Nonalcoholic Fatty Liver Disease: Indian Perspective

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Abbreviations

APRI

aspartate aminotransferase‐to‐platelet ratio index

AST

aspartate aminotransferase

BMI

body mass index

CI

confidence interval

DM

diabetes mellitus

FIB‐4

Fibrosis‐4

HCC

hepatocellular carcinoma

HDL

high‐density lipoprotein

ICON‐D

Indian Consortium on NAFLD

NAFLD

nonalcoholic fatty liver disease

NASH

nonalcoholic steatohepatitis

OR

odds ratio

PBC

primary biliary cholangitis

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India is the seventh largest and second most populous country in the world. It has a rapidly developing economy with an estimated gross domestic product of US $2.87 trillion. Easy access to calorie‐dense food and sedentary lifestyle together with the modern epidemics of diabetes mellitus (DM) and obesity have catapulted nonalcoholic fatty liver disease (NAFLD) into a substantial public health problem in India as in other parts of the world. NAFLD has emerged as one of the leading causes of cirrhosis, hepatocellular carcinoma (HCC), and liver transplant in India. ¹ Given its enormous population, the burden of NAFLD in India is likely to be substantial, which may significantly impact the limited health care resources in the country.

Prevalence

The prevalence of NAFLD among the general population in India ranges from 9% to 53%. ¹ , ² One of the caveats in interpreting epidemiological data on NAFLD from India is that many of the studies have been conducted in the hospital setting and are therefore liable to referral bias. Although differences in diagnostic techniques for NAFLD may partly account for the wide variation in reported prevalence, a possible rural‐urban divide and geographical variation are evident from the available data (Fig. 1). Most studies from urban centers have reported a higher prevalence as compared with those that cater to a largely rural population. One of the earlier population‐based studies from India that showed a prevalence rate of 8.7% in predominantly nonobese populations was from rural West Bengal (Table 1). ¹ More recently, a population‐based study from coastal south India reported an overall NAFLD prevalence rate of 49.8%; urban domicile was found to be associated with a higher risk for NAFLD after adjusting for sex, body mass index (BMI), DM, and metabolic syndrome (adjusted odds ratio [OR], 1.21; P = 0.048). ³ As a part of the ongoing community‐based Prospective Urban Rural Epidemiology (PURE) cohort study in north India, prevalence of NAFLD was found to be higher in urban communities (53.7%) in comparison with rural communities (30.2%) (P < 0.001). ⁴ Among the high‐risk groups, prevalence has been reported to be higher among those with type 2 DM, prediabetes, obesity, and metabolic syndrome. ¹ One of the multicenter studies across 101 Indian cities estimated the prevalence rate of NAFLD as 56.5% (n = 522) among 924 patients with type 2 DM. ⁵ Further worrisome are the recent data showing a high prevalence of NAFLD in obese Indian children.

FIG 1.

Prevalence of NAFLD in different geographical regions of India.

TABLE 1.

