Evaluation of Liver Function Dr. Baghbanian M. Gastroenterologist Shaheed Sadoughi hospital / 2012

liver tests (1) detect the presence of liver disease (2) distinguish different types of liver disorders (3) extent of liver damage (4) follow the response to treatment

Liver tests Can be normal in serious liver disease Can be abnormal in non hepatic diseases Rarely suggest a specific diagnosis They suggest a general category of liver disease, such as hepatocellular or cholestatic

liver carries out thousands of biochemical functions most cannot be easily measured by blood tests. Laboratory tests measure only a limited number of these functions.

Aminotransferases /Alkaline phosphatase do not measure liver function at all. Rather, they detect: liver cell damage interference with bile flow. Thus, no one test FOR assess the liver's total functional capacity.

Liver test Bilirubin aminotransferases alkaline phosphatase albumin prothrombin time tests.

USE MULTIPLE TEST for detection of liver disease probability of liver disease is high When : more than one of these tests are abnormal tests persistently abnormal on serial determinations probability of liver disease is lowWhen: all test results are normal

Tests Based on Detoxification and Excretory Functions Serum Bilirubin Blood Ammonia Serum Enzymes

Serum Bilirubin breakdown product of the porphyrin of heme-containing proteins two fractions: Conjugated = direct water soluble excreted by the kidney. Unconjugated = indirect insoluble in water bound to albumin in the blood.

Normal Serum Bilirubin Total = 1 - 1.5 mg/dL. Direct <15% of the total → considered indirect upper limit of normal for conjugated = 0.3 mg/dL.

Isolated unconjugated hyperbilirubinemia is rarely due to liver disease Causes: hemolytic disorders genetic conditions such as : Crigler-Najjar Gilbert's syndromes

bilirubin elevated but <15% direct should prompt a workup for hemolysis In the absence of hemolysis, an isolated, unconjugated hyperbilirubinemia in an otherwise healthy patient can be attributed to Gilbert's syndrome, and no further evaluation is required.

conjugated hyperbilirubinemia always implies liver or biliary tract disease. In most liver diseases, both conjugated and unconjugated fractions of the bilirubin tend to be elevated

rate-limiting step in bilirubin metabolism transport of conjugated bilirubin into the bile canaliculi not conjugation

Fractionation of the bilirubin rarely helpful in determining the cause of jaundice Except : purely unconjugated hyperbilirubinemia,.

Degree of elevation of bilirubin not as a prognostic marker But is important in : viral hepatitis: higher bilirubin→ greater hepatocellular damage. alcoholic hepatitis: Total serum bilirubin correlates with poor outcomes component of the Model for End stage Liver Disease (MELD) drug-induced liver disease: elevated total serum bilirubin indicates more severe injury.

Urine Bilirubin Unconjugated bilirubin binds to albumin in the serum and is not filtered by the kidney. any bilirubin in urine is conjugated bilirubin; the presence of bilirubinuria implies the presence of liver disease. In patients recovering from jaundice, the urine bilirubin clears prior to the serum bilirubin.

Blood Ammonia is produced during normal protein metabolism intestinal bacteriain the colon. liver plays : detoxification of ammonia by converting it to urea→ excreted by the kidneys Striated muscle →detoxification of ammonia(combination with glutamic acid )

Elevated ammonia levels Has very poor correlation with: presence or severity of acute encephalopathy hepatic function.

Elevated ammonia levels occasionally useful for occult liver disease in mental changes. correlate with outcome in fulminant hepatic failure. in severe portal hypertension and shunting around the liver even in normal or near-normal hepatic function.

Serum Enzymes The liver contains thousands of enzymes These enzymes have no known function probably cleared by reticuloendothelial cells liver cells damage → entrance of Enzymes into serum

3 type of LIVER enzyme tests enzymes whose elevation reflects damage to hepatocytes 2) enzymes whose elevation reflects cholestasis 3) enzyme tests that do not fit either pattern.

