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  The Liver Meeting
Digital Experience
November 13 - 16 - 2020
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In 20-Year NAFLD Study, Lean Have Higher Death Rate Than Obese
  AASLD The Liver Meeting Digital Experience, November 13-16, 2020
Mark Mascolini
In a 20-year record review of 4843 people with nonalcoholic fatty liver disease (NAFLD), lean people had a higher death rate than obese individuals, even though the lean group had lower frequencies of cardiometabolic comorbidities and a trend toward slower liver disease progression [1].
Mayo Clinic researchers who conducted this study noted that the natural history of lean NAFLD remains poorly understood [2-4]. Lack of data describing this cluster of NAFLD patients challenges clinicians when they try to counsel lean people or manage their disease.
To learn more about lean people with NAFLD and how they differ from their overweight and obese counterparts, a Mayo team identified all individuals in Olmsted County, Minnesota diagnosed with NAFLD from 1996 through 2016. They excluded people with other liver diagnoses, such as viral- or alcohol-related disease. The investigators identified NAFLD cirrhosis through liver biopsy results or through detection of one or more cirrhosis/decompensation codes. They created three study groups: lean NAFLD (body mass index [BMI] below 25 kg/m2), overweight NAFLD (25 to 30 kg/m2), and obese NAFLD (over 30 kg/m2).
The investigators used the Aalen-Johansen method to estimate probability of cirrhosis, decompensation, malignancies, cardiovascular events, or death in each weight group, treating death as a competing risk. Cox proportional hazards regression analysis weighed the impact of BMI categories on these outcomes. The researchers believe this is the largest contemporary study comparing lean NAFLD patients with the overweight and the obese
Among 4843 people with NAFLD and BMI available, 414 (8.5%) had lean NAFLD, 1189 (24.5%) overweight NAFLD, and 3231 (67%) obese NAFLD. Average age was similar in the lean (51.5 years), the overweight (54.1), and the obese (51.0), but women made up a higher proportion of the lean (65.9%) than the overweight (47.2%) or the obese (55.1%). Asian Americans were more likely to be lean (7.2%) than overweight (2.3%) or obese (4.5%). The same was true for African Americans: 6.0% lean, 4.2% overweight, 2.9% obese.
Lean people with NAFLD tended to have a lower prevalence of diabetes (23.2% vs 25.7% overweight and 39.3% obese), hypertension (29.2% vs 37.3% overweight and 44.5% obese) and hyperlipidemia (49.3% vs 64.9% and 69.2%).
Follow-up lasted a median of 6.4 years (range 0 to 20). In that time 74 lean people (17.9%), 148 overweight people (12.4%), and 347 obese people (10.7%) died. Regression analysis determined that the lean NAFLD group had almost a two thirds higher risk of all-cause death than obese people (adjusted hazard ratio [aHR] 1.63, 95% confidence interval [CI] 1.25 to 2.13, P  
The same type of analysis saw a trend toward a two thirds lower cirrhosis risk in lean than in obese people with NAFLD, a result suggesting a lower risk of liver disease progression in lean NAFLD patients than in the obese (aHR 0.33, 95% CI 0.1 to 1.05, P = 0.06). Regression analysis did not determine that risk of cardiovascular disease or malignancy differed between the lean and the overweight or obese.
What could explain the higher all-cause death risk in lean NAFLD patients, despite their lower risk of liver disease progression and lower rates of cardiometabolic diseases? Cause of death did not explain the incongruity because cardiovascular disease and malignancies were the top two causes in all three BMI groups, as they are in most NAFLD populations. Liver-related death rates were similar in the lean (1.4%) and the overweight (2%), but higher in the obese (10%).
The researchers then reviewed charts of the whole lean group with a BMI below 18.5 kg/m2 (the underweight cutoff) and a random sample of people with normal BMI (18.5 to 24.9 kg/m2) to look for underlying causes of increased mortality in lean people with NAFLD, such as cancer or surgery. They found none. Thus, the Mayo team said, it remains to be seen whether the higher death rate in lean than obese people with NAFLD can be explained by differences in NAFLD pathophysiology or perhaps by the "obesity paradox," in which obese people in certain groups tend to live longer than people who weigh less.
1. Ahmed OT, Gidener T, Mara K, Larson JJ, Themeau TM, Allen AM. The natural history of lean nonalcoholic fatty liver disease: a longitudinal US population study. AASLD The Liver Meeting Digital Experience, November 13-16, 2020. Abstract 86.
2. Wang AY, Dhaliwal J, Mouzaki M. Lean non-alcoholic fatty liver disease. Clin Nutr. 2019;38:975-981. doi: 10.1016/j.clnu.2018.08.008.
3. Wattacheril J, Sanyal AJ. Lean NAFLD: an underrecognized outlier. Curr Hepatol Rep. 2016;15:134-139. doi: 10.1007/s11901-016-0302-1.
4. VanWagner LB, Armstrong MJ. Lean NAFLD: a not so benign condition? Hepatol Commun. 2018;2:5-8. https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep4.1143