LABORATORY DIAGNOSIS IN LIVER DISEASES

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LABORATORY DIAGNOSIS IN LIVER DISEASES. Prof. Dr. Arzu SEVEN. 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. - PowerPoint PPT Presentation

Transcript of LABORATORY DIAGNOSIS IN LIVER DISEASES

  • LABORATORY DIAGNOSIS IN LIVER DISEASESProf. Dr. Arzu SEVEN

  • 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.

  • PROTEN SYNTHESS N LVERAlbumin Transthyretin(prealbumin)IgsCeruloplasmin1-antitrypsinHaptoglobulin2-microglobulinTransferrin-fetoproteinSome coagulation factors

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

  • METABOLC LVER DSEASES Clinical conditions associated with abnormal concentrations of liver_produced proteins in plasma :Genetic deficiency of 1-antitripsin presents in infancy as liver disease or in adulthood as lung disease Hepatic 1-antitrypsin belongs to the serpins, one of the family of serine protease inhibitors

  • 2. Genetic deficiency of ceruloplasmin leads to Wilsons 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

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

  • Lab: Serum ceruloplasminUrinary Cu>100 g/dHepatic Cu>250 g/dAST>ALTUntreated Wilsons disease is fatal

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

  • 3. Liver cancer is associated with particularly high plasma -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

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

  • Diagnosis by analysis of serum iron, ferritin and transferrin saturation

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

  • However some inactive prodrugs are converted to their active forms as a result of liver processingMetabolism 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

  • Phase II-conjugationCytoplasmic enzymes conjugate the functional groups introduced in the first phase by glucuronidation/sulfation/ acetylation /methylationCytocrome P-450 enzymes :Heme containing proteins Colocalize with NADPH:cyt P 450 reductase

  • Present in endoplasmic reticulumIn liver and in the epithelium of endoplasmic reticulumThere are 12 cyt P450 gene familiesCYP1, CYP2 and CYP3 are responsible for most of phase I drug metabolismInduction and inhibition of cyt P-450 enzymes is the mechanism of drug interactions.

  • Cytocrome P-450 gene polymorphisms determine response to many drugs

  • ALCOHOLIC LIVER DISEASEExcess 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

  • Alcohol acetaldehyde acetate A BA:alcohol dehydrogenase(NAD)B:aldehyde dehydrogenase(NAD)

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

  • NADH/NAD inhibition of -oxidation + TG synthesis

    Hepatic steatosis secreted into plasma as VLDL

  • Ethanol consumption affects the ubiqutin system of protein degradation, proteosome activity is decreased

    hepatocyte signalling system is deregulated

    apoptosis (feature of alcoholic liver disease)

  • Liver function tests:BilirubinAminotransferases (AST and ALT )Alkaline phosphatase (ALP )Gamma- glutamyl transpeptidase ( GT )Plasma proteinsProthrombin time

  • AST-ALTSensitive,albeit non-specific index of Acute damage to hepatocytes irrespective of aetiologyHepatitis,toxic injury,drug overdose

  • ALPntra-or extrahepatic cholestasisTumoursCirrhosisLiver is not the sole source of ALP activitySubstantial amounts ara present in bone,small intestine,placenta and kidney.

  • 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 GT suggests that the liver is

  • the source of increased ALP.

    GT

    Microsomal enzyme,widely distributed in tissues including liver and renal tubulesA very sensitive index of liver pathologyncreases in cholastasis

  • Alcohol and pheytoin induce enzyme activity.Prothrombin time (PT )

    A measure of the activities of certain coagulation factors,made by the liverA very short half-lifencreased PT may be the earliest indicator of reduced hepatic synthesis.

  • Acute liver disease

    Acute liver damage occurs for one of the three reasons:Poisoningnfectionnadequate perfusion

  • Chronic liver disease

    Three forms of chronic liver damage are:Alcoholic fatty liverChronic active hepatitisPrimary biliary cirrhosis

  • 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 ingestionViral hepatitisAutoimmune diseases

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