Enzymes that Reflect Damage to Hepatocytes include: aspartate aminotransferase (AST) = serum glutamic oxaloacetic transaminase (SGPT) alanine aminotransferase (ALT) = serum glutamic pyruvic transaminase(SGPT) sensitive indicators of liver cell injury most helpful in recognizing acute hepatocellular diseases (hepatitis)

AST is found in Liver cardiac muscle skeletal muscle kidneys brain pancreas lungs leukocytes, and erythrocytes

ALT is found primarily in the liver and is more specific for liver injury. The aminotransferases are normally present in the serum in low concentrations.

Aminotransferases damage to the liver cell → enzymes release into blood Liver cell necrosis is not required poor correlation with degree of liver cell damage not prognostic in acute hepatocellular disorders.

Levels of aminotransferases normal : 10-40 U/L. <300 U/L are nonspecific and may be found in any type of liver disorder. Minimal ALT elevations in asymptomatic blood donors rarely indicate severe liver disease; fatty liver is the most cause.

Aminotransferases >1000 U/L Extensive hepatocellular injury such: viral hepatitis ischemic liver injury (prolonged hypotension or acute heart failure) toxin- or drug-induced liver injury.

The pattern of the aminotransferase acute hepatocellular disorders: ALT ≥ AST. chronic viral hepatitis : ALT ≥ AST cirrhosis : AST ≥ ALT

Alcoholic liver disease AST/ALT >2:1 is suggestive AST/ALT >3:1 is highly suggestive The AST is rarely >300 U/L ALT is often normal. A low level of ALT in the serum is due to an alcohol-induced deficiency of pyridoxal phosphate.

Aproach to asymptomatic elevation of serum aminotransferase

Obstructive jaundice Aminotransferases not greatly elevated Exception: passage of a gallstone into the common bile duct → acute biliary obstruction → aminotransferases 1000–2000 → decrease quickly → liver-function tests rapidly evolve typical of cholestasis.

Aproach to isolated elevation of bilirubin

Enzymes that Reflect Cholestasis Are usually elevated in cholestasis Alkaline phosphatase 5'-nucleotidase Gama glutamyl transpeptidase (GGT)

Gama glutamyl transpeptidase (GGT) GGT is more diffuse in liver→ is less specific for cholestasis than alkaline phosphatase or 5'-nucleotidase. GGT in occult alcohol use? lack of specificity / questionable.

Serum alkaline phosphatase found in : Liver Bone Placenta Small intestine

ALKP non pathologically elevated Age > 60 Blood types O and B after fatty meal (influx of intestinal ALKP into the blood.) Children and adolescents undergoing rapid bone growth, (bone) Late in normal pregnancies (influx of placental )

Elevation of liver-derived alkaline phosphatase Not specific for cholestasis < 3 fold occur in : any type of liver disease. >4 fold occur in: cholestatic liver disorders infiltrative liver diseases such as cancer and amyloidosis

If an elevated ALKP is only finding First aproach : ALKP electrophoresis. Second approach : inactivation by heat heat-stable : placenta or a tumor is the source. heat –unstable: intestinal, liver, and bone measurement of serum 5'-nucleotidase or GGT

In the absence of jaundice or elevated aminotransferases, an elevated ALKP of liver origin Often: early cholestasis less often: hepatic infiltration by tumor or granulomata.

isolated elevations of the alkaline phosphatase Hodgkin's disease diabetes hyperthyroidism congestive heart failure amyloidosis inflammatory bowel disease.

Level of ALKP IS NOT helpful in distinguishing between intrahepatic and extrahepatic cholestasis obstructive jaundice due to cancer, common duct stone, sclerosing cholangitis, or bile duct stricture.

Alkaline phosphatase increased in : intrahepatic cholestasis due to drug-induced hepatitis primary biliary cirrhosis rejection of transplanted livers rarely, alcohol-induced steatohepatitis.

Serum alkaline phosphatase Greatly elevated in hepatobiliary disorders in AIDS AIDS cholangiopathy due to cytomegalovirus or cryptosporidial infection tuberculosis with hepatic involvement

Aproach to isolated elevation of ALKP

Serum Albumin Synthesized exclusively by hepatocytes. Long half-life: 18–20 days Not a good indicator of acute or mild hepatic dysfunction (slow turnover)

Hypoalbuminemia Common in chronic liver disorders such as cirrhosis than in acute liver disease Reflects severe liver damage and decreased albumin synthesis. is not specific for liver disease and occur in: protein malnutrition protein-losing enteropathies nephrotic syndrome chronic infections that inhibit albumin synthesis.

