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Liver Tests 

Liver Tests
Chapter:
Liver Tests
Author(s):

Sameer D. Saini

, and Akbar K. Waljee

DOI:
10.1093/med/9780190862800.003.0028
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date: 15 August 2020

  1. A. Introduction

    1. a. The liver has been called “the custodian of the milieu interieur.” Hepatic disorders, therefore, have far-reaching effects on homeostasis. Fortunately, there are several tests that can help determine the cause of liver injury and allow for assessment of the liver’s remaining synthetic capacity. The proper interpretation of liver enzymes and other liver tests is dependent on remembering the core functions of the liver, which include:

      1. i. Synthesis of intravascular proteins

      2. ii. Regulation of glucose metabolism

      3. iii. Production of key blood clotting factors

      4. iv. Detoxification of chemicals that enter the gastrointestinal (GI) tract

      5. v. Metabolism of byproducts of hemoglobin metabolism

    2. b. Blood tests that are used to assess the liver are commonly referred to as liver function tests (LFTs). Whereas some of these measures reflect the actual function of the liver (e.g., albumin, bilirubin, prothrombin time), other measures reflect injury to the organ (e.g., aspartate aminotransferase [AST], alanine aminotransferase [ALT], and alkaline phosphatase).

  2. B. General Approach

    1. a. Synthetic function

      1. i. Albumin. The liver is an important site of protein synthesis. Assessment of albumin levels can indicate how well the liver is making proteins, in general. If dietary intake is constant and the liver fails, it can take several weeks for albumin levels to fall. Therefore, in a patient with acute liver failure, the albumin level is often initially normal. Conversely, in patients with high levels of metabolic stress (sepsis, shock), albumin levels may drop quickly despite adequate liver function.

      2. ii. Prothrombin time (PT) is a function of plasma levels and the activity of factors I, II, V, VII, and X. The half-lives of some of these proteins are much shorter than that of albumin; therefore, the PT increases within hours of a significant decrease in the synthetic function of the liver and can serve as a sensitive marker of liver dysfunction.

      3. iii. Total bilirubin levels can also be used to assess liver function. Clinical jaundice is usually apparent in daylight when bilirubin levels exceed 3 mg/dL. While a complete discussion of bilirubin formation and elimination is beyond the scope of this chapter, in brief, bilirubin is formed by the breakdown and cleavage of the heme ring. The bilirubin is then conjugated (by the enzyme glucuronyl transferase) and excreted into the bile in water-soluble form. Elevations of bilirubin can thus be classified as predominantly unconjugated or conjugated. Most elevations in clinical practice are a mix of both.

        1. 1. Unconjugated (indirect). Levels of unconjugated bilirubin increase if production increases (e.g., as a result of hemolysis or hematoma) or hepatic uptake or conjugation decrease (as occurs in Gilbert’s syndrome or Crigler-Najjar syndrome, both caused by varying degrees of deficiencies of the enzyme glucuronyl transferase).

          Hot Key

          The most common cause of unconjugated hyperbilirubinemia in an otherwise healthy person is Gilbert’s syndrome. It often manifests after prolonged fasts or periods of systemic stress (such as hospitalization).

        2. 2. Conjugated (direct). Levels of conjugated bilirubin increase with decreased secretion of bilirubin into bile canaliculi (as occurs in Dubin-Johnson syndrome and Rotor’s syndrome). Biliary epithelial damage (as a result of hepatitis, toxins, or cirrhosis) or ductal obstruction (as a result of biliary stones, cholangitis, or pancreatic cancer) can also increase conjugated bilirubin levels.

      4. iv. Glucose levels may be decreased in patients with severe liver dysfunction secondary to disruptions in glycolysis and gluconeogenesis.

    2. b. Injury pattern. The two predominant patterns of liver injury are cholestatic and hepatocellular.

      1. i. Cholestatic pattern. The cholestatic pattern is characterized by elevations in alkaline phosphatase, bilirubin, and γ‎-glutamyl transpeptidase (GGT).

        1. 1. Alkaline phosphatase is an enzyme that hydrolyzes organic phosphate esters. Alkaline phosphatase is found primarily in liver and bone but may also be found in the small intestine, kidney, placenta, and leukocytes in other forms (known as isoenzymes). In the liver, alkaline phosphatase is found primarily on the surface of the bile canalicular membrane. Disproportionate elevations of alkaline phosphatase occur with any disease that obstructs bile flow (e.g., biliary stones, cholangitis, pancreatic cancer) or diseases that infiltrate the liver causing micro-obstruction or damage (e.g., tuberculosis, sarcoidosis, metastatic cancer). Primary biliary cirrhosis (PBC), an autoimmune disorder that damages the intrahepatic bile ducts, also leads to elevated alkaline phosphatase levels.