Proportion of Lean, Overweight, and Obese Patients With NAFLD in India

Authors	Location	No. of NAFLD Patients	BMI (kg/m2)	Lean NAFLD, n (%)	Overweight NAFLD, n (%)	Obese NAFLD, n (%)
Das et al. (2010) 23	Rural West Bengal (East India)	164	23 ± 4.2	52 (31.7)	23 (53.1)	25 (15.2)
Singh et al. (2013) 24	Cuttack (East India)	632	26.1 ± 3.3	101 (16)	141 (22.3)	390 (61.7)
Sinha et al. (2020) 25	Kolkata (East India)	120	24.8 ± 3.2	37 (30.8)	–	83 (69.2)
Singh et al. (2015) 9	Cuttack (East India)	336	26.34 ± 3.3	47 (14)	75 (22.3)	224 (66.6)
Madan et al. (2006) 26	New Delhi (North India)	51	26.7 (21.3‐32.5)	–	–	34 (69.4)
Duseja et al. (2007) 27	Chandigarh (North India)	100	28.7 (19‐34)	12 (12)	20 (20)	68 (68)
Bajaj et al. (2009) 28	Allahabad (North India)	39	26.7 ± 4.4	8 (18)	6 (15)	25 (67)
Agarwal et al. (2011) 29	New Delhi (North India)	71	27.5 ± 3.9	8 (11)	13 (18.3)	50 (70.7)
Kumar et al. (2013) 30	New Delhi (North India)	205	26 ± 3.6	27 (13.2)	37 (18)	141 (68.8)
Duseja et al. (2019) 2	Chandigarh (North India)	528	26.8	36 (6.8)	85 (16.1)	407 (77)
Amarapurkar et al. (2007) 31	Mumbai (West India)	92	26.6 ± 5.1	12 (13)	32 (34.8)	48 (52.2)
Uchil et al. (2009) 32 , *	Mumbai (West India)	225	28.5 ± 4.2	50 (22)	119 (53.2)	56 (24.8)
Shah et al. (2020) 33	Mumbai (West India)	250	30.21 ± 6.77	69 (27.6)		181 (72.4)
Chalmers et al. (2019) 3	Trivandrum (South India)	1040	26.9 ± 4.6	169 (16.3)	195 (18.8)	675 (64.9)
Duseja et al. (2021) 7	Multicenter (East, West, North and South India)	3553	27.6 ± 5.7	378 (10.6)	575 (16.2)	2580 (73)

^*Used Western cutoffs of BMI for defining normal weight (<25 kg/m²), overweight (25‐29.9 kg/m²), and obese (≥30 kg/m²).

Spectrum and Clinical Presentation

More important than the mere presence of fatty liver is the prevalence of progressive nonalcoholic steatohepatitis (NASH) with or without hepatic fibrosis that adds to the significant liver disease and extrahepatic disease burden. Even though earlier data had suggested a mild liver histology in Indian patients with NAFLD, ¹ a recent retrospective review of 1000 liver biopsy‐proven patients with NAFLD showed histological NASH in more than 60% of patients and advanced fibrosis (≥F3) in 35% of patients. ⁶ Further, an interim analysis of an ongoing real‐life, multicentric observational study (Indian Consortium on NAFLD [ICON‐D]) in approximately 3000 patients with NAFLD showed the presence of significant fibrosis in 19%, 21%, and 29% of patients as assessed by Fibrosis‐4 (FIB‐4), aspartate aminotransferase (AST)‐to‐platelet ratio index (APRI), and FibroScan, respectively. ⁷ The presence of metabolic risk factors and data on explant pathology also suggest NAFLD to be the predominant cause of cryptogenic cirrhosis and cryptogenic HCC in India (Table 2). Similar to data from the West, a recent Indian study has also shown a trend of NASH as the increasing cause of HCC over the years. ⁸

TABLE 2.

NAFLD as Cause of Cryptogenic Cirrhosis and Cryptogenic HCC: Evidence From Indian Studies

Study	No. of Patients	Evidence
Duseja et al. (2004)	‐Cryptogenic cirrhosis: 25 ‐Chronic viral hepatitis and PBC: 18	‐Patients with cryptogenic cirrhosis had significantly higher BMI, increased prevalence of DM, and lower HDL
Duseja et al. (2010)	‐Cryptogenic cirrhosis: 65 ‐Cryptogenic HCC: 39 ‐Cirrhosis of viral etiology: 50 ‐HCC of viral etiology: 39	‐Patients with cryptogenic cirrhosis had significantly higher BMI (26 versus 22.1 kg/m2) with a higher proportion of patients having abnormal waist circumference (58.5% versus 30%), DM (40% versus 10%), and low serum HDL (53.8% versus 6%) as compared with patients with cirrhosis of viral etiology ‐Patients with cryptogenic HCC had significantly higher BMI (24.4 versus 22.5 kg/m2) and a higher proportion of DM (38.5% versus 17.9%) compared with patients with HCC of viral etiologies
Nayak et al. (2010)	Explant histopathology of 103 liver transplant patients of which 30 were labeled as cryptogenic cirrhosis pretransplant	‐63.3% of patients with pretransplant diagnosis of cryptogenic cirrhosis were deemed to have underlying NAFLD ‐47% of these patients had metabolic risk factors such as DM and obesity
Nayak et al. (2012)	Explant histopathology of 372 adult liver transplant patients of which 84 were clinically considered to have cryptogenic cirrhosis pretransplant	‐After correlating pretransplant data with explant histopathology, NAFLD was finally diagnosed in 67.8% of patients who were labeled as cryptogenic prior to transplant
David et al. (2017)	Non‐B non‐C HCC: 47	‐One or more metabolic risk factors present in 85% of patients with non‐B non‐C HCC ‐Average duration of NAFLD risk factor prior to the diagnosis of HCC was 7.5 years

