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Liver Function T ests (LFT s)
Liver Function Tests (LFT s)
• Noninvasive methods for screening of liver dysfunction • Help in identifying general types of disorder • Assess severity and allow prediction of outcome • Disease and treatment follow up LFTS The conventional liver function test (LFT) consists of determination of serum/plasma levels of bilirubin and other liver enzymes. These include alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT). The breakdown of hepatocytes results in the release of aminotransferases (also referred to as transaminases) such as ALT (alanine aminotransferase) and AST(aspartate aminotransferase) into the blood. Serum/plasma concentrations of total protein and albumin are useful in assessing liver function. Major Metabolic Functions of the Liver • Synthetic Function Plasma proteins (albumin, globulins), cholesterol, triglycerides and lipoproteins • Detoxification and excretion Ammonia to urea (urea cycle), bilirubin, cholesterol, drug metabolites • Storage Function • Vitamins A, D, E, K and B12 • Production of bile salts Helps in digestion Some examples of liver dysfunction • Hepatocellular disease • Cholestasis (obstruction of bile flow • Cirrhosis • Hepatitis • Jaundice • Liver cancer • Steatosis (fatty liver) • Genetic Disorders • Hemochromatosis (iron storage) Liver Function T est Used to …… 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 Liver Function Tests (LFTs) Broadly classified as: 1.Tests to detect hepatic injury: • Mild or severe; acute or chronic • Nature of liver injury (hepatocellular or cholestasis)
2. Tests to assess hepatic function
Classification of LFTs Group I: Markers of liver dysfunction Serum bilirubin: total and conjugated Urine: bile salts and urobilinogen Total protein, serum albumin and albumin/globulin ratio Prothrombin Time Classification of LFTs Group II: Markers of hepatocellular injury
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST) Classification of LFTs Group III: Markers of cholestasis
Alkaline phosphatase (ALP)
ϒ-glutamyltransferase (GGT) Limitations of LFTs • Normal LFT values do not always indicate absence of liver disease • Liver has very large reserve capacity • Asymptomatic people may have abnormal LFT results Diagnosis should be based on clinical examination Serum Albumin • The most abundant protein synthesized by the liver • Normal serum levels: 3.5 – 5 g/dL • Synthesis depends on the extent of functioning liver cell mass • Longer half-life: 20 days • Its levels decrease in all chronic liver diseases. In acute liver disease both total protein and serum albumin concentrations are unaltered. In chronic liver disease total protein may be low or high. If total protein is high it is most likely due to polyclonal hypergammaglobulinemia. Serum Globulin • Normal serum levels: 2.5 – 3.5g/dL • and -globulins mainly synthesized by the liver • They constitute immunoglobulins (antibodies) • High serum -globulins are observed in chronic hepatitis and cirrhosis: • IgG in autoimmune hepatitis • IgA in alcoholic liver disease Prothrombin Time (PT) • Prothrombin: synthesized by the liver, a marker of liver function • Half-life: 6 hrs. (indicates the present function of the liver) • PT is prolonged only when liver loses more than 80% of its reserve capacity • Vitamin K deficiency also causes prolonged PT Clotting factors, with the exception of Factor VIII, are produced in the liver. Factor VII is one of the factors involved in the extrinsic pathway and has the shortest half-life among all clotting factors (4-6 hours). Therefore, within a short period after significant liver dysfunction, PT is prolonged and the magnitude of prolongation is correlated with the severity of liver dysfunction. Aspartate aminotransferase (AST) • Normal range: 8 – 20 U/L • AST is primarily a mitochondrial enzyme that is also found in the heart, muscle, kidney, and brain. • A marker of hepatocellular damage • High serum levels are observed in: Chronic hepatitis, cirrhosis and liver cancer In acute liver injury, AST levels are higher than ALT; however, after 24-48 hours ALT levels should be higher than AST. Alanine aminotransferase (ALT) • ALT is a cytosol enzyme and is more specific for liver disease than AST • Normal range (U/L): Male: 13-35 Female: 10-30 High serum levels in acute hepatitis (300- 1000U/L) Moderate elevation in alcoholic hepatitis (100- 300U/L) Minor elevation in cirrhosis, hepatitis C and non-alcoholic steatohepatitis (NASH) (50- 100U/L) Alanine aminotransferase (ALT) • Appears in plasma many days before clinical signs appear • A normal value does not always indicate absence of liver damage • Obese but otherwise normal individuals may have elevated ALT levels • ALT has a longer half-life than AST Alkaline phosphatase (ALP) • A non-specific marker of liver disease Alkaline phosphatase (ALP) is found in liver, bone, intestine, and placenta. ALP is located in the canalicular and sinusoidal membrane of the liver • Normal range: 40 – 125 U/L • Moderate elevation observed in: Infective hepatitis, alcoholic hepatitis and hepatocellular