Defining severe NAFLD based on ICD codes in large cohorts: Balancing feasibility and limitations

Abstract

Associations of muscle mass and grip strength with severe NAFLD: A prospective study of 333,295 UK Biobank participantsJournal of HepatologyVol. 76Issue 5PreviewCross-sectional studies have reported that lower muscle mass and strength are risk factors for non-alcoholic fatty liver disease (NAFLD). However, the evidence from prospective studies is limited. This study examined both the strength and pattern of the associations between these 2 physical capability markers and severe NAFLD using data from the UK Biobank study. Full-Text PDF All authors declared that no potential conflicts of interest should be disclosed in this study. The authors received no financial support to produce this manuscript. L.L proposed the idea and drafted the manuscript, X.Z revised the manuscript. We read Petermann-Rocha et al.'s original manuscript[1]Petermann-Rocha F. Gray S.R. Forrest E. et al.Associations of muscle mass and grip strength with severe NAFLD: a prospective study of 333,295 UK Biobank participants.J Hepatol. 2022; 76: 1021-1029Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar with great interest. The study was able to demonstrate that lower muscle mass and grip strength were associated with higher risk of developing severe non-alcoholic fatty liver disease (NAFLD) by using data from the UK Biobank study. It is well known that NAFLD is the most common liver disease worldwide.[2]Riazi K. Azhari H. Charette J.H. et al.The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis.Lancet Gastroenterol Hepatol. 2022; 7: 851-861Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar The overall prevalence of NAFLD was estimated to be 30% with 10.3% of these having advanced fibrosis. Identifying risk factors that contribute to the disease may help identify at-risk populations and develop prevention or treatment strategies. NAFLD is considered to be a “silent” disease with few or no symptoms. This is related to the fact that in large cohorts, the true prevalence of NAFLD is likely to be grossly underestimated due to the lack of biochemical and imaging tests, as well as possible other etiologies (e.g., HCV-related and HBV-related diseases due to underdiagnosis).[3]Setiawan V.W. Stram D.O. Porcel J. Lu S.C. Le Marchand L. Noureddin M. Prevalence of chronic liver disease and cirrhosis by underlying cause in understudied ethnic groups: the multiethnic cohort.Hepatology. 2016; 64: 1969-1977Crossref PubMed Scopus (192) Google Scholar Regarding the criteria for defining severe NAFLD outcomes in this study, we would like to discuss the following points: First, in this study, during a median follow-up of 10 years, 3311 participants were recorded as developing severe NAFLD among 333,295 participants without liver disease at baseline. The approximately 1% 10-year cumulative incidence of severe NAFLD is not outrageous when compared to previous meta-analysis results of an estimated 46.9/1000 person-years of ultrasound-diagnosed NAFLD.[2]Riazi K. Azhari H. Charette J.H. et al.The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis.Lancet Gastroenterol Hepatol. 2022; 7: 851-861Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar According to the previous study,[4]Corey K.E. Kartoun U. Zheng H. Shaw S.Y. Development and validation of an algorithm to identify nonalcoholic fatty liver disease in the electronic medical record.Dig Dis Sci. 2016; 61: 913-919Crossref PubMed Scopus (43) Google Scholar among individuals identified with NAFLD on chart review, only 55.2% of them carried an ICD-code diagnosis for NAFLD. Thus, the use of the ICD-code alone would miss 44.8% of NAFLD patients in cohort. Although the diagnosis rate of severe NAFLD is much higher than that of mild disease, there is no evidence that the underdiagnosis rate of severe NAFLD based on ICD codes is within acceptable limits. Second, severe NAFLD was defined as hospital admission or death in this study, with 3277 hospital admissions and 34 deaths. We totally agree that the deaths due to NAFLD is an important addition to cases of severe NAFLD. However, it is worth discussing whether it is reasonable to combine NAFLD caused death into severe NAFLD. Given that NAFLD is a chronic disease with a long survival, the association of risk factors with NAFLD incidence and mortality may vary significantly, as NAFLD mortality is also influenced by numerous post-diagnostic influences. The first priority for this study was to establish a role for muscle mass and grip strength as a potential independent major modifiable risk factor for severe NAFLD. For a scientific hypothesis to be accepted, study related to NAFLD death would need to be based on a separate study population. In addition, the leading causes of mortality among patients with NAFLD are CVD, followed by extra-hepatic cancers and liver-related complications.[5]Mantovani A. Scorletti E. Mosca A. Alisi A. Byrne C.D. Targher G. Complications, morbidity and mortality of nonalcoholic fatty liver disease.Metabolism. 2020; 111S154170PubMed Google Scholar The majority of people who die with NAFLD are not identified. Thus, we believe that identification of NAFLD patients from the deceased population is beyond the scope of this paper. Nevertheless, sensitivity analyses are worth doing to show whether the inclusion or exclusion of mortality data in the study, despite the limited sample size, affects the results. Third, for deaths caused by NAFLD in the study, the date of death rather than the date of diagnosis was used in the incidence model. This may be due to the fact that the date of diagnosis was not available in the UK Biobank for the deceased population. The plausibility of this approach deserves to be explored. Would it be more appropriate to exclude this part of the population due to missing important data? In conclusion, in large cohorts, risk factors for NAFLD disease progression and liver-related outcomes are still not fully understood due to the lack of validated identification methods. Small-scale validation of NAFLD cases diagnosed by ICD code or designing a classification algorithm for NAFLD in the electronic medical record could improve the accuracy of disease classification and facilitate NAFLD studies based on large longitudinal cohorts.