Effect of weight reduction on histological activity and fibrosis of lean nonalcoholic steatohepatitis patient

Introduction

Non-alcoholic fatty liver disease (NAFLD), the most prevalent chronic liver disorder worldwide, is a clinico-histopathological entity ranging from simple fat accumulation (steatosis) to non-alcoholic steatohepatitis (NASH).^[1,2] NASH is diagnosed by the joint presence of steatosis and inflammation along with hepatocyte injury (evident as hepatocyte ballooning).^[3] It is estimated that NASH occurs in 20% of patients with NAFLD, whereas in Bangladesh, it shows a higher proportion (42.4%).^[4,5] Due to its progressive nature, approximately 30% to 40% of patients with NASH develop fibrosis and others lead to advanced fibrosis or cirrhosis. Moreover, it is one of the most common indications of liver transplantation worldwide.^[5] The risk of progression to advanced hepatic complications is influenced by the severity of underlying liver histology as, it is documented that increased rate of deleterious outcomes are observed in patients with advanced fibrosis. However, with therapeutic interventions, reversal as well as prevention of further progression of fibrosis is possible as well.^[6]

NAFLD is commonly observed in obese people and is associated with insulin resistance (IR) and metabolic syndrome (MS). Nonetheless, NAFLD/NASH in non-obese or persons with normal body mass index (BMI) (i.e., < 25 kg/m²), termed as, “lean NASH” is not uncommon.^[7,8] As in Bangladesh, it was demonstrated that 25.6% of NAFLD patients were found non-obese, and among the non-obese NAFLD, 53.1% were documented as NASH.^[9] Considering the obesity, from another study, NASH is reported in 18.5% of obese and 2.7% of lean patients.^[10] Lean NASH is a distinct phenotype of NAFLD in terms of relationship with BMI, sharing the metabolic characters and liver pathology, as seen in obese persons having NASH.^[7] Despite this, the pathophysiologic issue behind NAFLD in lean subjects is not settled enough; it seems that there is no straight pathway to this multifactorial phenotype. Genetic predisposition along with environmental factors, such as dietary composition and gut microbiome may play an important role.^[11]

Treatment of NASH is applied with the targets of reducing the NASH-related mortality and prevention of the progression to cirrhosis or hepatocellular carcinoma (HCC). At present, the resolution of the histological findings of NASH is now approved as a surrogate endpoint. The major treatment offered for NAFLD remains lifestyle changes including weight reduction by a healthy diet and performing regular physical activity.^[12,13] It is evident that improvements of liver histology in NASH can be achieved through losing a certain amount of weight.^[14] Promrat et al. in his RCT showed that almost 7–10% of weight reduction can improve the NAFLD activity score (NAS) and its elements (steatosis, lobular inflammation and ballooning).^[15] Not only that, even a greater amount of weight reduction (≥ 10% of total body weight) make significant regression of hepatic fibrosis in NASH also. Most of these studies were performed among obese or overweight individuals.^[1] Single case report by Merchant et al. described that like obese NAFLD patients, lean NAFLD patients can get benefits in dietary modification as well as weight reduction strategy.^[16] This data is also supported by another study that concluded that change in the body weight is a potent independent issue for both the development and regression of NAFLD in non-obese individuals, regardless of baseline BMI.^[17] As none of the study focused on the benefits of weight reduction on histological activity in patients with lean NASH, the study was focused to explore the effect of weight reduction strategy in lean NASH individuals.

Materials and methods

Results

Total 40 patients of histologically proven NASH were initially selected for inclusion. Twenty patients were included in the lean group and another 20 patients were included in the non-lean group based on their BMI. Five patients from the lean group and 4 patients from the non-lean group were lost to follow-up (Figure 1). Total 31 NASH patients (15 patients in the lean group and 16 patients in the non-lean group) were considered for the final analysis.

