LO14 - Hepatitis Flashcards
Outline the metabolic consequence of hepatic failure.
impaired carbohydrate metabolism - decreased glycogen production, gluconeogenesis - impaired glycaemic control
impaired fat metabolism - decreased fatty acid oxidation; decreased synthesis of cholesterol, phospholipids and lipoproteins
impaired protein metabolism - decreased conversion of ammonia to urea, decreased production of plasma proteins, decreased amino acid metabolism
decreased storage of vitamins, iron as ferritin
impaired removal/excretion of excess drugs, hormones and other substances - increased activity of hormones, hypercalcaemia
What pharmacological treatments are available to assist patients to cease abusing alcohol? How do those drugs work, and how effective are they?
for acute alcohol withdrawal:
benzodiazepine - reduces severity of withdrawal symptoms, and anticonvulsant activity.
for ceasing alcohol long-term:
Acamprosate - MOA unknown; reduces symptoms of protracted alcohol withdrawal (anxiety, irritability, insomnia, craving); does not influence effects of alcohol, or cause unpleasant effects if alcohol consumed.
contraindications: renal failure (drug is renally excreted)
adverse effects: diarrhoea, nerves, fatigue
Naltrexone - blocks mu-opioid receptor, less pleasurable effects from alcohol consumption, fewer cravings for alcohol, most effective in binge drinking, heavy drinkers. does not produce unpleasant effects if alcohol consumed.
contraindications: opioid users, acute hepatitis/liver failure
adverse effects: nausea, headache, dizziness
Disulfiram - inhibits aldehyde dehydrogenase –> prevent’s metabolism of alcohol–> acetaldehyde
drinking etoh while taking disulfiram results in accumulation of acetaldehyde in blood –> tachycardia, dyspnoea, hyperventilation, vomiting, headache, sweating. may develop chest pain, hypotension, seizures, LOC, cardiorespiratory arrest. therefore acts as disincentive to take alcohol. effective only in highly motivated pts, with full compliance, who understand risks.
Always:
IV thiamine
Discuss the pathogenesis of the clinical features and complications of cirrhosis.
Pathogenesis:
Fibrosis- perisinusoidal stellate cells produce collagen –> excess collagen deposited in space of Disse (in between hepatocyte and vascular endothelium) –> impaired exchange of solutes between hepatocytes and plasma and narrowing of sinusoidal lumen
Parenchymal nodules - surviving hepatocytes regenerate and proliferate as spherical nodules within the confines of the fibrous septa.
Disruption of liver architecture - disruption of blood to hepatocytes –> hepatocellular death, ability of hepatocytes to secrete substances into plasma, and obliteration of biliary channels.
Clinical features: Portal hypertension leading to: Portosystemic venous shunts: haemorrhoids, oesophageal varices, caput medusa, congestive splenomegaly, portal vein thrombosis Ascites Jaundice Hepatic failure
Complications:
Hepatocellular carcinoma
Spontaneous bacterial peritonitis
Describe the metabolic consequences of obstruction to the biliary tree
Hyperbilirubinaemia – impaired outflow of conjugated bilirubin back-passage into blood hyperbilirubinaemia. Results in:
o Jaundice – deposition of bilirubin in skin and sclerae yellow discolouration.
o Dark urine – renal excretion of conjugated (water-soluble) bilirubin in urine.
o Pale stools – absence of bilirubin in GIT decreased urobilinogens (which usually pigment stools).
o Pruritis – deposition of irritant bile salts in skin.
Elevated ALP
o Biliary obstruction impaired outflow of hepatic ALP backflow into serum.
Malabsorption of fats and fat-soluble vitamins (ADEK) steatorrhoea, osteomalacia, bleeding tendency, weight loss.
Explain the pathophysiological basis of AST/ALT abnormalities
AST (aspartate aminotransferase) and ALT (alanine aminotransferase)
o Catalyse the transfer of aspartate and alanine to the alpha-keto group of ketoglutarate, which results in formation of pyruvate and oxaloacetate.
o ALT – highest concentration in liver.
o AST – in decreasing order of concentration, in liver, cardiac muscle, skeletal muscle, kidneys, brain, pancreas, lungs, leukocytes, erythrocytes. Therefore, less specific than ALT for liver disease.
o Intracellular enzymes released when hepatocytes are necrosed enter bloodstream.
