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Laboratory Tests of the Liver and Gallbladder

By

Christina C. Lindenmeyer

, MD, Cleveland Clinic

Last full review/revision Sep 2021| Content last modified Sep 2021
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Laboratory tests are generally effective for the following:

  • Detecting hepatic dysfunction

  • Assessing the severity of liver injury

  • Monitoring the course of liver diseases and the response to treatment

  • Refining the diagnosis

(See also the European Association for Study of Liver–Asociación Latinoamericana para el Estudio del Hígado Clinical Practice Guidelines.)

Many tests of liver biochemistry are called liver tests. These tests measure liver enzymes that are released into the bloodstream (eg, release of aminotransferases from injured liver cells or of alkaline phosphatase due to cholestasis) or assess liver function by evaluating hepatobiliary excretion (eg, bilirubin). Other tests are used to evaluate the liver’s synthetic capability (eg, prothrombin time [PT], usually reported as the international normalized ratio [INR]; albumin).

The most useful laboratory tests to screen for liver disorders are serum aminotransferases (the most commonly used liver tests), bilirubin, and alkaline phosphatase. Certain patterns of biochemical abnormalities help distinguish hepatocellular injury from impaired bile excretion (cholestasis—see table Common Patterns of Laboratory Test Abnormalities Common Patterns of Laboratory Test Abnormalities Laboratory tests are generally effective for the following: Detecting hepatic dysfunction Assessing the severity of liver injury Monitoring the course of liver diseases and the response to treatment... read more ). Tests that detect viral hepatitis, liver inflammation, or altered immunoregulation include hepatitis serologic tests Serology Acute viral hepatitis is diffuse liver inflammation caused by specific hepatotropic viruses that have diverse modes of transmission and epidemiologies. A nonspecific viral prodrome is followed... read more and measurement of immunoglobulins, antibodies, and autoantibodies.

A few laboratory tests are diagnostic by themselves; they include the following:

Table
icon

Tests for Liver Injury

Aminotransferases

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) leak from damaged cells; thus, these enzymes are sensitive indicators of liver injury. Markedly high values (> 500 IU/L; normal, 40 IU/L), which indicate acute hepatocellular necrosis or injury, usually result from the following:

High levels persist usually for days to weeks, depending on the etiology of the injury. The degree of elevation may not reflect the extent of liver injury. Serial measurements better reflect severity and prognosis than does a single measurement. A fall to normal indicates recovery unless accompanied by an increase in bilirubin and in prothrombin time (PT) or international normalized ratio (INR, which may indicate acute liver failure Fulminant Hepatitis Fulminant hepatitis is a rare syndrome of rapid (usually within days or weeks), massive necrosis of liver parenchyma and a decrease in liver size (acute yellow atrophy); it usually occurs after... read more , also called fulminant liver failure). Acute liver failure with hepatocyte necrosis results in fewer liver cells that can leak enzymes.

Aminotransferase levels may also be markedly high in the following:

Mild increases (< 300 IU/L) are nonspecific and often present in disorders such as

Aminotransferases can be mildly elevated or even normal in certain liver disorders, such as

Elevated ALT is somewhat specific for liver injury. Because AST is present in the heart, skeletal muscle, kidneys, red blood cells, and pancreas, elevated AST may reflect rhabdomyolysis Rhabdomyolysis Rhabdomyolysis is a clinical syndrome involving the breakdown of skeletal muscle tissue. Symptoms and signs include muscle weakness, myalgias, and reddish-brown urine, although this triad is... read more or injury to one of these organs. In most liver disorders, the ratio of AST to ALT is < 1. However, in alcohol-related liver disease, the ratio is characteristically > 2 because pyridoxal-5'-phosphate is commonly deficient in patients with alcohol-use disorders; it is required for ALT synthesis but is less essential for AST synthesis. This deficiency also explains why elevations of ALT and AST are typically low (< 300 IU/L) in these patients.

Lactate dehydrogenase (LDH)

LDH, commonly included in routine analysis, is present in many other tissues and is insensitive and nonspecific for hepatocellular injury. LDH is typically elevated in ischemic/hypoxic hepatitis and cancers that extensively infiltrate the liver.

