Approach to the Patient With Abnormal LFTs

Emerg Med 39(9):33, 2007

By Dr. Norton J. Greenberger, MD

The author explores the multiple causes of aminotransferase elevations, the differential diagnosis of jaundice, and the effective use of liver function tests.

Abnormalities in liver function tests (LFTs) noted on routine laboratory studies in asymptomatic patients are very common. Data on 15,676 adults over the age of 17 years from the third annual National Health and Nutrition Examination Survey (NHANES) was analyzed. Aminotransferase elevations were defined as aspartate aminotransferase (AST) levels greater than 37 U/L and alanine aminotransferase (ALT) levels greater than 42 U/L. They were classified as explained if there was evidence of hepatitis B, evidence of hepatitis C, evidence of iron overload (transferrin saturation higher than 50%), and alcohol consumption. The latter was defined, apparently liberally, as daily consumption of more than two drinks a day for men and one drink per day for women. Aminotransferase elevations were classified as unexplained if the above four factors were absent.

The prevalence of aminotransferase elevations in the United States in the NHANES survey was 7.9%. They were more common in men (9.3%) compared to women (6.6%) and in Mexican-Americans (14.9%) and non-Hispanic blacks (8.1%) compared to non-Hispanic whites (7.1%). A specific cause as defined above accounted for aminotransferase elevations in only 31% of the cases; these included alcohol (43%), hepatitis C (22%), hemochromatosis (11%), hepatitis B (3%), and any combination of theabove (19%).

Importantly, aminotransferase elevations were unexplained in 69% of cases, but were clearly associated with several factors: high body mass index (BMI, 29.5 or higher); increased waist circumference (100.8 cm or more); elevated triglycerides (2.26 µmol/L or higher); elevated fasting insulin (more than 94 µU/L); and type 2 diabetes and hypertension, especially in women. Unexplained aminotransferase elevations were strongly associated with adiposity and other features of the
metabolic syndrome.

Approximately 10% to 17% of patients with unexplained aminotransferase elevations have unsuspected cirrhosis and an even higher proportion have significant fibrosis. The spectrum of nonalcoholic fatty liver disease (NAFLD) includes simple hepatic steatosis, nonalcoholic steatohepatitis (NASH), and cirrhosis of the liver. The incidence of NAFLD and NASH correlates directly with BMI, the latter broken down into categories of 25-30, 30-35, 35-40, and greater than 40.

Thus, common causes of aminotransferase elevations include the spectrum of NAFLD, alcohol consumption, hepatitis B and C, and hemochromatosis. Uncommon causes in asymptomatic individuals include chronic acetaminophen use (greater than 4 grams/day), celiac sprue, and use of statins (especially in high doses).

DIFFERENTIAL DIAGNOSIS OF JAUNDICE

Liver function tests are integral to evaluating patients who present with jaundice. The age of the patient provides an important clue as to the underlying cause of this condition. (see table below) Thus, in individuals under age 30, viral hepatitis will be the cause of jaundice in 85% to 90% of patients. In patients between ages 40 and 60, alcoholic liver disease will account for 50% to 70% of cases. In patients over age 60 who present with jaundice but do not drink alcohol, take no medications, have not had a prior blood transfusion, and have not been exposed to patients with viral hepatitis, the two most likely causes will be gallstones and their complications or cancer of the pancreas, accounting for over 80% of patients.

Chronic hepatitis is the cause of jaundice in 5% to 10% of patients. Medications are the putative cause of less than 5% of cases. Drug-induced jaundice should be considered in any patient who also has fever, arthralgia, rash, and eosinophilia.

Sickle cell anemia is an important cause of jaundice. Also, Gilbert’s syndrome or chronic idiopathic unconjugated hyperbilirubinemia is present in 2% to 5% of the adult population. The only abnormality in this disorder is increased levels of unconjugated serum bilirubin (to values between 1.5 and 5.0 mg/dl); all other liver tests are normal. Primary biliary cirrhosis and primary sclerosing cholangitis round out the top 10 causes of jaundice.

