Need for a three-focused approach to nonalcoholic fatty liver disease


  • Potential conflict of interest: Nothing to report.

To the Editor:

We read with interest the reviews by Ghouri et al.1 and Martinez et al.2 Ghouri et al. analyzed the association of nonalcoholic fatty liver disease (NAFLD) with cardiovascular disease (CVD) and concluded that although a diagnosis of NAFLD should prompt diabetes screening, it is insufficient for considering patients to be at high risk for CVD. Martinez et al. evaluated noninvasive methods for assessing liver fibrosis and recommended that those tests with the highest diagnostic accuracy be validated against liver biopsy to facilitate their implementation in clinical practice.

We meta-analyzed prospective data regarding the natural history of NAFLD and studies assessing the diagnostic accuracy of noninvasive methods for liver disease severity against liver biopsy in NAFLD, and we reached the following conclusions3:

  • 1The two NAFLD histological subtypes, simple steatosis (SS) and nonalcoholic steatohepatitis (NASH), have different risks of liver-related complications: SS progresses to cirrhosis in less than 5% of cases; NASH progresses to cirrhosis in 10% to 15% of cases over 10 years and in 25% to 30% of cases in the presence of advanced fibrosis.3
  • 2NAFLD patients have a 1.44- to 2.05-fold higher rate of CVD (depending on whether the diagnosis is based on an aminotransferase elevation or radiological/histological criteria) than the general population; restricting the analysis to studies adjusting for metabolic syndrome did not change the risk. Importantly, CVD mortality did not differ among NAFLD histological subtypes.3
  • 3NAFLD conveys a 2-fold increased risk of developing diabetes in comparison with the general population3; restricting the analysis to studies adjusting for metabolic syndrome did not change the risk. Whether the risk of diabetes differs among NAFLD histological subtypes remains unclear: in a community-based study, the 13-year incidence of diabetes was 2.98-fold higher in NASH patients versus SS patients.3

According to our analysis, a diagnosis of NAFLD should prompt a thorough three-focus assessment of cardiovascular, metabolic, and liver-related risks (Table 1).4

Table 1. Suggested Evaluation of Patients With NAFLD
Disease RiskNAFLD Assessment
  • *

    According to recent guidelines, hemoglobin A1c can be used for screening for type 2 diabetes.

DiabetesMeasure the body mass index, waist circumference, fasting plasma glucose and insulin level, and hemoglobin A1c level.*
Perform the 75-g oral glucose tolerance test in NAFLD patients without known diabetes according to standard guidelines (i.e., the American Diabetes Association) to classify their glucose tolerance.
Calculate the fasting index of insulin resistance (homeostasis model assessment of insulin resistance), which is associated with the severity of liver disease and has prognostic value in NAFLD.
CVDAssess smoking status, measure blood pressure, plasma total cholesterol, low density lipoprotein(LDL)-cholesterol, high density lipoprotein(HDL) cholesterol and triglycerides.
Calculate the CVD risk score (i.e., Framingham risk score).
Perform B-mode carotid ultrasonography in patients without diabetes or established CVD who have intermediate CVD risk (Framingham risk score = 6%-20%) to measure carotid intima-media thickening according to recent guidelines6 (optional).
Liver-related (end-stage liver disease)Apply noninvasive tests (i.e., the serum cytokeratin 18 fragment assay, NAFLD fibrosis score, and FibroScan) to screen for the presence of NASH with or without advanced fibrosis.
If noninvasive tests yield a high probability of NASH (with or without advanced fibrosis), refer to a gastroenterologist for liver biopsy, the assessment of complications of cirrhosis (hepatic failure, portal hypertension, esophageal varices, and hepatocellular carcinoma), experimental treatments, and tight monitoring.
Liver biopsy remains necessary for staging and monitoring the course of liver disease in patients with NASH and if the diagnosis of NAFLD is in doubt.

Liver-related risk assessment remains problematic because it requires liver histology. Three noninvasive methods have been extensively validated: enzyme-linked immunosorbent assay-detected cytokeratin 18 fragments (9 studies enrolling 856 participants) for the detection of NASH and the NAFLD fibrosis score (13 studies enrolling 3064 participants) and FibroScan (6 studies enrolling 563 participants) for the detection of advanced fibrosis. We believe that these methods should be promptly implemented in diagnostic algorithms to select patients for liver biopsy in routine clinical practice while we continue to search for the ideal noninvasive marker.

Giovanni Musso M.D.*, Roberto Gambino Ph.D.†, Maurizio Cassader Ph.D.†, * Gradenigo Hospital Turin, Italy, † Department of Internal Medicine, University of Turin, Turin, Italy.