Pathophysiology of the liver Tornóci László Institute of Pathophysiology Semmelweis University

Significance of the liver Large organ of vital importance, kg Filter, getting 1/4 of cardiac output –20% a. hepatica (systemic, oxygenated) –80% v. portae (rich in nutrients, deoxygenated) The central organ of biochemistry: –synthesis, excretion, metabolism, biotransformation (“detoxification”) Storage (nutrients, iron) Digestion (emulsification of fat)

Metabolic consequences of liver diseases carbohydrates –hyperglycemia (postprandial) –hypoglycemia (in alcoholics, after prolonged fasting) proteins: albumin, coagulation factors  lipids:fatty liver decrease of catabolic/excretory function –e.g. estrogens, many drugs!

Clinical signs of liver diseases Nausea, temperature, fatigue Physical examination: –Palpable, tender liver, splenomegaly –jaundice (icterus), palmar erythema, spider naevi, excorations, less body hair –foetor hepatis Symptoms of portal hypertension –ascites, caput Medusae, esophageal varices Bleeding tendency Confusion, coma

Major laboratory signs of liver diseases Enzyme activities –parenchymal (ALT, AST) –obstructive (alkaline phosphatase, GGT) bilirubin albumin, A/G prothrombin time antigens, antibodies

Classification of liver diseases CauseClinical appearance hepatocellular (parenchymal) acute liver injury - atrophia hepatis flava chronic hepatitis cirrhosis hepatobiliar (cholestatic)obstructive jaundice vascular, other vascular, systemic, storage etc. diseases

Parenchymal liver diseases acquired –toxic effects (alcohol, mushroom, drug) –infections (hepatotropic and other viruses, etc) –autoimmune disorders congenital –inherited hyperbilirubinemias –other genetic syndromes (e.g. Wilson’s disease)

Effect of alcoholism on the liver Fatty liver, alcoholic hepatitis, cirrhosis Threshold dose for liver injury –In men g/day over years –In women g/day It turns into severe, irreversible process in only 15 % of the cases The risk factors for this are unknown Undernutrition is not a risk factor

Less alcohol causes cirrhosis in women

Drug induced liver injury Dose dependent –acetaminophen: minimum g, but 2 g may be enough in alcoholics (because of inducing P450 2E1) Idiosyncratic (independent of dose) –toxic reacion: halothane, methyldopa, phenytoin, “alternative medicines” –cholestasis: chlorpromazine, erythromycin, oral contraceptives, TPN

Hepatotropic viruses HAV (infectious hepatitis) HBV (serum hepatitis) HDV (delta agent, defect virus) HCV (parenteral nonA-nonB) HEV (enteral nonA-nonB) NANE (nonA-nonE) HGV (not significant clinically)

Overview of viral hepatitis types Major route of infection Fulminant course % Becomes chronic % Prevention A fecal-oral0.1neverIG, vaccine B percutaneous perinatal sexual IG, vaccine C percutaneous none D see HBV5-20 * see HBVHBV vaccine E water1-2 ** nevernone * : low in coinfection, high in superinfection **: 10-20% in pregnant women

Chronic hepatitis Caused by virus, drug or autoimmune disease Types of health problems caused –epidemiological (carriers of virus) –progressive liver damage is possible –may turn into cirrhosis –may cause hepatocellular carcinoma

Classification of chronic hepatitis The new classification is based on: –cause –grade (histologic assessment) –stage (by the degree of fibrosis) The old (histological) classification –chronic persistent hepatitis –chronic lobular hepatitis –chronic active hepatitis

Chronic viral hepatitis Huge epidemiological problem –no HBV vaccination programs in the developing countries yet The age and immune status determines whether the infection turns chronic –e.g. HBV infection becomes chronic in 90 % of newborns! Chronic HBV infections diagnosed in adults are not preceded by apparent acute hepatitis

HBV infection worldwide

Cirrhosis hepatis chronic, fibrotic process, leading to the progressive, irreversible destruction of liver parenchyma it can be caused by a number of chronic processes damaging the liver cells: –alcohol (Laennec cirrhosis) –chronic infection –biliary obstruction –congestion (cardiogenic cirrhosis) –inherited, metabolic disease

Survival of cirrhosis patients

Factors playing a role in the development of ascites

Factors that help hepatic coma to develop increased protein intake –e.g. bleeding from esophageal varices increased protein catabolism (infection, fever) alkalosis (intracellular trapping of ammonium)

Hepatic coma and blood ammonia levels

Inherited hyperbilirubinemias unconjugated –Gilbert (low UGT1A1 act., abnormal uptake) –Crigler-Najjar type I (no UGT1A1 act.) –Crigler-Najjar type II (medium UGT1A1 act.) conjugated –Dubin-Johnson (mutation of MRP2) –Rotor (unknown) UGT1A1 = bilirubin - UDP glucuronyl transferase MRP2 = multidrug resistance associated protein 2 (transports conjugated bilirubin into the bile)