Liver Diseases Lecture 10 PDF

Liver Disorders 1. Liver Four lobes Wikimedia Commons, 2024 Hepatic lobules Two primary sources of blood Hepatic artery Hepatic portal vein Bile is collected by bile canaliculi Wikimedia Commons, 2024 Transported in the com...

Liver Disorders 1. Liver Four lobes Wikimedia Commons, 2024 Hepatic lobules Two primary sources of blood Hepatic artery Hepatic portal vein Bile is collected by bile canaliculi Wikimedia Commons, 2024 Transported in the common hepatic duct 2. Functions of Liver Metabolism of carbohydrates, lipids and proteins Breakdown of red blood cells (reticuloendothelial system) Detoxification (excrete endogenous and exogenous compounds) Bilirubin metabolism Protein synthesis (e.g., albumin, acute phase proteins, coagulation factors) Storage of substances 3. Liver and metabolism of Carbohydrates Carbohydrate metabolism is tied to blood glucose levels Glucose levels are largely regulated by liver Influenced by: Insulin Glycogen Glucagon Glycogenolysis Gluconeogenesis 4. Liver and Lipid Metabolism Lipids are water-insoluble Transported as lipoproteins Liver and production of lipoproteins Metabolism of fatty acids (acetyl-coA) and triglycerides (energy) Conversion of carbohydrates and proteins into fats Conversion of cholesterol to bile Bile – continuously produced Water, bile salts, bilirubin, fatty acids, and cholesterol 5. Liver and Protein Metabolism Most important functions of liver: Production of plasma proteins Main producer of clotting factors Deamination of amino acids Conversion of amino acids (ammonia byproduct) Formation of waste products (ammonia) Urea production by liver 6. Liver and Bilirubin Metabolism Degradation of hemoglobin Unconjugated to conjugated bilirubin Glucuronic acid High concentrations of unconjugated bilirubin Cell damage, jaundice, toxicity (brain) Total bilirubin= unconjugated (indirect) bilirubin + conjugated (direct) bilirubin Liver Tests 7. Liver Function Tests (LFTs) Most LFT panels include: Alanine aminotransferase (ALT) Integrity of hepatocytes Bilirubin Alkaline phosphatase (ALP) Abundant in bile canaliculi Albumin 7.1 The Aminotransferases Involved in the metabolism of amino acids Alanine aminotransferase (ALT) test Sensitive, nonspecific Marker of acute damage of hepatocytes Hepatitis Toxic injury Acute liver damage Aspartate aminotransferase (AST) test Produced by hepatocytes, skeletal muscles, kidney, brain, and heart Less used in liver assessment Less specific information  7.2 Bilirubin Derived from heme (hemoglobin) Daily produced Unconjugated (indirect) bilirubin Conjugated (direct) bilirubin is excreted in bile Bile reaches the small intestine Conjugated bilirubin is degraded by bacteria in intestine Stercobilinogen Small amounts excreted in urine as urobilinogen Clinical significance Elevated total bilirubin (e.g., liver disease, hemolysis, biliary obstruction) Elevated indirect bilirubin (e.g., hemolysis, impaired liver function) Elevated direct bilirubin (e.g., liver disease, biliary obstruction) ❖ Jaundice Excess of bilirubin (>50 µmol/L) Three main causes: Hemolysis (pre-hepatic cause) Failure of the conjugating mechanism within the hepatocyte (hepatic cause) Obstruction in the biliary system (post-hepatic cause) Laboratory considerations Hemolysis: increased indirect bilirubin – risk of brain damage in newborns (phototherapy) Hepatocellular damage – elevated bilirubin, ALT and ALP Most common causes of acute jaundice in adults: viral hepatitis and paracetamol poisoning Biliary obstruction – elevated bilirubin and ALP Bile duct can be blocked by gallstones, pancreatic cancer, and lymph nodes 7.3 Alkaline Phosphatase (ALP) If present in blood, derived from liver, bone Intestine and placenta Increased ALP in blood Increased synthesis by