Tests for Cholestasis

Bilirubin

Bilirubin, the pigment in bile, is produced from the breakdown of heme proteins, mostly from the heme moiety of hemoglobin in senescent red blood cells. Unconjugated (free) bilirubin is insoluble in water and thus cannot be excreted in urine; most unconjugated bilirubin is bound to albumin in plasma. Bilirubin is conjugated in the liver with glucuronic acid to form the more water-soluble bilirubin diglucuronide. Conjugated bilirubin is then excreted through the biliary tract into the duodenum, where it is metabolized into urobilinogens (some of which are reabsorbed and resecreted into bile), then into orange-colored urobilins (most of which are eliminated in feces). These bile pigments give stool its typical color.

Hyperbilirubinemia results from one or more of the following:

Normally, total bilirubin is mostly unconjugated, with values of < 1.2 mg/dL (< 20 micromol/L). Fractionation measures the proportion of bilirubin that is conjugated (ie, direct, so-called because it is measured directly, without the need for solvents). Fractionation is most helpful for evaluating neonatal jaundice Evaluation Jaundice is a yellow discoloration of the skin and eyes caused by hyperbilirubinemia (elevated serum bilirubin concentration). The serum bilirubin level required to cause jaundice varies with... read more and for evaluating elevated bilirubin when other liver test results are normal, suggesting that hepatobiliary dysfunction is not the cause.

Unconjugated hyperbilirubinemia (indirect bilirubin fraction > 85%) reflects increased bilirubin production (eg, in hemolysis) or defective liver uptake or conjugation (eg, in Gilbert syndrome Gilbert Syndrome Hereditary or inborn metabolic disorders may cause unconjugated or conjugated hyperbilirubinemia (see Overview of bilirubin metabolism). Unconjugated hyperbilirubinemia: Crigler-Najjar syndrome... read more ). Such increases in unconjugated bilirubin are usually < 5 times normal (to < 6 mg/dL [< 100 micromol/L]) unless there is concurrent liver injury.

Conjugated hyperbilirubinemia (direct bilirubin fraction > 50%) results from decreased bile formation or excretion (cholestasis). When associated with other liver test abnormalities, a high serum bilirubin indicates hepatocellular and/or biliary tract dysfunction. Serum bilirubin is somewhat insensitive for liver dysfunction. However, the development of severe hyperbilirubinemia in primary biliary cholangitis Primary Biliary Cholangitis (PBC) Primary biliary cholangitis (PBC; formerly known as primary biliary cirrhosis) is an autoimmune liver disorder characterized by the progressive destruction of intrahepatic bile ducts, leading... read more (also called primary biliary cirrhosis), primary sclerosing cholangitis Primary Sclerosing Cholangitis (PSC) Primary sclerosing cholangitis (PSC) is patchy inflammation, fibrosis, and strictures of the bile ducts that has no known cause. However, 80% of patients also have inflammatory bowel disease... read more , alcohol-related hepatitis Alcohol-Related Liver Disease Alcohol consumption is high in most Western countries. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), 8.5% of US adults are estimated to have... read more Alcohol-Related Liver Disease , and acute liver failure Acute Liver Failure Acute liver failure is caused most often by drugs and hepatitis viruses. Cardinal manifestations are jaundice, coagulopathy, and encephalopathy. Diagnosis is clinical. Treatment is mainly supportive... read more suggests a poor prognosis.

Bilirubinuria reflects the presence of conjugated bilirubin in urine; bilirubin spills into urine because blood levels are markedly elevated, indicating severe disease. Unconjugated bilirubin is water insoluble and bound to albumin and so cannot be excreted in urine. Bilirubinuria can be detected at the bedside with commercial urine test strips in acute viral hepatitis Overview of Acute Viral Hepatitis Acute viral hepatitis is diffuse liver inflammation caused by specific hepatotropic viruses that have diverse modes of transmission and epidemiologies. A nonspecific viral prodrome is followed... read more or other hepatobiliary disorders, even before jaundice appears. However, the diagnostic accuracy of such urine tests is limited. Results can be falsely negative when the urine specimen has been stored a long time, vitamin C has been ingested, or urine contains nitrates (eg, due to urinary tract infections Introduction to Urinary Tract Infections (UTIs) Urinary tract infections (UTIs) can be divided into upper tract infections, which involve the kidneys (pyelonephritis), and lower tract infections, which involve the bladder (cystitis), urethra... read more ). Similarly, increases in urobilinogen are neither specific nor sensitive.

