Liver function tests

Definition

Liver function tests, or LFTs, include tests that are routinely measured in all clinical laboratories. LFTs include bilirubin, a compound formed by the breakdown of hemoglobin; ammonia, a breakdown product of protein that is normally converted into urea by the liver before being excreted by the kidneys; proteins that are made by the liver including total protein, albumin, prothrombin, and fibrinogen; cholesterol and triglycerides, which are made and excreted via the liver; and the enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and lactate dehydrogenase (LDH). Other liver function tests include serological tests (to demonstrate antibodies) and DNA tests for hepatitis and other viruses; and tests for antimitochondrial and smooth muscle antibodies, transthyretin (prealbumin), protein electrophoresis, bile acids, alpha-fetoprotein, and a constellation of other enzymes that help differentiate necrotic (characterized by death of tissues) versus obstructive liver disease.

Purpose

Liver function tests done individually do not give the physician very much information, but used in combination with a careful history, physical examination , and imaging studies, they contribute to making an accurate diagnosis of the specific liver disorder. Different tests will show abnormalities in response to liver inflammation; liver injury due to drugs, alcohol, toxins, or viruses; liver malfunction due to blockage of the flow of bile; and liver cancers.

Precautions

Blood for LFTs is collected by sticking a needle into a vein. The nurse or phlebotomist performing the procedure must be careful to clean the skin before sticking in the needle.

Bilirubin: Drugs that may cause increased blood levels of total bilirubin include anabolic steroids, antibiotics , antimalarials, ascorbic acid, Diabinese, codeine, diuretics , epinephrine, oral contraceptives, and vitamin A.

Ammonia: Muscular exertion can increase ammonia levels, while cigarette smoking produces significant increases within one hour of inhalation. Drugs that may cause increased levels include alcohol, barbiturates , narcotics, and diuretics. Drugs that may decrease levels include antibiotics, levodopa, lactobacillus, and potassium salts.

ALT: Drugs that may increase ALT levels include acetaminophen , ampicillin, codeine, dicumarol, indomethacin, methotrexate, oral contraceptives, tetracyclines , and verapamil. Previous intramuscular injections may cause elevated levels.

GGT: Drugs that may cause increased GGT levels include alcohol, phenytoin, and phenobarbital. Drugs that may cause decreased levels include oral contraceptives.

LDH: Strenuous activity may raise levels of LDH. Alcohol, anesthetics, aspirin , narcotics, procainamide, and fluoride may also raise levels. Ascorbic acid (vitamin C) can lower levels of LDH.

Description

The liver is the largest and one of the most important organs in the body. As the body's "chemical factory," it regulates the levels of most of the biomolecules found in the blood, and acts with the kidneys to clear the blood of drugs and toxic substances. The liver metabolizes these products, alters their chemical structure, makes them water soluble, and excretes them in bile. Laboratory tests for total protein, albumin, ammonia, transthyretin, and cholesterol are markers for the synthetic function of the liver. Tests for cholesterol, bilirubin, ALP, and bile salts are measures of the secretory (excretory) function of the liver. The enzymes ALT, AST, GGT, LDH, and tests for viruses are markers for liver injury.

Some liver function tests are used to determine if the liver has been damaged or its function impaired. Elevations of these markers for liver injury or disease tell the physician that something is wrong with the liver. ALT and bilirubin are the two primary tests used largely for this purpose. Bilirubin is measured by two tests, called total and direct bilirubin. The total bilirubin measures both conjugated and unconjugated bilirubin while direct bilirubin measures only the conjugated bilirubin fraction in the blood. Unconjugated bilirubin is formed in the reticuloendothelial (RE) cells in the spleen that remove old red blood cells from the circulation. The RE cells release the bilirubin into the blood, where it is bound by albumin and transported to the liver. The bilirubin is taken up by liver cells and conjugated to glucuronic acid, which makes the bilirubin water soluble. This form will react directly with a Ehrlich's diazo reagent, hence the name direct bilirubin. While total bilirubin is elevated in various liver diseases, it is also increased in certain (hemolytic) anemias caused by increased red blood cell turnover. Neonatal hyperbilirubinemia is a condition caused by an immature liver than cannot conjugate the bilirubin. The level of total bilirubin in the blood becomes elevated, and must be monitored closely in order to prevent damage to the brain caused by unconjugated bilirubin, which has a high affinity for brain tissue. Bilirubin levels can be decreased by exposing the baby to UV light. Direct bilirubin is formed only by the liver, and therefore, it is specific for hepatic or biliary disease. Its concentration in the blood is very low (0–0.2 mg/dL) and therefore, even slight increases are significant. Highest levels of direct bilirubin are seen in obstructive liver diseases. However, direct bilirubin is not sensitive to all forms of liver disease (e.g., focal intrahepatic obstruction) and is not always elevated in the earliest stages of disease; therefore, ALT is needed to exclude a diagnosis.

ALT is an enzyme that transfers an amino group from the amino acid alanine to a ketoacid acceptor (oxaloacetate). The enzyme was formerly called serum glutamic pyruvic transaminase (SGPT) after the products formed by this reaction. Although ALT is present in other tissues besides liver, its concentration in liver is far greater than any other tissue, and blood levels in nonhepatic conditions rarely produce levels of a magnitude seen in liver disease. The enzyme is very sensitive to necrotic or inflammatory liver injury. Consequently, if ALT or direct bilirubin is increased, then some form of liver disease is likely. If both are normal, then liver disease is unlikely.

These two tests along with others are used to help determine what is wrong. The most useful tests for this purpose are the liver function enzymes and the ratio of direct to total bilirubin. These tests are used to differentiate diseases characterized primarily by hepatocellular damage (necrosis, or cell death) from those characterized by obstructive damage (cholestasis or blockage of bile flow). In hepatocellular damage, the transaminases, ALT and AST, are increased to a greater extent than alkaline phosphatase. This includes viral hepatitis, which gives the greatest increase in transaminases (10–50-fold normal), hepatitis induced by drugs or poisons (toxic hepatitis), alcoholic hepatitis, hypoxic necrosis (a consequence of congestive heart failure), chronic hepatitis, and cirrhosis of the liver. In obstructive liver diseases, the alkaline phosphatase is increased to a greater extent than the transaminases (ALP>ALT). This includes diffuse intrahepatic obstructive disease which may be caused by some drugs or biliary cirrhosis, focal obstruction that may be caused by malignancy, granuloma from chronic inflamation, or stones in the intrahepatic bile ducts, or extrahepatic obstruction such as gall bladder or common bile duct stones, or pancreatic or bile duct cancer. In both diffuse intrahepatic obstruction and extrahepatic obstruction, the direct bilirubin is often greatly elevated because the liver can conjugate the bilirubin, but this direct bilirubin cannot be excreted via the bile. In such cases the ratio of direct to total bilirubin is greater than 0.4.

Aspartate aminotransferase, formerly called serum glutamic oxaloacetic transaminase (SGOT), is not as specific for liver disease as is ALT, which is increased in myocardial infarction, pancreatitis, muscle wasting diseases, and many other conditions. However, differentiation of acute and chronic forms of hepatocellular injury is aided by examining the ratio of ALT to AST, called the DeRitis ratio. In acute hepatitis, Reye's syndrome, and infectious mononucleosis the ALT predominates. However, in alcoholic liver disease, chronic hepatitis, and cirrhosis, the AST predominates.

Alkaline phosphatase is increased in obstructive liver diseases, but it is not specific for the liver. Increases of a similar magnitude (three- to five-fold normal) are commonly seen in bone diseases, late pregnancy, leukemia, and some other malignancies. The enzyme gamma-glutamyl transferase (GGT) is used to help differentiate the source of an elevated ALP. GGT is greatly increased in obstructive jaundice, alcoholic liver disease, and hepatic cancer. When the increase in GGT is two or more times greater than the increase in ALP, the source of the ALP is considered to be from the liver. When the increase in GGT is five or more times the increase in ALP, this points to a diagnosis of alcoholic hepatitis. GGT, but not AST and ALT, is elevated in the first stages of liver inflammation due to alcohol consumption, and GGT is useful as a marker for excessive drinking. GGT has been shown to rise after acute persistent alcohol ingestion and then fall when alcohol is avoided.

Lactate dehydrogenase (LDH) is found in almost all cells in the body. Different forms of the enzyme (isoenzymes) exist in different tissues, especially in heart, liver, red blood cells, brain, kidney, and muscles. LDH is increased in megaloblastic and hemolytic anemias, leukemias and lymphomas, myocardial infarction, infectious mononucleosis, muscle wasting diseases, and both necrotic and obstructive jaundice. While LDH is not specific for any one disorder, the enzyme is elevated (twoto five-fold normal) along with liver function enzymes in both necrotic and obstructive liver diseases. LDH is markedly increased in most cases of liver cancer. An enzyme pattern showing a marked increase in LDH and to a lesser degree ALP with only slightly increased transaminases (AST and ALT) is seen in cancer of the liver (space occupying disease). Such findings should be followed-up with imaging studies and measurement of alpha-fetoprotein and carcinoembryonic antigen, two tumor markers prevalent in hepatic cancers.

Some liver function tests are not sensitive enough to be used for diagnostic purposes, but are elevated in severe or chronic liver diseases. These tests are used primarily to indicate the extent of damage to the liver. Tests falling into this category are ammonia, total protein, albumin, cholesterol, transthyretin, fibrinogen, and the prothrombin time.

Analysis of blood ammonia aids in the diagnosis of severe liver diseases and helps to monitor the course of these diseases. Together with the AST and the ALT, ammonia levels are used to confirm a diagnosis of Reye's syndrome, a rare disorder usually seen in children and associated with infection and aspirin intake. Reye's syndrome is characterized by brain and liver damage following an upper respiratory tract infection, chickenpox, or influenza. Ammonia levels are also helpful in the diagnosis and treatment of hepatic encephalopathy, a serious brain condition caused by the accumulated toxins that result from liver disease and liver failure. Ammonia levels in the blood are normally very low. Ammonia produced by the breakdown of amino acids is converted to urea by the liver. When liver disease becomes severe, failure of the urea cycle results in elevated blood ammonia and decreased urea (or blood urea nitrogen, BUN). Increasing ammonia signals end-stage liver disease and a high risk of hepatic coma.

Albumin is the protein found in the highest concentration in blood, making up over half of the protein mass. Albumin has a half-life in blood of about three weeks and decreased levels are not seen in the early stages of liver disease. A persistently low albumin in liver disease signals reduced synthetic capacity of the liver and is a sign of progressive liver failure. In the acute stages of liver disease, proteins such as transthyretin (prealbumin) with a shorter half-life may be measured to give an indication of the severity of the disease.

Cholesterol is synthesized by the liver, and cholesterol balance is maintained by the liver's ability to remove cholesterol from lipoproteins, and use it to produce bile acids and salts that it excretes into the bile ducts. In obstructive jaundice caused by stones, biliary tract scarring, or cancer, the bile cannot be eliminated and cholesterol and triglycerides may accumulate in the blood as low-density lipoprotein (LDL) cholesterol. In acute necrotic liver diseases triglycerides may be elevated due to hepatic lipase deficiency. In liver failure caused by necrosis, the liver's ability to synthesize cholesterol is reduced and blood levels may be low.

