need liver transplantation or will get kernicterus (fatal neurologic damage).
Crigler-Najjar Syndrome Type 2
- autosomal dominant.
- less severe UGT1A1 deficiency.
- not usually lethal but can get kernicterus.
Gilbert Syndrome
- autosomal recessive. 6-10% population.
- mild, fluctuating unconjugated hyperbilirubinemia, 30% ↓ UGT1A1 activity.
- exacerbated by infection, strenuous exercise, fasting.
Dubin-Johnson Syndrome
- autosomal recessive.
- defective hepatocyte secretion of conjugated bilirubin from absent MDR2 (does bilirubin glucuronide transport).
- liver is brown, accumulated pigment granules.
- jaundiced but have normal life expenctancy.
Rotor Syndrome
- autosomal recessive.
- defective hepatocellular bilirubin uptake or excretion.
- jaundiced with normal life expectancy.
Cholestasis
- impaired bile formation or flow ⇒ accumulation of intrahepatic bile pigments.
- extrahepatic = duct obstruction
- intrahepatic = hepatocellular dysfunction or canalicular obstruction.
- consequences: jaundice, pruritus, xanthomas (skin accumulations of cholesterol), intestinal malabsorption, ↑ serum levels alkaline phosphatase and GGT.
-
morphology: bile pigment accumulates in hepatic parenchyma ⇒ dilated bile canaliculi and hepatocye degeneration.
- obstruction ⇒ distended proliferating bile ducts in portal tracts, edema, periductular neutrophils.
- prolonged ⇒ bile lakes, portal tract fibrosis, and cirrhosis.
- obstruction ⇒ distended proliferating bile ducts in portal tracts, edema, periductular neutrophils.
Progressive Familial Intrahepatic Cholestasis (PFIC)
- autosomal recessive disorders from mutated ATP-dependent transporter proteins.
- PFIC-1 = Bylder disease or Benign recurrent intrahepatic cholestasis.
-
PFIC-2 = mutated ABCB11 gene for bile salt export pump in canaliculi.
- have cholestasis, extreme pruritus, growth failure, progession to cirrhosis in 1st decade.
- GGT levels normal.
-
PFIC-3 = mutated ABCB4 gene for MDR3 protein for biliary phosphatidycholine secretion.
- ↑ GGT levels from biliary epithelium damage by bile salts.
Byler Disease
- PFIC-1. mutated ATP8B1 gene impairs bile secretion.
- cholestasis in infancy, progesses to liver failure by aduthood.
- no damage to canaliculi or biliary tree, normal GGT, normal bile ducts.
Benign Recurrent Inrahepatic Cholestasis
- mild form of PFIC-1. affects ATP8B1 gene.
- intermittent attacks of cholestasis, doesn not progress to chronic liver disease.
Hepatitis A Virus
- aka HAV. related to picornavirus.
- 25% acute hepatitis.
- ssRNA virus causing benign, self-limited disease.
- transmission: fecal-oral
- incubation: 2-4 weeks.
- damage from CD8+ T cell response.
- does not progress to chronic liver disease.
- detection: anti-HAV IgM in acute infection. IgG remains with immunity.
Hepatitis B Virus
- aka HBV. hepadnavirus.
- dsDNA virus,causes acute, self-limited hepatitis, non-progressive chronic hepatitis, progressive chronic disease with cirrhosis, fulminant hepatitis with massive liver necrosis, asyptomatic carrier state.
- Dane particle with outer surface protein and lipid envelope encasing electron-dense core.
- 4 reading frames: HBcAg (core antigen), HBeAg (into bloodstream), HBsAg (surface antigen), HBx (for viral replication).
- strong response by CD4+ and CD8+ IFN-gamma for resolution. damage via CD8+ cells.
- related to cancer development (hepatocellular carcinoma).
-
transmission: parenteral, sexual contact, perinatal.
- high prevalence = from childbirth.
- intermediate-prevalence = minor cuts or breaks in mucus membranes.
- low prevalence = IV drug abuse, unprotected sex.
- incubation: 1-4 months.
- 10% get chronic liver disease.
- morphology: finely granular ‘ground-glass’ cytoplasm with HBsAg.