Explain the pathophysiological basis of ALP/GGT abnormalities
ALP (alkaline phosphatase)
o Group of enzymes that catalyse hydrolysis of organic phosphate esters at an optimum alkaline pH.
o Found in liver, bone, GIT, first trimester placenta, and kidneys not specific for liver.
o If elevated, look at GGT – if this is high, suggests hepatobiliary origin; if normal, suggests bone origin.
o Biliary obstruction impaired outflow of hepatic ALP backflow into serum.
GGT (gamma-glutamyl transferase)
o Catalyses the transfer of gamma-glutamyl group from gamma-glutamyl peptides to other peptides and amino acids.
o Present in cell membrane of many tissues, including liver, bile ducts, kidneys, pancreas, spleen, heart, brain, seminal vesicles.
o Biliary obstruction increased serum concentration.
Explain the pathophysiological basis of bilirubin abnormalities
Bilirubin
o Product of heme metabolism in liver.
o Total bilirubin = conjugated (~30%) + unconjugated (~70%) bilirubin.
o Liver disease may either impair conjugation bilirubin ( unconjugated bilirubinaemia) or impair outflow of conjugated bile (e.g. cholestasis, intrahepatic inflammation and necrosis conjugated bilirubinaemia).
Explain the pathophysiological basis of albumin and prothrombin time abnormalities
Albumin
o Protein produced exclusively by liver.
o Half-life is 20 days. Therefore decrease in serum concentration indicates prolonged liver damage/injury.
Prothrombin time
221
o All clotting factors except VIII are synthesised exclusively by liver.
o Prolonged PT may indicate impaired synthetic function of liver. But need to exclude vitamin K deficiency as alternative cause.
Outline the LFT patterns you would expect in
1) hepatitis
2) hepatic infiltration
3) biliary obstruction; and
4) hepatic failure
Acute hep:
- AST/ALP: super high
- ALP/GGT: normal or slightly high
- bilirubin: super high
- albumin: normal
- PT: slightly elevated
Hep infiltration: everything normal except ALP raised
Biliary obstruction:
- AST/ALT: slightly elevated
- ALP/GGT: really high (especially ALP)
- bilirubin: really high
- albumin, PT: normal
Hepatic failure
- everything slightly elevated except reduced albumin
Compare and contrast hepatitis caused by the hepatotropic viruses HAV, HBV, HCV, HDV and HEV.
Hepatitis A
faecal-oral route.
acute, self-limited (mild flu-like illness to fulminant hepatitis)
Diagnosis: anti-HAV IgM.
Prevention: Vaccine (decreases risk of infection by 95%, sanitation)
Hepatitis E
faecal-oral route
Clinical features – same as HAV.
Diagnosis: HEV in serum or stool by PCR +/- anti-HEV IgM.
No vaccine
Hepatitis B
Risk factors: parenteral (IDU, needlesticks, contaminated blood products, etc), sexual (particularly anal sex), vertical, horizontal (most commonly child-to-child, e.g. by biting).
Acute infection or Chronic infection (1-10% in adults)
Hepatitis D
requires simultaneous presence of HBV
Co-infection: HBV and HDV co-infect a new pt –> acute hepatitis B + D (1-10% risk of chronic hepatitis)
Super-infection: HDV infection superimposed on pre-existing chronic HBV infection –> severe acute hepatitis with progression to chronic infection
Hepatitis C
Transmission in Australia: 82% IDU, 11% from endemic countries, 7% from blood products
Risk factors: sharing needles, contaminated blood products, prison, unsafe tattooing and body piercing
o Acute infection – 85% asymptomatic. Non-specific symptoms e.g. fatigue, nausea, arthralgia, myalgia, anorexia.
o Chronic injection (60-85% risk) – most asymptomatic. May have non-specific symptoms. 15% have extrahepatic manifestations: cryoglobulinaemia, membranoproliferative glomerulonephritis, leukocytoclastic vasculitis, thyroiditis.
