Long-term Prognosis of Patients With Alcohol-related Liver Disease or Non-alcoholic Fatty Liver Disease According to Metabolic Syndrome or Alcohol Use

Marie Decraecker; Dan Dutartre; Jean-Baptiste Hiriart; Marie Irles-Depé; Hortense Marraud des Grottes; Faiza Chermak; Juliette Foucher; Adèle Delamarre; Victor de Ledinghen

Disclosures

Liver International. 2022;42(2):350-362. 

In This Article

Discussion

The majority of patients share risk factors for ALD and NAFLD, and our study shows that ALD patients with metabolic syndrome and NAFLD patients with low to moderate alcohol use have an increased risk of mortality and morbidity. In the latter group, overall survival was reduced when alcohol intake was greater than 7 units/week, and even above 1 unit/week.

This study highlights the overlap of fatty liver diseases in their pathogenesis, evolution and outcomes. This prevalent burden mainly occurs in a context of metabolic syndrome and alcohol consumption. NAFLD is estimated to affect around 20% of the French population, but its definition is currently based on the elimination of reporting excessive alcohol consumption. After tobacco use, alcohol consumption is the second most important avoidable risk factor globally for illness and premature death, overall. In France, it is estimated that two million people are alcohol-dependent, and that 5 million adults are excessive users.[18] The average amount of alcohol consumed per capita per year is equivalent to 11.7 L of pure alcohol and moderate alcohol consumption is probably common in the NAFLD population.

Our findings are similar to those of a study published in 2019 finding higher overall and cause-specific liver mortality in ALD patients, compared to NAFLD ones. These differences in survival are mainly explained by the existence of more severe liver disease with frequent advanced liver fibrosis in the case of ALD.[19] In our cohort, the management of NAFLD patients was similar to that of ALD patients. The results of our analyses of the NAFLD group are consistent with another study where moderate alcohol consumption in the NAFLD population was associated with a risk of worsening markers of liver fibrosis.[11] A prospective US cohort of more than 4000 patients also showed that the consumption of more than 1.5 units per week increased the overall mortality risk in the NAFLD population by 41% (HR: 1.45; 95% CI: 1.01–2.10; P = .047).[20] A recent cohort study conducted in more than 8000 patients with NAFLD has also shown an excessive risk of mortality and morbidity even in the case of low to moderate alcohol consumption.[21] In case of cirrhosis in NAFLD patients, low to moderate alcohol intake remained associated with an excessive risk of mortality, liver transplantation (HR: 2.3), liver decompensation (HR: 1.7) and HCC (HR: 3.2).[22]

In other ways, our results are consistent with a study published by Younossi et al, where mortality was higher in subjects who combined alcohol consumption and metabolic syndrome.[6] Åberg et al. also showed that the coexistence of metabolic syndrome and alcohol consumption was associated with a higher risk of advanced chronic liver disease.[23] Several studies, therefore, corroborate our results, showing that the existence of several metabolic syndrome parameters in patients with ALD increases the risks of mortality and morbidity and liver fibrosis.[24,25]

In our study, survival appeared to be higher in patients with a higher waist circumference. In the NAFLD population, survival was higher than in the population with AFLD but obesity, high waist circumference and alcohol consumption are confounding factors. However, numerous studies have shown that obesity is associated with less severe liver fibrosis and more steatosis. However, steatosis is not statistically correlated with mortality or morbidity. The presence of diabetes is found to accelerate the natural progression of liver disease, and diabetes is the primary risk factor of advanced fibrosis in these patients.[2] Lastly, sarcopenia is underestimated in ALD patients and may influence overall survival.

While excessive alcohol consumption is responsible for insulin resistance and macrophagic infiltration into adipose tissue, moderate alcohol consumption can cause increased insulin sensitivity and serum adiponectin levels, preventing an increase in cardiovascular risk.[4,26] The hepatoprotective effect of alcohol on cardiovascular diseases, progression of hepatopathy and HCC is not yet demonstrated, especially in the NAFLD population, and currently published studies must be interpreted with caution in this regard. Cardiovascular mortality is the leading cause of death in the NAFLD population and the identification of protective factors remains particularly important here.

In addition, our study confirms that LSM is an efficient and independent prognostic factor in fatty liver diseases,[12,13,16] as already demonstrated by Shili-Masmoudi et al. Overall and cause-specific (especially liver- and cardiovascular-related) survival rates significantly decreased when LSM values increased. We found that LSM was superior to our clinical model in predicting overall survival, and the best accuracy was obtained using a mixt model of LSM associated with clinical data. Liver biopsy was not evaluated, because only a small number of patients had a liver biopsy in our unit (16%). This low rate is concordant with current guidelines and the non-invasive assessment of liver fibrosis appears to be a key tool from the first consultation and should be added to the clinical parameters for the prognostic assessment of each patient. The prediction of survival of patients with fatty liver diseases should be based on the initial LSM, and non-invasive diagnosis of fibrosis would also allow the development of a personalized follow-up, with adapted patient management.

To our knowledge, it is the first study which evaluates the relationships between alcohol use and NAFLD, and metabolic syndrome and ALD. Our study included a large number of patients with fatty liver disease, with a long-term follow-up. Strengths of our study include its prospective design, and the large, nationally representative, well-characterized, population-based cohort of men and women with longitudinal and complete follow-up data. Our study is retrospective but data were recorded prospectively and we focused on hard endpoints (death, liver transplantation, cancer and cardiovascular events) with a higher incidence of outcomes (28% total morbidity, 17% total mortality), especially in the NAFLD group, which increased the power of our analysis. Regarding outcomes, we were not able to lead a Cox regression due to a lack of temporal data. Among NAFLD group, less than 10% were lost to follow-up, raising the significant prognosis impact of alcohol on mortality and morbidity in this population.

We studied the association between statin drugs and cardiovascular-related mortality, in univariate analysis, it was not found to be associated with cardiovascular-related mortality (P-value = .79). Statin drugs statistically increased the risk of cardiovascular-related outcomes (OR: 3.36 [2.54–4.44] P-value <.0001). Statin drugs significantly decreased the liver-related mortality (OR: 0.441 [0.292–0.665]) and liver-related outcomes (OR = 0.37 [0.28–0.486]).

We comprehensively collected alcohol consumption data during the interviews conducted by experienced senior practitioners for the inclusion of patients with ALD. Nevertheless, underreporting alcohol use and recall bias are concerns in any observational study, particularly in the NAFLD group. Alcohol consumption rates were collected at inclusion, at the same time of liver stiffness measurement. A recent study concluded that reported alcohol consumption is stable over time, except for patients consuming more than 250 g of alcohol per week, where consumption seems to decrease with age.[21,27] Nevertheless, we may have underestimated alcohol use and should have collected the AUDIT score. However, when we started our study in 2003, we did not use this score.[28]

The majority of patients have shared risk factors for ALD and NAFLD and our study showed that alcohol intake should be considered as a continuous variable (units/day or units/week) acting with increasing components of metabolic syndrome as additive factors on the mortality and morbidity risk.

Therefore, the limitation of alcohol use in NAFLD patients and management of metabolic syndrome in ALD should be emphasized in clinical practice and in international guidelines.

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