The liver is responsible for production of the vitamin K clotting factors. In obstructive liver diseases a deficiency of vitamin K-derived clotting factors results from failure to absorb vitamin K. In obstructive jaundice, intramuscular injection of vitamin K will correct the prolonged prothrombin time. In severe necrotic disease, the liver cannot synthesize factor I (fibrinogen) or factors II, VII, IX, and X from vitamin K. When attributable to hepatic necrosis, an increase in the prothrombin time by more than two seconds indicates severe liver disease.

Serum protein electrophoresis patterns will be abnormal in both necrotic and obstructive liver diseases. In the acute stages of hepatitis, the albumin will be low and the gamma globulin fraction will be elevated owing to a large increase in the production of antibodies. The alpha-1 globulin and alpha-2 globulin fractions will be elevated owing to production of acute phase proteins as a response to inflamation. In biliary cirrhosis the beta globulin may be elevated owing to an increase in beta lipoprotein. In hepatic cirrhosis the albumin will be greatly decreased, and the pattern will show bridging between the beta and gamma globulins owing to production of IgA. The albumin to globulin ratio (A/G) ratio will fall below one.

The most prevalent liver disease is viral hepatitis. Tests for this condition include a variety of antigen and antibody markers and nucleic acid tests. Acute viral hepatitis is associated initially with 20- to 100-fold increases in transaminases and is followed shortly afterward by jaundice. Such patients should be tested for hepatitis B surface antigen (HbsAg) and IgM antibodies to hepatitis B core antigen (anti-HBc IgM), and anti-hepatitis C virus (anti-HVC) to identify these causes. In addition to hepatitis A-E, viral hepatitis may be caused by Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections of the liver. Tests for these viruses such as the infectious mononucleosis antibody test, anti-viral capsid antigen test (anti-VCA), and anti-CMV test are useful in diagnosing these infections.

Liver disease may be caused by autoimmune mechanisms in which autoantibodies destroy liver cells. Autoimmune necrosis is associated with systemic lupus erythematosus and chronic viral hepatitis usually caused by hepatitis B and hepatitis C virus infections. These conditions give rise to anti-smooth muscle antibodies and anti-nuclear antibodies, and tests for these are useful markers for chronic hepatitis. Antibodies to mitochondrial antigens (antimitochondrial antibodies) are found in the blood of more than 90% of persons with primary biliary cirrhosis, and those with M2 specificity are considered specific for this disease.

Preparation

Patients are asked to fast and to inform clinicians of all drugs, even over-the-counter drugs, that they are taking. Many times liver function tests are done on an emergency basis and fasting and obtaining a medical history are not possible.

Aftercare

Patients will have blood drawn into a vacuum tube and may experience some pain and burning at the site of injection. A gauze bandage may be placed over the site to prevent further bleeding. If the person is suffering from severe liver disease, they may lack clotting factors. The nurse or caregiver should be careful to monitor bleeding in these patients after obtaining blood.

Normal results

Reference ranges vary from laboratory to laboratory and also depend upon the method used. However, normal values are generally framed by the ranges shown below. Values for enzymes are based upon measurement at 37°C.

• ALT: 5–35 IU/L. (Values for the elderly may be slightly higher, and values also may be higher in men and in African-Americans.)
• AST: 0–35 IU/L.
• ALP: 30–120 IU/LALP is higher in children, older adults and pregnant females.
• GGT: males 2–30 U/L; females 1–24 U/L.
• LDH: 0–4 days old: 290–775 U/L; 4–10 days: 545–2000 U/L; 10 days–24 months: 180–430 U/L; 24 months–12 years: 110–295 U/L; 12–60 years: 100–190 U/L; 60 years: >110–210 U/L.
• Bilirubin: (Adult, elderly, and child) Total bilirubin: 0.1–1.0 mg/dL; indirect bilirubin: 0.2–0.8 mg/dL; direct bilirubin: 0.0–0.3 mg/dL. (Newborn) Total bilirubin: 1–12 mg/dL. Note: critical values for adult: greater than 1.2 mg/dL. Critical values for newborn (requiring immediate treatment): greater than 15 mg/dL.
• Ammonia: 10–70 micrograms per dL (heparinized plasma). Normal values for this test vary widely, depending upon the age of the patient and the type of specimen.
• Albumin: 3.2–5.4 g/L.

Abnormal results

ALT: Values are significantly increased in cases of hepatitis, and moderately increased in cirrhosis, liver tumor, obstructive jaundice, and severe burns. Values are mildly increased in pancreatitis, heart attack, infectious mononucleosis, and shock. Most useful when compared with ALP levels.

AST: High levels may indicate liver cell damage, hepatitis, heart attack, heart failure, or gall stones.

ALP: Elevated levels occur in diseases that impair bile formation (cholestasis). ALP may also be elevated in many other liver disorders, as well as some lung cancers (bronchogenic carcinoma) and Hodgkin's lymphoma. However, elevated ALP levels may also occur in otherwise healthy people, especially among older people.

GGT: Increased levels are diagnostic of hepatitis, cirrhosis, liver tumor or metastasis, as well as injury from drugs toxic to the liver. GGT levels may increase with alcohol ingestion, heart attack, pancreatitis, infectious mononucleosis, and Reye's syndrome.

LDH: Elevated LDH is seen with heart attack, kidney disease, hemolysis, viral hepatitis, infectious mononucleosis, Hodgkin's disease, abdominal and lung cancers, germ cell tumors, progressive muscular dystrophy, and pulmonary embolism. LD is not normally elevated in cirrhosis.

Bilirubin: Increased indirect or total bilirubin levels can indicate various serious anemias, including hemolytic disease of the newborn and transfusion reaction. Increased direct bilirubin levels can be diagnostic of bile duct obstruction, gallstones, cirrhosis, or hepatitis. It is important to note that if total bilirubin levels in the newborn reach or exceed critical levels, exchange transfusion is necessary to avoid kernicterus, a condition that causes brain damage from bilirubin in the brain.

Ammonia: Increased levels are seen in primary liver cell disease, Reye's syndrome, severe heart failure, hemolytic disease of the newborn, and hepatic encephalopathy.

Albumin: Albumin levels are increased due to dehydration. They are decreased due to a decrease in synthesis of the protein which is seen in severe liver failure and in conditions such as burns or renal disease that cause loss of albumin from the blood.

Patient education

Health-care providers should inform the patient of any abnormal results and explain how these values reflect the status of their liver disease. It is important to guide the patient in ways to stop behaviors such as taking drugs or drinking alcohol, if these are the causes of the illness.

Resources

books

Burtis, Carl A. and Edward R. Ashwood. Tietz Textbook of Clinical Chemistry. Philadelphia: W. B. Saunders, 1999.

Cahill, Matthew. Handbook of Diagnostic Tests. 2nd ed. Springhouse, PA: Springhouse Corporation, 1999.

Henry, J. B. Clinical Diagnosis and Management by Laboratory Methods. 20th ed. Philadelphia: W. B. Saunders, 2001.

Wallach, Jacques. Interpretation of Diagnostic Tests. 7th ed. Philadelphia: Lippincott Williams & Wilkins, 2000.

other

Jensen, J. E. Liver Function Tests. [cited April 4, 2003]. <http://www.gastromd.com/lft.html>.

National Institutes of Health. [cited April 4, 2003]. <http://www.nlm.nih.gov/medlineplus/encyclopedia.html>.

Worman, Howard J. Common Laboratory Tests in Liver Disease. [cited April 4, 2003]. <http://www.cpmcnet.columbia.edu/dept/gi/labtests.html>.

Jane E. Phillips, Ph.D.
Mark A. Best, M.D.

Liver function tests

Definition

Liver function tests, or LFTs, include tests that are routinely measured in all clinical laboratories. LFTs include bilirubin, a compound formed by the catabolism of hemoglobin; ammonia, a product of protein catabolism that is normally converted into urea by the liver before being excreted by the kidneys ; proteins that are made by the liver including total protein, albumin, prothrombin, and fibrinogen; cholesterol and triglycerides, which are made and excreted via the liver; and the enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and lactate dehydrogenase (LDH). Other liver function tests include serological (tests to demonstrate antibodies) and DNA tests for hepatitis and other viruses , tests for antimitochondrial and smooth muscle antibodies, transthyretin (prealbumin), protein electrophoresis, bile acids, alpha-fetoprotein, and a constellation of other enzymes that help differentiate necrotic versus obstructive liver disease.

Purpose

Liver function tests done individually do not give the physician very much information, but used in combination along with a careful history, physical examination , and imaging studies they contribute to making an accurate diagnosis of the specific liver disorder. Different tests will show abnormalities in response to liver inflammation, liver injury due to drugs, alcohol, toxins or viruses, liver malfunction due to blockage of the flow of bile, and liver cancers.

Precautions

Blood for LFTs is collected by venipuncture. The nurse or phlebotomist performing the procedure must be careful to observe universal precautions for the prevention of transmission of bloodborne pathogens. Blood for ammonia testing should be iced immediately after collection, stored anaerobically until measured, and assayed within 30 minutes to prevent an increase in ammonia caused by deamination of amino acids in the blood. Hemolysis will falsely increase tests for LD, AST, and ALT.

Bilirubin: Drugs that may cause increased blood levels of total bilirubin include anabolic steroids, antibiotics , antimalarials, ascorbic acid, Diabinese, codeine, diuretics, epinephrine, oral contraceptives, and vitamin A .

Ammonia: Muscular exertion can increase ammonia levels, while cigarette smoking produces significant increases within one hour of inhalation. Drugs that may cause increased levels include alcohol, barbiturates, narcotics, and diuretics. Drugs that may decrease levels include broad-spectrum antibiotics, levodopa, lactobacillus, and potassium salts.

ALT: Drugs that may increase ALT levels include acetaminophen, ampicillin, codeine, dicumarol, indomethacin, methotrexate, oral contraceptives, tetracyclines, and verapamil. Previous intramuscular injections may cause elevated levels.

GGT: Drugs that may cause increased GGT levels include alcohol, phenytoin, and phenobarbital. Drugs that may cause decreased levels include oral contraceptives.

LD: Strenous activity may raise levels of LDH. Alcohol, anesthetics, aspirin, narcotics, procainamide, and fluoride may also raise levels. Ascorbic acid (vitamin C ) can lower levels of LDH.

Description

The liver is the largest and one of the most important organs in the body. As the body's "chemical factory," it regulates the levels of most of the biomolecules found in the blood, and acts with the kidneys to clear the blood of drugs and toxic substances. The liver metabolizes these products, alters their chemical structure, makes them water soluble, and excretes them in bile. Laboratory tests for total protein, albumin, ammonia, transthyretin, and cholesterol are markers for the synthetic function of the liver. Tests for cholesterol, bilirubin, ALP, and bile salts are measures of the secretory (excretory) function of the liver. The enzymes ALT, AST, GGT, LD, and tests for viruses are markers for liver injury.