        2. 2. GGT is an enzyme found in many tissues but is absent in bone. Therefore, it is useful when evaluating the cause of an elevated alkaline phosphatase level. If both GGT and alkaline phosphatase are elevated, the liver is a likely source of the problem. Conversely, elevation of alkaline phosphatase with a normal GGT suggests a bone source. GGT is also elevated in patients with alcoholic liver disease and can serve as a marker of ongoing alcohol intake.

        3. 3. If GGT is not available and there are questions regarding the source of an elevated alkaline phosphatase, an alternative approach is to fractionate the alkaline phosphatase to quantify the isoenzymes.

      2. ii. Hepatocellular pattern. The hepatocellular pattern is associated with elevations in AST (serum glutamate oxaloacetate transaminase [SGOT]), ALT (serum glutamate pyruvate transaminase [SGPT]), and LDH (lactate dehydrogenase).

        1. 1. AST is an enzyme found in the cytosol and mitochondria of hepatocytes. However, it is also found in cardiac muscle; renal, brain, pulmonary, and pancreatic tissue; leukocytes; and erythrocytes. AST is a sensitive indicator of hepatic injury but is not specific.

        2. 2. ALT is an enzyme found only in the cytosol of hepatocytes. Because it is found only in the liver, ALT is a very specific indicator of hepatocellular injury.

        3. 3. LDH is an enzyme that is found in many tissues; isoenzyme 5 (LDH-5) is found in the liver. LDH levels increase with any hepatocellular injury.

        4. 4. Bilirubin in typically normal initially in a patient with hepatocellular injury. Over the subsequent 2 to 5 days, however, the bilirubin often becomes elevated in response to the original hepatocellular injury. Bilirubin often normalizes last during recovery.

          • MNEMONIC: Causes of Significantly Increased (>1000 U/L) AST and ALT Levels (“Tainted Mushrooms Can Cause Bad Hepatitis, So Watch Out!”)

          • Tylenol or Tetracycline toxicity

          • Mushrooms (Amanita phalloides)

          • Carbon tetrachloride toxicity (rare)

          • Congestive hepatopathy

          • Budd- Chiari syndrome

          • Hepatitis (viral)

          • Shock liver (due to hypotension of any cause)

          • Wilson’s disease (subtype associated with fulminant hepatic necrosis)

          • Other toxins (e.g., halothane, valproic acid, vitamin A)

  3. C. Common Liver Function Test Abnormalities

    These are summarized in the Table 28.1.

Table 28.1 Common Liver Test Abnormalities*

Disease

AST

ALT

Alkaline Phosphatase

Bilirubin

Comments

Cholelithiasis

N

N

N

N

Usually asymptomatic because stones remain in the gallbladder. Occasionally, postprandial “biliary” pain may occur.

Choledocholithiasis

N/↑

N/↑

↑↑

Biliary colic; may lead to cholangitis.

Cholecystitis

N/↑

N/↑

N/↑

N/↑

Positive Murphy’s sign; fever; elevated WBC count.

Cholangitis

↑↑

↑↑

↑↑↑

Look for Charcot’s triad (fever, right upper quadrant pain, jaundice).

Viral hepatitis

↑↑↑↑

↑↑↑↑

↑↑↑↑

ALT > AST; enzymes are usually markedly elevated (>1000 U/L) in acute viral hepatitis.

Alcoholic hepatitis

↑↑↑

↑↑↑

↑↑

↑↑↑

AST > ALT, typically in a 2:1 ratio; AST usually <300 U/L unless in combination with another insult.

Congestive hepatopathy

↑↑↑

↑↑

↑↑↑

PT often rises early

Metastatic disease

↑↑↑

N

Consider this diagnosis with isolated increased alkaline phosphatase.

* These disorders may also present with variable liver function test abnormalities.

ALT = alanine aminotransferase; AST = aspartate aminotransferase; N = normal; PT = prothrombin time; WBC = white blood cell.

Suggested Further Readings

Beste LA, Moseley RH, Saint S, Cornia PB. Clinical problem-solving. Too much of a good thing. N Engl J Med 2016;374:873–8.Find this resource:

Chalasani NP, Hayashi PH, Bonkovsky HL, Navarro VJ, Lee WM, Fontana RJ. ACG clinical guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol 2014;109:950–66; quiz 67.Find this resource:

Giannini EG, Testa R, Savarino V. Liver enzyme alteration: a guide for clinicians. CMAJ 2005;172:367–79.Find this resource: