Evaluation of liver function Normal Liver Function Metabolic
Evaluation of liver function
Normal Liver Function • Metabolic Functions • Synthetic Functions • The liver is composed of three systems: – the hepatocyte, • concerned with metabolic reactions and macromolecular, especially protein, synthesis and degradation; – The biliary system, • involved with the metabolism of bilirubin and bile salts; – the reticuloendothelial system, • concerned with the immune system and the production of heme and globin metabolites (e. g. , bilirubin).
liver function test profile • The function of each of these systems can be measured conveniently and virtually noninvasively
Metabolic Tests • Bilirubin • Normal Bilirubin Metabolism • Causes of Elevated Serum Levels of unconjugated Bilirubin • Causes of Elevated Serum Levels of Conjugated Bilirubin
Metabolic Tests • • Ammonia Lipids Bile Salts Drug Metabolism
Lipids • Decrease in the HDL • Decreased synthesis of LCAT • and lipoprotein lipases
Synthetic Functions • Protein Synthesis – Albumin – Other Serum Proteins • Alpha-I-Antitrypsin (AAT) • Ceruloplasmin – Clotting Factors – Des-Camma-Carboxy Prothrombin (DCP)
Tests of Liver Injury • Plasma Enzyme Levels – Cellular Locations of Enzymes – Mechanisms of Enzyme Release • Aminotransferases (Transaminases)
• Lactate Dehydrogenase • • Enzymes Primarily Reflecting Canalicular Injury Alkaline Phosphatase (ALP) Gamma-Glutamyl Transferase (GGT) Other Enzymes
• Alpha-Fetoprotein (AFP) • Autoimmune Markers – Antimitochondrial Antibody Is a Marker for Primary Biliary Cirrhosis (PBC). – ANCA is a Marker for Primary Sclerosing Cholangitjs. – Serum Markers for Autoimmune Hepatitis.
Markers of Hepatitis Virus Infection • Viruses are the cause of 80 -90% of acute and chronic hepatitis. • Most viral-induced liver pathology is caused by five viruses – Cause hepatocyte injury – Hepatitis A, B, C, D, and E
Hepatitis B • Hepatitis B is transmitted – Primarily by body fluids, especially serum; – By sex – From mother to baby. • Hepatitis B produces several protein antigens – Core antigen (HBc. Ag) – Surface antigen (HBs. Ag or HBs) – e antigen (HBe. Ag) • Antibodies to each of these antigens can also be measured
• Acute HBV Hepatitis: HBs. Ag, Ig. M anti-HBc • Chronic HBV Hepatitis: HBs. Ag, Ig. G anti-HBc, Ig. G anti-HBs • Monitoring chronic HBV infection: HBs, HBe. Ag, Ig. G anti-HBs, Ig. G anti-Hbe, and ultrasensitive quantitative PCR.
• Serologic marker
Hepatitis C Recombinant immunoassay (RIBA) test
Hepatitis D
Hepatitis E
Hepatitis G
Diagnosis of Liver Diseases • Hepatitis – Alcoholic Hepatitis. – Chronic Hepatitis. – Cirrhosis
• In this section, the major hepatic disorders are discussed with emphasis on laboratory evaluations that enable diagnoses to be made, often without the need to perform invasive procedures such as liver biopsies.
• in acute hepatitis – the principal changes are significant elevations of aminotransferases; • in cirrhosis, – these tend to remain normal or become slightly elevated • the total protein and albumin are depressed, • ammonia concentrations in serum are elevated. • In post-hepatic biliary obstruction, – Bilirubin and alkaline phosphatase become elevated;
• in space-occupying diseases of the liver, alkaline phosphatase and lactate dehydrogenase are elevated. • In fulminant hepatic failure, the aminotransferases and ammonia are elevated while total protein and albumin are depressed.
