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

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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)

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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

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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...)

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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

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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

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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)

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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

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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

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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

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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

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Liver cirrhosis  diffuse irreversible liver remodeling  necrosis, inflammation, fibrosis, nodular regeneration and formation of vascular anastomoses in liver  Greek: kirrhos "yellowish" and -osis "condition"  leads to:  loss of hepatic parenchyma  impaired hepatic blood flow  portal hypertension  liver failure

Cirrhosis - etiology

 alcohol  chronic viral hepatitis B, C  biliary cirrhosis: due to progressive cholestasis  metabolic disorders:  Wilson's disease, hemochromatosis, porphyries, glycogenosis  cardiac cirrhosis  autoimmune cirrhosis  nutritional disorders: malnutrition, obesity  drugs: methotrexate, amiodaron  idiopathic

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Morphology of cirrhosis 1. Micronodular:  regenerative nodules < 3 mm, divided by thick fibrous connective tissue  chronic alcoholism, metabolic disorders 2. Macronodular:  regenerative nodules > 3 mm  viral hepatitis B, C 3. Mixed type:  large and small nodules

Cirrhosis - pathogenesis

 ATP deficiency:  due to abnormal cellular energy metabolism   oxygen metabolites:

–  ·O2 , ·HO2, H2O2  deficiency of antioxidants:  glutathione  damage of protective enzymes:  glutathione peroxidase, superoxide dismutase

 lipid peroxidation  damage of plasma membranes and cell organelles (lysosomes, endoplasmic reticulum)   cytosolic Ca2+  activating proteases and other enzymes  necrosis of hepatocytes

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Silbernagel: Color Atlas of Pathophysiology

Silbernagel: Color Atlas of Pathophysiology

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Compensated cirrhosis

 latent / subclinical  mimics chronic hepatitis

 Subjective symptoms (non-specific):  occasional bleeding from nose, gums, to skin, mucosae  dyspepsia  menstrual disorders  Objective symptoms:  hepatomegaly, progressive splenomegaly  portal hypertension  perimaleolar edemas, nykturia  jaundice  sudden hematemesis

Compensated cirrhosis

 Lab: - AST > ALT -  albumin -  γ-globulin -  bilirubin -  Quick (INR)

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Decompensated cirrhosis

 Parenchymal destruction  metabolic decompensation:  jaundice  hemorrhages  hypoalbuminemia  edemas, ascites

 Portal hypertension  vascular decompensation:  ascites  esophageal varices  portosystemic encephalopathy

Decompensated cirrhosis

 Lab: - in urine: urobilinogen and urobilin (bilirubin in jaundice) - hyperbilirubinemia - anemia, thrombocytopenia, leucopenia (hypersplenism) -  transaminases -  albumin, cholesterol -  Quick (INR) -  sNa+

 severity correlates with prothrombin time (Quick)

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Cirrhosis – symptoms I.

 weakness, fatigue  loss of appetite, loss of weight (big abdomen, skinny extremities)  slow reactions: due to encephalopathy  pale, icteric skin  spider nevi:  vascular lesions consisting of a central arteriole surrounded by many smaller vessels due to an increase in estradiol  glazed red lips and tongue  palmar erythema

Cirrhosis – symptoms II.

 nail changes:  nail clubbing: angle between the nail plate and proximal nail fold > 180 degrees, thickening of the distal finger  Muehrcke's nails: white lines (leukonychia) that extend all the way across the nail and lie parallel to the lunula (half moon) due to hypoalbuminemia  Terry’s nails: "ground glass" appearance, proximal 2/3 of the nail plate appears white with distal 1/3 red due to  vascularity and  connective tissue within the nail bed, hypoalbuminemia

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Cirrhosis – symptoms III.