Some liver function tests are used to determine if the liver has been damaged or its function impaired. Elevations of these markers for liver injury or disease tell the physician that something is wrong with the liver. ALT and bilirubin are the two primary tests used largely used for this purpose. Bilirubin is measured by two tests, called total and direct bilirubin. The total bilirubin measures both conjugated and unconjugated bilirubin while direct bilirubin measures only the conjugated bilirubin fraction in the blood. Unconjugated bilirubin is formed from heme in the reticuloendothelial cells in the spleen that remove old red blood cells from the circulation. The RE cells release the bilirubin into the blood where it is bound by albumin and transported to the liver. The bilirubin is taken up by liver cells and conjugated to glucuronic acid, which makes the bilirubin water soluble. This form will react directly with a Ehrlich's diazo reagent, hence the name direct bilirubin. While total bilirubin is elevated in various liver diseases, it is also increased in certain (hemolytic) anemias caused by increased red blood cell turnover. Neonatal hyperbilirubinemia is a condition caused by an immature liver than cannot conjugate the bilirubin. The level of total bilirubin in the blood becomes elevated, and must be monitored closely in order to prevent damage to the brain caused by unconjugated bilirubin, which has a high affinity for brain tissue. Bilirubin levels can be decreased by exposing the baby to UV light. Direct bilirubin is formed only by the liver, and therefore, it is specific for hepatic or biliary disease. Its concentration in the blood is very low (0-0.2 mg/dL) and therefore, even slight increases are significant. Highest levels of direct bilirubin are seen in obstructive liver diseases. However, direct biliruibn is not sensitive to all forms of liver disease (e.g., focal intrahepatic obstruction) and is not always elevated in the earliest stages of disease, and therefore, ALT is needed to exclude a diagnosis.

ALT is an enzyme that transfers an amino group from the amino acid alanine to a ketoacid acceptor (oxaloacetate). The enzyme was formerly called serum glutamic pyruvic transaminase (SGPT) after the products formed by this reaction. Although ALT is present in other tissues besides liver, its concentration in liver is far greater than any other tissue, and blood levels in nonhepatic conditions rarely produce levels of a magnitude seen in liver disease. The enzyme is very sensitive to necrotic or inflammatory liver injury. Consequently, if ALT or direct bilirubin are increased, then some form of liver disease is likely. If both are normal, then liver disease is unlikely.

These two tests along with others are used to help determine what is wrong. The most useful tests for this purpose are the liver function enzymes and the ratio of direct to total bilirubin. These tests are used to differentiate diseases characterized primarily by hepatocellular damage (necrosis) from those characterized by obstructive damage (cholestasis or blockage of bile flow). In hepatocellular damage, the transaminases, ALT and AST, are increased to a greater extent than alkaline phosphatase. This includes viral hepatitis, which gives the greatest increase in transaminases (10-50 fold normal), hepatitis induced by drugs or poisons (toxic hepatitis), alcoholic hepatitis, hypoxic necrosis (a consequence of congestive heart failure ), chronic hepatitis, and cirrhosis of the liver. In obstructive liver diseases, the alkaline phosphatase is increased to a greater extent than the transaminases (ALP>ALT). This includes diffuse intrahepatic obstructive disease which may be caused by some drugs or biliary cirrhosis, focal obstruction that may be caused by malignancy, granuloma, or stones in the intrahepatic bile ducts, or extrahepatic obstruction such as gall bladder or common bile duct stones, or pancreatic or bile duct cancer . In both diffuse intrahepatic obstruction and extrahepatic obstruction, the direct bilirubin is often greatly elevated because the liver can conjugate the bilirubin, but this direct bilirubin cannot be excreted via the bile. In such cases the ratio of direct to total bilirubin is greater than 0.4.

Aspartate aminotransferase, formerly called serum glutamic oxaloacetic transaminase (SGOT), is not as specific for liver disease as is ALT, which is increased in myocardial infarction , pancreatitis , muscle wasting diseases, and many other conditions. However, differentiation of acute and chronic forms of hepatocellular injury are aided by examining the ratio of ALT to AST, called the DeRitis ratio. In acute hepatitis, Reye's syndrome, and infectious mononucleosis the ALT predominates. However, in alcoholic liver disease, chronic hepatitis, and cirrhosis the AST predominates.

Alkaline phosphatase is increased in obstructive liver diseases, but it is not specific for the liver. Increases of a similar magnitude (three-to five-fold normal) are commonly seen in bone diseases, late pregnancy , leukemia, and some other malignancies. The enzyme gamma-glutamyl transferase (GGT) is used to help differentiate the source of an elevated ALP. GGT is greatly increased in bstructive jaundice , alcoholic liver disease, and hepatic cancer. When the increase in GGT is two or more times greater than the increase in ALP, the source of the ALP is considered to be from the liver. When the increase in GGT is five or more times the increase in ALP, this points to a diagnosis of alcoholic hepatitis. GGT, but not AST and ALT, is elevated in the first stages of liver inflammation due to alcohol consumption, and GGT is useful as a marker for excessive drinking. GGT has been shown to rise after acute persistent alcohol ingestion and then fall when alcohol is avoided.

Lactate dehydrogenase (LD) is found in almost all cells in the body. Different forms of the enzyme (isoenzymes) exist in different tissues, especially in heart , liver, red blood cells, brain, kidney and muscles. LD is increased in megaloblastic and hemolytic anemias, leukemias and lymphomas, myocardial infarction, infectious mononucleosis, muscle wasting diseases, and both necrotic and obstructive jaundice. While LD is not specific for any one disorder, the enzyme is elevated (two-to five-fold normal) along with liver function enzymes in both necrotic and obstructive liver diseases. LD is markedly increased in most cases of liver cancer . An enzyme pattern showing a marked increase in LD and to a lesser degree ALP with only slightly increased transaminases (AST and ALT) is seen in cancer of the liver (space occupying disease). Such findings should be followed-up with imaging studies and measurement of alpha-fetoprotein and carcinoembryonic antigen, two tumor markers prevalent in hepatic cancers.

Some liver function tests are not sensitive enough to be used for diagnostic purposes, but are elevated in severe or chronic liver diseases. These tests are used primarily to indicate the extent of damage to the liver. Tests falling into this category are ammonia, total protein, albumin, cholesterol, transthyretin, fibrinogen, and the prothrombin time.

Analysis of blood ammonia aids in the diagnosis of severe liver diseases and helps to monitor the course of these diseases. Together with the AST and the ALT, ammonia levels are used to confirm a diagnosis of Reye's syndrome, a rare disorder usually seen in children and associated with infection and aspirin intake. Reye's syndrome is characterized by brain and liver damage following an upper respiratory tract infection, chickenpox, or influenza . Ammonia levels are also helpful in the diagnosis and treatment of hepatic encephalopathy, a serious brain condition caused by the accumulated toxins that result from liver disease and liver failure. Ammonia levels in the blood are normally very low. Ammonia produced by the breakdown of amino acids is converted by the liver to urea. When liver disease becomes severe, failure of the urea cycle results in elevated blood ammonia and decreased urea (or blood urea nitrogen, BUN). Increasing ammonia signals end-stage liver disease and a high risk of hepatic coma .

Albumin is the protein found in the highest concentration in blood, making up over half of the protein mass. Albumin has a half-life in blood of about three weeks and decreased levels are not seen in the early stages of liver disease. A persistently low albumin in liver disease signals reduced synthetic capacity of the liver and is a sign of progressive liver failure. In the acute stages of liver disease, proteins such as transthyretin (prealbumin) with a shorter half-life may be measured to give an indication of the severity of the disease.

Cholesterol is synthesized by the liver and cholesterol balance is maintained by the liver's ability to remove cholesterol from lipoproteins, and use it to produce bile acids and salts that it excretes into the bile ducts. In obstructive jaundice caused by stones, biliary tract scarring, or cancer, the bile cannot be eliminated and cholesterol and triglycerides may accumulate in the blood as low-density lipoprotein cholesterol. In acute necrotic liver diseases triglycerides may be elevated due to hepatic lipase deficiency. In liver failure caused by necrosis, the liver's ability to synthesize cholesterol is reduced and blood levels may be low.

The liver is responsible for production of the vitamin K clotting factors. In obstructive liver diseases a deficiency of vitamin K-derived clotting factors results from failure to absorb vitamin K. In obstructive jaundice, intramuscular injection of vitamin K will correct the prolonged prothrombin time. In severe necrotic disease, the liver cannot synthesize factors I (fibrinogen) or factors II, VII, IX, and X from vitamin K. When attributable to hepatic necrosis, an increase in the prothrombin time by more than two seconds indicates severe liver disease.

Serum protein electrophoresis patterns will be abnormal in both necrotic and obstructive liver diseases. In the acute stages of hepatitis, the albumin will be low and the gamma globulin fraction will be elevated owing to a large increase in the production of antibodies. The alpha-1 globulin and alpha-2 globulin fractions will be elevated owing to production of acute phase proteins. In biliary cirrhosis the beta globulin may be elevated owing to an increase in beta lipoprotein. In hepatic cirrhosis the albumin will be greatly decreased, and the pattern will show bridging between the beta and gamma globulins owing to production of IgA. The albumin to globulin ratio (A/G) ratio will fall below one.

The most prevalent liver disease is viral hepatitis. Tests for this condition include a variety of antigen and antibody markers and nucleic acid tests that are discussed in detail elsewhere (see entry on hepatitis tests). Acute

KEY TERMS

Bile acid —A detergent that is made in the liver and excreted into the intestine to aid in the absorption of fats.

Biliary —Relating to bile.

Cirrhosis —A liver disease where there is a loss of normal liver tissues, replaced by scar tissue. This is usually caused by chronic alcohol abuse but can be caused by blockage of the bile ducts.

Detoxification —A process of altering the chemical struction of a compound to make it less toxic.

Hepatitis —Inflammation of the liver.

Hepatocyte —Liver cell.

Isoenzyme —One of a group of enzymes that brings about the same reactions on the same chemicals, but are different in their physical properties.

Jaundice —Hyperbilirubinemia or too much bilirubin in the blood. Bilirubin will be deposited in the skin and the mucosal membranes. The whites of the eyes and the skin appear yellow.

Neonatal jaundice —A disorder in newborns where the liver is too premature to conjugate bilirubin which builds up in the blood.

viral hepatitis is associated initially with 20 to 100 fold increases in transaminases and is followed shortly afterward by jaundice. Such patients should be tested for hepatitis B surface antigen (HbsAg) and IgM antibodies to hepatitis B core antigen (anti-HBc IgM), and anti-hepatitis C virus (anti-HVC) to identify these causes. In addition to hepatitis A-G, viral hepatitis may be caused by Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections of the liver. Tests for these viruses such as the infectious mononucleosis antibody test, anti-viral capsid antigen test (anti-VCA), and anti-CMV test are useful in diagnosing these infections.

Liver disease may be caused by autoimmune mechanisms in which autoantibodies destroy liver cells. Autoimmune necrosis is associated with systemic lupus erythematosus and chronic viral hepatitis usually caused by hepatitis B and hepatitis C virus infections. These conditions give rise to anti-smooth muscle antibodies and anti-nuclear antibodies, and tests for these are useful markers for chronic hepatitis. Antibodies to mitochondrial antigens (antimitochondrial antibodies) are found in the blood of more than 90% of persons with primary biliary cirrhosis, and those with M2 specificity are considered specific for this disease.

Preparation

Patients are asked to fast and to inform clinicians of all drugs, even over the counter drugs, that they are taking. Many times liver function tests are done on an emergency basis and fasting and obtaining a medical history are not possible.