cells lining bile canaliculi Cholestasis (intrahepatic or extrahepatic) Infiltrative diseases of the liver Cirrhosis Increased ALP – no apparent cause Gamma-glutamyl transpeptidase (GGT) Hepatic source 7.4 Plasma Proteins Albumin Liver production Biological half-life in plasma: around 20 days Hypoalbuminemia is observed in: Advanced chronic liver disease Severe acute liver damage 7.5 Prothrombin Time (PT) Time it takes for the blood to clot Measured in seconds Hepatic synthesis function Prothrombin Made by the liver Helps blood to clot Enzymatic cascade activates prothrombin It has a very short half-life (60 to 72hrs) Laboratory consideration Normal PT = normal amount of blood-clotting protein Increased prothrombin time Earliest indicator of hepatic synthesis 8. Gamma-Glutamyl Transpeptidase (GGT) Very sensitive marker of liver pathology (endoplasmic reticulum of hepatocytes) Detoxification Widely distributed Increased by: Alcohol ingestion Drugs such as phenytoin Particularly associated with cholestasis Outcomes: Increased ALT and GGT? Increased GGT and normal ALT? Acute/Chronic Liver Disease 9. Acute Liver Disease Common causes of acute liver disease Poisoning, infection, inadequate perfusion Poisoning Paracetamol overdose Plant and fungal toxins Liver infection Infective hepatitis Hepatitis A, B and C Inadequate liver perfusion Wider perfusion condition E.g., Blood loss All organs and tissues affected 9.1 Acute Liver Disease - Outcome It can progress in one of the three ways: ❖Resolve ❖Progress to acute hepatic failure Medical emergency Not compensated Renal failure It may lead to increased blood ammonia ❖Lead to chronic hepatic damage 10. Chronic Liver Disease Develops gradually May lead to long-term liver damage Chronic liver damage includes: Alcoholic liver disease Chronic active hepatitis Primary biliary cirrhosis – chronic autoimmune disease Nonalcoholic fatty liver disease It may progress to cirrhosis Late stage of fibrosis of the liver Cirrhosis 11. Cirrhosis Final stage of chronic liver damage Scarring of liver Decreased function Commonly associated with chronic conditions of liver Irreversible Wikimedia Commons, 2024 In case of alcohol abuse, the preceding stage is reversible Only 30% of patients with alcoholic disease progress to cirrhosis It may lead to liver failure Liver is unable to perform its functions  11.1 Diagnosis of Cirrhosis and Liver Failure Early (stable period) May last for years No good biochemical indicators Late stages Jaundice, encephalopathy, ascites, bleeding, terminal liver failure Laboratory considerations: Liver biopsy (golden standard for diagnosis) Not recommended when low platelet count/ clotting factors Antigen or antibody (hepatitis) Serum and urine copper levels (Wilson disease) Serum iron and ferritin (hemochromatosis) Albumin and Prothrombin time Imaging tests (ascites) Liver Diseases 12. Gilbert Syndrome Genetic liver disease (autosomal recessive disorder) Most common cause of hereditary hyperbilirubinemia Reduced activity of glucuronyl transferase Decreased conjugation of bilirubin 30% of normal enzymatic activity remains High levels of unconjugated bilirubin Most common sign https://medxlife.in/modern-topics/gilberts-syndrome/ Laboratory considerations Total bilirubin and indirect bilirubin Glucuronyl transferase 13. Crigler-Najjar Syndrome Rare Genetic disorder Type I - autosomal recessive trait No bilirubin conjugation Lack of glucuronyl transferase Severe unconjugated bilirubinemia Potential life threatening Daily phototherapy Laboratory considerations Liver enzymes – normal Total bilirubin – 20-50 mg/dL (RI: 0.2-1.3 mg/dL) Type II – autosomal dominant trait Decreased glucuronyl transferase Chronic bilirubinemia Liver enzymes - normal Total bilirubin – 7-20 mg/dL 14. Dubin-Johnson