Serum Globulins Immunoglobulins produced by B lymphocytes Globulins are increased in chronic hepatitis and cirrhosis.

increased Serum Globulins In cirrhosis: due to the increased synthesis of antibodies against intestinal bacteria. Cause : cirrhotic liver fails to clear bacterial antigens that normally reach through the hepatic circulation.

Specific globulins are helpful in recognition of certain liver diseases Diffuse polyclonal IgG ↑ in autoimmune hepatitis IgM ↑in primary biliary cirrhosis IgA ↑ in alcoholic liver disease.

Coagulation Factors Are made exclusively in hepatocytes. Exception: factor VIII, (which is produced by vascular endothelial cells)

Coagulation Factors Half-lives are shorter than albumin 6 h for factor VII to 5 days for fibrinogen. Single best acute measure of hepatic synthetic function FOR diagnosis and assessing the prognosis of acute parenchymal liver disease.

Coagulation Factors Prothrombin time : measures factors II, V, VII, and X. (25710) Depends on vitamin K: synthesis of factors II, VII, IX, and X (29710)

Prothrombin time May be elevated in : hepatitis cirrhosis vitamin K deficiency obstructive jaundice fat malabsorption

prothrombin time >5 s above control If not corrected by parenteral vitamin K is a poor prognostic sign in acute viral hepatitis and other acute and chronic liver diseases.

MELD (model of end stage liver disease) Allocate for liver transplantation. Has 3 component: INR, Total serum bilirubin Creatinine

Percutaneous Liver Biopsy Is a safe procedure Easily performed at the bedside With local anesthesia and ultrasound guidance.

Percutaneous Liver Biopsy Indication Hepatocellular disease of uncertain cause Prolonged hepatitis (chronic active hepatitis) (3) Unexplained hepatomegaly (4) Unexplained splenomegaly (5) Hepatic filling defects IN imaging (6) Fever of unknown origin (7) Staging of malignant lymphoma

Liver biopsy is most accurate in disorders causing diffuse changes IN liver Sampling error in focal infiltrative disorders such as hepatic metastases. Should not be the initial procedure in cholestasis.

Liver biopsy Contraindications Significant ascites Prolonged INR Under these circumstances, the biopsy can be performed via the transjugular approach

Ultrasonography First diagnostic test in cholestasis: dilated intrahepatic extrahepatic biliary tree gallstones. space-occupying lesions IN liver, →distinguish between cystic and solid masses, and helps direct percutaneous biopsies.

Ultrasound with Doppler Detect the patency of the : portal vein hepatic artery hepatic veins First test in patients suspected Budd-Chiari syndrome.

Abnormal in... Liver Test Cirrhosis, severe hepatocellular injury Albumin Cholestasis, hepatocellular enzyme induction, canalicular injury, children during bone growth, bone disease, pregnancy (placenta origin) Alkaline phosphatase Hepatocellular injury (ethanol, drug-induced hepatitis, hepatitis B and C, ischemic injury, chronic liver disease, NAFLD, chronic viral hepatitis, alcoholism, nonspecific viral injury, and cholestatic or replacement disease); acute biliary obstruction; rarely in hyperthyroidism, celiac disease, skeletal muscle disease Aminotransferases (AST, ALT) Any acute or chronic liver disease; congenital disorders of bilirubin metabolism. Bilirubin Cholestasis 5′ nucleotidase Cholestasis; medications, ethanol; rarely anorexia nervosa, hyperthyroidism, myotonic dystrophy GGT Impaired synthesis of vitamin K-dependent coagulation factors INR Ischemic injury, Epstein-Barr virus infection, hemolysis, solid tumor Lactate dehydrogenase Alcohol consumption, gout Uric acid

Aproach to cholestatic liver enzyme elevations