Discuss the pathogenesis of virally induced chronic hepatitis
o Progression from acute to chronic disease signifies failure of the immune response to eradicate the virus.
o HBV and HCV are not directly toxic to hepatocytes. Liver injury results from host immunologic response to viruses.
o Evoke both cellular and humoral responses
Define autoimmune hepatitis
Chronic hepatitis of unknown aetiology characterised by hyperglobulinaemia, presence of circulating antibodies, and inflammatory changes on liver histology
What are the clinical features of autoimmune hepatitis
- varies from asymptomatic to liver failure
- 25% acute hepatitis and systemic signs (fever, malaise, urticarial rash, polyarthritis, pleurisy, pulmonary infiltrates, GN).
- 75% insidious disease/incidental finding (abnormal LFTs).
- Extra-hepatic manifestations – haemolytic anaemia, idiopathic thrombocytopaenic purpura, type 1 DM, thyroiditis, coeliac disease, ulcerative colitis.
Outline the spectrum of liver disease associated with alcohol abuse.
Steatosis
o Normal Alcohol intake -> microvesicular lipid droplets accumulate in hepatocytes
o Chronic alcohol intake -> large macrovesicular globules of lipid ->compress and displace nucleus to periphery of hepatocyte
o Initially occurs in centrilobular region, in severe cases it may involve entire lobule.
o Fatty change is completely reversible with abstinence from alcohol.
o Usually asymptomatic, may have mild hepatomegaly or mild LFT derangements.
Alcoholic hepatitis
- Characterised by:
Hepatocyte swelling and necrosis - Swelling due to accumulation of fat, water and proteins.
Mallory bodies - Eosinophilic accumulations of intracellular protein within cytoplasm of hepatocytes.
Neutrophils
Fibrosis -> activation of sinusoidal stellate cells and portal tract fibroblasts -> sinusoidal and perivenular fibrosis.
- Clinical features
Fever
Hepatomegaly - may be tender - due to steatosis and swelling of hepatocytes
Jaundice
Anorexia
Bruit over liver – indicates severe hepatitis
Hepatic encephalopathy
Bleeding
Cirrhosis
Hepatocellular carcinoma
- At increased risk.
List factors predisposing to the development of cirrhosis of the liver.
- Alcoholic liver disease 60-70%
- Viral hepatitis 10%
- Biliary diseases 5-10%
- Primary biliary cirrhosis - presumably autoimmune disease; chronic, progressive cholestatic liver disease -> Destruction of intrahepatic bile ducts, portal inflammation, scarring.
- Secondary biliary cirrhosis - prolonged obstruction of extrahepatic biliary tree -> periportal fibrosis -> hepatic scarring and nodule formation -> hepatic cirrhosis. (Causes: gallstones, malignancies of biliary tree or head of pancreas, strictures, biliary atresia, CF, choledochal cysts)
- Primary sclerosing cholangitis - inflammation and obliterative fibrosis of intrahepatic and extrahepatic bile ducts, with dilation of preserved segments. Unknown cause.
- Inherited metabolic liver disease
- Haemochromatosis 5% - excess iron deposition in organs micronodular cirrhosis in liver
- Wilson disease – autosomal recessive disorder marked by accumulation of toxic levels of copper in many tissues, principally liver, brain and eye.
- Alpha1-antitrypsin deficiency.
- Autoimmune hepatitis
- Hepatic venous outflow obstruction
- Cardiac cirrhosis = development of chronic liver injury and cirrhosis secondary to long-standing right-sided congestive heart failure.
- Budd-Chiari syndrome - caused by occlusion of hepatic veins, classic triad of abdo pain, ascites and hepatomegaly. (Causes: idiopathic (50%), thrombosis of hepatic vein, compression of hepatic vein by outside structure (e.g. tumour). )
- Idiopathic (cryptogenic) 10-15%
- Secondary to NAFLD = condition that resembles alcohol-induced liver disease, but occurs in pts who are not heavy drinkers. Strong associations with obesity, dyslipidaemia, hyperinsulinaemia and insulin resistance, and type 2 DM.
