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The nomenclature for non-alcoholic fatty liver disease (NAFLD) versus its alcohol-generated cousin, AFLD, needs to be re-evaluated since the two phenotypes show some overlap, according to a paper by Australian and U.S. liver specialists.

The current definition of NAFLD and its distinction from AFLD is based solely on the intake level of ethanol, noted Jacob George, MBBS, PhD, of the University of Sydney in Australia, and colleagues. "For NAFLD, it is assumed that the amount of alcohol consumed is below the threshold where alcohol would have a significant impact on clinical phenotype, disease progression, and outcomes," the team wrote in . Although there is no current agreement on the threshold that rules out NAFLD, a level of 30 grams a day for men and 20 grams a day for women is , according to practice guidance from the American Association for the Study of Liver Diseases.

Furthermore, the criteria for diagnosing NAFLD have not been revisited since Jurgen Ludwig and colleagues it in 1980 as a disease that histologically mimics alcoholic steatohepatitis and can similarly progress to cirrhosis. Controversy on the impact of moderate alcohol consumption on the prognosis of NAFLD endures, with some studies suggesting protective effects.

A study by for example, reported that in a large, well-characterized population with biopsy-proven NAFLD, modest alcohol consumption was associated with less disease severity. In contrast, observed that moderate alcohol consumption correlated with fibrosis progression in NAFLD.

Limitations in the ability to define the natural history of NAFLD and compare or pool results from clinical trials led to historically heterogeneous definitions of NAFLD. Last year, the recommended NAFLD case definitions based on phenotype (fatty liver vs steatohepatitis), activity, disease stage, and disease etiology.

According to the new paper by George and associates -- titled "Are Non-alcoholic Fatty Liver Disease and Alcoholic Fatty Liver Disease More Than Just Semantics?" -- it may now be time to recognize a more nuanced disease spectrum with considerable overlap between the two phenotypes:

• True alcohol-related liver disease

• Predominant AFLD compounded by metabolic co-factors

• True NAFLD with virtually zero alcohol intake and disease progression due to metabolic factors

• Fatty liver disease due to an abnormal metabolic milieu but with an alcohol intake of ≤30 g/d (probably most common)

"The latter group, currently encompassed by the term NAFLD, could not truly be defined as having NAFLD with no contribution from alcohol, nor does the term recognize the existence of systemic metabolic dysfunction in these patients," the team wrote.

The authors proposed an alternative in which NAFLD would be struck from the lexicon in favor of a term that better reflects individual clinical phenotypes. "Clearly, there is a need, and this is a call to update the current nomenclature for fatty liver diseases, by international consensus." The consensus should develop appropriate terminology that reflects pure metabolic dysfunction -- predominant fatty liver and alcohol-predominant fatty liver at either end of the spectrum, George, et al. stated.

"Patients with fatty liver disease due predominantly to metabolic dysfunction could be further stratified according to alcohol use, while those with alcohol-predominant fatty liver disease could be stratified according to coexisting metabolic features. This we suggest is more than an issue of semantics and nomenclature, since without more precise use of terms to define fatty liver diseases, neither science nor patient care can be optimal," the authors concluded.

In addition, they pointed to data suggesting that there is no safe limit for alcohol consumption, referring, for example, to a Finnish following 6,732 individuals with no baseline liver disease for an average of 11 years. The results showed that alcohol use was a significant risk factor for severe liver disease, even within the currently used limits for defining NAFLD.

"Based on current evidence, one could argue that the conventional threshold of alcohol consumption for a diagnosis of NAFLD should be updated to zero or near to zero," George and colleagues wrote. They also pointed out that in daily clinical practice physicians lack the time necessary for detailed histories of patients' ethanol ingestion.

"With evidence that the safe limit for alcohol is zero, we are beginning to recognize the influence of many patterns of modest amounts of alcohol on liver disease," the team continued. "Until evidence points to a specific diagnostic test rather than merely exclusion criteria for diagnosis, we are calling for a consensus to develop a more appropriate nomenclature."

Need for Physician Education

Asked for his perspective on the paper, Zachary H. Henry, MD, MS, of the University of Virginia Health System in Charlottesville, told MedPage Today that although there may not be a need for "this much scrutiny over redefining the diagnoses of alcohol-related and non-alcohol-related fatty liver disease in clinical practice," he can understand how this may be important for clinical trial design.

Rather, said Henry, who was not involved in the research, "we need to be a bit more flexible in our terminology for AFLD and NAFLD, with an understanding that many patients likely have some sort of overlap between the two and that we need to treat both."

That approach will require physician education in order to ensure acknowledgment of the potential impact of both disease types. "But I'm not sure this requires a complicated naming algorithm," he said. "I do agree with the authors that many gastroenterologists do not recognize the influence of both conditions, often labeling a patient as having one or the other without accepting an overlap." Hence, educating physicians will be an important next step regardless of specific nomenclature, he said.

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