The differential diagnosis of jaundice is shown in the table above. It should be emphasized that the disorders listed in the table will account for more than 98% of all patients who present with jaundice. I have not included patients with jaundice caused by metastatic liver disease because in that setting the diagnosis would be obvious.

LFTs AND JAUNDICE

Liver function tests used in the differential diagnosis of jaundice are listed in the table below. To illustrate the use of these tests, I have listed the typical findings in an acute disorder such as viral hepatitis, a chronic parenchymal liver disease such as cirrhosis, and obstructive jaundice as might occur from a common bile duct stone or pancreatic cancer. Serum bilirubin levels may range from 1 to 20 mg/dl in acute viral hepatitis, cirrhosis of the liver, and obstructive jaundice. Levels rarely exceed 20 mg/dl in obstructive jaundice. The highest serum bilirubin levels are seen in chronic parenchymal liver disease such as cirrhosis, complicated by oliguric hepatic failure (hepatorenal syndrome). In the other disorders, because bilirubin is excreted largely in the urine, serum bilirubin levels will rise to 15 to 20 mg/dl and then plateau.

Aminotransferase elevations are classically elevated to values above 400 U/L in acute viral hepatitis, but are characteristically less than 400 in both cirrhosis of the liver and obstructive jaundice. However, in obstructive jaundice due to choledocholithiasis with concurrent ascending cholangitis, serum aminotransferase values can be as high as 1000 U/L, thus mimicking viral hepatitis. The tip-off to this diagnosis, though, is that the elevations will fall rapidly within two to four days. The serum alkaline phosphatase level is minimally elevated in acute viral hepatitis, may be minimally or moderately elevated in chronic liver diseases such as cirrhosis, but is disproportionately elevated to values that are 4 to 10 times normal in patients with obstructive disease, with the obstructive process being either extrahepatic or intrahepatic.

Serum albumin and globulin are usually normal in acute viral hepatitis and obstructive disease, while albumin is decreased and globulin is increased in chronic liver disease such as cirrhosis. Coagulation studies such as prothrombin time (PT) and activated partial thromboplastin time (aPTT) are usually normal in acute viral hepatitis. If a patient with acute viral hepatitis has a prolonged PT, one must be concerned about the possibility of submassive necrosis and incipient liver failure. In cirrhosis of the liver, the PT and aPTT are usually prolonged. In obstructive disease, particularly if the obstruction has been present for more than a few months, the PT may be prolonged but will respond to vitamin K administration.

Cholesterol levels are usually normal in acute viral hepatitis, normal to decreased in cirrhosis of the liver, and normal to increased in obstructive disease. The serologies useful in the differential diagnosis include hepatitis A, B, and C, as well as Epstein-Barr virus and cytomegalovirus. Hepatitis A does not lead to chronic liver disease. An abdominal ultrasound examination can be very helpful in the differential diagnosis, especially in patients with a serum bilirubin level greater than 10 mg/dl. In this regard, abdominal ultrasound has a sensitivity and specificity of 93% to 95%, if the serum bilirubin level is over 10 mg/dl and this abnormality has been present for more than 10 days. In this setting, an ultrasound showing evidence of dilated intrahepatic ducts clearly points to extrahepatic obstruction. Conversely, in this same setting, if the intrahepatic ducts are not dilated, it points to an intrahepatic cause for cholestasis.

SPECTRUM OF DISORDERS CAUSING INTRAHEPATIC CHOLESTASIS

It is not generally appreciated that patients can present with jaundice and obstructive-type chemistries that are not related to extrahepatic obstruction. Rather, they can be related to several disorders that are capable of causing intrahepatic cholestasis, summarized in the table below. Hepatocellular causes of intrahepatic cholestasis include viral hepatitis, especially type A. Acute hepatitis A can be associated with prolonged jaundice and obstructive liver tests for as long as four months. Patients with alcoholic liver disease can also present with a cholestatic picture.

With regard to canalicular causes of intrahepatic cholestasis, the important ones to consider are drugs, sepsis, and the postoperative state. Serum bilirubin levels as high as 40 mg/dl have been well documented in patients postoperatively, particularly if their course has been complicated by massive bleeding, as in a ruptured abdominal aortic aneurysm, and accompanied by hypoxemia, hypotension, and renal failure.

