Module 7 Pathophysiology PDF

MODULE 7: PATHOPHYSIOLOGY I. HEPATOBILLIARY TREE DISORDERS [A. Hepatitis] -- liver inflammation Etiology: \- viral infection \- toxins \- drugs \- other immune mediated **I. Viral Hepatitis** Acute Viral Hepatitis Definition -- viral hepatitis lasting [\< 6 months] Clinical Features: \-...

MODULE 7: PATHOPHYSIOLOGY I. HEPATOBILLIARY TREE DISORDERS [A. Hepatitis] -- liver inflammation Etiology: \- viral infection \- toxins \- drugs \- other immune mediated **I. Viral Hepatitis** Acute Viral Hepatitis Definition -- viral hepatitis lasting [\< 6 months] Clinical Features: \- most are subclinical \- early symptoms or prodrome ([flu-like illness]) may precede jaundice by 1-2 weeks \- nausea, vomiting, anorexia, taste/smell disturbance (aversion to cigarettes) headaches, fatigue, malaise, myalgias \- low-grade fever may be present arthralgia and urticaria (especially hepatitis B) \- clinical jaundice (icteric) phase (50% of cases) lasting days to week - Pale stools and dark urine 1-5 days prior to icteric phase - Hepatomegaly plus RUQ pain - Splenomegaly and cervical lymphadenopathy (10-20% of cases) \- Hepatic enzymes - Hepatocellular necrosis which causes increased AST, ALT \> 10-20X normal - ALP and Bilirubin minimally increased - WBC normal or slightly decreased initially [Viral Hepatitis -- (A&E=Acute, B&D= Acute & Chronic, C=Chronic)] [**A**. HEPATITIS A VIRUS (Acute) ] ETIOLOGY \- Hepatitis A Virus (Most Common Viral Hepatitis Worldwide) PATHOGENESIS \- Fecal-Oral Transmission \- 2-6wk Incubation \- Virus is Directly Cytopathic to the Liver -- But Does NOT lead to Cirrhosis Clinical Features: \- Acute Symptoms ONLY; No Chronic. \- Viremia \> Fever, Malaise, Anorexia, Nausea, Arthralgia Signs: \- Jaundice (After 1-2wks) (Due to Intrahepatic Cholestasis) - Inc Conjugated Bilirubin \- +/- Hepatomegaly \- +/- Splenomegaly \- +/- Tender Lymphadenopathy \- Rarely - Hepatic Encephalopathy & Death. Investigations: \- LFTs - (Everything Raised) \- Hep A Serology \- Hep A PCR Prognosis: \- Usually Self-Limiting with Supportive Treatment Only [B. HEPATITIS E VIRUS (ACUTE)] \- (Very Similar to Hepatitis A; But HIGH MORTALITY in PREGNANCY \[20% \> DIC in 3rd Trimester\]) Etiology: -- Hepatitis E Virus (A Herpesvirus) Pathogenesis: \- Virus is Directly Cytopathic to the Liver Clinical Features: \- Fecal-Oral Transmission (Incl. Vectors: Dogs/Pigs/Rodents) Clinical Picture: \- (Same as Hep A) Investigations: \- LFTs ʹ (Everything Raised) \- Hep E Serology \- Hep E PCR Prognosis: \- 1-2% Mortality (From Fulminant Hepatic Failure) \- 20% Mortality in Pregnancy (From DIC in 3rd Trimester) [ACUTE AND CHRONIC VIRAL HEPATITIS] [A. HEPATITIS B VIRUS (HBV)] \- transmission via parenteral route or equivalent \- vertical transmission - occurs during 3rd trimester or early post-partum - HBsAg +ve, HBeAg +ve mothers ----\> 90% of infants infected - HBsAg +ve, anti-HBe +ve mothers ---- \> 10-15% infected - give HBIG and full HBV vaccination to newborns of HBsAg +ve mothers (90% effective) \- incubation period 6 weeks to 6 months \- infectivity: during HBsAg positivity \- high-risk groups - neonates of carriers ("vertical transmission") - partners of acutely and chronically infected individuals, with male homosexuals at particular risk - IV drug users - hospital employees - patients from endemic country **[Hepatitis B serology:]** \- HBsAg: surface antigen \- HBeAg: e antigen (a component of HBV core); marker of viral replication \- HBcAg: core antigen (cannot be measured in serum) \- Both HBsAg and HBeAg are present during acute hepatitis B \- Anti-HBs follows HBsAg clearance and confers long-term immunity \- Anti-HBe and anti-HBc appear during the acute and chronic phases of the illness but do not provide immunity! \- Anti - HBe indicates low infectivity Prevention: \- HBV vaccine = recombinant