Alkaline phosphatase

An increase in levels of this hepatocyte enzyme suggests cholestasis. Results may not be specific because alkaline phosphatase consists of several isoenzymes and has a widespread extrahepatic distribution (eg, in the placenta, the small intestine, white blood cells, kidneys, and particularly bone).

Alkaline phosphatase levels increase to 4 times normal 1 to 2 days after onset of biliary obstruction, regardless of the site of obstruction. Levels may remain elevated for several days after the obstruction resolves because the half-life of alkaline phosphatase is about 7 days. Increases of up to 3 times normal occur in many liver disorders, including

Isolated elevations (ie, when other liver test results are normal) may accompany

Isolated elevations also occur in the absence of any apparent liver or biliary disorder, as in the following:

Levels of gamma-glutamyl transpeptidase or 5-nucleotidase, which are more specific to the liver, can differentiate hepatic from extrahepatic sources of alkaline phosphatase better than fractionation of alkaline phosphatase, which is technically difficult. Also, in otherwise asymptomatic older people, an increase in alkaline phosphatase usually originates in bone (eg, in Paget disease) and may not require further investigation for liver injury.

5–Nucleotidase

Increases in levels of this enzyme are as sensitive as alkaline phosphatase for detecting cholestasis and biliary obstruction but are more specific, almost always indicating hepatobiliary dysfunction. Because levels of alkaline phosphatase and 5-nucleotidase do not always correlate, one can be normal while the other is increased.

Gamma–glutamyl transpeptidase (GGT)

Levels of this enzyme increase in hepatobiliary dysfunction, especially cholestasis, and correlate loosely with levels of alkaline phosphatase and 5-nucleotidase. Levels do not increase because of bone lesions, during childhood, or during pregnancy. However, alcohol and certain drugs (eg, some anticonvulsants, warfarin) can induce hepatic microsomal (cytochrome P-450) enzymes, markedly increasing GGT and thus somewhat limiting its specificity.

Tests of Hepatic Synthetic Capacity

Prothrombin time (PT) and international normalized ratio (INR)

PT may be expressed in time (seconds) or, preferably, as a ratio of the patient’s measured PT to the laboratory’s control value (INR—see Testing Testing Unusual or excessive bleeding may be indicated by several different signs and symptoms. Patients may present with unexplained nosebleeds (epistaxis), excessive or prolonged menstrual blood flow... read more ). The INR is more accurate than PT for monitoring anticoagulation. PT or INR is a valuable measure of the liver’s ability to synthesize fibrinogen and vitamin K–dependent clotting factors: factors II (prothrombin), VII, IX, and X. Changes can occur rapidly because some of the involved clotting factors have short biologic half-lives (eg, 6 hours for factor VII). Abnormalities indicate severe hepatocellular dysfunction, an ominous sign in acute liver disorders. In chronic liver disorders, an increasing PT or INR indicates progression to liver failure. The PT or INR does not increase in mild hepatocellular dysfunction and is often normal in cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more .

Serum proteins

Hepatocytes synthesize most serum proteins, including alpha- and beta-globulins, albumin, and most clotting factors (but not factor VIII, produced by the vascular endothelium, or gamma-globulin, produced by B cells). Hepatocytes also make proteins that aid in the diagnosis of specific disorders:

These proteins usually increase in response to damage (eg, inflammation) to various tissues, so that elevations may not specifically reflect liver disorders.

Serum albumin commonly decreases in chronic liver disorders because of an increase in volume of distribution (eg, due to ascites Ascites Ascites is free fluid in the peritoneal cavity. The most common cause is portal hypertension. Symptoms usually result from abdominal distention. Diagnosis is based on physical examination and... read more ), a decrease in hepatic synthesis, or both. Values < 3 g/dL (< 30 g/L) suggest decreased synthesis, caused by one of the following:

Because albumin has a half-life of about 20 days, serum levels take weeks to increase or decrease.

