Pathophysiology of the liver. Jaundice. The State Education Institution of Higher Professional Training The First Sechenov Moscow State Medical University under Ministry of Health of the Russian Federation  Department of Pathophysiology Pathophysiology of the liver. Jaundice. Lecture presentation Professor Pirozhkov S.V. 2015-2016 education year

Liver insufficiency is a decrease of one or many functions of the liver below the level required to maintain normal homeostasis

Etiology of liver insufficiency Damage to the liver parenchyma or bile ducts - hepatitis (viral, bacterial, toxic, autoimmune) - dystrophy - cirrhosis - tumors - parasites - gall bladder stones, inflammation of the bile ducts with cholestasis 2. Extrahepatic factors - heart failure, shock - general hypoxia - renal failure - protein malnutrition - metastases in the liver

Manifestations of liver failure I. Disorders of carbohydrate metabolism Manifestations Their mechanisms * Decrease in glucose - Increased insulin tolerance resistance of hepatocytes * Increased plasma - Decreased capacity to lactate level utilize lactic acid in gluconeogenesis * Hypoglycemia - Depletion of glycogen stores - Decreased capacity to synthesize glycogen - Decreased glucagon resposiveness of hepatocytes

Manifestations of liver failure II. Disorders of amino acids and ammonia metabolism Manifestations Mechanisms/explanations * Elevated levels of plasma Decreased metabolism of aromatic amino acids and amino acids in the liver methionine * Normal or depressed plasma Branched-chain amino levels of the branched-chain acids are largely utilized amino acids by skeletal muscles (Leu, Iso-Leu, Val) * Reduction in blood Decreased urea synthesis urea nitrogen in the ornitine cycle * Accumulation of ammonia Decreased utilization of in the blood ammonia for urea synthesis

Manifestations of liver failure III. Disorders of protein synthesis and degradation Manifestations Mechanisms/explanations * Hypoprothrombinemia Reduced synthesis of prothrombin; reduced absorption of vitamin K due to cholestasis * Hypoalbuminemia Decrease in the number and function of hepatocytes; loss of albumin into the ascitic fluid * Decreased plasma Decreased rate of its level of factor V synthesis * Increased production of A response stimulated by fibrinogen (possibly abnormal) IL-1 and IL-6 and other acute phase reactants (C-reactive protein etc.) * Decreased plasma activity Impairment of its synthesis of choline esterase in the liver cells

Manifestations of liver failure IV. Disorders of lipid metabolism Manifestations Their mechanisms * Accumulation of lipids Decreased apoprotein in hepatocytes (lipidosis) synthesis * Decrease in total plasma Decreased synthesis of cholesterol level (free and cholesterol; decrease in esterified) lecithine-cholesterol acyl transferase activity (severe liver injury) * Increase in total plasma Abnormal bile evacuation cholesterol (cholestasis)

Manifestations of liver failure V. Disorders of detoxification and neutralization of biologically active substances ■ Decreased capacity to neutralize toxic products of amino acids metabolism (phenol, indol, cadaverin etc.) ■ Decreased capacity to neutralize hormones: - insulin, glucagon - (proteolysis, deamination) - thyroxine, triiodothyronine (deiodination) - estrogens, including estradiol (conversion to estriol and estrone, and further conjugation with glucuronic acid) - adrenalin (О-methylation, deamination) ■ Decreased capacity to metabolize drugs

Manifestations of liver insufficiency Coma Fetor hepaticus Esophageal varices Spider angiomas Gastropathy Gynecomastia Melena Jaundice Splenomegaly Ascitis «Caput medusae» Loss of pubic hair Testicular atrophy Ascitis Liver «flap» (asterixis) Rectal varices (hemorrhoids) Hemorrhagic diathesis Anemia Ankle edema Manifestations of liver insufficiency

TYPES OF HEPATIC COMA ● Porto-systemic shunting ● Hepatocellular

NH3 Bilirubin Indol Scatol Intestinal flora Main factors of neurotoxicity in hepatic encephalopathy Bilirubin Inhibition of dopamine and norepinephrine synthesis; increased production of serotonin NH3 Toxins False neuromediators Indol Scatol Intestinal flora Tryptophan Thyrosine Phenylalanine Thyramine Octopamine

Manifestations of liver failure VI. Disorders of bilirubin pigments metabolism Manifestations Mechanisms * Accumulation of Decreased activity of unconjugated bilirubin UDP-glucuronosyl in blood plasma transferase in hepatocytes * Accumulation of Cytolysis of hepatocytes, conjugated bilirubin cholestasis in blood plasma J A U N D I C E

METABOLISM OF BILIRUBIN IN THE LIVER ALB – albumin; GSTr – glutathione-S transferase UCB – unconjugated bilirubin; GLT-glucuronosyl transferase BM(D)G – bilirubin mono(di)glucuronide АLB Transporter-protein UCB GLT BMG GSTr-UCB UCB BDG UCB АLB-UCB GSTr GLT Sinusoid Disse space

TYPES OF THE SECONDARY (ACQUIRED) JAUNDICE ● Hemolytic ● Hepatocellular ● Obstructive

Types and mechanisms of hereditary jaundice Bilirubin glucuronide Watersoluble bilirubin glucuronide Dubin-Johnson and Rotor syndromes 3 Glucuronyltransferase Crigler-Nadjjar syndrome and neonatal jaundice 2 Watersoluble bilirubin Gilbert syndrome 1 Bilirubin formed in other parts of the mononuclear phagocyte system Hemoglobin Kupffer cell