COMMENTARY

New Studies Highlight Increasing Global Prevalence of NAFLD/NASH and Its Considerable Toll

William F. Balistreri, MD

Disclosures

January 18, 2017

In This Article

Patient Outcomes in NAFLD/NASH

Disease Progression and Regression

Kleiner and colleagues[7] determined the changes in histologic features of NAFLD through progression and regression in 394 prospectively followed adults. With the NAFLD phenotype, 44% with steatosis progressed to borderline NASH or definite steatohepatitis, while steatosis resolved in 13%. An increased ALT level, worsening NAFLD activity score, and weight gain between biopsies correlated with progression. Furthermore, 43% with borderline NASH progressed to definite steatohepatitis, while 23% regressed to steatosis and 4% to non-NAFLD. Of note, in those with definite steatohepatitis, 20% regressed to borderline NASH, 11% to steatosis, and 11% to non-NAFLD. Weight loss correlated with resolution of steatohepatitis. In those without baseline fibrosis, fibrosis nonetheless developed in 44% of those with steatosis, 52% with borderline NASH, and 44% with definite steatohepatitis at baseline. In those with baseline fibrosis, this worsened in 21% of those with steatosis, 30% of those with borderline NASH, and 29% with definite steatohepatitis. Conversely, fibrosis regressed in 53% of those with steatosis, 34% of those with borderline NASH, and 36% of those with definite steatohepatitis. Cirrhosis developed in 1% of those with steatosis, 8% of those with borderline NASH, and 9% with definite steatohepatitis.

The investigators therefore documented the highly variable natural history of NAFLD phenotypes, which raises the possibility of validating biomarkers to track regression/progression and identifying specific environmental (including the microbiome) and genetic factors that govern these changes.

Mortality Risk in Lean Patients With NAFLD

We have data on obese patients with NAFLD, who make up the majority of those with the disease, but long-term outcomes in lean NAFLD patients are not known.

Using data from NHANES III, Younossi and colleagues[8] selected 10,563 adults and determined the established causes of death and the association between independent predictors of death in lean (BMI < 25) and overweight/obese (BMI > 25) persons with NAFLD. The overall prevalence of NAFLD in this population was 22.7%, and 18% within that cohort were lean. A total of 2324 died during the follow-up (874 from cardiovascular and 48 from liver-specific causes). The presence of diabetes and having a higher AST/ALT were independently associated with liver-specific mortality. The risk for all-cause and cardiovascular mortality was higher in obese/overweight persons with NAFLD than in the obese/overweight control group. Lean persons with NAFLD did not have an increased overall or disease-specific mortality.

Effect of NASH on the Risk for Hepatocellular Carcinoma

The incidence of hepatocellular carcinoma (HCC) has increased fourfold in patients with NASH-related cirrhosis.[9]

In an effort to inform HCC screening and treatment strategies, Stine and colleagues[9] assessed the impact of NASH on the development of HCC in adult patients with and without cirrhosis. After reviewing 734 studies for their meta-analysis, they included 19 with 168,571 participants, 86% of whom had cirrhosis. The prevalence of HCC in aggregate was 12%. NASH, even in noncirrhotic patients, was associated with a greater risk for HCC when compared with other etiologies of liver disease. These data emphasize that aggressive surveillance for HCC should be instituted in patients with NASH, even in those without cirrhosis.

Treatment Impact on NASH Histologic Activity/Fibrosis

An effective treatment strategy for patients with NASH should protect them from progression to cirrhosis by suppressing the underlying cause of fibrogenesis.

Ratziu and colleagues[10] analyzed biopsies obtained during the elafibranor versus placebo clinical trial to determine whether treatment-induced changes in individual histologic features of NASH altered the rate of fibrosis progression. Changes in both lobular inflammation and ballooning were highly and positively correlated with changes in fibrosis. Among patients with a 2-point score reduction in inflammation, fibrosis improved in 67% and none worsened. In contrast, if inflammation progressed, 56% of patients had worsening fibrosis and only 6% improved. A 2-point reduction in the degree of ballooning correlated with an improvement in fibrosis in 71% (0% worsening); conversely, a 1-point increase resulted in worsening fibrosis (35%) and improvement in only 26%. In contrast, there was no association between changes in steatosis scores and changes in fibrosis. An activity index, defined as the sum of the lobular inflammation and ballooning scores, demonstrated a positive linear relationship with mean changes in the fibrosis score. This supports the concept that resolution of NASH can reverse fibrosis or halt progression and thus is reasonably likely to predict long-term clinical benefit.

Liver Histology Changes and Renal Function in Adults With NASH

Cross-sectional studies have demonstrated a strong relationship between NAFLD/NASH and impaired renal function/chronic kidney disease. However, because the longitudinal relationship between changes in liver histology and renal function is not well studied, Corey and colleagues[11] assessed changes in estimated glomerular filtration rate (eGFR) in adults with NASH. They reported that resolution of NASH, improvement in NAFLD activity score, and improvement in fibrosis were not significantly associated with mean change or rapid decline in eGFR (> 4 mL/min/year) at the end of treatment from baseline. However, compared with placebo-treated patients, a significantly higher proportion of patients in clinical trials who received obeticholic acid (40% vs 24%) or pioglitazone (27% vs 14%) had rapid decline in eGFR. Thus, an improvement in liver histology in adults with NASH is not associated with improved renal function.

Of note, because obeticholic acid and pioglitazone were associated with a decrease in eGFR, renal function should be carefully monitored in those receiving treatment for NASH with these agents.

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