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Liver Failure Cirrhosis

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Liver Failure Cirrhosis 21. 4. 2020 Liver failure Cirrhosis (GM) Kristína Repová, MD, PhD Institute of Pathophysiology Faculty of Medicine, Comenius University in Bratislava [email protected] Liver: anatomy, histology, physiology Liver cirrhosis Portal hypertension Ascites Hepatic failure 1 21. 4. 2020 Liver Biggest parenchymal organ: 1 200 – 1 600 g Blood flow through liver: 25% CO – 1.5 l/min Nutritive circulation – hepatic artery (25% blood flow, P = 100 mmHg): O2 Functional circulation – portal vein (75% blood flow, P = 10 mmHg): nutrients from the intestine, ingested toxins and medications, pancreatic hormones connected by sinusoids drain: central vein → hepatic vein → inferior vena cava Hepatic artery (oxygenated blood from heart) bile duct Portal vein (blood from bowels) 2 21. 4. 2020 Portal lobule Classic hepatic lobule (drains bile: (drains blood: portal vein, hepatocytes → hepatic artery → sinusoids → bile duct central vein) Portal acinus (O2 and nutrients: hepatic artery, portal vein → hepatocytes) Liver functions 1. Metabolism 2. Hematopoiesis 3. Hemodynamics 4. Detoxification 5. Thermoregulation 5. Homeostasis and hemocoagulation 6. Storage 7. Immune functions 3 21. 4. 2020 Liver functions 1. Metabolic: Carbohydrates: regulation of glucose concentration in blood (glucostatic function): glucose uptake – can take up about 87% of the glucose delivered by the portal blood glycogenesis, storage of glucose - glycogen glycogenolysis gluconeogenesis from lactate, amino acids, glycerol glucolysis metabolism of galactose, fructose and sorbitol pentose-phosphate cycle NADPH Liver functions Lipids: uptake, oxidation and transformation of free fatty acids synthesis of plasma lipoproteins transformation of lipoproteins catabolization of LDL, VLDL and chylomicron remnants secretion of enzymes for lipoprotein metabolism: hepatic triglyceride lipase (HTL) and lecithin-cholesterol- acyltransferase (LCAT) ketogenesis: β-oxidation → ketones: acetone is expired / urine 3-hydroxybutyrate and acetacetate → source of energy extrahepataly (CNS...) 4 21. 4. 2020 Liver functions Proteins: synthesis and degradation of amino acids synthesis of glycoproteins, coagulation factors (fibrinogen, prothrombin, factors V, VII, IX, and X) synthesis of proteins of acute phase reaction: C-reactive protein, fibrinogen, haptoglobin, ceruloplasmin and α1- antichymotrypsin, α1-antitrypsin, α2-macroglobulin synthesis of transport proteins: albumin, ceruloplasmin, haptoglobin, transcobalamin, transcortin transferrin conversion of ammonia to urea Liver functions Hormones: the impact on the liver, metabolism inactivation of the hormones in liver thyroxine, tetraiodothyronine (T4), converted in the liver to triiodothyronine (T3) growth hormone, modified by liver-produced growth hormone– releasing hormone (GHRH) insulin and glucagon, degraded in liver, kidney,... catecholamines, steroid hormones (glucocorticoids, androgens, oestrogens and gestagens) Bilirubin metabolism Porphyrin metabolism: haemoproteins (haemoglobin, myoglobin, cytochromes, oxygenases, catalases, peroxidase) Bile acid metabolism 5 21. 4. 2020 Liver functions Vitamin metabolism: provitamins vitamins, storage of vitamins carotenes vitamin A 25-hydroxylation of provitamin D (calcidiol) cleavage of side chain of vitamin K storage of vitamin B12 and folate synthesis of nicotinic acid from Trp formation of coenzymes from B vitamins Liver functions 2. Hematopoiesis: during embryogenesis and pathologic conditions (bone marrow hematologic malignities) activation of extramedular hematopoiesis in liver indirect role in hematopoiesis: storage of B12, folic acid, iron (ferritin) 3. Hemodynamic function: regulates blood flow to right heart liver can hold or deliver up to 20% of total volume of circulating blood 6 21. 4. 2020 Liver functions 4. Biotransformation and detoxification: Biotransformation: inactivation by chemical reactions: oxidation, hydroxylation, cyt P450-mediated conjugation reactions excreted in the urine and/or bile Ammonia detoxification and bicarbonate neutralization: urea cycle (liver) / glutamine cycle (liver, skeletal muscles, brain) bicarbonate neutralization Alcohol degradation Liver functions 5. Thermoregulation: increased metabolic activity in liver heat 6. Maintenance of hemostasis and hemocoagulation 7. Storage capacity: glycogen, VT A, K, C, D, B12, folic acid, iron, copper 8. Immune functions: Kupffer cells and sinusoidal endothelial cells phagocyte material and microorganisms from portal blood Reticuloendothelial system (RES, Kupffer cells): Filter function Phagocytosis Metabolization of foreign substances Clearance function (mucopolysaccharides, fibrinolysis activators, antigens) Elimination of endotoxins Metabolization of lipoproteins induce tolerance to antigens (from GIT) 7 21. 