Hepatitis • Manifestation – fatigue and anorexia – Jaundice may be present – the most common cause (> 90% of cases) of hepatitis is viral, • with about 50% due to hepatitis a, 25% to hepatitis A, and 20% to hepatitis C. • The cause of acute hepatitis – Viral, (> 90% of cases) – Chemical exposure • such as to carbon tetrachloride or chloroform – Drugs • such as acetaminophen, especially in children, • Alcohol
Hepatitis • The cardinal finding in hepatitis – Rise in the aminotransferases to values of more than 200 IU/L and often to 500 or even 1000 IU/L. – Exception • Hepatitis C – Only modest elevations of ALT (but not AST) – The AST/ALT ratio generally favors ALT • Bilirubin – – Frequenlly elevated, both direct and indirect Frank jaundice occurs in about 70% of cases of acute hepatitis A 33% of cases of hepatitis B About 20% of acute hepatitis C cases
Hepatitis • LD levels – Mildly elevated, typically around 300 -500 IU/L. • Total protein and albumin – Normal ranges • The gammaglobulin fractions – may be elevated as a result of infection
Causes of hepatitis • Given the pattern of the above analytes suggestive of hepatitis, • Screens for specific causes should be made, – Viral causes, – Nonviral causes • Determination of serological markers – Screening for anti hepatitis A Ig. M – and for HBs. Ag • If negative, further screening for hepatitis B should be undertaken – Determination of serum titers of anti·HBc. Ag Ig. M and Ig. G ('core window'),
Causes of hepatitis • anti-H Bs. Ag Ig. G – Hepatitis B is the cause of the infection – Past exposure • Chronic active or persistent hepatitis – HBs. AG is continuously present, • elevated titers of anti HBs. Ag Ig. G occur – Long after the aminotransferases return to normal levels.
Causes of hepatitis • Screens for hepatitis C should also be performed. • If these are negative, other viral causes should be sought, – Cytomegalovirus & Epstein-Barr virus.
Causes of hepatitis • Nonviral causes, – Chemical toxins, – Less common causes • Wilson's disease, • Autoimmune hepatitis, – In the chronic form » often accompanied by elevations in ANA titers, • Polyclonal increases in the gammaglobulins – Alcoholic Hepatitis
Causes of hepatitis • Alcoholic Hepatitis – the above-described pattern of abnormal analyte • AST much of it mitochondrial AST – disproportionately elevated over ALT. – GGT, often out of proportion to elevations in alkaline phosphatase. – Total protein & albumin • Normal
Chronic Hepatitis • Ongoing hepatocyte damage, • Chronic inflammation in hepatocytes on biopsy. • Causes – Mainly by chronic hepatitis B or C infections, • Detection – Persisting HBs. Ag – RT-PCR , for hepatitis C sequences,
Chronic Hepatitis • Chronic Hepatitis – Is a Major predisposing factor for • Cirrhosis & Hepatocellular carcinoma – Leading causes of death from liver disease. – Asymptomatic or mildly symptomatic. – Mild elevation of AST and ALT • Mild elevation only of ALT – Hepatitis C
Cirrhosis • Parenchymal fibrosis and hepatocytic nodular regeneration • Caused by – Alcoholism – Panhepatic hepatitis, – Chronic active hepatitis, – Toxins and drugs, – Diseases of the biliary tract • Primary and secondary biliary cirrhosis.