-
detection: HBsAg before symptoms (anorexia, fever, jaundice). HBeAg and HBV DNA after HBsAG and before disease onset, persistence of HBeAg means chronic disease. Anti-HBcAg IgM first, then anti-HBeAg IgM and anti-HBcAg IgG. anti-HBsAg means end of acute disease and immunity.
- chronic carrier = HBsAg in serum for 6 months.
- detect by HBsAg or Ab to HBcAg.
Hepatitis C Virus
- aka HCV. flaviridae.
- ssRNA, enveloped. substantial genomic variability (quasispecies).
- E2 envelope protein targeted by Abs, also most variable.
- antibodies don’t cause immunity.
- 80-85% go on to chronic liver disease. cirrhosis in 20-30%.
- damage is immune mediated.
- transmission: parenteral, intransal cocaine.
- risk groups: IV drug abusers, multiple sexual partners.
- incubation: 7-8 wks.
- morphology: portal lymphoid aggregates, bile duct reactive changes, lobular regions of macrovesicular steatosis.
-
detection: HCV RNA in blood for 1-3 wks during active infection with transaminase elevation. anti-HCV Ab in 50-70% in acute, 90% in chronic.
- PCR for HCV RNA.
- tx: for chronic use IFN-gamma and ribovarin.
Hepatitis D Virus
- aka HDV.
- circular defective ssRNA, requires host RNA polymerase activity.
- only replicates and infects when encapsulated by HBsAg, so only when with HBV.
- ranges mild to fulminant, chronicity rare (5% for co-infection, <70% with superinfection).
- high prevalence in Africa, Middle East, Italy, and Amazon basin.
- Dane-like particle with HBV envelope. makes delta antigen.
- incubation: 1-4 months.
- detection: HDV RNA in blood and liver during infection, recent exposure has anti-HDV IgM, anti-HBcAg IgM = co-infection, HBsAg = superinfection
- have a vaccine.
Hepatitis E Virus
- aka HEV. Calicivirus.
- non-enveloped ssRNA, self-limiting, does not become chronic liver disease.
- transmission: water-borne enteric infection (fecal-oral) via monkeys, cats, pigs, dogs.
- epidemic in Asia, Africa, Mexico.
- endemic in India = 30-60% acute hepatitis.
- high rate of fatal fulminant hepatitis in pregnant women.
- incubation: 4-5 wks.
-
detection: HEV antigen in hepatocytes (PCR), RNA and virions in stool and serum before onset.
- IgG anti-HEV = immunity.
Hepatitis G Virus
- aka HGV.
- non-pathogenic RNA virus in 1-4% blood donors.
- replicates in marrow and spleen.
Acute Asymptomatic Viral Hepatitis with Recovery
- identified by ↑ transaminases or anti-viral Ab titers.
- HAV and HBV frequently subclinical.
Acute Symptomatic Viral Hepatitis with Recovery
- asymptomatic pre-icteric phase, symptomatic icteric phase, convalescence.
- peak infectivity during last few days of asymptomatic days and first few symptomatic days.
Chronic Hepatitis
- symptomatic disease with biochemical or serologic evidence of ongoing heptaic damage of more than 6 months.
- HCV>>HBV or HDV
- younger patients more likely to develop this, maternal-fetal transmission.
- causes ongoing liver injury, cirrhosis, hepatocellular carcinoma, immune complex disease with vasculitis and glomerulonephritis.
- 35% chronic HCV develop cryoglobulinemia.
-
morphology: mild to severe cirrhosis. mild = limited to portal tracts.
- extension of chronic inflammation from portal tracts with interface hepatitis, linking of portal-portal and portal-central regions = bridging necrosis.
- continued loos of hepatocytes ⇒ fibrous septum formation, associated hepatocyte regeneration causes cirrhosis.
- major cause of morbidity and mortality in HIV pts. second most common cause of death in AIDs.
Carrier State (viral hepatitis)
- harbors and tramsits hepatitis without symptoms.
- patients with chronic disease and few/no symptoms, and those with few or no adverse effects (healthy carriers).
- for HBV, healthy carriers lack HBeAg but have anti-HBeAg, normal aminotransferase levels, low serum HBV DNA, no significant necrosis or inflammation.
HIV and Chronic Viral Hepatitis
- 10% HIV pts have HBV, 30% have HCV causing aggressive liver disease.