4. 2020 Diagnosis of liver disease history physical examination laboratory tests USG CT NMR cholangiography histologic tests serologic tests Evaluation of liver function detect the presence of liver disease distinguish among different types of liver disorders gauge the extent of known liver damage follow the response to treatment 1. Detoxification and excretory functions: serum bilirubin urine bilirubin blood ammonia serum enzymes: damage to hepatocytes: aminotransferases (transaminases): aspartate aminotransferase (AST) and alanine aminotransferase (ALT) cholestasis: alkaline phosphatase, γ-glutamyl transpeptidase 2. Biosynthetic function of the liver: serum albumin serum globulins coagulation factors 8 21. 4. 2020 1. Detoxification and excretory functions Serum bilirubin: the yellow breakdown product of normal heme catabolism (hemoglobin, myoglobin, cytochromes, catalase, peroxidase) unconjugated (indirect): insoluble in water, bound to albumin liver : hemolysis, genetic disorders (Crigler-Najjar, Gilbert syndrome) conjugated (direct): liver: bilirubin is conjugated with glucuronic acid soluble in water bile small intestine large intestine feces OR secreted by urine : liver disease, bile duct obstruction total bilirubin with liver enzymes = liver disease, bile duct obstruction total bilirubin without liver enzymes = hemolysis, Gilbert syndrome Urine bilirubin: always conjugated liver disease 1. Detoxification and excretory functions Blood ammonia: Formation of ammonia: cellular metabolism: by transdeamination of amino acids by deamination of biogenic amines by deamination of amino group of purines; pyrimidine metabolism in the intestinal lumen: by action of intestinal bacteria, from nitrogenous components of the diet, deamination of glutamine, and breakdown of urea by urease present in colonic flora Transport of ammonia: free NH3: tissues NH3 blood liver urea kidney glutamate: tissues: NH3 + α-ketoglutarate glutamate glutamine: brain, muscle: glutamate + NH3 glutamine : severe portal hypertension, portal blood shunting around the liver correlate with outcome in fulminant hepatic failure 9 21. 4. 2020 1. Detoxification and excretory functions Serum enzymes: damage to hepatocytes: aminotransferases (transaminases): aspartate aminotransferase (AST): in liver > myocardium > skeletal muscle > kidneys > brain > pancreas > lungs > leukocytes > erythrocytes alanine aminotransferase (ALT): in liver : damage to the liver cell membrane permeability: viral hepatitis, ischemic liver injury (prolonged hypotension or acute heart failure), toxin- or drug-induced liver injury (paracetamol), acute phase of biliary obstruction (passage of a gallstone into the common bile duct) ALT ≥ AST: acute hepatocellular disorders AST:ALT > 2:1 (3:1): alcoholic liver disease, cirrhosis 1. Detoxification and excretory functions Serum enzymes: cholestasis: alkaline phosphatase (ALP): in or near the bile canalicular membrane of hepatocytes isoenzymes found in the liver, bone, placenta, small intestine normal : > 60 yrs.; children and adolescents undergoing rapid bone growth; late in normal pregnancies : cholestatic liver disorders, infiltrative liver diseases (cirrhosis, cancer, amyloidosis), bone conditions characterized by rapid bone turnover (e.g., Paget's disease), Hodgkin`s disease, diabetes, ... γ-glutamyl transpeptidase (GGT): in the endoplasmic reticulum and in bile duct epithelial cells ALP >> GGT: bone disease, pregnancy GGT >> ALP: alcohol, drugs 10 21. 4. 2020 2. Biosynthetic function of the liver Serum albumin: long half-life: 18–20 days : chronic liver disorders (cirrhosis), severe liver damage, albumin synthesis, protein malnutrition, protein-losing enteropathy, nefrotic syndrome, chronic infections N/ synthesis, but hypoalbuminemia: volume of distribution in ascites Serum globulins: chronic liver diseases, chronic autoimmune hepatitis, liver cirrhosis insufficient RES filter Ag from portal blood pass to systemic circulation B-lymphocytes: γ-globulins (immunoglobulins) and hepatocytes: α-, β- globulins IgG: autoimmune hepatitis, cirrhosis; IgM: primary biliary cirrhosis; IgA: alcoholic liver disease Coagulation factors: shorter serum half-lives serum prothrombin time (Quick): hepatitis, cirrhosis, vitamin K deficiency (obstructive jaundice, fat malabsorption) Liver: anatomy, histology, physiology Liver cirrhosis Portal hypertension Ascites Hepatic failure 11 21. 4. 2020 Liver cirrhosis diffuse irreversible liver remodeling necrosis, inflammation, fibrosis, nodular regeneration and formation of vascular anastomoses in liver Greek: kirrhos
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