Aftercare

Patients will have blood drawn into a vacuum tube and may experience some pain and burning at the site of injection. A gauze bandage may be placed over the site to prevent further bleeding. If the person is suffering from severe liver disease, they may lack clotting factors. The nurse should be careful to monitor bleeding in these patients after obtaining blood.

Results

Reference ranges vary from laboratory to laboratory and also depend upon the method used. However, normal values are generally framed by the ranges shown below. Values for enzymes are based upon measurement at 37°C.

• ALT: 5-35 IU/L (values for the elderly may be slightly higher, and values also may be higher in men and in African-Americans).
• AST: 0-35 IU/L.
• ALP: 30-120 IU/LALP is higher in children, older adults and pregnant females.
• GGT: males 2-30 U/L; females 1-24 U/L.
• LD: 0-4 days old: 290-775 U/L; 4-10 days: 545-2000 U/L; 10 days-24 months:180-430 U/L; 24 months-12 years:110-295 U/L; 12-60 years:100-190 U/L; 60 years: >110-210 U/L.
• Bilirubin: (Adult, elderly, and child) Total bilirubin:0.1-1.0 mg/dL; indirect bilirubin: 0.2-0.8 mg/dL; direct bilirubin: 0.0-0.3 mg/dL. (Newborn) Total bilirubin: 1-12 mg/dL. Note: critical values for adult: greater than1.2 mg/dL. Critical values for newborn (requiring immediate treatment): greater than 15 mg/dL.
• Ammonia: 10-70 micrograms per dL (heparinized plasma). Normal values for this test vary widely, depending upon the age of the patient and the type of specimen.
• Albumin: 3.2-5.4 g/L.

Abnormal results

ALT: Values are significantly increased in cases of hepatitis, and moderately increased in cirrhosis, liver tumor, obstructive jaundice, and severe burns . Values are mildly increased in pancreatitis, heart attack, infectious mononucleosis, and shock . Most useful when compared with ALP levels.

AST: High levels may indicate liver cell damage, hepatitis, heart attack, heart failure, or gall stones.

ALP: Elevated levels occur in diseases that impair bile formation (cholestasis). ALP may also be elevated in many other liver disorders, as well as some lung cancers (bronchogenic carcinoma) and Hodgkin's lymphoma. However, elevated ALP levels may also occur in otherwise healthy people, especially among older people.

GGT: Increased levels are diagnostic of hepatitis, cirrhosis, liver tumor or metastasis, as well as injury from drugs toxic to the liver. GGT levels may increase with alcohol ingestion, heart attack, pancreatitis, infectious mononucleosis, and Reye's syndrome.

LD: Elevated LD is seen with heart attack, kidney disease, hemolysis, viral hepatitis, infectious mononucleosis, Hodgkin's disease, abdominal and lung cancers, germ cell tumors, progressive muscular dystrophy and pulmonary embolism. LD is not normally elevated in cirrhosis.

Bilirubin: Increased indirect or total bilirubin levels can indicate various serious anemias, including hemolytic disease of the newborn and transfusion reaction. Increased direct bilirubin levels can be diagnostic of bile duct obstruction, gallstones, cirrhosis, or hepatitis. It is important to note that if total bilirubin levels in the newborn reach or exceed critical levels, exchange transfusion is necessary to avoid kernicterus, a condition that causes brain damage.

Ammonia: Increased levels are seen in primary liver cell disease, Reye's syndrome, severe heart failure, hemolytic disease of the newborn, and hepatic encephalopathy.

Albumin: Albumin levels are increased due to dehydration . They are decreased due to a decrease in synthesis of the protein which is seen in severe liver failure and in conditions such as burns or renal disease that cause loss of albumin from the blood.

Health care team roles

A physician will order the liver function tests that he or she feels are necessary, and the nurse or phlebotomist will draw the blood. Patients will probably be referred to an internist or hepatologist if results are abnormal. LFTs are performed by clinical laboratory scientists/medical technologists or clinical laboratory technicians/medical laboratory technicians.

Patient education

Health care providers should inform the patient of any abnormal results and explain how these values reflect the status of their liver disease. It is important to guide the patient in ways to stop behaviors such as taking drugs or drinking alcohol, if these are the causes of the illness.

Resources

BOOKS

Burtis, Carl A., and Edward R. Ashwood. Tietz Textbook of Clinical Chemistry. Philadelphia: W.B. Saunders, 1999.

Cahill, Matthew. Handbook of Diagnostic Tests, 2nd ed. Springhouse, PA: Springhouse Corporation, 1999.

Pagana, Kathleen Deska, and Timothy James Pagana. Mosby's Manual of Diagnostic and Laboratory Tests. Philadelphia: Mosby, Inc., 1998.

Jane E. Phillips, PhD

Liver Function Tests

Definition

Liver function tests, or LFTs, include tests that are routinely measured in all clinical laboratories. LFTs include bilirubin, a compound formed by the catabolism of hemoglobin; ammonia, a product of protein catabolism that is normally converted into urea by the liver before being excreted by the kidneys; proteins that are made by the liver including total protein, albumin, prothrombin, and fibrinogen; cholesterol and triglycerides, which are made and excreted via the liver; and the enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and lactate dehydrogenase (LDH). Other liver function tests include serological (tests to demonstrate antibodies) and DNA tests for hepatitis and other viruses, tests for antimitochondrial and smooth muscle antibodies, transthyretin (prealbumin), protein electrophoresis, bile acids, alpha-fetoprotein, and a constellation of other enzymes that help differentiate necrotic versus obstructive liver disease.

Purpose

Liver function tests done individually do not give the physician very much information, but used in combination along with a careful history, physical examination, and imaging studies they contribute to making an accurate diagnosis of the specific liver disorder. Different tests will show abnormalities in response to liver inflammation, liver injury due to drugs, alcohol, toxins or viruses, liver malfunction due to blockage of the flow of bile, and liver cancers.

Precautions

Blood for LFTs is collected by venipuncture. The nurse or phlebotomist performing the procedure must be careful to observe universal precautions for the prevention of transmission of bloodborne pathogens. Blood for ammonia testing should be iced immediately after collection, stored anaerobically until measured, and assayed within 30 minutes to prevent an increase in ammonia caused by deamination of amino acids in the blood. Hemolysis will falsely increase tests for LD, AST, and ALT.

Bilirubin: Drugs that may cause increased blood levels of total bilirubin include anabolic steroids, antibiotics, antimalarials, ascorbic acid, Diabinese, codeine, diuretics, epinephrine, oral contraceptives, and vitamin A.

Ammonia: Muscular exertion can increase ammonia levels, while cigarette smoking produces significant increases within one hour of inhalation. Drugs that may cause increased levels include alcohol, barbiturates, narcotics, and diuretics. Drugs that may decrease levels include broad-spectrum antibiotics, levodopa, lactobacillus, and potassium salts.

ALT: Drugs that may increase ALT levels include acetaminophen, ampicillin, codeine, dicumarol, indomethacin, methotrexate, oral contraceptives, tetracyclines, and verapamil. Previous intramuscular injections may cause elevated levels.

GGT: Drugs that may cause increased GGT levels include alcohol, phenytoin, and phenobarbital. Drugs that may cause decreased levels include oral contraceptives.

LD: Strenous activity may raise levels of LDH. Alcohol, anesthetics, aspirin, narcotics, procainamide, and fluoride may also raise levels. Ascorbic acid (vitamin C ) can lower levels of LDH.

Description

The liver is the largest and one of the most important organs in the body. As the body's "chemical factory," it regulates the levels of most of the biomolecules found in the blood, and acts with the kidneys to clear the blood of drugs and toxic substances. The liver metabolizes these products, alters their chemical structure, makes them water soluble, and excretes them in bile. Laboratory tests for total protein, albumin, ammonia, transthyretin, and cholesterol are markers for the synthetic function of the liver. Tests for cholesterol, bilirubin, ALP, and bile salts are measures of the secretory (excretory) function of the liver. The enzymes ALT, AST, GGT, LD, and tests for viruses are markers for liver injury.

Some liver function tests are used to determine if the liver has been damaged or its function impaired. Elevations of these markers for liver injury or disease tell the physician that something is wrong with the liver. ALT and bilirubin are the two primary tests used largely used for this purpose. Bilirubin is measured by two tests, called total and direct bilirubin. The total bilirubin measures both conjugated and unconjugated bilirubin while direct bilirubin measures only the conjugated bilirubin fraction in the blood. Unconjugated bilirubin is formed from heme in the reticuloendothelial cells in the spleen that remove old red blood cells from the circulation. The RE cells release the bilirubin into the blood where it is bound by albumin and transported to the liver. The bilirubin is taken up by liver cells and conjugated to glucuronic acid, which makes the bilirubin water soluble. This form will react directly with a Ehrlich's diazo reagent, hence the name direct bilirubin. While total bilirubin is elevated in various liver diseases, it is also increased in certain (hemolytic) anemias caused by increased red blood cell turnover. Neonatal hyperbilirubinemia is a condition caused by an immature liver than cannot conjugate the bilirubin. The level of total bilirubin in the blood becomes elevated, and must be monitored closely in order to prevent damage to the brain caused by unconjugated bilirubin, which has a high affinity for brain tissue. Bilirubin levels can be decreased by exposing the baby to UV light. Direct bilirubin is formed only by the liver, and therefore, it is specific for hepatic or biliary disease. Its concentration in the blood is very low (0-0.2 mg/dL) and therefore, even slight increases are significant. Highest levels of direct bilirubin are seen in obstructive liver diseases. However, direct biliruibn is not sensitive to all forms of liver disease (e.g., focal intrahepatic obstruction) and is not always elevated in the earliest stages of disease, and therefore, ALT is needed to exclude a diagnosis.

ALT is an enzyme that transfers an amino group from the amino acid alanine to a ketoacid acceptor (oxaloacetate). The enzyme was formerly called serum glutamic pyruvic transaminase (SGPT) after the products formed by this reaction. Although ALT is present in other tissues besides liver, its concentration in liver is far greater than any other tissue, and blood levels in nonhepatic conditions rarely produce levels of a magnitude seen in liver disease. The enzyme is very sensitive to necrotic or inflammatory liver injury. Consequently, if ALT or direct bilirubin are increased, then some form of liver disease is likely. If both are normal, then liver disease is unlikely.

These two tests along with others are used to help determine what is wrong. The most useful tests for this purpose are the liver function enzymes and the ratio of direct to total bilirubin. These tests are used to differentiate diseases characterized primarily by hepatocellular damage (necrosis) from those characterized by obstructive damage (cholestasis or blockage of bile flow). In hepatocellular damage, the transaminases, ALT and AST, are increased to a greater extent than alkaline phosphatase. This includes viral hepatitis, which gives the greatest increase in transaminases (10-50 fold normal), hepatitis induced by drugs or poisons (toxic hepatitis), alcoholic hepatitis, hypoxic necrosis (a consequence of congestive heart failure ), chronic hepatitis, and cirrhosis of the liver. In obstructive liver diseases, the alkaline phosphatase is increased to a greater extent than the transaminases (ALP > ALT). This includes diffuse intrahepatic obstructive disease which may be caused by some drugs or biliary cirrhosis, focal obstruction that may be caused by malignancy, granuloma, or stones in the intrahepatic bile ducts, or extrahepatic obstruction such as gall bladder or common bile duct stones, or pancreatic or bile duct cancer. In both diffuse intrahepatic obstruction and extrahepatic obstruction, the direct bilirubin is often greatly elevated because the liver can conjugate the bilirubin, but this direct bilirubin cannot be excreted via the bile. In such cases the ratio of direct to total bilirubin is greater than 0.4.