HBsAg \- Seroconversion rates about 94% after 3 injections \- Hepatitis B immune globulin (HBIG) = antiHBs - for needle stick, sexual contact, and neonates born to mothers with acute or chronic infection [B.] [HEPATITIS C VIRUS (HCV)] \- Transmission is chiefly parenteral - Transfusions (HCV is the most common cause of post-transfusion hepatitis) - IV drugs use - Sexual transmission occurs but risk is less than with HBV - 40% of cases have no risk factors \- Clinical incubation period 5-10 weeks \- AST and ALT levels fluctuate (unlike Hep A or B) \- More than half progress to chronic liver disease (see below) \- Serology - HCV RNA (detected by PCR assay) o anti-HCV - develops in 6-8 weeks in 85% of patients - persists in chronic infection and does not confer immunity Prevention: \- no accepted vaccine for HCV [C. HEPATITIS D (HDV)] \- infectious only in the presence of HBV because HBV surface antigens are required for replication \- 2 patterns of transmission - nonparental transmission by close personal contact in endemic areas (Mediterranean) - transmission by blood products in non-endemic areas (IV drugs, blood transfusions) \- coinfection: simultaneous HBV and HDV infection \- superinfection: appears as clinical exacerbation in a chronic HBV patient \- predisposes to severe or fulminant course \- Serology: HBsAg, anti-HDV IgM or anti-HDV IgG Prevention: HBV vaccine D. HEPATITIS E VIRUS (HEV) \- fecal-oral transmission occurring in epidemics in Asia, Africa, Central America \- Most have mild disease, but in 3^rd^ trimester of pregnancy 10-20% have fulminant liver failure \- Serology: Anti-HEV Prevention: no vaccine available DRUG INDUCED LIVER DISEASE / DRUG INDUCED HEPATITIS SPECIFIC DRUGS: I. [Acetaminophen ] - Metabolized by hepatic cytochrome P450 system - Can cause fulminant hepatic failure (transaminases \> 1,000 U/L) - Requires 10-15g in normals, 4-6g in alcoholics/anticonvulsant users **Mechanism:** - High acetaminophen doses saturate glucuronidation and sulfation elimination pathways, therefore a reactive metabolite is formed which covalently binds to hepatocyte membrane **Presentation:** - First 24 hrs: nausea and vomiting usually within 4-12 hours - Next 24-48 hrs: hepatic necrosis resulting in increased aminotransferases, jaundice, possibly hepatic encephalopathy, acute renal failure death - After 48 hrs: continue hepatic necrosis/resolution - Note: potential delay in presentation in sustained-release products **-** Blood levels of acetaminophen correlate with the severity of hepatic injury **Therapy:** - Gastric lavage/emesis (if 2 hrs after ingestion) - Oral charcoal - N-acetylcysteine PO/IV within 8-10 hours of ingestion, most effective for up to 72 hours (promotes hepatic glutathione synthesis) [II. Chlorpromazine] - Cholestasis in 1% after 4 weeks; often with fever, rash, jaundice, pruritus and eosinophilia [III. INH] - 20% develop elevated transaminases but \< 1% develop clinically significant disease - Susceptibility to injury increases with age [IV. Methotrexate ] - May rarely cause cirrhosis, especially in the presence of obesity, diabetes, alcoholism - Scarring develops without symptoms or changes in liver enzymes, therefore biopsy may be needed in long-term treatment [V. Amiodarone] - Can cause same histology and clinical outcome as alcoholic hepatitis A. [Cholelithiasis] **Pathogenesis:** - Imbalance of cholesterol and its solubilizing agents, bile salts and lecithin concentrations - If hepatic cholesterol secretion is excessive then bile salts and lecithin are "overloaded", supersaturated cholesterol precipitates and can form gallstones **Types of Stones:** \- Cholesterol (80%) = mixed (\>70% cholesterol by weight), radiolucent - Risk factors: - Female, fat, fertile, forties - North American First Nations People have highest Incidence - Diabetes Mellitus (DM), Pancreatitis