 Dupytren's contracture:  thickening and shortening of palmar fascia that leads to flexion deformities of the fingers  hemorrhage:  petechiae, hematomas, gum and nose bleeding  loss of hairs on chest in men, gynecomastia  ascites  umbilical / inguinal hernia  menstrual disorders, dicreaed libido in males

Cirrhosis - complications

 portal hypertension  ascites  hepatocellular carcinoma  infections  GIT diseases:  peptic ulcer, gastritis, pancreatitis, esophageal reflux, cholelithiasis  hemorrhage  cardiomyopathies  herniae  osteopenia

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 Liver: anatomy, histology, physiology  Liver cirrhosis  Portal hypertension  Ascites  Hepatic failure

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Portal circulation

 venous blood from stomach, intestines, spleen, pancreas, and gallbladder  portal vein  liver  normal pressure in portal vein: 5 –10 mmHg  portal pressure depends on:  blood volume and pressure from v. mesenterica  resistance of intrahepatel circulation  lumen and tonus of portal circulation  pressure in v. cava inferior

 Portal hypertension:  pressure in v. portae > 5 mmHg

Portal hypertension – classification, etiology

1. Prehepatic (children): c) postsinusoidal: portal or splenic vein thrombosis venous occlusive disease of the venules and small veins massive splenomegaly 3. Posthepatic: 2. Intrahepatic: Budd-Chiari syndrome: a)presinusoidal: obstruction of the large hepatic primary biliary cirrhosis veins granuloma in schistosomiasis right heart failure chronic hepatitis constrictive pericarditis tuberculosis restrictive cardiomyopathy b) sinusoidal: cirrhosis acute hepatitis, alcoholic hepatitis toxins amyloidosis

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Silbernagel: Color Atlas of Pathophysiology

Portal hypertension - mechanisms   portal resistance due to:   mechanical resistance: hepatocyte edema deposits of extracellular matrix rebuilding of hepatic tissue   dynamic resistance: vasoconstriction in hepatic microcirculation: active vasoconstriction of smooth muscle cells = activated Ito cells  vasoconstrictors: endothelin, epinephrine, vasopressin, angiotensin II  vasodilators: NO   portal blood flow:  splanchnic vasodilatation  hyperkinetic circulation

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Portal hypertension - symptoms

Prehepatic:  liver functions are normal in the beginning  collateral circulation  splenomegaly  bleeding from esophageal varices Intrahepatic:  complications of portal hypertension Posthepatic:  acute: sudden painful hepatomegaly, splenomegaly, ascites bleeding from esophageal varices shock with liver failure, death  chronic: progressive hepatomegaly and ascites recurrent GIT bleeding, ascites

Portal hypertension - complications

 Collateral circulation:  collaterals between v. portae and v. cava inferior (portal bypass circuits)   portal hypertension  veins in esophageal submucosa  esophageal varices  risk of rupture  massive bleeding – most frequent cause of death  veins in rectal submucosa  hemorrhoids  veins in the area of parietal peritoneum  caput Medusae  a part of substances flow directly into peripheral circulation (shunt the liver without being detoxicated) = portocaval shunt  toxins  encephalopathy, endotoxemia  vasodilators (glucagon, VIP, substance P, prostacyclins, NO)  systemic blood pressure  cardiac output  hyperperfusion of the abdominal organs = hyperdynamic circulation  collateral flow  Splenomegaly and hypersplenism:  anemia  thrombocytopenia  leukopenia  Ascites

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Silbernagel: Color Atlas of Pathophysiology

 Liver: anatomy, histology, physiology  Liver cirrhosis  Portal hypertension  Ascites  Hepatic failure

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Ascites

 accumulation of fluid in the peritoneal cavity

Etiology:  liver cirrhosis, portal hypertension  infections: bacterial, tuberculosis, parasitic, mycotic  tumors: primary and metastatic liver tumors  liver congestion: right heart failure, constrictive pericarditis  hypoalbuminemia: nephrotic syndrome, malnutrition  pancreatic diseases: acute pancreatitis  ovarial diseases  chylous ascites: lymph outflow blockage

Liver damage

 plasma albumin portal hypertension  inactivation of ADH, aldosterone vasodilatation

 splanchnic Na+, H O retention  oncotic pressure 2 capillary pressure  plasma volume