Aspartate aminotransferase, formerly called serum glutamic oxaloacetic transaminase (SGOT), is not as specific for liver disease as is ALT, which is increased in myocardial infarction, pancreatitis, muscle wasting diseases, and many other conditions. However, differentiation of acute and chronic forms of hepatocellular injury are aided by examining the ratio of ALT to AST, called the DeRitis ratio. In acute hepatitis, Reye's syndrome, and infectious mononucleosis the ALT predominates. However, in alcoholic liver disease, chronic hepatitis, and cirrhosis the AST predominates.

Alkaline phosphatase is increased in obstructive liver diseases, but it is not specific for the liver. Increases of a similar magnitude (three- to five-fold normal) are commonly seen in bone diseases, late pregnancy, leukemia, and some other malignancies. The enzyme gamma-glutamyl transferase (GGT) is used to help differentiate the source of an elevated ALP. GGT is greatly increased in obstructive jaundice, alcoholic liver disease, and hepatic cancer. When the increase in GGT is two or more times greater than the increase in ALP, the source of the ALP is considered to be from the liver. When the increase in GGT is five or more times the increase in ALP, this points to a diagnosis of alcoholic hepatitis. GGT, but not AST and ALT, is elevated in the first stages of liver inflammation due to alcohol consumption, and GGT is useful as a marker for excessive drinking. GGT has been shown to rise after acute persistent alcohol ingestion and then fall when alcohol is avoided.

Lactate dehydrogenase (LD) is found in almost all cells in the body. Different forms of the enzyme (isoenzymes) exist in different tissues, especially in heart, liver, red blood cells, brain, kidney and muscles. LD is increased in megaloblastic and hemolytic anemias, leukemias and lymphomas, myocardial infarction, infectious mononucleosis, muscle wasting diseases, and both necrotic and obstructive jaundice. While LD is not specific for any one disorder, the enzyme is elevated (two- to five-fold normal) along with liver function enzymes in both necrotic and obstructive liver diseases. LD is markedly increased in most cases of liver cancer. An enzyme pattern showing a marked increase in LD and to a lesser degree ALP with only slightly increased transaminases (AST and ALT) is seen in cancer of the liver (space occupying disease). Such findings should be followed-up with imaging studies and measurement of alpha-fetoprotein and carcinoembryonic antigen, two tumor markers prevalent in hepatic cancers.

Some liver function tests are not sensitive enough to be used for diagnostic purposes, but are elevated in severe or chronic liver diseases. These tests are used primarily to indicate the extent of damage to the liver. Tests falling into this category are ammonia, total protein, albumin, cholesterol, transthyretin, fibrinogen, and the prothrombin time.

Analysis of blood ammonia aids in the diagnosis of severe liver diseases and helps to monitor the course of these diseases. Together with the AST and the ALT, ammonia levels are used to confirm a diagnosis of Reye's syndrome, a rare disorder usually seen in children and associated with infection and aspirin intake. Reye's syndrome is characterized by brain and liver damage following an upper respiratory tract infection, chickenpox, or influenza. Ammonia levels are also helpful in the diagnosis and treatment of hepatic encephalopathy, a serious brain condition caused by the accumulated toxins that result from liver disease and liver failure. Ammonia levels in the blood are normally very low. Ammonia produced by the breakdown of amino acids is converted by the liver to urea. When liver disease becomes severe, failure of the urea cycle results in elevated blood ammonia and decreased urea (or blood urea nitrogen, BUN). Increasing ammonia signals end-stage liver disease and a high risk of hepatic coma.

Albumin is the protein found in the highest concentration in blood, making up over half of the protein mass. Albumin has a half-life in blood of about three weeks and decreased levels are not seen in the early stages of liver disease. A persistently low albumin in liver disease signals reduced synthetic capacity of the liver and is a sign of progressive liver failure. In the acute stages of liver disease, proteins such as transthyretin (prealbumin) with a shorter half-life may be measured to give an indication of the severity of the disease.

Cholesterol is synthesized by the liver and cholesterol balance is maintained by the liver's ability to remove cholesterol from lipoproteins, and use it to produce bile acids and salts that it excretes into the bile ducts. In obstructive jaundice caused by stones, biliary tract scarring, or cancer, the bile cannot be eliminated and cholesterol and triglycerides may accumulate in the blood as low-density lipoprotein cholesterol. In acute necrotic liver diseases triglycerides may be elevated due to hepatic lipase deficiency. In liver failure caused by necrosis, the liver's ability to synthesize cholesterol is reduced and blood levels may be low.

The liver is responsible for production of the vitamin K clotting factors. In obstructive liver diseases a deficiency of vitamin K-derived clotting factors results from failure to absorb vitamin K. In obstructive jaundice, intramuscular injection of vitamin K will correct the prolonged prothrombin time. In severe necrotic disease, the liver cannot synthesize factors I (fibrinogen) or factors II, VII, IX, and X from vitamin K. When attributable to hepatic necrosis, an increase in the prothrombin time by more than two seconds indicates severe liver disease.

Serum protein electrophoresis patterns will be abnormal in both necrotic and obstructive liver diseases. In the acute stages of hepatitis, the albumin will be low and the gamma globulin fraction will be elevated owing to a large increase in the production of antibodies. The alpha-1 globulin and alpha-2 globulin fractions will be elevated owing to production of acute phase proteins. In biliary cirrhosis the beta globulin may be elevated owing to an increase in beta lipoprotein. In hepatic cirrhosis the albumin will be greatly decreased, and the pattern will show bridging between the beta and gamma globulins owing to production of IgA. The albumin to globulin ratio (A/G) ratio will fall below one.

The most prevalent liver disease is viral hepatitis. Tests for this condition include a variety of antigen and antibody markers and nucleic acid tests that are discussed in detail elsewhere (see entry on hepatitis tests). Acute viral hepatitis is associated initially with 20 to 100 fold increases in transaminases and is followed shortly afterward by jaundice. Such patients should be tested for hepatitis B surface antigen (HbsAg) and IgM antibodies to hepatitis B core antigen (anti-HBc IgM), and anti-hepatitis C virus (anti-HVC) to identify these causes. In addition to hepatitis A-G, viral hepatitis may be caused by Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections of the liver. Tests for these viruses such as the infectious mononucleosis antibody test, antiviral capsid antigen test (anti-VCA), and anti-CMV test are useful in diagnosing these infections.

Liver disease may be caused by autoimmune mechanisms in which autoantibodies destroy liver cells. Autoimmune necrosis is associated with systemic lupus erythematosus and chronic viral hepatitis usually caused by hepatitis B and hepatitis C virus infections. These conditions give rise to anti-smooth muscle antibodies and anti-nuclear antibodies, and tests for these are useful markers for chronic hepatitis. Antibodies to mitochondrial antigens (antimitochondrial antibodies) are found in the blood of more than 90% of persons with primary biliary cirrhosis, and those with M2 specificity are considered specific for this disease.

Preparation

Patients are asked to fast and to inform clinicians of all drugs, even over the counter drugs, that they are taking. Many times liver function tests are done on an emergency basis and fasting and obtaining a medical history are not possible.

Aftercare

Patients will have blood drawn into a vacuum tube and may experience some pain and burning at the site of injection. A gauze bandage may be placed over the site to prevent further bleeding. If the person is suffering from severe liver disease, they may lack clotting factors. The nurse should be careful to monitor bleeding in these patients after obtaining blood.

Results

Reference ranges vary from laboratory to laboratory and also depend upon the method used. However, normal values are generally framed by the ranges shown below. Values for enzymes are based upon measurement at 98.6°F (37°C).

• ALT: 5-35 IU/L (values for the elderly may be slightly higher, and values also may be higher in men and in African-Americans).
• AST: 0-35 IU/L.
• ALP: 30-120 IU/LALP is higher in children, older adults and pregnant females.
• GGT: males 2-30 U/L; females 1-24 U/L.
• LD: 0-4 days old: 290-775 U/L; 4-10 days: 545-2000 U/L; 10 days-24 months:180-430 U/L; 24 months-12 years:110-295 U/L; 12-60 years:100-190 U/L; 60 years: >110-210 U/L.
• Bilirubin: (Adult, elderly, and child) Total bilirubin: 0.1-1.0 mg/dL; indirect bilirubin: 0.2-0.8 mg/dL; direct bilirubin: 0.0-0.3 mg/dL. (Newborn) Total bilirubin: 1-12 mg/dL. Note: critical values for adult: greater than 1.2 mg/dL. Critical values for newborn (requiring immediate treatment): greater than 15 mg/dL.
• Ammonia: 10-70 micrograms per dL (heparinized plasma). Normal values for this test vary widely, depending upon the age of the patient and the type of specimen.
• Albumin: 3.2-5.4 g/L.

Abnormal results

ALT: Values are significantly increased in cases of hepatitis, and moderately increased in cirrhosis, liver tumor, obstructive jaundice, and severe burns. Values are mildly increased in pancreatitis, heart attack, infectious mononucleosis, and shock. Most useful when compared with ALP levels.

AST: High levels may indicate liver cell damage, hepatitis, heart attack, heart failure, or gall stones.

ALP: Elevated levels occur in diseases that impair bile formation (cholestasis). ALP may also be elevated in many other liver disorders, as well as some lung cancers (bronchogenic carcinoma) and Hodgkin's lymphoma. However, elevated ALP levels may also occur in otherwise healthy people, especially among older people.

GGT: Increased levels are diagnostic of hepatitis, cirrhosis, liver tumor or metastasis, as well as injury from drugs toxic to the liver. GGT levels may increase with alcohol ingestion, heart attack, pancreatitis, infectious mononucleosis, and Reye's syndrome.

LD: Elevated LD is seen with heart attack, kidney disease, hemolysis, viral hepatitis, infectious mononucleosis, Hodgkin's disease, abdominal and lung cancers, germ cell tumors, progressive muscular dystrophy and pulmonary embolism. LD is not normally elevated in cirrhosis.

Bilirubin: Increased indirect or total bilirubin levels can indicate various serious anemias, including hemolytic disease of the newborn and transfusion reaction. Increased direct bilirubin levels can be diagnostic of bile duct obstruction, gallstones, cirrhosis, or hepatitis. It is important to note that if total bilirubin levels in the newborn reach or exceed critical levels, exchange transfusion is necessary to avoid kernicterus, a condition that causes brain damage.

Ammonia: Increased levels are seen in primary liver cell disease, Reye's syndrome, severe heart failure, hemolytic disease of the newborn, and hepatic encephalopathy.

Albumin: Albumin levels are increased due to dehydration. They are decreased due to a decrease in synthesis of the protein which is seen in severe liver failure and in conditions such as burns or renal disease that cause loss of albumin from the blood.

Health care team roles

A physician will order the liver function tests that he or she feels are necessary, and the nurse or phlebotomist will draw the blood. Patients will probably be referred to an internist or hepatologist if results are abnormal. LFTs are performed by clinical laboratory scientists/medical technologists or clinical laboratory technicians/medical laboratory technicians.