carcinoma Alkaline phosphatase (ALP) • High levels are observed in: Extrahepatic obstruction (obstructive jaundice) and intrahepatic cholestasis • Very high levels are observed in: Bone diseases Production of ALP is increased during cholestasis (intrahepatic or extrahepatic), which results in elevated activity of ALP in serum; If ALP level is raised, then the next question is whether the source of this enzyme is the liver or not. Alkaline phosphatase (ALP) In cholestasis ALP and GGT levels are raised indicating that the liver is the source of ALP. If ALP activity is increased but activity of GGT is normal, then it is unlikely that the liver is the source of excess ALP. In children showing only elevated ALP, it is most likely related to osteoblastic activity in their growing bones. In elevated ALP with normal bilirubin, ALT and AST may be seen in patients with hepatic metastasis or bone metastasis. -glutamyltransferase (GGT) • Used for glutathione synthesis • Normal range: 10 – 30U/L • Moderate elevation observed in: Infective hepatitis and prostate cancers • GGT is increased in alcoholics despite normal liver function tests Highly sensitive to detecting alcohol abuse GGT is a well-established marker for alcohol abuse. A normal liver function test (except elevated GGT) is a characteristic of excessive alcohol intake. Measurement of gamma-glutamyl trans-peptidase (GGT) levels can be used to determine if the source of ALP is the liver or not because GGT is solely produced by the biliary epithelium. GGT is a microsomal enzyme. BILIRUBIN METABOLISM In the first step of bilirubin synthesis, the heme molecule is stripped from the hemoglobin molecule. Heme then passes through various processes of porphyrin catabolism, which varies according to the region of the body in which the breakdown occurs. The production of biliverdin from heme is the first major step in the catabolic pathway, after which the enzyme biliverdin reductase performs the second step, producing bilirubin from biliverdin. Ultimately, bilirubin is broken down within the body, and its metabolites excreted through bile and urine elevated levels may indicate certain diseases. It is responsible for the yellow color of healing bruises and the yellow discoloration in jaundice. Its breakdown products, such as stercobilin, cause the brown color of feces. A different breakdown product, urobilin, is the main component of the straw-yellow color in urine. In the liver, bilirubin is conjugated with glucuronic acid by the enzyme glucuronyltransferase, first to bilirubin glucuronide and then to bilirubin diglucuronide, making it soluble in water The conjugated version is the main form of bilirubin present in the "direct" bilirubin fraction. Much of it goes into the bile and thus out into the small intestine. Though most bile acid is reabsorbed in the terminal ileum to participate in enterohepatic circulation, conjugated bilirubin is not absorbed and instead passes into the colon. There, colonic bacteria deconjugate and metabolize the bilirubin into colorless urobilinogen, which can be oxidized to form urobilin and stercobilin. Urobilin is excreted by the kidneys to give urine its yellow color and stercobilin is excreted in the feces giving stool its characteristic brown color. A trace (~1%) of the urobilinogen is reabsorbed into the enterohepatic circulation to be re-excreted in the bile. Bilirubin • A by product of red blood cell breakdown
• It is the yellowish pigment observed in jaundice
• High bilirubin levels are observed in:
Gallstones, acute and chronic hepatitis
Bilirubin In hemolytic anemia, indirect bilirubin concentration may be increased. Defects in the uptake of unconjugated bilirubin by hepatocytes may also increase the concentration of unconjugated bilirubin (indirect bilirubin) in serum. An increased concentration of conjugated bilirubin (direct bilirubin) is seen in cholestatic jaundice. Most of the normal bilirubin found in serum or plasma is unconjugated (indirect bilirubin). Serum bilirubin levels • Normal 0.2 – 0.8 mg/dL • Unconjugated (indirect): 0.2 – 0.7 mg/dL • Conjugated (direct): 0.1 – 0.4 mg/dL Latent jaundice: Above 1 mg/dL Jaundice: Above 2 mg/dL Bilirubin levels and jaundice Class of Jaundice Causes
Pre-hepatic or hemolytic Abnormal red cells; antibodies; drugs
and toxins; thalessemia Hemoglobinopathies, Gilbert’s, Crigler-Najjar syndrome
Hepatic or Hepatocellular Viral hepatitis, toxic hepatitis,
tumors of the bile duct, carcinoma of pancreas Summary Key points regarding interpretation of liver function tests include: In acute liver disease without cholestasis, levels of ALT and AST are significantly elevated and ALP is raised, but usually less than three times the upper limit of the normal value. Therefore, ALT and AST levels exceeding 500 U/L are a common finding in acute liver disease. In acute cholestasis, ALT and AST are raised but levels are not very high. ALP is usually more than three times the upper limit of the normal value with a parallel increase in GGT levels. Thank you very much for your attention
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