Obesity, Weight Gain Linked to Fibrosis Progression in NAFLD

Obesity and weight gain are independently associated with an increased risk for fibrosis progression in patients with nonalcoholic fatty liver disease (NAFLD), a large cohort study has found. Weight loss was negatively associated with fibrosis progression.

“This association remained significant after adjustment for confounders including baseline BMI [body mass index], indicating that weight change per se is an independent risk factor for fibrosis progression. Higher BMI at baseline was also positively associated with APRI [aspartate aminotransferase to platelet ratio index] progression,” the researchers write.

The study, by Yejin Kim, MHS, Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea, and colleagues, was published online July 15 in Clinical Gastroenterology and Hepatology.

The researchers analyzed data from 40,700 adults who received comprehensive annual or biennial examinations as part of the Kangbuk Samsung Health Study. They included participants with fatty liver, as evidenced on abdominal ultrasonography, who had undergone a health examination between 2002 and 2016 and who had had two or more follow-up visits through the end of 2016. Patients were followed for a median of 6 years.

The authors explain that they used APRI score to assess fibrosis progression because it is noninvasive and the formula includes neither BMI nor age. The study’s primary endpoint was the development of intermediate to high probability of advanced fibrosis, as assessed by APRI.

The researchers first adjusted for age and sex, and later adjusted for center, year of screening examination, smoking status, alcohol consumption, regular exercise, education level, BMI, diabetes history, cardiovascular disease history, and hypertension history. A second model also adjusted for homeostatic model assessment of insulin resistance (HOMA-IR) and high-sensitivity C-reactive protein (hsCRP).

There were 275,421.5 person-years of follow-up, during which 5454 patients with low APRI progressed to intermediate or high APRI.

When stratified into quintiles by weight change, those with the greatest weight loss (-43.4 to -2.3 kg) had a significantly reduced risk for progression (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.62 – 0.74), compared with those whose weight was stable. Similarly, patients with small degrees of weight loss (-2.2 to -0.6 kg) had a reduced risk for progression (HR, 0.86; 95% CI, 0.78 – 0.94).

By contrast, any weight gain appeared to increase progression risk. Specifically, those who gained a smaller amount of weight (0.7 to 2.1 kg) showed a 17% risk increase (HR, 1.17; 95% CI, 1.07 – 1.28), and those who gained more (2.2 to 26.5 kg) had a 71% increased risk (HR, 1.71; 95% CI, 1.58 – 1.85).

These associations were not mediated by inflammation or insulin resistance after adjustment for HOMA-IR and hsCRP.

Compared with those whose baseline BMI was from 18.5 to 22.9 kg/m2, the HRs for APRI progression were as follows: 1.67 (95% CI, 0.74 – 3.73) for BMI of <18.5 kg/m2; 1.13 (95% CI, 1.02 – 1.26) for BMI of 23 – 24.9 kg/m2; 1.41 (95% CI, 1.28 – 1.55) for BMI of 25 – 29.9 kg/m2; and 2.09 (95% CI, 1.86 – 2.36) for BMI of ≥ 30. All values were determined after adjusting for age, sex, health center, year of screening examination, smoking status, alcohol consumption, exercise, education, diabetes history, cardiovascular disease history, and hypertension history. These associations remained significant after adjustments for HOMA-IR and hsCRP.

“When the impact of weight change on APRI worsening was compared with that of other metabolic factors, increasing quintiles of weight change, triglyceride, uric acid, and HOMA-IR and decreasing quintiles of high-density lipoprotein cholesterol were associated with increased risk of APRI worsening in a dose-response manner (all P for trend <.001), with weight change showing the greatest magnitude of association among the metabolic factors evaluated,” the authors explain.

The associations of both weight change and BMI with APRI progression were still seen in patients with NAFLD who had no history of diabetes or cardiovascular disease.

“Although the mechanisms underlying the association between excessive adiposity or fat gain and the fibrosis progression are not yet fully understood, insulin resistance and inflammation are thought to be involved,” the researchers write. “However, after adjustment for HOMA-IR and hsCRP, the association between obesity, weight gain, and fibrosis progression remained significant. Multiple other factors, including oxidative stress and lipotoxicity, have also been implicated in fibrosis progression.”

Study limitations include the use of ultrasonography to diagnose NAFLD. Although liver biopsy is considered the gold standard, it is not be feasible in a large, low-risk population, and abdominal ultrasound is acceptable, the authors say. Also, although APRI “has demonstrated a reasonable utility as a noninvasive method for the prediction of histologically confirmed advanced fibrosis…there are no currently available longitudinal data to support the use of worsening noninvasive fibrosis markers as an indicator of histologic progression of fibrosis stage over time.”

The study was conducted among fairly healthy young and middle-aged Koreans and may not be generalizable to those of other ages, or to groups in which comorbidities are more prevalent, or to other racial or ethnic groups.

“In this large cohort study of young and middle-aged adults with NAFLD, obesity and weight gain were significantly and independently associated with an increased risk of developing fibrosis progression. Strategies for maintaining a healthy weight and preventing weight gain may help reduce fibrosis progression and its associated consequences in individuals with NAFLD,” the researchers conclude.

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