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LABORATORY DIAGNOSIS IN LIVER DISEASES

LABORATORY DIAGNOSIS IN LIVER DISEASES. The metabolic pathways of glycolysis,the Krebs cycle,amino acid synthesis and degradation and the process of oxidative phosphorylation are all carried out in hepatocytes,which are well endowed with mitochondria.

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LABORATORY DIAGNOSIS IN LIVER DISEASES

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  1. LABORATORY DIAGNOSIS IN LIVER DISEASES

  2. The metabolic pathways of glycolysis,the Krebs cycle,amino acid synthesis and degradation and the process of oxidative phosphorylation are all carried out in hepatocytes,which are well endowed with mitochondria. • The liver contains an extensive reticuloendothelial system for the synthesis of blood cells.

  3. Protein synthesis in liver • Albumin • Transthyretin(prealbumin) • Igs • Ceruloplasmin • α1-antitrypsin • Haptoglobulin • β2-microglobulin • Transferrin • α-fetoprotein • Some coagulation factors

  4. Albumin is the major protein product of the liver. • İt has a long biological half-life in plasma • (about 20 days ) • Hypoalbuminemia is a feature of advanced chronic liver disease.

  5. Metabolic liver diseases • Clinical conditions associated with abnormal concentrations of liver_produced proteins in plasma : • Genetic deficiency of α1-antitripsin presents in infancy as liver disease or in adulthood as lung disease Hepatic α1-antitrypsin belongs to the serpins, one of the family of serine protease inhibitors

  6. 2. Genetic deficiency of ceruloplasmin leads to Wilson’s disease, a condition associated with liver and CNS damage. Ceruloplasmin is the major cupper containing protein of liver and plasma functions as a ferrooxidase hepatic manifestations are fulminant hepatitis + chronic hepatitis + cirrhosis

  7. Neuropsychiatric changes include behavioral changes + psychosis • Cupper accumulates in liver, brain,cornea, kidney and joints • Corneal rings(Kayser_Fleischer) • Hemolysis + proximal renal tubular dysfunction + osteopenia + osteoarthropathy

  8. Lab: • Serum ceruloplasmin • Urinary Cu>100 μg/d • Hepatic Cu>250 μg/d • AST>ALT • Untreated Wilson’s disease is fatal

  9. Treatment: • Chelation therapy with D-penicillamine(1-2g/d)

  10. 3. Liver cancer is associated with particularly high plasma α-fetoprotein (AFP) concentrations. AFP and albumin have sequence homology in the fetus, AFP appears to serve physiologic functions similiar to albumin in adult By the end of first year of life, AFP in plasma is replaced by albumin

  11. 4. Hemochromatosis • Hereditary hemochromatosis (HHC) is an autosomal recessive disorder of iron retention that damages liver, pancreas , heart joints, gonads and skin • Lethargy + hepatomegaly + skin pigmentation(grayish color) + sometimes DM

  12. Diagnosis by analysis of serum iron, ferritin and transferrin saturation

  13. Drug metabolism • Most drugs are metabolized by the liver. • Low substrate specificity of some hepatic enzymes produces a wide-ranging capability for drug metabolism • Hepatic metabolism usually increases the hydrophilicity of drugs and therefore their ability to be excreted. • Metabolites produced are less pharmacologically active than the substrate drug.

  14. However some inactive prodrugs are converted to their active forms as a result of liver processing • Metabolism proceeds in 2 phases: • Phase I-addition of the polar group: • The polarity of the drug is increased by oxidation or hydroxylation catalyzed by cytocrome P-450 oxidases

  15. Phase II-conjugation • Cytoplasmic enzymes conjugate the functional groups introduced in the first phase by glucuronidation/sulfation/ acetylation /methylation • Cytocrome P-450 enzymes : • Heme containing proteins • Colocalize with NADPH:cyt P 450 reductase

  16. Present in endoplasmic reticulum • In liver and in the epithelium of endoplasmic reticulum • There are 12 cyt P450 gene families • CYP1, CYP2 and CYP3 are responsible for most of phase I drug metabolism • Induction and inhibition of cyt P-450 enzymes is the mechanism of drug interactions.

  17. Cytocrome P-450 gene polymorphisms determine response to many drugs

  18. ALCOHOLIC LIVER DISEASE • Excess intake of ethyl alcohol remains the most common cause of liver disease in the western world. • Alcohol leads to alcoholic hepatitis, steatosis due to fat deposition/fibrosis(cirrhosis) liver failure

  19. Alcohol acetaldehyde acetate • A B • A:alcohol dehydrogenase(NAD⁺) • B:aldehyde dehydrogenase(NAD⁺)

  20. Ethanol oxidation as a result of increased NADH/NAD⁺ alters the redox potential of hepatocyte • This inhibits oxidation of lactate to pyruvate (a step that requires NAD⁺ as a cofactor) lactic acidosis + risk for hypoglycemia

  21. NADH/NAD⁺ inhibition of β-oxidation + TG synthesis • Hepatic steatosis secreted into plasma as VLDL

  22. Ethanol consumption affects the ubiqutin system of protein degradation, proteosome activity is decreased hepatocyte signalling system is deregulated apoptosis (feature of alcoholic liver disease)

  23. Liver function tests: • Bilirubin • Aminotransferases (AST and ALT ) • Alkaline phosphatase (ALP ) • Gamma- glutamyl transpeptidase ( γ GT ) • Plasma proteins • Prothrombin time

  24. AST-ALT • Sensitive,albeit non-specific index of • Acute damage to hepatocytes irrespective of aetiology • Hepatitis,toxic injury,drug overdose

  25. ALP • İntra-or extrahepatic cholestasis • Tumours • Cirrhosis • Liver is not the sole source of ALP activity • Substantial amounts ara present in bone,small intestine,placenta and kidney.

  26. In normal blood,ALP activity is derived mainly from bone and liver,with small amounts from intestine. • Placental ALP appears in maternal blood in the third trimester of pregnancy. • The liver and bone isoenzymes can be separated by electrophoresis. • Elevated γ GT suggests that the liver is

  27. the source of increased ALP. • γ GT • Microsomal enzyme,widely distributed in tissues including liver and renal tubules • A very sensitive index of liver pathology • İncreases in cholastasis

  28. Alcohol and pheytoin induce enzyme activity. • Prothrombin time (PT ) • A measure of the activities of certain coagulation factors,made by the liver • A very short half-life • İncreased PT may be the earliest indicator of reduced hepatic synthesis.

  29. Acute liver disease • Acute liver damage occurs for one of the three reasons: • Poisoning • İnfection • İnadequate perfusion

  30. Chronic liver disease • Three forms of chronic liver damage are: • Alcoholic fatty liver • Chronic active hepatitis • Primary biliary cirrhosis

  31. Cirrhosis is the terminal stage of chronic liver damage and only occasionally follows an acute course. • The most common causes of cirrhosis are • Chronic excess alcohol ingestion • Viral hepatitis • Autoimmune diseases

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