ASCITES edemas

 plasma volume

ADH

volumereceptors, Sp. baroreceptors RAAS aldosterone

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Ascites - complications

 spontanous bacterial peritonitis:  bacterial migration through intestine wall  dissemination through blood or lymph route  impaired immune response  oppression of abdominal organs herniae  elevated diaphragm and decreased mobility  decreased vital capacity  impaired mobility of the patient

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 Liver: anatomy, histology, physiology  Liver cirrhosis  Portal hypertension  Ascites  Hepatic failure

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Liver insufficiency

 severe deterioration in liver function  manifestation of the failure is present when the hepatic cells are required to provide more „metabolic work“  in basal conditions the failure could not be necessarily manifested  big functional reserve  signs only after massive liver damage Liver failure (LF)

 manifestation of the insufficient hepatic functions are present already in basal conditions

Liver failure - pathogenesis

 Hepatocyte damage  functional liver mass  Portal hypertension  collateral circulation  changed liver blood flow

1. Endogenous LF (spontaneous):  failure of hepatocyte`s function  due to diffuse liver damage in acute diseases / end of chronic liver diseases  acute – fulminant LF 2. Exogenous LF (indirect, induced):  in liver cirrhosis  due to:  protein intake, GIT bleeding, surgery, infections, diuretics, sedatives, alcohol

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Liver failure

 Hyperacute LF:  interval between onset of jaundice and encephalopathy: < 7 days

 Acute LF:  interval between onset of jaundice and encephalopathy: 8 – 28 days (4 weeks)

 Subacute LF:  interval between onset of jaundice and encephalopathy: 5 – 26 weeks (6 months)

 Chronic LF:  liver cirrhosis with collateral circulation

Acute LF - etiology

 Viral hepatitis:  Liver tumors:  A, B (B+D), C, E  primary  Toxic damage:  metastatic  paracetamol  Ischemia:  non-steroidal anti-  heart failure, shock inflammatory drugs  acute thrombosis of hepatic  herbicides veins (acute Budd-Chiari sy.)  Amanita phalloides  Acute liver steatosis:  alcoholics  pregnancy

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Chronic LF - etiology

 Liver cirrhosis with:  Nitrogen (ammonium) overload ( symptoms of encephalopathy): food -  protein intake bleeding (esophageal varices)  drugs: diuretics ( liver hypoperfusion, hypokalemia, alkalosis, encephalopathy), sedatives, ...  ion imbalance: vomiting diarrhea after surgery after infections alcohol abuse  changes in intestinal microflora during chronic constipation

Liver failure – impaired functions

1. Impaired metabolism: 5. Hematologic disorders: a) carbohydrates a) Anemia b) proteins b) Hemorrhagic diathesis c) lipids 6. Lesions of skin and mucosa d) bilirubin excretion 7. Hepatopulmonary syndrome e) hormone degradation 8. Hepatorenal syndrome f) water and electrolytes 9. Encephalopathy 2. Acid-base imbalance 3. Changes in circulation 4. Impaired resorption of vitamins

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1a) Impaired metabolism of carbohydrates

 severe acute liver diseases:

 hypoglycemia:  NEFA  inhibition of glycolysis  glucose intake  impaired gluconeogenesis to CNS

 hepatogenic diabetes: chronic liver damage  hyperglycemia and  tolerance of glucose:  insulin resistance – impaired degradation of glucocorticoid,  first pass effect in glucose transport from GIT through liver  postprandial hyperglycemia ...   plasma insulin and glucagon:   release of insulin and glucagon by pancreas   uptake of insulin and glucagon by damaged hepatocytes

1b) Impaired metabolism of proteins

  protein synthesis:   albumin  oncotic pressure (usually not in acute disorders, half-life of albumin is 21 days)   γ-globulins (Ig)   globulins α1, α2 and β – in more severe stages   factors of coagulation  hemorrhagic diathesis

 changed spectrum of plasmatic enzymes  damaged integrity of hepatocytes:  ALT, AST, cholestasis:  ALP and GMT  impaired ammonium degradation  encephalopathy

