Less is more? Screening for steatosis in older populations

Knowledge about prognosis in NAFLD is, despite the massive efforts made in the past decades, still elusive. Previous studies have clearly shown that the histological parameter that best predicts overall mortality as well as liver‐related outcomes is fibrosis stage.1 However, if steatosis in itself, without inflammation or more advanced stages of fibrosis, is associated with adverse outcomes has been a topic of much debate. It is especially hard to tease out the individual effect of hepatic steatosis in the milieu of the metabolic syndrome. In a comparison to matched controls from the general population, patients with NAFLD but without advanced fibrosis had a similar overall survival.2 However, a larger study based on administrative coding from national registers and histopathology records found that simple steatosis was also associated with increased mortality.3 Such epidemiological studies are important because they can with relative ease capture a large population but might be biased by misclassification or residual confounding not reported or captured in the registers. Further, the prognosis in patients diagnosed with NAFLD at an older age is infrequently reported. A recent study in Hepatology suggested that the impact of the NAFLD diagnosis on mortality is diminished with increasing age at diagnosis.4 In this issue of Hepatology, we get another piece to try to fit into the puzzle of NAFLD epidemiology. Van Kleef et al. used the Rotterdam study to examine the prognosis of NAFLD in an older Dutch population.5 In brief, the Rotterdam study is a cohort study that invited persons from the general population to participate starting in 2009 and also included some liver‐related parameters. Here, the authors had data from hepatic ultrasound on more than 4000 older individuals and data on transient elastography from close to 2600. In contrast to solely using register‐based data, accurate capture of confounders such as hypertension, type 2 diabetes, and similar traits of the metabolic syndrome can be better captured and quantified in this setting. By linkage to mortality registers, the authors could ascertain deaths as well as causes of death. The mean age of the participants was 74 years, and approximately 88% had some metabolic risk factor such as hypertension, whereas 55% had metabolic syndrome, including 18% with diabetes. During around 7 years of follow‐up, 793 persons died. Strikingly, using several definitions of hepatic steatosis, NAFLD, and metabolic dysfunction–associated fatty liver disease, no association was seen between steatosis and increased mortality. Perhaps more surprisingly, no association was found between liver stiffness, measured with transient elastography, and mortality. Metabolic risk factors were present in a large proportion of the cohort, and current guidelines suggest that such persons should be screened for hepatic steatosis or fibrosis.6 The authors conclude that such a screening might not be justified in older populations based on these data. A few caveats exist. First, it is like other large‐scale initiatives built on the concept of active participation. Selection bias of a relatively healthy cohort cannot be excluded. As also suggested by the authors, a plausible explanation for the findings could be that persons that develop cirrhosis due to NAFLD do so at younger ages and that a survivor effect therefore could confound the results. For several reasons, persons with fatty liver reaching old age might be different from the full NAFLD population. Second, diagnostic thresholds for (pre)diabetes and hypertension are developed in middle‐aged adults but have been questioned in older populations.7,8 Many older adults with mild diabetes could revert to prediabetes or even to normoglycemia, and hypertension with a cutoff of 130/85 mmHg is less likely to lead to morbidity and mortality. However, the data are still applicable to older populations and give valuable information on the effectiveness of a potential screening initiative. Finally, hepatic ultrasound can miss cases with lower grades of steatosis.9 These data suggest that mass screening for liver disease in older populations is unlikely to be of strong benefit. This is further consistent with a recent publication from Germany. In a predominantly young population, indiscriminate screening, albeit with a lab‐based methodology, was of little effect to accurately capture advanced fibrosis.10 Combined, the studies by van Kleef et al.5 and others suggest that we need to improve our definitions of patients thought to be at risk for hepatic fibrosis and cirrhosis, where any screening initiative could be considered. A careful balance must be made between screening too many persons, with the risk of overdiagnosis and cost‐effectiveness issues, and examining too few, with the opposite risk of finding persons with cirrhosis too late. Such a balance is difficult to achieve in any field but must be made a priority in hepatology.