Data from India corroborate that NAFLD is associated with several extrahepatic conditions, such as cardiovascular disease, chronic kidney disease, polycystic ovarian syndrome, obstructive sleep apnoea, vitamin D deficiency, and hypothyroidism. ¹ NAFLD also has been shown to affect quality of life, particularly in overweight/obese patients with NAFLD.

Pathogenesis and Risk Factors

As in the rest of the world, both environmental and genetic factors have been shown to be involved in the pathogenesis of Indian patients with NAFLD. Globally, multiethnic studies have suggested that Indians are more predisposed to insulin resistance and its consequences, including NAFLD. Most of the data from India suggest the presence of insulin resistance in patients with NAFLD; however, a small study suggested occurrence of NAFLD without insulin resistance. ⁹ Earlier data from India had suggested certain subtle differences between Indian patients with NAFLD and their Western counterparts, with Indian patients having lower BMI and fewer cases of morbid obesity, diabetes, hypertension, or metabolic syndrome. ¹ However, most patients (85%‐90%) with NAFLD in India are still overweight or obese as per the Asia‐Pacific cutoffs for BMI, and around 10% to 15% of the patients are “lean” with a normal BMI (<23 kg/m²) (Table 1). The interim results of the ongoing real‐life study from India (ICON‐D) in approximately 3500 patients (mean BMI, 27.6 ± 5.7 kg/m²) showed the presence of overweight (BMI, 23‐24.9 kg/m²) in 16%, obesity (BMI ≥ 25 kg/m²) in 73%, and lean NAFLD (BMI < 23 kg/m²) in 10.6% of patients ⁷ (Table 1). Overall, metabolic syndrome was present in 43%, and at least one metabolic risk factor was present in 93% of patients with NAFLD (the commonest being central obesity in 84%). ⁷ Indian data in lean patients with NAFLD suggest that although their total body fat is comparable with lean individuals without NAFLD, they are metabolically unhealthy, with an expanded visceral adipose tissue mass similar to overweight or obese patients with NAFLD. ¹ In addition to metabolic risk factors, studies from India have also suggested the role of small intestinal bacterial overgrowth, endotoxemia, and toll‐like receptor expression in the pathogenesis of NAFLD. ¹⁰ Dietary constituents and cooking medium vary greatly in different geographic regions of India. A substantial proportion of Indians consume a purely vegetarian diet. The influence of diet on the risk for NAFLD is an underexplored area. A small study from the rural area of Maharashtra state suggested that the risk for NAFLD did not differ between those consuming vegetarian and mixed diets. ¹¹

Among the genetic studies, earlier Indian data had suggested the lack of association of NAFLD with HFE gene mutations. ¹ PNPLA3 and TM6SF2 gene polymorphisms have been shown to be closely associated with prevalence and severity of NAFLD in India. A recent exome‐wide association study showed a novel association of nuclear polymorphism rs4788084 with hepatic fat content, which regulates the expression of IL‐27, an immune‐regulatory gene. ¹² A novel variant of phosphatidylethanolamine N‐methyltransferase (involved in fatty acid metabolism), identified using whole‐exome sequencing, was shown to confer a three times greater risk for NAFLD in lean individuals. ¹³ There are some data that suggest that the genetic predisposition to NAFLD may vary according to ancestral ethnicity. A recent study found that the TM6SF2 variant (rs58542926) was significantly associated with NAFLD susceptibility in individuals from South Indian ethnicity (OR, 1.9; 95% confidence interval [CI]: 1.5‐3), while the PNPLA3 variant (rs2281135) conferred a higher risk for NAFLD in those of North East Indian ancestry (OR, 2.7; 95% CI: 1.37‐5.3). ¹⁴ Concomitant variants in both genes were common in patients with NAFLD irrespective of ethnicity, and the authors concluded that the presence of an additional variant compounded the risk for NAFLD. ¹⁴

