June 2008 Clinical Laboratory News: Liver Disease and Beyond

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June 2008: Volume 34, Number 6


Liver Disease and Beyond
Is Widespread ALT Screening the Answer?
By Deborah Levenson 

It’s no wonder that hepatologists and gastroenterologists bemoan rising rates of liver diseases—especially hepatitis C and nonalcoholic fatty liver disease (NAFLD)—that are asymptomatic in their early stages. Prevalence of both conditions has reached epidemic levels in the U.S. An estimated 4 million Americans suffer from hepatitis C, sometimes with concurrent hepatitis B infection, and up to 25% of the population has NAFLD. Elevated levels of the liver enzymes alanine aminotransferase (ALT) and aspartate amino-transferase (AST) included in routine testing panels often are the first sign that a patient has NAFLD, hepatitis C, or hepatitis B, but further testing is needed to diagnose these conditions. Now a growing number of papers, including a recent statement from the American Association for the Study of Liver Diseases (AASLD), point to potential new uses for these common, well-established, and inexpensive tests.

“It’s underappreciated that ALT is a marker of overall health,” explained Henry C. Bodenheimer, Jr., MD, Chief of the Division of Digestive Diseases at Beth Israel Medical Center in New York, N.Y. and a member of the AASLD committee that issued the statement. “Evolving data show that ALT levels are higher in people with coronary artery disease and for other reasons that aren’t related to liver disease.”

As hepatologists and gastroenterologists ponder stepping up the use of ALT to catch liver disease and possibly other problems that can lead to premature mortality, both lab directors and clinicians worry about the large number of overweight and obese people with fatty liver potentially included in labs’ ALT and AST reference populations. The fear, they say, is that the ubiquity of fatty liver has skewed values such that the normal range does not truly reflect liver health. To correct this situation, some laboratorians and clinicians have suggested abandoning traditionally defined reference intervals in favor of cutpoints.

A Focus on Overall Health

What’s prompting the recent attention to these liver enzymes? Several population studies conclusively demonstrate a strong association between ALT levels and subsequent liver disease mortality, and now a burgeoning body of evidence suggests that ALT can predict mortality from conditions that don’t originate in the liver, according to the AASLD statement (Hepatology 2008; 47: 1363–1370). It highlights population data from three recent papers. One study found a correlation between ALT values and cardiovascular mortality in a cohort of 142,055 people ages 35 to 39 who participated in a large Korean health insurance program (BMJ 2004; 328: 983). After getting baseline demographic and laboratory data, the researchers followed the cohort for eight to 10 years and used death certificates to determine survival and cause of death. Among the male subjects, those with ALT levels ≥100 U/L had nearly three times the risk of death from cardiovascular causes than those with ALT values < 20 U/L. In women, there was a similar trend, but the overall incidence of cardiovascular events was low, so researchers had trouble extrapolating the data, the AASLD statement notes.

Another study discussed in the AASLD statement was done at the Mayo Clinic. The Mayo researchers concluded that AST and ALT levels obtained during routine care were associated with 10-year mortality in community residents from Olmstead County, Minn. (Hepatology 2007; 47: 880–887). The researchers followed all 6,823 county residents who got ALT measurements during 1995. Of these, 13.4% had abnormal results. Researchers determined that the standardized mortality ratio associated with ALT between 1 and 2 times the upper limit of normal (ULN) was 1.21, while the ratio in those with ALT greater than 2 times the ULN was 1.51. An ALT less than the ULN was associated with lower than expected risk of death.

A third study found increased risk of coronary heart disease in patients who did not have viral hepatitis or excessive alcohol intake but had elevated serum ALT activity. (Hepatology 2006; 43: 1145–1151). A multicenter team of researchers used data from NHANES III to correlate ALT activity and risk of coronary artery disease in the general U.S. population. Among the NHANES population, 7,596 met the inclusion criteria, meaning complete lab data with ALT activity and no history of hepatitis B or C or excessive alcohol use. Of these subjects, 7,259 had ALT within normal limits (≤43 U/L) and 267 had elevated ALT activity. In comparing these two groups, researchers found that those with elevated ALT had higher total cholesterol, lower HDL-C, and higher blood pressure. They were also more likely to be diabetic. Using a formula that incorporated these and other coronary artery risk disease factors, the researchers estimated that men with elevated levels of ALT had a 1.3-fold increase in the risk of coronary artery disease within 10 years, and women had 2.1-fold greater risk.

Taken together, these papers argue for greater attention to ALT as a screen for other diseases, the AASLD statement maintains. However, it notes that research hasn’t pinpointed what else besides liver disease raises ALT values, but lists as possible culprits other risk factors including obesity, serum cholesterol, and plasma glucose concentration.

ALT as a Marker of Health and Disease

The recent statement from the American Association for the Study of Liver Diseases makes the following points, both pro and con, about ALT screening in the general population:

Pro

  • The primary reason for ALT screening, chronic liver disease, is an important public health problem.
  • Most chronic liver disease is detectable and treatable at early stages.
  • ALT is a simple, inexpensive test.
  • The benefits outweigh the economic costs and psychological risks.

