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NAFLD Linked to Adverse Outcomes Regardless of BMI, New Research Suggests


Individuals with "lean NAFLD" may be at similar risk of NASH, cirrhosis, nonliver cancer, and death as as those with NAFLD and overweight or obesity, authors say.

NAFLD Linked to Adverse Outcomes Regardless of BMI, Suggests New Research / image credit liver disease / image credit ©Wowow/stock.adobe.com

Individuals with nonalcoholic fatty liver disease (NAFLD) and BMI <25.0 kg/m2, so called “lean NAFLD,” had fewer metabolic comorbidities compared to their counterparts with NAFLD and overweight or obesity but were at similar or greater risk of adverse outcomes, according to new research from a group led by investigators at Stanford university Medical Center.

Results of the retrospective cohort study suggest that NAFLD, while frequently associated with obesity, may carry a similar risk of outcomes that include advanced liver disease, nonliver cancers, and cardiovascular disease, regardless of patients’ BMI. In fact, investigators cite recent studies demonstrating that it is the presence of metabolic abnormalities, eg, hypertriglyceridemia and insulin resistance, which drives the development of fatty liver and not the condition of being overweight or obese. Along with these data, they wrote, their current findings underscore the need for the same level of care and intervention for patients with lean NAFLD as for those with NAFLD and excess weight.

“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,” Mindie Nguyen, MD, MAS, professor of medicine at Stanford University Medical Center, and a team of investigators wrote in the Journal of Clinical and Translational Hepatology. An opposing theory also has support however, and suggests that the risk for adverse outcomes among individuals with lean NAFLD is lower given the lower burden of metabolic dysfunction.

Overall, little research has been devoted to NAFLD in individuals of average weight, leaving an important gap in understanding and the potential for disparate clinical practice.

To help address the uncertainties, Nguyen and colleagues 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. Investigators followed participants from first presentation with confirmed NAFLD to death, loss to follow-up, or end of the study period. Among exclusion criteria were significant alcohol use, viral hepatitis, autoimmune or other metabolic liver diseases, according to the study.

The primary outcomes were NASH incidence, cirrhosis incidence, and overall mortality. Investigators additionally performed subgroup analysis for liver-related and nonliver-related death and used uni- and multivariable logistic regression to identify factors associated with lean NAFLD.


The research team identified and enrolled a final cohort of 9061 participants with confirmed NAFLD and available BMI data. Investigators classified participants according to BMI categories as lean (<25.0 kg/m2), overweight (≥25.0 and ≤29.9 kg/m2), and obese, (≥30.0 kg/m2). For Asian participants, they used BMI cutoffs defined for this population by the World Health Organization for overweight (>23.0 kg/m2) and obesity (≥27.5 kg/m2).

Characteristics. According to the published findings, more than half the study cohort had obesity (58.1%); slightly less than one-third were categorized as overweight (31.7%); and 10.2% were classified as lean. Researchers noted that lean participants, on average, were older (mean age, 53.7 years) compared with overweight (51.8 years) and obese (48.7 years) participants (P < .0001). Women and persons of Asian descent were more common in the lean NAFLD subgroup while the obese group had higher percentages of men and persons of Hispanic origin.

Nguyen et al reported that lean NAFLD participants were more likely to have NASH (29.2%) or cirrhosis (25.3%) than those with overweight (24.1% and 20.7%, respectively) or obesity (22.5% and 19.2%, respectively) (P < .0001). Nonliver cancer was also more common among participant with lean NAFLD (25.3% vs 18% for those with overweight and obesity; P < .0001). The subgroups with overweight and obesity, in contrast, were more likely to have metabolic diseases such as diabetes mellitus, hypertension, and hyperlipidemia.

NASH, cirrhosis risk. When the team evaluated risk of NASH and cirrhosis by weight category, they found no statistically significant differences among the groups (NASH, P = .20; cirrhosis, P = .22). The sensitivity analysis yielded similar findings, with no significant differences in the risk 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% 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.

Risk of mortality. Mortality among the overweight and obese subgroups was similar for overall and liver-specific causes of death. The group of participants with lean NAFLD, however, had higher mortality rates both overall (P = .01) and for nonliver-related causes (P = .02) compared to the overweight and obese groups, although not for liver-related causes (P = .71). This finding may have been the result of differences in age-related mortality, according to the investigators, as the lean group was significantly older than the other groups. Results of a multivariable analysis adjusted for age, sex, race, ethnicity, and diabetes provided support for their thinking, showing that 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.

Taken together, concluded Nguyen et al, these findings indicate that “lean NAFLD is not benign” and that clinicians should not assume further or more intensive diagnostic workup or intervention is unnecessary. They reiterate that care for these patients should be provided at the same level as it is for individuals with overweight and obese NAFLD.

Source: Nguyen VH, Ha A, Rouillard NA, et al. Differential mortality outcomes in real-world patients with lean, nonobese, and obese nonalcoholic fatty liver disease. Disease. J Clin Transl Hepatol. 2023;11(7):1448-1454. doi: 10.14218/JCTH.2023.00016

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