Other Laboratory Tests

Ammonia

Nitrogen compounds that enter the colon (eg, ingested protein, secreted urea) are degraded by resident bacteria, liberating ammonia. The ammonia is then absorbed and transported via the portal vein to the liver. The healthy liver readily clears the ammonia from the portal vein and converts it to glutamine, which is metabolized by the kidneys into urea to be excreted. In patients with portosystemic shunting and chronic liver disease, the diseased liver does not clear ammonia, which then enters the systemic circulation, possibly contributing to portosystemic (hepatic) encephalopathy Portosystemic Encephalopathy Portosystemic encephalopathy is a neuropsychiatric syndrome that can develop in patients with liver disease. It most often results from high gut protein or acute metabolic stress (eg, gastrointestinal... read more . Elevated ammonia levels occur in hepatic encephalopathy, but levels may be falsely low or high. In advanced liver disorders, the following may increase ammonia levels:

Because the degree of elevation in the ammonia level correlates poorly with severity of hepatic encephalopathy, this level has limited usefulness in monitoring therapy.

In acute liver failure, elevated arterial ammonia levels occur due to severe acute hepatocyte dysfunction and/or necrosis, as opposed to portosystemic shunting, and may be a poor prognostic indicator.

Serum immunoglobulins

Antimitochondrial antibodies

These heterogeneous antibodies are positive, usually in high titers, in > 95% of patients with primary biliary cholangitis. They are also occasionally present in the following:

  • Autoimmune hepatitis

  • Drug-induced hepatitis

  • Other autoimmune disorders, such as connective tissue disorders, myasthenia gravis, autoimmune thyroiditis, Addison disease, and autoimmune hemolytic anemia

Other antibodies

Other antibodies may help in diagnosis of the following:

  • Autoimmune hepatitis: Smooth muscle antibodies against actin, antinuclear antibodies (ANA) that provide a homogeneous (diffuse) fluorescence, and antibodies to liver-kidney microsome type 1 (anti-LKM1) are often present.

  • Primary biliary cholangitis: Antimitochondrial antibody is key to the diagnosis.

  • Primary sclerosing cholangitis: Perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) can help raise the index of suspicion.

Isolated abnormalities of any of these antibodies are never diagnostic and do not elucidate pathogenesis.

Alpha–fetoprotein (AFP)

AFP, a glycoprotein normally synthesized by the yolk sac in the embryo and then by the fetal liver, is elevated in neonates and hence the pregnant mother. AFP decreases rapidly during the first year of life, reaching adult values (normally, < 10 to 20 ng/mL or < 10 to 20 mg/L depending on the laboratory) by the age of 1 year. An increase in AFP, no matter how small, should prompt consideration of primary hepatocellular carcinoma Hepatocellular Carcinoma Hepatocellular carcinoma usually occurs in patients with cirrhosis and is common in areas where infection with hepatitis B and C viruses is prevalent. Symptoms and signs are usually nonspecific... read more (HCC). Serum AFP generally correlates with tumor size, differentiation and metastatic involvement. Because small tumors may produce low levels of AFP, increasing values suggest the presence of HCC, especially when tumors are > 3 cm in diameter. AFP also helps predict prognosis.

Mild AFP elevations also occur in acute and chronic hepatitis, probably reflecting liver regeneration; AFP can occasionally increase to 500 ng/mL in acute (fulminant) liver failure Acute Liver Failure Acute liver failure is caused most often by drugs and hepatitis viruses. Cardinal manifestations are jaundice, coagulopathy, and encephalopathy. Diagnosis is clinical. Treatment is mainly supportive... read more . High AFP levels can occur in a few other disorders (eg, embryonic teratocarcinomas, hepatoblastomas in children, some hepatic metastases from gastrointestinal tract cancers, some cholangiocarcinomas), but these circumstances are not common and usually can be differentiated based on clinical and histopathologic grounds.

Sensitivity, specificity, and peak levels of AFP in patients with HCC vary by population, reflecting differences in factors such as hepatitis prevalence and ethnicity. In areas with a relatively low prevalence of hepatitis (eg, North America, western Europe), AFP cutoff values of 20 ng/mL (20 mcg/L) have a sensitivity of 39 to 64% and a specificity of 76 to 91%. However, not all HCCs produce AFP. Thus, AFP is not an ideal screening test but does have a role in detecting HCC and may be used to monitor response to treatment. Levels exceeding normal (> 20 ng/mL [20 mcg/L]), especially when increasing, strongly suggest HCC. In cirrhotic patients with a mass and a high value (eg, > 200 ng/mL [200 mcg/L]), the predictive value is high. The combined use of AFP and ultrasonography typically provides adequate screening.

Tests for hepatic fibrosis

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