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1c) Impaired metabolism of lipids

  and prolonged alimentary lipemia   plasmatic non-esterified fatty acids (NEFA)   β-lipoproteinemia   NEFA metabolism in liver  synthesis of complex lipids   plasmatic cholesterol, LDL, HDL  impaired resorption of lipids (and fat-soluble vitamins) during cholestasis

1d) Impaired metabolism of bilirubin and bile acids

 Cholestasis   posthepatal jaundice   serum cholestrol   serum bile acids  pruritus  bile acids in sinoatrial node  bradycardia   ALP  impaired lipid digestion: diarrhea, steatorhea, decreased absorption of lipid-soluble substances (VT A, D, E, K)

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1e) Impaired metabolism of hormones

  degradation of hormones in liver, blood flows through portocaval shunts

  estrogens  hyperestrogenism:  females: menstrual irregularities  males: gynecomastia, hair loss, testicular atrophy  spider nevi   androgens:  females: virilization, menstrual irregularities  males: androgens  estrogens   ADH:  water retention   aldosterone:  retention of Na+, loss of K+

1f) Impaired metabolism of water and electrolytes

 Mechanisms:  hypoalbuminemia, circulatory changes, RAAS and ADH activation

 water and Na+ retention:  edemas, ascites, volume overload of CVS  ADH:  diluted and distributive hyponatremia  Na+-K+ ATP pump failure:  hyponatremia  RAAS:  hypokalemia: metabolic alkalosis, muscle weakness, hypomotility of GIT, arrhythmias

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2. Acid-base imbalance:

 NH4 alkalosis encephalopathy hepatopulmonary syndrome  estradiol hepatal hydrothorax ascites  diaphragm CNS Hyperventilation hypoxemia

Respiratory alkalosis dyspnoe

  aldosterone  K+ extracellular alkalosis and intracellular acidosis: +  weak ionization of ammonium to NH4 , remains in non-ionized form, that diffuses easily and leaks to brain cells  encephalopathy  Hypoalbimunemia  metabolic alkalosis

2. Acid-base imbalance: acidosis

 ADH  dilutive  Na+  dilutive metabolic acidosis  chronic respiratory alkalosis, diarrhea, bicarbonate loss  kidneys  hyperchloremic metabolic acidosis  lactate, ketoacids  metabolic acidosis

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3. Changes in circulation

 Mechanism:   levels of vasodilators in circulation - NO   levels of vasoconstrictors in circulation (ANF, endothelin, serotonin)  sympathetic activation

 Hyperkinetic circulation:   cardiac output ( heart rate,  stroke volume)  vasodilatation: splanchnic  vasoconstriction: muscles, kidneys   plasma volume (vasodilation,  BP  Na+ and water retention)

 tachycardia,  BP, vasodilation in skin

4. Impaired resorption of vitamins

 Fat-soluble vitamins:  VT K  impaired formation of coagulation factors  VT D  impaired calcium metabolism  Water-soluble vitamins:

 VT B12 and folic acid  megaloblastic anemia  VT B  rhagades and fissures at the angles of the mouth, stomatitis

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5. Hematologic diorders 5a) Anemia  Etiology:  bleeding  hypersplenism  impaired iron resorption  impaired VT B12 and folic acid resorption  toxic bone marrow failure

5b) Hemorrhagic diathesis

  production of coagulation factors:  VT K-dependent - f. II, VII, IX a X  insufficient production – f . I, V, XI a XII   synthesis of antikoagulation factors  thrombocytopenia and thrombocytopathia:   production –  thrombopoietin production by liver, toxic bone marrow failure, VT B12 deficiency   scavenging of thrombocytes in hypersplenism  cholestasis  deficiency of bile acids  production of micelles   VT K resorption

 endothelial dysfunction and  fragility of capillaries   fibrinolysis  antithrombin III,  plasminogen  disorder of inactivation of coagulation factors in liver  DIC

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6. Lesions of skin and mucosa  spider nevi  palmar erythema  changes of nails  changes of hair  mouth rhagares  glazing lips and tongue