Patient education

Health care providers should inform the patient of any abnormal results and explain how these values reflect the status of their liver disease. It is important to guide the patient in ways to stop behaviors such as taking drugs or drinking alcohol, if these are the causes of the illness.

KEY TERMS

Bile acid— A detergent that is made in the liver and excreted into the intestine to aid in the absorption of fats.

Biliary— Relating to bile.

Cirrhosis— A liver disease where there is a loss of normal liver tissues, replaced by scar tissue. This is usually caused by chronic alcohol abuse but can be caused by blockage of the bile ducts.

Detoxification— A process of altering the chemical struction of a compound to make it less toxic.

Hepatitis— Inflammation of the liver.

Hepatocyte— Liver cell.

Isoenzyme— One of a group of enzymes that brings about the same reactions on the same chemicals, but are different in their physical properties.

Jaundice— Hyperbilirubinemia or too much bilirubin in the blood. Bilirubin will be deposited in the skin and the mucosal membranes. The whites of the eyes and the skin appear yellow.

Neonatal jaundice— A disorder in newborns where the liver is too premature to conjugate bilirubin which builds up in the blood.

Resources

BOOKS

Burtis, Carl A., and Edward R. Ashwood. Tietz Textbook of Clinical Chemistry. Philadelphia: W.B. Saunders, 1999.

Cahill, Matthew. Handbook of Diagnostic Tests, 2nd ed. Springhouse, PA: Springhouse Corporation, 1999.

Pagana, Kathleen Deska, and Timothy James Pagana. Mosby's Manual of Diagnostic and Laboratory Tests. Philadelphia: Mosby, Inc., 1998.

Liver Function Tests

Definition
Purpose
Precautions
Description
Preparation
Aftercare
Normal results

Definition

Liver function tests, or LFTs, include tests that are routinely measured in all clinical laboratories. LFTs include bilirubin, a compound formed by the breakdown of hemoglobin; ammonia, a breakdown product of protein that is normally converted into urea by the liver before being excreted by the kidneys; proteins that are made by the liver, including total protein, albumin, prothrombin, and fibrinogen; cholesterol and triglycerides, which are made and excreted via the liver; and the enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and lactate dehydrogenase (LDH). Other liver function tests include serological tests (to demonstrate antibodies); DNA tests for hepatitis and other viruses; and tests for antimitochondrial and smooth muscle antibodies, transthyretin (prealbumin), protein electrophoresis, bile acids, alpha-fetoprotein, and a constellation of other enzymes that help differentiate

KEY TERMS

Bile acid— A detergent that is made in the liver and excreted into the intestine to aid in the absorption of fats.

Biliary— Relating to bile.

Cirrhosis— A liver disease where there is a loss of normal liver tissues, replaced by scar tissue. This is usually caused by chronic alcohol abuse, but also can be caused by blockage of the bile ducts.

Detoxification— A process of altering the chemical structure of a compound to make it less toxic.

Hepatitis— Inflammation of the liver.

Hepatocyte— Liver cell.

Isoenzyme— One of a group of enzymes that brings about the same reactions on the same chemicals, but are different in their physical properties.

Jaundice— Hyperbilirubinemia, or too much bilirubin in the blood. Bilirubin will be deposited in the skin and the mucosal membranes. The whites of the eyes and the skin appear yellow.

Lipoprotein— A chemical combination of a protein and a lipid (fats).

Neonatal jaundice— A disorder in newborns where the liver is too premature to conjugate bilirubin, which builds up in the blood.

necrotic (characterized by the death of tissue) versus obstructive liver disease.

Purpose

Liver function tests done individually do not give the physician much information, but used in combination with a careful history, physical examination, and imaging studies, they contribute to making an accurate diagnosis of the specific liver disorder. Different tests will show abnormalities in response to liver inflammation; liver injury due to drugs, alcohol, toxins, or viruses; liver malfunction due to blockage of the flow of bile; and liver cancers.

Precautions

Blood for LFTs is collected by sticking a needle into a vein. The nurse or phlebotomist (person trained to draw blood) performing the procedure must be careful to clean the skin before sticking in the needle.

Bilirubin: Drugs that may cause increased blood levels of total bilirubin include anabolic steroids, antibiotics, antimalarials, ascorbic acid, Diabinese, codeine, diuretics, epinephrine, oral contraceptives, and vitamin A.

Ammonia: Muscular exertion can increase ammonia levels, while cigarette smoking produces significant increases within one hour of inhalation. Drugs that may cause increased levels include alcohol, barbiturates , narcotics, and diuretics. Drugs that may decrease levels include antibiotics, levodopa, lactobacillus, and potassium salts.

ALT: Drugs that may increase ALT levels include acetaminophen , ampicillin, codeine, dicumarol, indomethacin, methotrexate, oral contraceptives, tetracyclines , and verapamil. Previous intramuscular injections may cause elevated levels.

GGT: Drugs that may cause increased GGT levels include alcohol, phenytoin, and phenobarbital. Drugs that may cause decreased levels include oral contraceptives.

LDH: Strenuous activity may raise levels of LDH. Alcohol, anesthetics, aspirin , narcotics, procainamide, and fluoride may also raise levels. Ascorbic acid (vitamin C) can lower levels of LDH.

Description

The liver is the largest and one of the most important organs in the body. As the body’s “chemical factory,” it regulates the levels of most of the biomolecules found in the blood, and acts with the kidneys to clear the blood of drugs and toxic substances. The liver metabolizes these products, alters their chemical structure, makes them water soluble, and excretes them in bile. Laboratory tests for total protein, albumin, ammonia, transthyretin, and cholesterol are markers for the synthetic (chemical-producing) function of the liver. Tests for cholesterol, bilirubin, ALP, and bile salts are measures of the secretory (excretory) function of the liver. The enzymes ALT, AST, GGT, LDH, and tests for viruses are markers for liver injury.

Some liver function tests are used to determine if the liver has been damaged or its function impaired. Elevations of these markers for liver injury or disease tell the physician that something is wrong with the liver. ALT and bilirubin are the two primary tests used largely for this purpose. Bilirubin is measured by two tests, called total and direct bilirubin. While total bilirubin is elevated in various liver diseases, it is also increased in certain (hemolytic) anemias caused by increased red blood cell turnover. Neonatal hyper-bilirubinemia (jaundice) is a condition caused by an immature liver than cannot conjugate (process) the bilirubin. The level of total bilirubin in the blood becomes elevated and must be monitored closely in order to prevent damage to the brain caused by uncon-jugated bilirubin, which has a high affinity for brain tissue. Bilirubin levels can be decreased by exposing the baby to UV light. Direct bilirubin is formed only by the liver, and therefore, it is specific for hepatic or biliary disease. Its concentration in the blood is very low (0–0.2 mg/dL) and therefore, even slight increases are significant. Highest levels of direct bilirubin are seen in obstructive liver diseases. However, direct bilirubin is not sensitive to all forms of liver disease and is not always elevated in the earliest stages of disease. Therefore, ALT is needed to exclude a diagnosis.

Although ALT is present in other tissues, its concentration in the liver is far greater than any other tissue. The enzyme is very sensitive to liver injury. Consequently, if ALT or direct bilirubin is increased, then some form of liver disease is likely. If both are normal, then liver disease is unlikely.

These two tests, along with others, are used to help make a diagnosis. The most useful tests for this purpose are the liver function enzymes and the ratio of direct to total bilirubin. These tests are used to differentiate diseases characterized primarily by hepatocellular damage (necrosis, or cell death) from those characterized by obstructive damage (cholestasis or blockage of bile flow). Liver cell damage may be caused by viral hepatitis, hepatitis induced by drugs or poisons (toxic hepatitis), alcoholic hepatitis, hypoxic necrosis (a consequence of congestive heart failure), chronic hepatitis, and cirrhosis of the liver. Obstructive liver diseases include intrahepatic (within the liver) obstructive disease or extrahepatic (outside the liver) obstruction. In both cases, the direct bilirubin is often greatly elevated because the liver can conjugate the bilirubin, but this direct bilirubin cannot be excreted via the bile. In such cases the ratio of direct to total bilirubin is greater than 0.4

Aspartate aminotransferase (AST) is not as specific for liver disease as ALT is. However, differentiation of acute and chronic forms of liver disease is aided by examining the ratio of ALT to AST, called the DeRitis ratio. In acute hepatitis, Reye’s syndrome, and infectious mononucleosis, the ALT predominates. However, in alcoholic liver disease, chronic hepatitis, and cirrhosis, the AST predominates.

Alkaline phosphatase (ALP)is increased in obstructive liver diseases, but it is not specific for the liver. Increases are commonly seen in bone diseases, late pregnancy, leukemia, and some other malignancies. The enzyme gamma-glutamyl transferase (GGT) is used to help differentiate the source of an elevated ALP. GGT is greatly increased in obstructive jaundice, alcoholic liver disease, and hepatic cancer. When the increase in GGT is two or more times greater than the increase in ALP, the source of the ALP is considered to be from the liver. When the increase in GGT is five or more times the increase in ALP, this points to a diagnosis of alcoholic hepatitis. GGT, but not AST and ALT, is elevated in the first stages of liver inflammation due to alcohol consumption, and GGT is useful as a marker for excessive drinking. GGT has been shown to rise after acute persistent alcohol ingestion and then fall when alcohol is avoided.

Lactate dehydrogenase (LDH) is found in almost all cells in the body. LDH is increased in megaloblastic and hemolytic anemias, leukemias and lymphomas, myocardial infarction, infectious mononucleosis, muscle wasting diseases, and both necrotic and obstructive jaundice. LDH is markedly increased in most cases of liver cancer. An enzyme pattern showing a marked increase in LDH and to a lesser degree ALP with only slightly increased transaminases (AST and ALT) is seen in cancer of the liver.

Some liver function tests are not sensitive enough to be used for diagnostic purposes, but are elevated in severe or chronic liver diseases. These tests are used primarily to indicate the extent of damage to the liver. Tests falling into this category are ammonia, total protein, albumin, cholesterol, transthyretin, fibrinogen, and the prothrombin time.

Analysis of blood ammonia aids in the diagnosis of severe liver diseases and helps to monitor the course of these diseases. Together with the AST and the ALT, ammonia levels are used to confirm a diagnosis of Reye’s syndrome, a rare disorder usually seen in children and associated with infection and aspirin intake. Reye’s syndrome is characterized by brain and liver damage following an upper respiratory tract infection, chickenpox, or influenza. Ammonia levels are also helpful in the diagnosis and treatment of hepatic encephalopathy, a serious brain condition caused by the accumulated toxins that result from liver disease and liver failure. Ammonia levels in the blood are normally very low. Increasing ammonia signals end-stage liver disease and a high risk of hepatic coma.

Albumin is the protein found in the highest concentration in blood, making up over half of the protein mass. A persistently low albumin in liver disease is a sign of progressive liver failure. In the acute stages of liver disease, proteins such as transthyretin (prealbumin) may be measured to give an indication of the severity of the disease.