Con

  • Not enough data demonstrates the diagnostic accuracy of ALT in the general population.
  • Further data are needed to determine appropriate ages and intervals of ALT screening.

Time for Widespread ALT Testing?

Despite this evidence, AASLD doesn’t endorse ALT or AST as a population screen for non-liver disease. While the tests meet several recognized criteria for screening tests, not enough data are available to demonstrate diagnostic accuracy in the general population or the necessary intervals for screening, the statement notes. “While we wait for these data, we highlight that ALT is an excellent screening test in individuals at risk of liver disease. Subsequently, an abnormal ALT result, as determined by a properly defined normal range, must trigger an appropriate clinical evaluation.”

Several hurdles stand in the way of using ALT as a screening test, explained Henry Bodenheimer, MD, Chief, Division of Digestive Diseases at Beth Israel Medical Center in New York, N.Y. and a member of the AASLD Public Policy Committee that wrote the report. Among them are data on how age modifies ALT’s sensitivity, which would guide determinations about when to begin and repeat screening. The test’s lack of specificity may warrant repeat measures, and there isn’t enough data to determine how many tests are needed for a definitive result, Bodenheimer explained.

While Bodenheimer was enthusiastic about data in the Olmstead County study, some researchers question the data because they are based on single measurements of ALT. A recent paper by Johns Hopkins Bloomberg School of Public Health researchers highlights a reason for repeat testing: short-term variability. The Hopkins study looked at measurements of AST, ALT, and other liver enzymes obtained 17 days apart from NHANES III participants. Upper reference limits values for ALT were higher than 40 U/L for men and 31 U/L for women. Of those with an initially elevated AST level, the proportion of the cohort with a persistently elevated level was 64% (95% CI, 54.8%–73.0%). For ALT, that proportion was 68.8% (95% CI, 59.2%–77.3%). “If retested, more than 30% of adults with elevated AST, ALT, or bilirubin levels would be reclassified as normal,” the authors write (Annals of Internal Medicine 2008; 148: 348–352).

Disparate Values for the Upper Limit of Normal ALT

This chart shows the alanine aminotransferse (ALT) activity of one standardized sample, as reported by 11 different labs and expressed as a multiple of the sex-specific upper limit of normal (ULN) for each of them. Because the different labs used disparate ULN values, the results of this one sample were variably interpreted as 0.66 to 1.75 times the ULN for a man, and 0.87 to 1.73 times the ULN for a woman. If the sample were from a woman, three labs would have reported it as normal, whereas eight would have considered it elevated. If the sample were from a man, seven labs would have called it normal and four would have deemed it elevated.

Source: Archives of Internal Medicine 2008; 168; 664. Copyright © 2008, American Medical Association

Fatty Liver Disease: A Diagnostic Problem

Not everyone sees a need for screening either the general population or those with weight problems for fatty liver. Frank Herlong, MD, Associate Professor of Medicine at The Johns Hopkins University School of Medicine explained the issues involved in this debate. While ALT and AST are sensitive, ubiquitous, and cheap, “there’s no definitive way to diagnose fatty liver disease other than biopsy,” he noted.

Meanwhile, simple fatty liver may not be a serious health problem. But when it progresses to steatohepatitis, characterized by inflammation and scarring, serious problems can develop. “Steatohepatitis is an important precursor to cirrhosis, a common indication for liver transplant,” Herlong explained. At the same time, no treatment has been shown to definitively reverse fatty liver. While the American College of Gastroenterology (ACG) notes that ongoing studies are examining the efficacy of various interventions, including lipid lowering medications, insulin sensitizing drugs, inflammation-decreasing antioxidants, and anti-apoptotic and anti-cytokine medications, both ACG and Herlong pointed out that for all stages of fatty liver disease, the widely accepted treatment strategy is the same: weight loss through diet and exercise.

A Matter of Philosophy

Varying stances on population screening for fatty liver may result from different philosophies about medical practice and use of resources, along with tolerance for uncertainty. “ALT is far from a perfect screening test, but it’s the best we’ve got,” Herlong said. “The question then becomes, when you find an elevated ALT concentration, how extensively should you seek an explanation? Do you assume the elevation is from fatty liver in patients with appropriate risk factors and to what extent do you rule out other conditions? Some patients with an elevated ALT may have more serious forms of liver disease, such as hepatitis B or C. There’s no right or wrong answer.”

Herlong advocates targeted ALT screening for diabetic, obese patients older than 45, and others who are at greatest risk for steatohepatitis. “I don’t think the good should be the victim of the perfect,” he explained. “ALT identifies those patients for whom we have an intervention that might reduce morbidity and mortality. And research is beginning to identify more effective interventions beyond weight loss.”

The Case against Widespread ALT Screening

Opponents of more widespread ALT screening point out that the test is often redundant and that recommendations for wider screening are based on population studies. “Large populations smooth out the intraindividual variation in the analyte,” said Steve Kazmierczak, PhD, Professor of Pathology and Director of Clinical Chemistry and Toxicology at Oregon Health and Sciences University in Portland. “Clearly, ALT screening is appropriate if a physician thinks a patient is at risk for fatty liver disease, hepatitis B or C, or uses alcohol too much. But to do the test in the general population—that’s a little premature.”