Diagnosis and Treatment

The diagnosis and treatment of patients with NAFLD in India has largely been on the same lines as suggested by various international societies and Indian National Association for the Study of the Liver. ¹ However, because of the limitations in resources, separate guidelines have been suggested for the management and referral of patients from primary health care level to secondary and tertiary care levels. ¹⁵ , ¹⁶ Among the various noninvasive scores, APRI has been found to be more accurate than FIB‐4 in ruling out significant fibrosis in the community setting. True to the concept of population‐based differences, different cutoffs for the Indian population have been suggested for controlled attenuation parameter, FIB‐4, and FibroScan‐AST scores for the assessment of hepatic steatosis, hepatic fibrosis, and NASH. ¹⁷ , ¹⁸ The large real‐life data from the country suggest that in clinical practice, liver biopsy is not a well‐accepted modality for determining disease severity, and the practice of liver biopsy in NAFLD in India may be restricted to only tertiary care centers. ⁷

Lifestyle interventions are the primary modality for the management of NAFLD and have been shown to improve biochemical and histological outcomes in Indian patients. ¹ A study with paired liver biopsies in 58 morbidly obese patients showed improvement in all histological parameters of NAFLD, including steatosis, ballooning, lobular inflammation, NAFLD Activity Score, and fibrosis, at 1‐year follow‐up after bariatric surgery. ¹⁹ Of various endoscopic bariatric therapies, only a small amount of data for eight patients described the utility of intragastric balloon for inducing weight loss in morbidly obese patients with cirrhosis (4‐cryptogenic cirrhosis) on the transplant wait list. ²⁰ Pharmacotherapy in patients with NASH was earlier restricted to the use of vitamin E and pioglitazone. ¹ However, based on the recent data, the drug controller general of India has approved the use of saroglitazar, a dual peroxisome proliferator‐activated receptor α/γ agonist, in a dosage of 4 mg/day for use in patients with NASH with F1‐3 fibrosis. ²¹ Although not recommended, the data on the use of vitamin D supplementation, high‐potency multistrain probiotic, glucagon‐like peptide‐1 (GLP‐1) agonists, and sodium‐glucose co‐transporter‐2 (SGLT‐2) inhibitors also have been encouraging in Indian patients with NAFLD.

NASH‐related decompensated cirrhosis and HCC are leading indications for liver transplant in India; however, there is a paucity of Indian data on transplant outcomes in patients with NASH. Given the high prevalence of NAFLD among the general population in India, donor steatosis in the living donor liver transplantation program is also a vexing problem. ²²

Prevention and Control

With NAFLD being a lifestyle disease, efforts for prevention and control are required not only at the individual and family level but also at the government and administrative level. The recent integration of NAFLD into the National Program on Prevention and Control of Cancer, Diabetes, Cardiovascular disease and Stroke by the Ministry of Health and Family Welfare of India is an encouraging step in this direction. ¹⁶ In fact, India has become the first country to include NAFLD in one of its national programs.

Conclusion

NAFLD has emerged as a major public health issue in India that is responsible for significant burden of hepatic and extrahepatic disease. Education of healthy lifestyle to children and adolescents in schools and colleges may be the need of the hour. Efforts are also required to change the perception of both physicians and the public toward this ongoing silent pandemic. Although much progress has been witnessed in the last one or two decades in NAFLD research in India, a lot more needs to be done.