Cholesterol is synthesized by the liver. Its balance is maintained by the liver’s ability to remove cholesterol from lipoproteins, and use it to produce bile acids and salts that it excretes into the bile ducts. In obstructive jaundice caused by stones, biliary tract scarring, or cancer, the bile cannot be eliminated. Cholesterol and triglycerides may accumulate in the blood as low-density lipoprotein (LDL) cholesterol. In acute necrotic liver diseases, triglycerides may be elevated. In liver failure caused by necrosis, the liver’s ability to synthesize cholesterol is reduced, and blood levels may be low.

The liver is responsible for production of the vitamin K clotting factors. In obstructive liver diseases a deficiency of vitamin K-derived clotting factors results from failure to absorb vitamin K. In obstructive jaundice, an intramuscular injection of vitamin K will be given. In severe necrotic disease, the liver cannot synthesize clotting factors from vitamin K.

The most prevalent liver disease is viral hepatitis. Tests for this condition include a variety of antigen and antibody markers and nucleic acid tests. In addition to hepatitis A-E, viral hepatitis may be caused by Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections of the liver. Tests for these viruses such as the infectious mononucleosis antibody test, anti-viral capsid antigen test (anti-VCA), and anti-CMV test are useful in diagnosing these infections.

Liver disease may be caused by autoimmune mechanisms in which autoantibodies destroy liver cells. Autoimmune necrosis is associated with systemic lupus erythematosus and chronic viral hepatitis, usually caused by hepatitis B and hepatitis C virus infections. These conditions give rise to anti-smooth muscle antibodies and anti-nuclear antibodies, and tests for these are useful markers for chronic hepatitis. Anti-bodies to mitochondrial antigens (antimitochondrial antibodies) are found in the blood of more than 90% of persons with primary biliary cirrhosis.

Preparation

Patients are asked to fast and to inform clinicians of all drugs, even over-the-counter drugs, that they are taking. Many times liver function tests are done on an emergency basis. Thus fasting and obtaining a medical history may not be possible.

Aftercare

Patients will have blood drawn into a vacuum tube and may experience some pain and burning at the site of injection. A gauze bandage may be placed over the site to prevent further bleeding. If the patient is suffering from severe liver disease, he or she may lack clotting factors. The nurse or caregiver should be careful to monitor bleeding in these patients after obtaining blood.

Normal results

Reference ranges vary from laboratory to laboratory and also depend upon the method used. However, normal values are generally framed by the ranges shown below.

• ALT: 5-35 IU/L. (Values for the elderly may be slightly higher, and values also may be higher in men and in African-Americans.)
• AST: 0–35 IU/L.
• ALP: 30-120 IU/LALP is higher in children, older adults and pregnant females.
• GGT: males 2-30 U/L; females 1-24 U/L.
• LDH: 0-4 days old: 290–775 U/L; 4–10 days: 545–2000 U/L; 10 days–24 months: 180–430 U/L; 24 months–12 years: 110–295 U/L; 12–60 years: 100–190 U/L; 60 years: >110–210 U/L.
• Bilirubin: (Adult, elderly, and child) Total bilirubin: 0.1-1.0 mg/dL; indirect bilirubin: 0.2-0.8 mg/dL; direct bilirubin: 0.0-0.3 mg/dL. (Newborn) Total bilirubin: 1-12 mg/dL. Note: critical values for adult: greater than 1.2 mg/dL. Critical values for newborn (requiring immediate treatment): greater than 15 mg/dL.
• Ammonia: 10-70 micrograms per dL (heparinized plasma). Normal values for this test vary widely, depending upon the age of the patient and the type of specimen.
• Albumin: 3.2-5.4 g/L.

Abnormal results

ALT: Values are significantly increased in cases of hepatitis, and moderately increased in cirrhosis, liver tumor, obstructive jaundice, and severe burns. Values are mildly increased in pancreatitis, heart attack, infectious mononucleosis, and shock. Most useful when compared with ALP levels.

AST: High levels may indicate liver cell damage, hepatitis, heart attack, heart failure, or gall stones.

ALP: Elevated levels occur in diseases that impair bile formation (cholestasis). ALP may also be elevated in many other liver disorders, as well as some lung cancers (bronchogenic carcinoma) and Hodgkin’s lymphoma. However, elevated ALP levels may also occur in otherwise healthy people, especially among older people.

GGT: Increased levels are diagnostic of hepatitis, cirrhosis, liver tumor or metastasis, as well as injury from drugs toxic to the liver. GGT levels may increase with alcohol ingestion, heart attack, pancreatitis, infectious mononucleosis, and Reye’s syndrome.

LDH: Elevated LDH is seen with heart attack, kidney disease, hemolysis, viral hepatitis, infectious mononucleosis, Hodgkin’s disease, abdominal and lung cancers, germ cell tumors, progressive muscular dystrophy, and pulmonary embolism. LD is not normally elevated in cirrhosis.

Bilirubin: Increased indirect or total bilirubin levels can indicate various serious anemias, including hemolytic disease of the newborn and transfusion reaction. Increased direct bilirubin levels can be diagnostic of bile duct obstruction, gallstones, cirrhosis, or hepatitis. It is important to note that if total bilirubin levels in the newborn reach or exceed critical levels, exchange transfusion is necessary to avoid kernicterus, a condition that causes brain damage from bilirubin in the brain.

Ammonia: Increased levels are seen in primary liver cell disease, Reye’s syndrome, severe heart failure, hemolytic disease of the newborn, and hepatic encephalopathy.

Albumin: Albumin levels are increased due to dehydration. They are decreased due to a decrease in synthesis of the protein which is seen in severe liver failure and in conditions such as burns or renal disease that cause loss of albumin from the blood.

Patient education

Health-care providers should inform the patient of any abnormal results and explain how these values reflect the status of their liver disease. It is important to guide the patient in ways to stop behaviors such as taking drugs or drinking alcohol, if these are the causes of the illness.

Resources

BOOKS

Feldman, M, et al. Sleisenger & Fordtran’s Gastrointestinal and Liver Disease. 8th ed. St. Louis: Mosby, 2005.

McPherson RA et al. Henry’s Clinical Diagnosis and Management By Laboratory Methods. 21st ed. Philadelphia: Saunders, 2007.

OTHER

Jensen, J. E. Liver Function Tests. [cited April 4, 2003]. http://www.gastromd.com/lft.html.

National Institutes of Health. [cited April 4, 2003]. http://www.nlm.nih.gov/medlineplus/encyclopedia.html.

Worman, Howard J. Common Laboratory Tests in Liver Disease. [cited April 4, 2003]. http://www.cpmcnet.columbia.edu/dept/gi/labtests.html.

Jane E. Phillips, Ph.D.

Mark A. Best, M.D.

Rosalyn Carson-DeWitt, MD

Liver removal seeHepatectomy

Liver function tests

Definition

Liver function tests, or LFTs, include tests that are routinely measured in all clinical laboratories. LFTs include bilirubin, a compound formed by the breakdown of hemoglobin; ammonia, a breakdown product of protein that is normally converted into urea by the liver before being excreted by the kidneys; proteins that are made by the liver, including total protein, albumin, prothrombin, and fibrinogen; cholesterol and triglycerides, which are made and excreted via the liver; and the enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and lactate dehydrogenase (LDH). Other liver function tests include serological tests (to demonstrate antibodies); DNA tests for hepatitis and other viruses ; and tests for anti-mitochondrial and smooth muscle antibodies, transthyretin (prealbumin), protein electrophoresis, bile acids, alpha-fetoprotein, and a constellation of other enzymes that help differentiate necrotic (characterized by the death of tissue) versus obstructive liver disease.

Purpose

Liver function tests done individually do not give the physician much information, but used in combination with a careful history, physical examination, and imaging studies, they contribute to making an accurate diagnosis of the specific liver disorder. Different tests will show abnormalities in response to liver inflammation; liver injury due to drugs, alcohol, toxins, or viruses; liver malfunction due to blockage of the flow of bile; and liver cancers.

Precautions

Blood for LFTs is collected by sticking a needle into a vein. The nurse or phlebotomist (person trained to draw blood) performing the procedure must be careful to clean the skin before sticking in the needle.

Bilirubin: Drugs that may cause increased blood levels of total bilirubin include anabolic steroids, antibiotics , antimalarials, ascorbic acid, Diabinese, codeine, diuretics , epinephrine, oral contraceptives, and vitamin A.

Ammonia: Muscular exertion can increase ammonia levels, while cigarette smoking produces significant increases within one hour of inhalation. Drugs that may cause increased levels include alcohol, barbiturates , narcotics, and diuretics. Drugs that may decrease levels include antibiotics, levodopa, lactobacillus, and potassium salts.

ALT: Drugs that may increase ALT levels include acetaminophen , ampicillin, codeine, dicumarol, indomethacin, methotrexate, oral contraceptives, tetracyclines, and verapamil. Previous intramuscular injections may cause elevated levels.

GGT: Drugs that may cause increased GGT levels include alcohol, phenytoin, and phenobarbital. Drugs that may cause decreased levels include oral contraceptives.

LDH: Strenuous activity may raise levels of LDH. Alcohol, anesthetics, aspirin , narcotics, procainamide, and fluoride may also raise levels.

Ascorbic acid (vitamin C ) can lower levels of LDH.

KEY TERMS

Bile acid —A detergent that is made in the liver and excreted into the intestine to aid in the absorption of fats.

Biliary —Relating to bile.

Cirrhosis —A liver disease where there is a loss of normal liver tissues, replaced by scar tissue. This is usually caused by chronic alcohol abuse, but also can be caused by blockage of the bile ducts.

Detoxification —A process of altering the chemical structure of a compound to make it less toxic.

Hepatitis —Inflammation of the liver.

Hepatocyte —Liver cell.

Isoenzyme —One of a group of enzymes that brings about the same reactions on the same chemicals, but are different in their physical properties.

Jaundice —Hyperbilirubinemia, or too much bilirubin in the blood. Bilirubin will be deposited in the skin and the mucosal membranes. The whites of the eyes and the skin appear yellow.

Lipoprotein —A chemical combination of a protein and a lipid (fats).

Neonatal jaundice —A disorder in newborns where the liver is too premature to conjugate bilirubin, which builds up in the blood.

Description

The liver is the largest and one of the most important organs in the body. As the body's “chemical factory,” it regulates the levels of most of the bio-molecules found in the blood, and acts with the kidneys to clear the blood of drugs and toxic substances. The liver metabolizes these products, alters their chemical structure, makes them water soluble, and excretes them in bile. Laboratory tests for total protein, albumin, ammonia, transthyretin, and cholesterol are markers for the synthetic (chemical-producing) function of the liver. Tests for cholesterol, bilirubin, ALP, and bile salts are measures of the secretory (excretory) function of the liver. The enzymes ALT, AST, GGT, LDH, and tests for viruses are markers for liver injury.

Some liver function tests are used to determine if the liver has been damaged or its function impaired. Elevations of these markers for liver injury or disease tell the physician that something is wrong with the liver. ALT and bilirubin are the two primary tests used largely for this purpose. Bilirubin is measured by two tests, called total and direct bilirubin. While total bilirubin is elevated in various liver diseases, it is also increased in certain (hemolytic) anemias caused by increased red blood cell turnover. Neonatal hyperbilirubinemia (jaundice) is a condition caused by an immature liver than cannot conjugate (process) the bilirubin. The level of total bilirubin in the blood becomes elevated and must be monitored closely in order to prevent damage to the brain caused by unconjugated bilirubin, which has a high affinity for brain tissue. Bilirubin levels can be decreased by exposing the baby to UV light. Direct bilirubin is formed only by the liver, and therefore, it is specific for hepatic or biliary disease. Its concentration in the blood is very low (0–0.2 mg/dL) and therefore, even slight increases are significant. Highest levels of direct bilirubin are seen in obstructive liver diseases. However, direct bilirubin is not sensitive to all forms of liver disease and is not always elevated in the earliest stages of disease. Therefore, ALT is needed to exclude a diagnosis.