Figure 1

Flow chart of patient selection

Comparison of baseline characteristics is enlisted in Table 2. No statistically significant difference was noted between the lean and non-lean patients in relation to age, sex, HOMA IR, serum lipid profile, liver biochemistry, and liver histology. BMI, waist circumference (WC) and FBS were significantly high in non-lean group than in lean group (P = 0.000 and P = 0.01, respectively). Non-lean group had a significantly higher number of diabetes and hypertensive patients (7 cases each) than that of the lean group (0 and 1 case respectively; P = 0.004 and P = 0.018 respectively).

Following a year of exercise and diet restriction regimen, only improvement in weight was found to be significantly higher in the non-lean group than lean group (Table 3). In the non-lean group, mean weight reduction was 3.71 ± 4.58 kg, and in the lean group, mean weight reduction was 0.88 ± 2.79 kg (P = 0.045). Improvement in other anthropometric, biochemical and histological parameters between lean and non-lean group did not differ significantly.

Table 4 shows the effect of weight reduction on overall histological activity and fibrosis score of lean and non-lean NASH patient. Any amount of weight reduction was found in 8 lean patients and 11 non-lean patients. Weight reduction of ≥ 5% from the baseline was found in 5 lean and 6 non-lean patients and of ≥ 7% from the baseline was found in 2 lean and 6 non-lean patients. Any amount of weight reduction was associated with significantly improved steatosis, ballooning, and NAS score after one year in both lean and non-lean patients (P = 0.001, P = 0.005, and P = 0.000 respectively for lean, and P = 0.016, P = 0.016 and P = 0.000, respectively, for non-lean patients). Weight reduction ≥ 5% was associated with a significant improvement in the NAS score in both lean and non-lean NASH patients (P = 0.009 and P = 0.01, respectively). But, weight reduction of ≥ 7% was found to improve the NAS score significantly only in the non-lean patients (P = 0.01).

Logistic regression analysis was done to find out the best predictor of patient response. As shown in Table 2, only improvement in weight was found to differ across groups. Therefore, univariate analysis was done for the category of patients (lean and non-lean) and weight reduction (Table 5). Weight reduction was found to have a significant effect on the histological improvement at the end of the treatment in univariate analysis (OR 25.5; 95% CI 3.58–181.61; P = 0.001). On multivariate analysis, the lean patients were found to have higher odds than the non-lean patients for histological improvement, although it was not statistically significant (OR 3.56; 95% CI 0.34–37.80; P = 0.293). On the

other hand, weight reduction was independently associated with a significant improvement in the histological status (steatosis, ballooning and NAS) of NASH patients (OR 40.04; 95% CI 3.73–429.38; P = 0.002).

Discussion

NASH has become an important health concern as it is associated with progressive liver disease, cardiovascular mortality and type-2 diabetes.^[22] Various modalities of treatment are being tested for the management of NASH.^[22] Among different drugs tested,^[23] vitamin E,^[24,25] pioglitazone,^[25] liraglutide,^[26] telmisartan,^[27] pentoxifylline^[28] were found to improve histological activity and fibrosis in different degrees. But these must be balanced with their potential adverse effects. Therefore, diet and lifestyle modification, with weight reduction remains the mainstay of treatment in these patients.^[16,22] Previous studies testing the effectiveness of lifestyle modification in NAFLD have found that 7 to 10% weight loss is accompanied by a remarkable normalization of liver enzymes and a systematic reduction of liver fat.^[29] But, no previous study tested the effect of weight reduction on non-obese lean NASH patients. This study was the first attempt to test and compare the effect of weight reduction in lean and non-lean NASH patients.

We initially included 40 patients of histologically proven NASH in the study, among whom 9 patients were lost to follow-up. Total 15 lean NASH cases and 16 non-lean NASH cases were tested in the final analysis. Both groups were advised moderate intensity exercise and dietary restriction for one year. Our results show that both lean and non-lean patients achieved weight reduction at the end of the treatment, with the reduction being significant in the non-lean group. 8 and 11 lean and non-lean patients respectively achieved any amount of weight reduction, 5 and 6 lean and non-lean patients respectively achieved ≥ 5% weight reduction, and 2 and 6 lean and non-lean patients respectively achieved ≥ 7% weight reduction.