Cirrhosis • Systemic diseases – Hemochromatosis, abnormal iron deposition in tissues – Wilson's disease, copper deposits in liver – alpha-I antitrypsin deficiency, because of proteolysis in hepatocytes, • Chronic hepatitis due to – Persistent circulating hepatitis B or C – Autoimmune disease • with elevated ANA or ASMA anti-smooth muscle antibody (ASMA), antinuclear antibody (ANA) continuing
Diagnosis of fibrosis and/or necrosis and inflammation of the liver – Invasive procedure • Liver biopsy. – The definitive diagnosis – Morbidity – Confounding problem of sampling – Non-invasive procedure • Serum analytes
Diagnosis of fibrosis and/or necrosis and inflammation of the liver • Serum analytes – PGA index, • Prothrombin time (PT), gamma-glutamyl transferase & apolipoprotein A 1 • Ranges of values, four categories, in order of severity • With severity of disease – – apo-A I, decreases Prothrombin time increases These scores are then summed. Higher PGA scores, » degree of hepatic fibrosis and with the severity of cirrhosis
Diagnosis of fibrosis and/or necrosis and inflammation of the liver • Other indices – Fibrotest & the Actitest index • Measurement of six analyts – Apolipoprotein A-1, GGT, haptoglobin, total bilirubin, alpha-2 macroglobulin and ALT • Also; age & gender • Scores are computed on a scale of 0 to 1, corresponding to – Histopathological staging system, – Necroinflammatory activity
Diagnosis of fibrosis and/or necrosis and inflammation of the liver • There is some disagreement as to the efficacy of these indices – Discordances between liver biopsy & Fibro- and Actitest results – Conditions that are unrelated to liver fibrosis can change the index
Biochemical & Clinical Correlations of Cirrhosis
Primary & secondary biliary cirrhosis • Usually beginning as an obstructive pattern – Alkaline phosphatase & sometimes bilirubin are elevated • Progresses to one which resembles hepatitis • With time, gives way to a cirrhotic pattern
Primary & secondary biliary cirrhosis • Diagnostic of primary biliary cirrhosis – a persistent obstructive pattern – no evidence of mass lesions or stones causing blockage of bile flow, – the presence of anti-M 2 antimitochondrial antibody • Secondary biliary cirrhosis – Serum p. ANCA antibodies p. ANCA; perinuclear antineutrophil cytoplasmic antibodies
Posthepatic & Posthepatocytic Biliary Obstruction • Blockage of – the intrahepatic, – extrahepatic ducts – Blockage of bilirubin excretion • Causes – Cholelithiasis, the most common cause – Primary biliary cirrhosis (PBC) – Inflammation of the biliary tract • Gram-negative sepsis
Posthepatic & Posthepatocytic Biliary Obstruction • Drugs, – the neuroleptics, like chlorpromazine, can cause cholestatic jaundice. • Mass lesions – such as carcinoma of the head ofthe pancreas • These conditions cause elevated bilirubin, most of it direct, ALP & GGT • Hyperbilirubinemia of other causes – Indirect type • Hemolysis – may be triggered by hepatic disease.
Posthepatic & Posthepatocytic Biliary Obstruction • Viral hepatitis may precipitate hemolysis in patients with glucose-6 -phosphate dehydrogenase deficiency.
Space-Occupying Lesions • due to – Metastatic cancer, – Lymphoma, primary hepatocellular carcinoma • The cardinal finding – Isolated increases in LD & alkaline phosphatase. • Mainly LD 5 • If a malignant tumor spreads widely through the liver, – Mild elevation in the aminouansferases, – Hyperbilirubinemia – Low protein & albumin
Space-Occupying Lesions • Serodiagnostic tests. – alpha-fetoprotein (AFP) • Hepatocellular carcinoma.
Fulminant Hepatic Failure • Acute fulminant hepatic failure – Uncommon but highly fatal condition • Massive destruction of liver tissue • The causes – Largely unknown – Reye's syndrome – Acute hepatitis B with hepatitis D superinfection, – Alcoholism, & cirrhosis. – Fatty liver of pregnancy
Fulminant Hepatic Failure • Diagnosis – Patients develop ascites – encephalopathy due to hyperammonemia – Total serum protein & serum albumin are depressed. – Severe coagulopathies, • Particularly disseminated intravascular coagulopathy – Anemia – Renal failure – Hypoglycemia
Fulminant Hepatic Failure • Lactic acidosis – Poor tissue perfusion • May become Hypernatremic & hypokalemic. – Perhaps, failure of the liver to clear aldosterone • Rapid increases in serum levels of the aminotransferases – AST, levels of over 20 000 IU/L, • at least 1. 5 times greater than ALT
Fulminant Hepatic Failure • Overall – Pattern resembles hepatitis & end-stage cirrhosis combined – Except • Usually in acute hepatitis, save alcoholic hepatitis, AST and ALT rise in a ratio of about 1: 1 or in a ratio that favors ALT • LD, alkaline phosphatase & bilirubin all increase markedly.
Fulminant Hepatic Failure • All of the changes occur over a period of about 1 week. • After another week, the serum AST & ALT return to low, or undetectable • Therapy or Cure – Supportive therapy, restoration of normal liver function – Liver transplantation
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