Other disorders that can give rise to obstructive-type liver tests include primary biliary cirrhosis, primary sclerosing cholangitis, and sarcoidosis.

ABNORMAL LFTs IN SPECIFIC CLINICAL SETTINGS

Specific clinical settings in which abnormal LFTs may be seen include Gilbert’s syndrome, cirrhosis of the liver, and chronic hepatitis.

Gilbert’s syndrome. Gilbert’s syndrome is characterized by unconjugated hyperbilirubinemia but with normal tests of liver function. Patients with Gilbert’s syndrome may have elevations in their serum bilirubin levels after fasting, recent viral infections, or strenuous exercise. The importance of making this diagnosis is that it is an innocent disorder and should not result in detailed laboratory studies or invasive diagnostic procedures.

Cirrhosis of the liver. The typical liver test abnormalities in cirrhotic patients include hyperbilirubinemia, prolonged PT, hypocholesterolemia, and hyperglobulinemia. A diagnosis of cirrhosis can be made at the bedside, after the initial evaluation, if two physical findings and two laboratory findings are present. The two physical findings are ascites and asterixis (the latter indicating portal systemic encephalopathy) and the two laboratory findings are hypoalbuminemia (serum albumin less than 2.8 gm/dl) and prolonged PT (INR greater than 1.6).

Chronic hepatitis. This disorder may be due to autoimmune disorders, hepatitis B, C, or D (as well as certain drugs), Wilson’s disease, alpha 1-antitrypsin deficiency, NAFLD, and hemochromatosis.

EFFECT OF ACUTE ALCOHOL INTAKE

It has been demonstrated that if an individual ingests more than 70 grams of alcohol (more than 1 gm/kg for four consecutive days), it can result in an elevation of serum aminotransferases to more than twice the normal levels. How does one approach such a patient?

The first important step is to take a detailed history to look for potential hepatic insults. A careful drug history should be taken to make sure that there are no medications being used that can result in elevated aminotransferase levels, with particular attention paid to acetaminophen and the statins. Key findings on the physical examination are enlargement of the liver to more than 14 cm, a palpable left lobe of the liver, and a palpable spleen. If any of these findings is present, it would warrant conducting detailed liver tests and, in many instances, a liver biopsy. It would be prudent to recheck ALT/AST values at three and six months to determine if there is a persistent elevation.

Other conventional laboratory tests should be reviewed, specifically serum albumin, serum globulins, serum cholesterol, coagulation function, and a complete blood count. In particular, a decreased platelet count in the setting of elevated serum aminotransferases is an important clue pointing to the presence of chronic liver disease and incipient portal hypertension. A detailed alcohol history should be taken as well. In individuals who are overweight, there is a direct correlation between the degree of obesity and the likelihood of abnormal LFTs, as well as underlying fibrosis. A recent weight gain of 10 to 15 pounds alone could be responsible for the development of NAFLD.

back to top

Suggested Reading Abdo A, et al.: Liver abnormalities in patients with celiac disease. Clin Gastroenterol Hepatol 2(2):107, 2004. Ahmed ?A and Keeffe?EB Chronic hepatitis C with normal aminotransferase levels. Gastroenterology 126(5): 1409, 2004. Angulo P: Nonalcoholic fatty liver disease. N Eng J Med 346(16):1221, 2002. Chalasani N, et al.: Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity. Gastroenterology 126(5):1287, 2004. Clark JM and Diehl AM: Nonalcoholic fatty liver disease: an underrecognized cause of cryptogenic cirrhosis. JAMA 289(22):3000, 2003. Clark JM, et al.: The prevalence and etiology of elevated aminotransferase elevations in the United States. Am J Gastroenterol 98(5):960, 2003. Marchesini G, et al.: Nonalcoholic fatty liver, steatohepatitis and metabolic syndrome. Hepatology 37(4):917, 2003.

Printable version of this article

E-mail this article