Interpretation of Abnormal Liver Enzymes

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Although the patterns of liver enzyme elevations are not always consistent between patients with similar disease states, there are some general rules that can be applied to interpreting enzymes. Aminotransferase elevations are typically seen with hepatocellular injury and often occur in the setting of normal or near normal bilirubin and alkaline phos-phatase. In almost all liver diseases except those that are alcohol related, the ratio of AST/ALT is less than one, until cirrhosis develops when there is often a reversal of this ratio.

The most common cause of ALT elevation is drug-induced toxicity, which is generally mild and transient. Continued use of the offending agent will often lead to persistent ALT elevations, but values generally remain below 300 U/L. Common offending agents include NSAIDs, antibiotics, statin compounds, antiseizure medications, antiretrovirals for human immunodeficiency virus, and isoniazid. Serial enzyme assessment is necessary when patients are consuming these agents. Herbal and complementary medicine hepatotoxicity is increasingly being recognized and will also require further study to assess how to follow patients on these drugs.

Chronic viral infections, such as hepatitis B (HB) or HC, and fatty liver disease are the most common causes of persistently elevated enzymes. Again, enzymes rarely rise above 300 U/L in these settings. HC is the most common chronic hepatotropic infection in Western countries, is asymptomatic, and ALT can range from normal to 10-fold above normal values. HB affects 400 million worldwide and can also present with a spectrum of aminotransferase abnormalities ranging from normal levels to the thousands (U/L). Nonalcoholic fatty liver disease is increasingly recognized even in those without the classic risk factors of obesity and diabetes mellitus. Steatosis may develop from medication use, including corticosteroids, amiodarone, and tamoxifen. There is more evidence lately that steatosis may not cause significant enzyme elevations. The typical pattern of enzyme elevation is AST/ALT ratio of less than one, with numbers sometimes as high as fivefold the upper limit of normal. Unfortunately, there is no relationship between liver enzymes and degree of steatosis, or even the presence of inflammation, or nonalcoholic steatohepatitis (NASH), which is thought to be the more aggressive variant of this condition. Liver biopsy is necessary to confirm the diagnosis of NASH, though imaging may be suggestive of steatosis.

Alcohol-related liver injury is still a common phenomenon, and clinical examination requires diligence in history taking. An AST/ALT ratio of greater than two is often, but not always, seen in the setting of acute injury. GGT may also be greater than twice the normal. These values are generally below 300 U/L, except in the setting of concurrent acetaminophen toxicity, when the values may be in the thousands.

Autoimmune hepatitis is another cause ofALT elevation. In some cases, it presents with significant enzyme elevations, with or without jaundice. With corticosteroid therapy, enzymes typically normalize within weeks or months. Wilson's disease can cause ALT elevations, but is relatively rare and seen almost exclusively in patients under the age of 40 years. Iron overloaded states, the most important of which is hereditary hemochromatosis, can also elevate amino-transferases, and most commonly presents in the fifth or sixth decades of life. Figure 104-2 outlines the evaluation of persistently elevated ALT.

There are generally only the three following conditions where very high aminotransferase levels (ie, > 2000 IU) are seen: (1) ischemic liver injury, (2) acute viral hepatitis, and (3) drug-induced hepatotoxicity. Hepatitis A and HB, and in some countries E, are the viruses most likely to cause very high enzyme elevations, but all more commonly present without jaundice and generally are not symptomatic in immune competent adults.

Alkaline phosphatase elevation as an isolated finding should first be confirmed to be of hepatic origin by evaluating GGT or 5'NT. Once this has been confirmed, the next step is ultrasound or computed tomography scan to assess for biliary tree dilatation or infiltrative process. If the biliary tree is dilated, the next step is endoscopic retrograde cholangiography (ERCP). Although a percutaneous transhepatic cholangiogram can also be performed, the ERCP is the preferred diagnostic test in most scenarios due to relatively lower morbidity and ability to perform therapeutic measures more easily. If the biliary tree is normal, then a liver biopsy to assess for infiltrative disease or small bile duct disease states such as primary biliary cirrhosis (PBC) may be more appropriate. Occasionally, infiltrative disorders or systemic infections will result in profoundly high alkaline phosphatase levels. In fulminant Wilson's disease, alkaline phosphatase levels may be disproportionately low. Often, more than one diagnostic test is necessary to make the diagnosis with alkaline phosphatase elevations (see Figure 104-2). Although a space-occupying lesion in the liver may cause one or more enzyme abnormalities, often the enzymes are normal or minimally elevated.

Isolated hyperbilirubinemia is generally not due to obstructive biliary disease, yet ERCP is often performed in this setting in clinical practice. The lack of alkaline phos-phatase or GGT elevation is an indicator that a disproportionate rise in bilirubin is not likely due to obstructive biliary tract disease. If the fractionated form of bilirubin is predominantly unconjugated, then extrahepatic sources such as hemolysis must be considered. Another clinically challenging scenario is distinguishing intrahepatic cholestasis from biliary tract obstruction. Again, a multitude of laboratory and imaging studies is usually required to assess this, because the bilirubin and alkaline phosphatase with GGT are elevated in both conditions. One must keep in mind that biliary tract disease or obstruction will generally have imaging consistent with this, unless it is an acute presentation, in

Persistently Elevated ALT

Assess for diabetes, hyperlipidemia, and obesity

Screen for viral hepatitis check iron studies, ANA, SMA

Young with no other risk factors

Review medications and herbal supplements; stop temporally related ones

Assess for diabetes, hyperlipidemia, and obesity

Ultrasonography

Screen for viral hepatitis check iron studies, ANA, SMA

Young with no other risk factors

Check ceruloplasmin ± 24 hour urinary Cu

Evaluate alpha-1 AT phenotype and screen for celiac disease if other studies negative

Ultrasonography

Check ceruloplasmin ± 24 hour urinary Cu

♦ Liver biopsy

FIGURE 104-2. Algorithm to evaluate persistently elevated alanine aminotransferase (ALT). ANA = antinuclear antibody; AT = a-1-antitrypsin; Cu = copper; SMA = smooth muscle antibody.

which case imaging may not reflect changes such as dilated bile ducts. Ultrasound is the most reasonable first line examination, because it can reliably assess for bile duct dilatation. If present, then ERCP can be performed. Cholangiography often is performed early in the examination process in spite of other imaging tests not supporting the diagnosis of biliary tract obstruction. If there is no evidence of bile duct dilatations, ERCP rarely reveals an abnormality. Liver biopsy in those settings should be the initial diagnostic test.

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