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