Prevalence of patients with normal BMI in our cohort of Indian patients with NAFLD was 14.3%. Globally, the prevalence of lean NAFLD among patients with NAFLD has been estimated to be around 20% (5, 6). In Indians, the pooled proportion of lean individuals among patients with NAFLD is 16.97% while the pooled prevalence of lean NAFLD in the general community is 6.5%. The reported proportion of lean patients in previous Indian studies on NAFLD ranges from 6.8–31.7% (22–24). Apart from regional variations, the wide range in the reported proportion of lean patients in Indian studies is also partially attributable to differences in the modalities for the diagnosis of NAFLD and BMI cut-off used for defining lean patients. None the less, the available evidence suggests that although uncommon, the actual burden of lean NAFLD in India is still likely to be substantial given the extremely high prevalence of NAFLD in India. Larger, multicentric studies are required to better estimate the true burden of lean NAFLD. Further, community-based studies are the need of the hour to assess the prevalence of lean NAFLD among the general population.
Recent western studies have suggested that lean patients with NAFLD are younger than their obese counterparts (25, 26). However, we did not observe any difference in age between our lean and non-lean patients. Similar findings have been reported in two other studies from north and south India (8, 27). This suggests that Indian lean patients are detected with NAFLD at an older age than western patients. It could also be indicative of a referral bias due to the common perception among clinicians that NAFLD in individuals with normal body weight is mild.
Bulk of the available evidence suggests that metabolic co-morbidities like central obesity, hypertension, T2DM, and metabolic syndrome are less common in lean patients with NAFLD compared to obese patients (5, 6, 7). Similarly, our patients with lean NAFLD were less likely to have central obesity, hypertension, and metabolic syndrome compared to non-lean patients. In our cohort, elevated triglycerides and low HDL were observed in a similar proportion of lean and non-lean patients with Novelties is line with the findings of a meta-analysis that reported no difference in elevated triglycerides or dyslipidemia among lean and obese patients (5). This is an intriguing observation. Similar risk of dyslipidemia among lean and non-lean patients may be indicative of increased adipose tissue insulin resistance with consequential increase in peripheral lipolysis and serum lipid profile derangements despite the quantitatively lower total body fat mass in lean patients (8). Contrary to the available evidence, we did not observe any difference in T2DM among lean and non-lean patients. This is difficult to explain and may be related to the low prevalence of T2DM in our cohort.
We used multiple non-invasive techniques for assessing the various histologic facets of NAFLD to amplify the robustness of our inferences. Biochemical liver function perturbations as assessed by AST and ALT were similar between the lean and non-lean patients in our cohort. We did not observe any difference in the severity of steatosis on non-invasive assessment by ultrasound and CAP. Non-invasive detection of NASH, the diagnosis of which has both prognostic and therapeutic implications, has long been an unmet met. The FAST score encompasses measures of steatosis (CAP), inflammation (AST) and fibrosis (LSM) and may be considered a non-invasive analogue of the histological steatosis, activity and fibrosis (SAF) score (16). It was recently shown by Newsome et al to have a high discriminatory ability for the detection of patients with NASH and significant fibrosis and has been validated in multiple geographic regions including India (16, 17, 28). There was no difference in FAST scores among the lean and non-lean patients in our cohort. With respect to fibrosis, FIB-4 and LSM were similar among lean and non-lean patients and there was no difference in the proportion of patients in whom advanced fibrosis was ruled out or ruled in using both these modalities. Our observations strongly suggest that liver disease in lean patients with NAFLD is not milder than that in their non-lean counterparts.
Our observations on non-invasive assessment were further corroborated on histology although it was available in only 149 patients. We observed no difference in steatosis, lobular inflammation, ballooning, NAS or fibrosis stages among lean and non-lean patients. Further, there was no difference in the number of patients with NASH, significant or advanced fibrosis between these two groups. Although some studies have suggested that lean or non-obese patients NAFLD have relatively mild disease on histology, there are several reports to the contrary (5, 8, 9, 25, 29–35). Two other studies from the Indian subcontinent have assessed liver histology in lean or non-obese patients with NAFLD and both reported that these patients do not have a lower risk of NASH or advanced fibrosis (8, 9).
There are few important caveats in interpreting the available evidence on the severity of liver disease in lean patients with NAFLD. There is a variation in the BMI cut-off used for defining lean among the various studies (5, 8, 9, 25, 29–35). Many studies have clubbed overweight with lean patients into non-obese NAFLD adding further heterogeneity to the evidence. As such this BMI based categorisation into lean, overweight and NAFLD is partly arbitrary. Hence, we assessed the risk of advanced fibrosis, the main determinant of clinical outcomes, with BMI as a continuous measure. We did not find BMI to be a significant predictor for ruling out or ruling in advanced fibrosis as assessed by FIB-4 scores thereby suggesting that BMI does not impact the risk of advanced fibrosis. Age is another confounding factor in assessing liver disease severity in lean patients. On the one hand there is a correlation between age and BMI while on the other age is a known risk factor for fibrosis and poor clinical outcomes (36). Indeed, age was an independent predictor for advanced fibrosis on multivariate analysis in our cohort with an aOR of 0.91 (0.89–0.94) and 1.06 (1.04–1.09) for ruling out (FIB-4 < 1.3) and ruling in (FIB-4 > 2.67) advanced fibrosis, respectively. This confounding effect of age was elegantly demonstrated in a recent longitudinal study of Caucasian patients with NAFLD, where an apparent link between BMI and clinical events like T2DM, hepatocellular carcinoma and cardiovascular events disappeared after adjustment for age (26). Previous longitudinal studies have also demonstrated that NAFLD in lean patients can progress to severe liver disease and clinical events may occur without substantial increase in BMI on follow-up (26, 35). Taken together, the evidence suggests that a BMI-guided approach to risk stratification in patients with NAFLD may not be prudent. Further long-term follow-up studies are needed to get a better understanding of the natural history and prognosis in lean patients with NAFLD.
We acknowledge the limitations of our study including the unavailability of CAP, LSM and histological data in all patients. This reflects the constraints of real-world clinical practice as it is not feasible to perform liver biopsy or FibroScan in all patients due to logistic and ethical concerns. In our institute, CAP function in FibroScan was incorporated in 2015. Hence, CAP parameter was not available in patients who presented prior 2015. Assessment of insulin resistance and measurement of other markers of metabolic dysfunction like serum uric acid and hs-CRP were not done as these are not a part of the routine evaluation and management of patients of NAFLD at our institute. Lastly, the inclusion of a control group of patients without NAFLD would have added further granularity to our observations and inferences.
In conclusion, lean patients with NAFLD are less likely to have abdominal obesity, hypertension and metabolic syndrome compared to their non-lean counterparts. However, there is no difference in biochemical parameters, non-invasive assessment of liver disease severity, and the histologic presence of NASH and significant or advanced fibrosis among lean and non-lean Indian patients with NAFLD.