A recent review article on ALT as a marker of NAFLD in relation to diabetes and CVD takes the same stance for slightly different reasons. Authors from the Netherlands point out that ALT is an acceptable marker of less serious stages of fatty liver in epidemiological studies, but that its use in diagnosing and monitoring disease needs further study because of confounding factors like alcohol intake, cormorbid liver disease, and hepatoxic medications (Diabetes/Metabolism Research and Reviews 2006; 22: 437–443).

Kazmierczak pointed out another potential problem with current testing methods for AST and ALT: lack of a standard methodology. For example, some labs use slightly more expensive assays that incorporate vitamin B6 into the reagent. Labs that don’t use methods incorporating vitamin B6 assume that the patient serum will contain enough vitamin B6 for the enzymes to remain fully active to react. “While B6 deficiency isn’t as common as B12 deficiency, it’s more common in alcoholics,” Kazmierczak explained, adding that an alcoholic patient whose ALT test is run in a lab that doesn’t use a method that incorporates vitamin B6 into the assay reagent stands a chance of reporting falsely low results.

Problems with Reference Populations

A more serious problem results in part from the obesity epidemic and its implications for reference ranges and reference testing. In a recent letter published in Archives of Internal Medicine, researchers from the Nonalcoholic Steatohepatitis Network point out that establishing a reference range for an assay and laboratories’ subsequent verification of this range may be hampered by inclusion of overweight or obese people with underlying NAFLD and unhealthy levels of ALT (Archives of Internal Medicine 2008; 168: 663–666). “As obesity increases in the general population, reference populations could increasingly include individuals with unsuspected NAFLD, which would skew the upper reference limit to inappropriately high levels,” they write.

The authors back up this premise with results from their own study, which surveyed the directors of 11 labs used by the Nonalcoholic Steatohepatitis Clinical Research Network’s (NASH-CRN) hospitals regarding their results for ALT determinations of five samples used in their CAP accreditation process. The labs compared results of these five samples to those from a single sample with an ALT level near the upper reference range reported by most laboratories. The directors, none of whom reported excluding overweight or obese people from their local reference populations, reported using upper limits of normal (ULN) in these populations that varied from 35 U/L to 79 U/L for men and 31 U/L and 55 U/L for women. These disparate ULNs would result in the labs reporting vastly different interpretations of the value for the single sample, the authors point out. If the sample were from a woman, three labs would have reported it as normal, whereas eight would have considered it elevated. If the sample were from a man, seven labs would have called it normal and four would have deemed it elevated (See Figure). The authors urge lab directors to consider how the obesity rates might adversely alter the makeup of their reference populations, and urge directors to abandon laboratory-specified reference ranges in favor of absolute values. They recommend 30 U/L for men and 19 U/L for women as cutpoints.

Renewed Attention to Reference Ranges

The lead author of 2000 National Academy for Clinical Biochemistry guidelines on liver disease agreed with the NASH-CRN call for health-related reference ranges and measures that exclude people likely to have liver disease from reference populations, saying that the guidelines also expressed need for these measures. D. Robert Dufour, MD, Consultant to the Veterans Affairs (VA) Medical Center in Washington, D.C., and Professor Emeritus of Pathology at The George Washington University, noted that his VA lab excluded from reference populations those who had liver disease risk factors and saw the ULN decrease to 33 U/L for males and 19 U/L for females, similar to what’s described in the research letter. While he agreed there is a clear need to establish a cutpoint for ALT, Dufour said now isn’t the time because there’s a dearth of data about what it should be.

Dufour likened the situation with ALT to “where we were with cholesterol 30 years ago,” when there was similar evidence that supported abandoning reference ranges for cutpoints. The difference between what was considered normal now versus then is stark. “Then the ULN for cholesterol for someone in their 20s was 260 mg/dL, and for someone in their 60s, it was 340 mg/dL. That was the upper 95% of an apparently healthy population,” he recalled, noting that prospective studies have since underscored the dangers associated with cholesterol levels over 200 mg/dL.

As with cholesterol, establishing cutpoints for ALT will be a major effort for the lab community. Laboratorians will have to take the lead in generating the necessary data and proposing ALT cutpoints. Such a move will also require diagnostics companies to standardize their tests, Dufour pointed out. But such an effort has precedent. “We’ve seen this done with the creation of the eGFR. It led to the recognition that there wasn’t much standardization among labs. Then companies started to get involved,” he recalled.

Bodenheimer said the AASLD statement serves as a challenge to labs: Evaluate problems with the ALT reference range and reference populations to improve patient care through more precise testing. An author of the Hopkins paper agrees. Epidemiologist Jeanne Clark, MD, Associate Professor of Medicine and Epidemiology, thinks the current situation could even mar patient view of labs. “The current situation makes it pretty confusing to compare ALT results between labs. Labs may test the same sample and tell the patient he or she is fine, or not. From the patient perspective, that can be confusing.”

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