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Higher Risk of Liver Events, Nonliver
Cancer, Death With Lean vs Nonlean NAFLD
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EASL International Liver Congress, June 23-26, 2021
Mark Mascolini
People with lean nonalcoholic fatty liver disease (NAFLD) run a higher risk of liver events, nonliver cancer, chronic kidney disease, and death than people with the more typical nonlean NAFLD, according to a nationwide analysis in France [1]. Among 18,248 study participants with NAFLD, almost 1 in 6 had lean NAFLD.
Severity and natural history of NAFLD in lean people remain hotly debated, partly because data on this condition come mainly from in-hospital cohorts. To explore lean NAFLD prevalence, risk factors, and mortality in a population-based study, French researchers analyzed data from the nationwide CONSTANCES cohort, which includes more than 200,000 people providing a representative sample of the adult population in France [2]. CONSTANCES has enrolled cohort members from 21 centers in 19 departments across the country.
This analysis included people who entered CONSTANCES from 2012 through 2017 who did not have HBV or HCV infection or other chronic liver disease (except NAFLD) and who did not drink alcohol at a rate above 30 g daily in men or 20 g daily in women.
Researchers defined a lean person as having a body mass index (BMI) below 25 kg/m2 or below 23 kg/m2 if Asian. They identified NAFLD by a combination of the Fatty Liver Index (FLI greater than 60) and the Forns Index (FI greater than 6.9). The investigators defined four groups of clinical outcomes by ICD-10 code: severe liver events, cardiovascular disease, nonliver cancers, and chronic kidney disease.
In an evaluable population of 106,848 people, 18,248 (17%) had NAFLD, including 2753 with lean NAFLD (15% of the NAFLD group and 2.6% of the overall group). Among the 18,248 people with NAFLD, 16.3% had a lean BMI, 41% were overweight, and 42.7% were obese. Median follow-up lasted 30 months.
Age averaged 44.2 in people with lean NAFLD, 55.0 in those with nonlean NAFLD, and 48.7 in those without NAFLD. Respective proportions of men were 43.6%, 69.7%, and 39.3%, of Europeans 74.3%, 89.1%, and 95.9%, of Asians 14.4%, 0.4%, and 0.5%, of North Africans 10.7%, 10.1%, and 3.1%, and of sub-Saharan Africans 0.6%, 0.4%, and 0.5%. In the lean NAFLD, nonlean NAFLD, and non-NAFLD groups, proportions with diabetes were 10.6%, 17.8%, and 2.4%, with high cholesterol 24.9%, 32.2%, and 7.2%, and with high blood pressure 30.9%, 31.3%, and 11.9%.
Among lean people in the study group, 85% with three metabolic risk factors (diabetes, high blood pressure, and high cholesterol) had NAFLD. Among lean people with those three metabolic risks plus high triglycerides, the same fraction, 85%, had NAFLD. But 56% of people with lean NAFLD had no recorded metabolic risk factors, and 18% had only 1.
An analysis adjusted for age, sex, diabetes, high blood pressure, cholesterol, alanine aminotransferase (ALT), schooling, and ethnicity identified three factors that independently boosted odds of lean NAFLD or nonlean NAFLD versus no NAFLD and two factors that independently lowered chances of lean NAFLD or nonlean NAFLD at the following odds ratios (OR) (and 95% confidence intervals):
Increase odds
- Alcohol more than 10 g daily: Lean NAFLD OR 2.25 (2.01 to 2.51), nonlean NAFLD OR 1.45 (1.38 to 1.53)
- Tobacco more than 10 pack-years: Lean NAFLD OR 1.79 (1.62 to 1.99), nonlean NAFLD OR 1.65 (1.60 to 1.71)
- Soft drinks more than 1 daily: Lean NAFLD OR 1.70 (1.02 to 2.84), nonlean NAFLD OR 2.20 (1.69 to 2.85)
Decrease odds
- Coffee more than 1 cup daily: Lean NAFLD OR 0.56 (0.51 to 0.61), nonlean NAFLD 0.65 (0.63 to 0.67)
- Exercise more than 2 hours weekly: Lean NAFLD OR 0.69 (0.62 to 0.77), nonlean NAFLD OR 0.53 (0.50 to 0.55)
Compared with people who had nonlean NAFLD, those with lean NAFLD did significantly worse in rates of several liver events and nonliver events:
- Elevated ALT: 34.4% lean NAFLD vs 20.9% nonlean NAFLD (P < 0.001)
- Advanced fibrosis: 3.6% lean NAFLD vs 1.7% nonlean NAFLD (P < 0.001)
- Liver events over 5 years: significantly greater with lean NAFLD vs nonlean NAFLD or no NAFLD (P < 0.0001)
- Hepatocellular carcinoma over 5 years: significantly greater with lean NAFLD vs nonlean NAFLD or no NAFLD (P < 0.0001)
- Chronic kidney disease over 5 years: significantly greater with lean NAFLD vs nonlean NAFLD or no NAFLD (P < 0.0001)
- Cardiovascular disease over 5 years: significantly greater with lean NAFLD vs no NAFLD (P < 0.0001)
Through 5 years of follow-up, overall mortality proved significantly greater with lean NAFLD than nonlean NAFLD or no NAFLD (about 5% vs about 1% and 1%, P < 0.0001).
Compared with people who did not have NAFLD, those with lean NAFLD ran a higher risk of three morbidities and overall death in an analysis adjusted for age, sex, diabetes, high blood pressure, cholesterol, ALT, tobacco use, alcohol use, exercise, coffee, and soft drinks at the following hazard ratios (HR) (and 95% confidence intervals):
- Liver event: HR 6.19 (4.35 to 8.82)
- Hepatocellular carcinoma: HR 4.12 (2.14 to 7.94)
- Chronic kidney disease: HR 4.42 (2.73 to 7.15)
- Overall death: HR 3.40 (2.53 to 4.59)
Compared with the no-NAFLD group, people with nonlean NAFLD did not run a higher risk of death but did have a higher risk of two clinical outcomes:
- Liver event: HR 1.79 (1.01 to 3.15)
- Cardiovascular disease: HR 1.91 (1.56 to 2.34)
Compared with people who had nonlean NAFLD, those with lean NAFLD had a higher risk of three clinical outcomes and overall death in an analysis adjusted for the same variables note above:
- Liver event: HR 4.20 (2.91 to 6.07)
- Extrahepatic cancer: HR 1.69 (1.08 to 2.65)
- Chronic kidney disease: HR 5.40 (3.24 to 9.00)
- Overall death: HR 6.63 (4.50 to 8.63)
The French team concluded that lean NAFLD is not rare in the general population and that it presents a greater risk of liver events, nonliver cancer, chronic kidney disease, and death than nonlean NAFLD. The absence of recorded metabolic disorders in more than half of these people with lean NAFLD, the researchers speculated, could represent clinical failure to screen for these problems in lean people.
References
1. Nabi O, Lapidus N, Lacombe K, et al. Lean NAFLD from the general French population have more severe liver disease and poorer clinical outcomes (NASH-CO Study). EASL International Liver Congress, June 23-26, 2021. Abstract OS-612.
2. CONSTANCES. https://www.constances.fr/index_EN.php
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