7. Hepatopulmonary syndrome

 the onset of respiratory insufficiency in a patient with advanced liver failure

 Mechanism:  intrapulmonal vascular dilation ( eNOS, iNOS)  Hyperkinetic circulation +  CO:  ventilation (N) – perfusion () mismatch  blood flow through non-ventilated alveoli  intrapulmonal right-left shunts  interstitial lung edema due to endotoxin (from GIT)-induced endothelial injury  alveolo-capillary membrane thickening limitation of oxygen diffusion  portopulmonary anastomoses

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7. Hepatopulmonary syndrome

 Consequences:  arterial hypoxemia,  oxygen saturation  cyanosis, dyspnoe – more severe in standing position  nail clubbing, spider nevi

7. Hepatopulmonary syndrome

Rodríguez-Roisin, Krowka. N Engl J Med. 358(22):2378-87

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8. Hepatorenal syndrome

 functional renal damage  life-threatening complication of severe liver disease  dysbalance between vasodilators and vasoconstrictors:  peripheral arterial vasodilation: overproduction of vasodilator substances  renal vasoconstriction: overproduction of endothelin due to endotoxemia  activation of a hepatorenal baroreflex that stimulates renal sympathetic nerves, leading to sodium retention  renal ischemia with subsequent oliguria and renal failure

8. Hepatorenal syndrome

bowels: Liver cirrhosis blood: endotoxins, leukotriens substance P portal  protein hypertension synthesis impaired inactivation in liver

hypoproteinemia vasodilatation  capillary  oncotic pressure pressure  CO (hyperkinetic  BP circulation) peripheral hepatic ascites Sp. activation edemas encephalopathy renal hypovolemia vasoconstriction

 renal perfusion oliguria  GFR  synthesis of vasodilators in aldosterone kidneys + renin H2O, Na resorption (NO, prostaglandins) ADH angiotensin II

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9. Encephalopathy

 Neurologic and psychiatric changes in LF  Usually reversible  Most severe stage = coma

 Classification:  Acute encephalopathy – in endogenous acute LF, fast progression to coma, convulsions, brain edema  Chronic encephalopathy – always with collateral circulation

9. Encephalopathy - mechanisms  Causes and mechanisms:   ammonium  toxic substances produced by bacteria in bowels (mercaptans, phenol, FA)   permeability of blood-brain barrier (TNF, IL-1)  impaired neurotransmission, including false neurotransmitters  changed energy metabolism in brain  endotoxins, cytokins, NO

 Factors contributing to liver encephalopathy:  GIT bleeding   protein intake  constipation ( absorption of toxins)  electrolyte imbalance, metabolic alkalosis

 renal failure ( urea to intestines  NH3)  drugs

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9. Encephalopathy - pathogenesis

• mercaptans • phenols, FA brain • endotoxin NH3 peripheral circulation Encephalopathy

liver

NH3 NH3

portal hypertension - hepatocyte shunts damage bowels • mercaptans bleeding • phenols, FA bacteria • endotoxin NH3 proteins food endogenous

9. Encephalopathy – stages

I. Mild  sleep inversion, euphoria, depression, severe mood swings, tremor, impaired handwriting II. Moderate  lethargy, mild disorientation, amnesia, overt change in personality, inappropriate behavior, slurred speech, asterixis (flapping), ataxia III. Severe  somnolence, paranoia, bizarre behavior, hyperactive reflexes, nystagmus, rigidity IV. Coma  coma, dilated pupils, opisthotonus

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Toxins Inflammation Alcohol Venous congestion Amanita phalloides, vir. hepatitis, (right heart failure) Genetic factors organic solvents cholangitis

Acute LF Chronic LF

Cirrhosis

Liver failure

hypo portal varices cholestasis NH  urea albuminemia hypertension 3  lipid ascites exsudative GIT resorption enteropathy bleeding

 aldosterone  VT K  enteric amino acid false transmitters  clotting  K+ breakdown factors

 NH3 alkalosis hyperventilation encephalopathy

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