Any amount of weight reduction was found to be significantly associated with improvement in steatosis, ballooning and NAS score in both lean and non-lean patients. More than or equal to 5% weight reduction was associated with improvement in overall NAS score in both groups without showing significant improvement in individual scores. But ≥ 7% reduction in weight was not associated with any further improvement in NAS score of lean patients. In comparison, non-lean patients showed a significant improvement in NAS score with ≥ 7% reduction. In a meta-analysis research, Musso et al. described that body weight reduction through sedentary life style changes was associated with a significant histological improvement of NASH patient. But, they could not quantify the cut off value.^[30] Promrat et al. have shown that weight reduction of more than 7% sustained over 48 weeks is associated with a significant reduction in the histological severity of obese NASH patients.^[16] Vilar-Gomez et al. found that a 10% reduction in weight over 52 weeks was associated with the highest reduction in NAS reduction, NASH resolution and fibrosis regression in non-lean NASH.^[31] Our study suggests that weight reduction of more than ≥ 5% benefits the histologic activity of liver in both lean and non-lean (obese) NASH patients.

Although improvement in NAS score was noted in both groups of patients, neither group achieved improvement in fibrosis with weight reduction over the year. This may indicate that the effect of weight loss on fibrosis is smaller than the effect on overall histologic activity, and thus, could not be detected with our sample size or that longer than a year study is needed to detect changes in fibrosis score. These findings are correlated with that of Promrat et al.^[16]

In the multivariate analysis, we had a unique finding that lean NASH cases have higher odds of achieving improvement in NAS score than non-lean NASH cases. Also, weight reduction was independently associated with a significant improvement in liver histology. Kim et al. have reviewed that visceral obesity as opposed to general obesity, high fructose and cholesterol intake, and genetic risk factors were linked with non-obese NAFLD.^[32] Lifestyle modification, including dietary changes and physical activity to reduce visceral adiposity through weight reduction was suggested to be a standard care in non-obese NAFLD patients in their study. Fracanzani et al. found that lean and non-lean NAFLD patients had an increasing risk of NASH with increasing visceral obesity.^[32] They used WC to represent visceral obesity, which is a relatively accurate surrogate marker.^[33] We measured WC before and after the intervention and noted a statistically similar decrease in both lean and non-lean patients. Therefore, our findings indicate that overall body weight reduction independent of reduction in visceral adiposity is also beneficial for improvement in overall histologic activity of lean in comparison to non-lean NASH patients.

NAFLD is a common disease in non-obese (lean) people in the South Asian region.^[35] Alazawi et al. found that Bangladeshi ethnicity is an independent risk factor for developing NAFLD^[36] and prevalence of NASH was found to be high in NAFLD patients in Bangladesh.^[22] Hence, it is pertinent to focus on the treatment of lean non-obese NASH patients alongside their obese counterparts. Weight reduction strategy could be a good starting point, as we have shown that any amount of weight reduction is associated with improvement in histology of liver.

However, this study was limited in the absence of a control group. Also, a precise cut-off value of weight reduction for significant improvement in histological activity of liver in the study could not be evaluated due to the small sample size. Therefore, large randomized control trials addressing the issue of cut-off point of weight reduction as well as trials assessing the correlation of percent weight reduction with reduction in NAS score are some good topics for future research.

Conclusion

A weight reduction strategy of one year significantly improves the histologic activity of liver in both lean and non-lean NASH patients.

Ethical consideration and informed written consent

The researcher was duly concerned about the ethical issues related to the study. Formal ethical clearance was taken from the Institutional Review Board of BSMMU for conducting the study, as well as a formal permission was taken from the responders. Confidentiality was maintained properly. Informed written consent was taken from the subject informing the nature and purpose of the study, procedure of the study, the right to refuse, accept and withdraw to participate in the study as well as the participants didn’t gain financial benefit from this study. The present study posed a very low risk to the participants, as procedures such as medical treatments, invasive diagnostics or procedures causing psychological, spiritual or social harm were not included.