Syndrome Autosomal recessive genetic defect Conjugated bilirubinemia Bilirubin is not transported efficiently out of hepatocytes and into bile Signs Jaundice (early adolescence) Laboratory considerations: Dark pigmentation in liver Upper abdominal pain Increased serum bilirubin Anorexia Nausea Vomiting 15. Hepatitis Inflammation of liver Causes: virus, bacteria, toxic chemicals, drugs, alcohol Hepatitis Five types of hepatitis virus (A, B, C, D, and E) Pixabay.com Acute (6 months or less) or chronic (> 6 months) First symptoms Fatigue, jaundice, fever, nausea, tea-coloured urine, clay-coloured feces Acute hepatitis panel: Anti-HAV immunoglobulin M (IgM), HBAg, anti-HBc IgM, and anti-HCV 15.1 Hepatitis A HAV, single stranded RNA virus Transmission – fecal-oral route Greatest risk 2 weeks before symptoms Virus infects liver, excreted via bile into feces Contaminated food Pixabay.com 70% to 80% individuals - jaundice Prevention HAV vaccine is available for people travelling to endemic areas 15.2 Hepatitis B HBV, DNA virus Contains: central core and envelope (surface antigen) Transmission: contact with blood, semen, vaginal fluid Wikimedia Commons, 2024 Acute hepatitis B Incubation – 60 to 90 days Anorexia, vomiting, abdominal pain, dark urine, jaundice (30% to 50%) Most adults recover within 6 months 15-25% develop chronic liver disease HBV vaccine 15.3 Hepatitis C HCV, enveloped single-stranded RNA virus Transmission: Blood transfusion (before 90s) Contaminated needles Incubation- 2 to 26 weeks 60% to 70% are asymptomatic Symptoms Wikimedia Commons, 2024 Anorexia, malaise, fatigue, abdominal pain and jaundice 60% to 85% develop chronic hepatitis C 10% to 20% with chronic hepatitis develop cirrhosis 1% to 5% develop hepatocellular carcinoma No vaccine 15.4 Laboratory Diagnosis of Viral Hepatitis Non-specific blood tests Bilirubin Liver enzymes :ALT, AST, ALP, GGT Specific blood tests Antibodies to individual viral antigens (A, B, and C) or antigens of the virus (hepatitis B) Anti-HAV immunoglobulin M (IgM) Hepatitis B surface antigen (HBsAg) Anti-hepatitis surface antigen (Anti-HBs) Anti-hepatitis core antigen (Anti-HBc) Anti-hepatitis core antigen IgM (Anti-HBc IgM) Anti-HCV With hepatitis B, antibody tests establish a current, chronic, or past infection 16. Hereditary Hemochromatosis Or primary hemochromatosis Autosomal recessive genetic disease Accumulation of iron in organs Most common cause of iron overload 75% of individuals are asymptomatic Increased absorption or iron (3X) Early symptoms Fatigue, impotence, and arthralgia At diagnosis Organ injury, diabetes mellitus Skin hyperpigmentation (“bronze skin”, hemosiderin), arthropathy, cardiomyopathy, etc. Cirrhosis and hepatocellular carcinoma (200 X more common) 16.1 Diagnosis of Hereditary Hemochromatosis Mistaken for fatigue, fibromyalgia, or depression Late diagnosis ❖Clinical evaluation ❖Blood tests Serum iron Ferritin Transferrin saturation (TSAT)- 70% or greater Amount of transferrin bound to iron Liver function tests ALT, AST, ALP, bilirubin Total protein and albumin Glucose levels ❖Genetic testing 17. Wilson Disease Autosomal recessive genetic disease Disease of copper metabolism Copper: absorbed in intestine – associated with ceruloplasmin in liver – transport to other tissues Excess copper: excreted by liver in bile= feces Not able to associate copper to protein nor to excrete in bile Damage to the liver, brain, and eyes It may also damage heart and kidney Hepatic disturbances at early age Late diagnosis Active hepatitis, cirrhosis, and fulminant liver failure Laboratory considerations Serum copper – low Wikimedia Commons, 2024 Elevated AST, ALT, GGT and bilirubin (extent of disease) Kayser-Fleischer rings Decreased Ceruloplasmin, increased urinary copper excretion