NAFLD Presents Similar Risk for Adverse Outcomes Regardless of BMI

Mindie Nguyen, MD, MAS

Credit: Stanford Medicine

Although nonalcoholic fatty liver disease (NAFLD) is frequently associated with obesity, it can also affect lean individuals with a healthy body mass index (BMI) – according to findings from a retrospective cohort study conducted at Stanford University Medical Center, NAFLD may carry a similar risk of advanced liver disease, nonliver cancers, and cardiovascular disease, regardless of patients’ BMI.

Patients with NAFLD and BMI <25.0 kg/m2, coined “lean NAFLD,” had fewer metabolic comorbidities than patients considered to be overweight or obese but presented similar risk for nonalcoholic steatohepatitis (NASH), cirrhosis, nonliver cancer, and mortality, suggesting healthcare providers should provide the same level of care and intervention for patients with lean NAFLD as they would for patients considered overweight and obese.¹

The most common chronic liver condition in the United States, NAFLD is estimated to affect about 25% of adults in the US. Although it is usually associated with obesity, NAFLD can also manifest at lower overall BMI in what is generally considered to be a less severe form of the disease. However, the concept of reduced risk of poor clinical outcomes in lean NAFLD is highly debated and has not yet been comprehensively explored.^2,3

“Lean NAFLD may have metabolic abnormalities similar to those with obese NAFLD albeit at a lower frequency and may have a higher risk for adverse outcomes, including death. However, others have suggested that those with lean NAFLD are at a lower risk for adverse outcomes, given their lower rate of metabolic abnormalities,” wrote Mindie Nguyen, MD, MAS, professor of medicine at Stanford University Medical Center, and a team of investigators.¹

To address uncertainties regarding the impact of BMI on NAFLD, investigators compared long-term outcomes in consecutive patients with imaging-confirmed NAFLD considered lean, overweight, and obese who presented at any clinic at Stanford Healthcare between March 1, 1995, and December 31, 2021. Patients were followed from first presentation with confirmed NAFLD to death, loss to follow-up, or end of the study period. Patients with significant alcohol use, viral hepatitis, autoimmune, or other metabolic liver diseases were excluded from the study.¹

The primary outcomes were NASH incidence, cirrhosis incidence, and overall mortality. Investigators additionally performed subgroup analysis for liver-related and nonliver-related deaths.¹

In total, 9061 patients with NAFLD had BMI data available and were thus enrolled in the study. Investigators classified participants as lean, defined as having BMI <25.0 kg/m2, overweight, defined as having BMI ≥25.0 and ≤29.9 kg/m2, and obese, defined as having BMI ≥30.0 kg/m2. Different cutoffs were implemented for Asian participants, with investigators setting the definitions for overweight and obesity as >23.0 kg/m2 and ≥27.5 kg/m2, respectively.¹

The majority of study participants were considered obese (58.1%), followed by overweight (31.7%) and lean (10.2%). On average, lean patients were older (mean age, 53.7 years; Standard deviation [SD], 17.4) compared with overweight (mean age, 51.8 years; SD, 15.5) and obese (mean age, 48.7 years; SD, 15.1) patients (P < .0001).¹

Investigators pointed out lean NAFLD patients were also more likely to have NASH (29.2%) or cirrhosis (25.3%) than the overweight (24.1% and 20.7%, respectively) or obese groups (22.5% and 19.2%, respectively) (P < .0001), as well as nonliver cancer (25.3% for lean vs 18% for overweight and obese; P < .0001). In contrast, the overweight and obese cohorts were more likely to have metabolic diseases such as diabetes mellitus, hypertension, and hyperlipidemia.¹

Upon analysis, there were no statistically significant differences in the risk of developing NASH (P = .20) or cirrhosis (P = .22) among the groups. Similar findings were observed in the sensitivity analysis, with no significant differences in the rates of NASH (P = .99) or cirrhosis (P = .73) development and no statistically significant difference in the risk of NASH (Adjusted hazard ratio [aHR], 0.93; 95% Confidence interval [CI]. 0.72–1.21; P = .59) or cirrhosis (aHR, 0.88; 95% CI, 0.69–1.12; P = .30) development between lean and nonlean patients.¹

Of note, the lean group had greater rates of overall (P = .01) and nonliver-related (P = .02) mortality compared to the overweight and obese groups. However, investigators attributed this finding to differences in age-related mortality, as the lean group was significantly older than the other groups. This suspicion was confirmed by findings from a multivariable analysis adjusted for age, sex, race, ethnicity, and diabetes, which showed lean NAFLD was not independently associated with overall (aHR, 1.07; 95% CI, 0.77–1.47; P = .20), liver-related (aHR, 1.34; 95% CI, 0.36–4.96; P = .66) or nonliver-related (aHR, 1.00; 95% CI, 0.71–1.41; P = .99) mortality.¹

“Taken together, lean NAFLD is not benign. Therefore, healthcare providers should provide the same level of care and intervention as for those with overweight and obese NAFLD,” investigators concluded.¹

References:

1. Nguyen VH, Ha A, Rouillard NA, et al. Differential Mortality Outcomes in Real-world Patients with Lean, Nonobese, and Obese Nonalcoholic Fatty Liver Disease. J Clin Transl Hepatol. 2023;11(7):1448-1454. doi: 10.14218/JCTH.2023.00016.
2. American Liver Foundation. NASH Definition & Prevalence. Nonalcoholic Steatohepatitis (NASH). November 1, 2023. Accessed January 4, 2024. https://liverfoundation.org/liver-diseases/fatty-liver-disease/nonalcoholic-steatohepatitis-nash/nash-definition-prevalence/
3. Albhaisi S, Chowdhury A, Sanyal AJ. Non-alcoholic fatty liver disease in lean individuals. JHEP Rep. 2019;1(4):329-341. Published 2019 Aug 30. doi:10.1016/j.jhepr.2019.08.002