Although ALT is present in other tissues, its concentration in the liver is far greater than any other tissue. The enzyme is very sensitive to liver injury. Consequently, if ALT or direct bilirubin is increased, then some form of liver disease is likely. If both are normal, then liver disease is unlikely.

These two tests, along with others, are used to help make a diagnosis. The most useful tests for this purpose are the liver function enzymes and the ratio of direct to total bilirubin. These tests are used to differentiate diseases characterized primarily by he-patocellular damage (necrosis, or cell death) from those characterized by obstructive damage (cholestasis or blockage of bile flow). Liver cell damage may be caused by viral hepatitis, hepatitis induced by drugs or poisons (toxic hepatitis), alcoholic hepatitis, hypoxic necrosis (a consequence of congestive heart failure ), chronic hepatitis, and cirrhosis of the liver. Obstructive liver diseases include intrahepatic (within the liver) obstructive disease or extrahepatic (outside the liver) obstruction. In both cases, the direct bilirubin is often greatly elevated because the liver can conjugate the bilirubin, but this direct bilirubin cannot be excreted via the bile. In such cases the ratio of direct to total bilirubin is greater than 0.4.

Aspartate aminotransferase (AST) is not as specific for liver disease as ALT is. However, differentiation of acute and chronic forms of liver disease is aided by examining the ratio of ALT to AST, called the DeRitis ratio. In acute hepatitis, Reye's syndrome, and infectious mononucleosis, the ALT predominates. However, in alcoholic liver disease, chronic hepatitis, and cirrhosis, the AST predominates.

Alkaline phosphatase (ALP)is increased in obstructive liver diseases, but it is not specific for the liver. Increases are commonly seen in bone diseases, late pregnancy, leukemia, and some other malignancies. The enzyme gamma-glutamyl transferase (GGT) is used to help differentiate the source of an elevated ALP. GGTis greatly increased in obstructive jaundice, alcoholic liver disease, and hepatic cancer . When the increase in GGT is two or more times greater than the increase in ALP, the source of the ALP is considered to be from the liver. When the increase in GGT is five or more times the increase in ALP, this points to a diagnosis of alcoholic hepatitis. GGT, but not AST and ALT, is elevated in the first stages of liver inflammation due to alcohol consumption, and GGT is useful as a marker for excessive drinking. GGT has been shown to rise after acute persistent alcohol ingestion and then fall when alcohol is avoided.

Lactate dehydrogenase (LDH) is found in almost all cells in the body. LDH is increased in megaloblastic and hemolytic anemias, leukemias and lymphomas, myocardial infarction, infectious mononucleosis, muscle wasting diseases, and both necrotic and obstructive jaundice. LDH is markedly increased in most cases of liver cancer . An enzyme pattern showing a marked increase in LDH and to a lesser degree ALP with only slightly increased transaminases (AST and ALT) is seen in cancer of the liver.

Some liver function tests are not sensitive enough to be used for diagnostic purposes, but are elevated in severe or chronic liver diseases. These tests are used primarily to indicate the extent of damage to the liver. Tests falling into this category are ammonia, total protein, albumin, cholesterol, transthyretin, fibrinogen, and the prothrombin time.

Analysis of blood ammonia aids in the diagnosis of severe liver diseases and helps to monitor the course of these diseases. Together with the AST and the ALT, ammonia levels are used to confirm a diagnosis of Reye's syndrome, a rare disorder usually seen in children and associated with infection and aspirin intake. Reye's syndrome is characterized by brain and liver damage following an upper respiratory tract infection, chickenpox, or influenza . Ammonia levels are also helpful in the diagnosis and treatment of hepatic encephalopathy, a serious brain condition caused by the accumulated toxins that result from liver disease and liver failure. Ammonia levels in the blood are normally very low. Increasing ammonia signals end-stage liver disease and a high risk of hepatic coma .

Albumin is the protein found in the highest concentration in blood, making up over half of the protein mass. A persistently low albumin in liver disease is a sign of progressive liver failure. In the acute stages of liver disease, proteins such as transthyretin (prealbumin) may be measured to give an indication of the severity of the disease.

Cholesterol is synthesized by the liver. Its balance is maintained by the liver's ability to remove cholesterol from lipoproteins, and use it to produce bile acids and salts that it excretes into the bile ducts. In obstructive jaundice caused by stones, biliary tract scarring, or cancer, the bile cannot be eliminated. Cholesterol and triglycerides may accumulate in the blood as low-density lipoprotein (LDL) cholesterol. In acute necrotic liver diseases, triglycerides may be elevated. In liver failure caused by necrosis, the liver's ability to synthesize cholesterol is reduced, and blood levels may be low.

The liver is responsible for production of the vitamin K clotting factors. In obstructive liver diseases a deficiency of vitamin K-derived clotting factors results from failure to absorb vitamin K. In obstructive jaundice, an intramuscular injection of vitamin K will be given. In severe necrotic disease, the liver cannot synthesize clotting factors from vitamin K.

The most prevalent liver disease is viral hepatitis. Tests for this condition include a variety of antigen and antibody markers and nucleic acid tests. In addition to hepatitis A-E, viral hepatitis may be caused by Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections of the liver. Tests for these viruses such as the infectious mononucleosis antibody test, anti-viral capsid antigen test (anti-VCA), and antiCMV test are useful in diagnosing these infections.

Liver disease may be caused by autoimmune mechanisms in which autoantibodies destroy liver cells. Autoimmune necrosis is associated with systemic lupus erythematosus and chronic viral hepatitis, usually caused by hepatitis B and hepatitis C virus infections. These conditions give rise to anti-smooth muscle antibodies and anti-nuclear antibodies, and tests for these are useful markers for chronic hepatitis. Antibodies to mitochondrial antigens (antimitochondrial antibodies) are found in the blood of more than 90% of persons with primary biliary cirrhosis.

Preparation

Patients are asked to fast and to inform clinicians of all drugs, even over-the-counter drugs, that they are taking. Many times liver function tests are done on an emergency basis. Thus fasting and obtaining a medical history may not be possible.

Aftercare

Patients will have blood drawn into a vacuum tube and may experience some pain and burning at the site of injection. A gauze bandage may be placed over the site to prevent further bleeding. If the patient is suffering from severe liver disease, he or she may lack clotting factors. The nurse or caregiver should be careful to monitor bleeding in these patients after obtaining blood.

Results

Reference ranges vary from laboratory to laboratory and also depend upon the method used. However, normal values are generally framed by the ranges shown below.

• ALT: 5–35 IU/L. (Values for the elderly may be slightly higher, and values also may be higher in men and in African-Americans.)l AST: 0–35 IU/L.
• ALP: 30–120 IU/LALP is higher in children, older adults and pregnant females.
• GGT: males 2–30 U/L; females 1–24 U/L.
• LDH: 0–4 days old: 290–775 U/L; 4–10 days: 545-2000 U/L; 10 days–24 months: 180–430 U/L; 24 months–12 years: 110–295 U/L; 12–60 years: 100-190 U/L; 60 years: 110–210 U/L.
• Bilirubin: (Adult, elderly, and child) Total bilirubin:0.1–1.0mg/dL; indirect bilirubin: 0.2–0.8mg/dL; direct bilirubin: 0.0–0.3 mg/dL. (Newborn) Total bilirubin:1–12 mg/dL. Note: critical values for adult: greater than 1.2 mg/dL. Critical values for newborn (requiring immediate treatment): greater than 15 mg/dL.
• Ammonia: 10–70 micrograms per dL (heparinized plasma). Normal values for this test vary widely, depending upon the age of the patient and the type of specimen.
• Albumin: 3.2–5.4 g/L.

Abnormal results

ALT: Values are significantly increased in cases of hepatitis, and moderately increased in cirrhosis, liver tumor, obstructive jaundice, and severe burns. Values are mildly increased in pancreatitis, heart attack , infectious mononucleosis, and shock. Most useful when compared with ALP levels.

AST: High levels may indicate liver cell damage, hepatitis, heart attack, heart failure, or gall stones.

ALP: Elevated levels occur in diseases that impair bile formation (cholestasis). ALP may also be elevated in many other liver disorders, as well as some lung cancers (bronchogenic carcinoma) and Hodgkin's lymphoma. However, elevated ALP levels may also occur in otherwise healthy people, especially among older people.

GGT: Increased levels are diagnostic of hepatitis, cirrhosis, liver tumor or metastasis , as well as injury from drugs toxic to the liver. GGT levels may increase with alcohol ingestion, heart attack, pancreatitis, infectious mononucleosis, and Reye's syndrome.

LDH: Elevated LDH is seen with heart attack, kidney disease, hemolysis, viral hepatitis, infectious mononucleosis, Hodgkin's disease, abdominal and lung cancers, germ cell tumors, progressive muscular dystrophy, and pulmonary embolism . LD is not normally elevated in cirrhosis.

Bilirubin: Increased indirect or total bilirubin levels can indicate various serious anemias, including hemolytic disease of the newborn and transfusion reaction. Increased direct bilirubin levels can be diagnostic of bile duct obstruction, gallstones, cirrhosis, or hepatitis. It is important to note that if total bilirubin levels in the newborn reach or exceed critical levels, exchange transfusion is necessary to avoid kernicterus, a condition that causes brain damage from bilirubin in the brain.

Ammonia: Increased levels are seen in primary liver cell disease, Reye's syndrome, severe heart failure, hemolytic disease of the newborn, and hepatic encephalopathy.

Albumin: Albumin levels are increased due to dehydration . They are decreased due to a decrease in synthesis of the protein which is seen in severe liver failure and in conditions such as burns or renal disease that cause loss of albumin from the blood.

Patient education

Health-care providers should inform the patient of any abnormal results and explain how these values reflect the status of their liver disease. It is important to guide the patient in ways to stop behaviors such as taking drugs or drinking alcohol, if these are the causes of the illness.

Resources

BOOKS

Feldman, M, et al.. Sleisenger … Fordtran's Gastrointestinal and Liver Disease. 8th ed. St. Louis: Mosby, 2005.

McPherson RA et al. Henry's Clinical Diagnosis and Management By Laboratory Methods. 21st ed. Philadelphia: Saunders, 2007.

OTHER

Jensen, J. E. Liver Function Tests. [cited April 4, 2003].

http://www.gastromd.com/lft.html.

National Institutes of Health. [cited April 4, 2003]. http://www.nlm.nih.gov/medlineplus/encyclopedia.html.

Worman, Howard J. Common Laboratory Tests in Liver Disease. [cited April 4, 2003]. http://www.cpmcnet.columbia.edu/dept/gi/labtests.html.

Jane E. Phillips Ph.D.

Mark A. Best M.D.

Rosalyn Carson-DeWitt MD