Characterizing Nonalcoholic Fatty Liver Disease (NAFLD) in Lean Individuals at a Tertiary Care Hospital: A Cross-sectional Study

INTRODUCTION

In terms of chronic liver illness, steatosis belongs to one of the most common causes. Non-alcoholic fatty liver disease (NAFLD) prevalence has risen significantly, increasing from 25% between 1990 and 2006 to 38% from 2016 to 2019, and the trend is not declining ^1,2 This has made it most especially common and the leading reason for liver transplants in the US ^3,4 Non-alcoholic fatty liver disease encompasses a broad range of conditions, from mild fatty liver to more advanced stages like steatohepatitis, cirrhosis, and hepatocellular carcinoma.^5,6 Previously only associated with obesity, NAFLD can also develop in people who appear to be at a healthy body weight, an entity known as lean NAFLD that accounts for around 20% of NAFLD patients.⁷ Being obese is the primary risk factor; nevertheless, the identification of NAFLD in non-obese persons has risen since its first documentation in Asian populations and subsequently observed in European and US populations.⁸

According to two comprehensive studies, the global rates of non-obese and lean fatty liver illness are estimated at 12.1% and 5.1%, respectively. The highest incidence of lean NAFLD was observed in Asia, with a rate of 4.8%, followed by Oceania at 3.5%, and North America at 3.1%. Europe reported the lowest prevalence (2.2%). By country, the United States has the lowest prevalence of lean NAFLD at 3.1%, while China has the highest at 5.5%.^5,9 Initially, lean NAFLD was believed to be comparatively benign with favorable outcomes compared to overweight or obese NAFLD patients. However, as seen in other studies, higher rates of mortality have been reported for lean NAFLD.^7,10,11

A healthy weight is defined by a body mass index (BMI) of 18.5 – 24.9 kg/m², while a BMI over 30 kg/m² is considered obese.¹² For non-Asian populations, similar BMI standards apply, but the criteria for Asian individuals are adjusted, with normal weight classified as a BMI of 18.5–22.9 kg/m² and obesity defined as a BMI above 25 kg/m². Furthermore, waist circumference measurements deemed abnormal are set at 102 cm or more for men and 88 cm or more for women among non-Asians, whereas for Asians, these thresholds are reduced to 85 cm for men and between 74 and 80 cm for women.¹³

This study investigates lean fatty liver disease and evaluates BMI standards from both Asian and Western perspectives. It also reviews the diagnostic criteria for metabolic dysfunction-associated fatty liver disease (MAFLD) and metabolic dysfunction-associated steatotic liver disease (MASLD) for lean individuals and aims to enhance the identification and classification of lean steatotic in our population. Additionally, fatty liver disease now serves as a broad term for various types of steatosis, and non-alcoholic steatohepatitis (NASH), that has evolved into metabolic dysfunction-associated steatohepatitis (MASH).^14,15

MATERIALS AND METHODS

This prospective cross-sectional investigation, executed between January 2023 and March 2024, enrolled 111 individuals aged 18–85 years who were diagnosed with fatty liver disease. The diagnosis was confirmed using ultrasonography, which revealed increased echogenicity of the liver parenchyma, impaired intrahepatic artery visibility, and diaphragm-related changes. To quantify liver fibrosis and fat accumulation, vibration-controlled transient elastography (VCTE) was done using FibroTouch® equipment from HiSKY Medical Technologies.¹⁶ Control attenuation parameters (CAP) and liver stiffness measures (LSM) were applied to determine the degree of fat and scarring. The sample was estimated based on an anticipated lean fatty liver disease prevalence of 5%, with a 95% confidence level and a 5% margin of error.¹⁷ To account for probable dropouts and non-compliance, a total of 111 participants were recruited. Participants with a BMI up to 25 kg/m² were included, except for those with secondary causes of hepatic steatosis or fibrosis, such as autoimmune liver diseases, Wilson’s disease, drug-induced hepatic steatosis, viral hepatitis (hepatitis B or C), pregnancy, or excessive alcohol intake (>30 g/day for men and >20 gm/day for women).^18–21 Elevated ALT levels were over 33 IU/L for males and 19–25 IU/L for women.²²

To establish a diagnosis of MAFLD, we followed the 2020 expert consensus, which requires proof of hepatic steatosis (detected via ultrasonography or VCTE) and one of the following: overweight/obesity (BMI ≥ 25 kg/m²) or lean/normal weight (BMI ≤ 25 kg/m²) along with metabolic dysregulation.²³ Metabolic dysregulation was defined by the presence of at least two factors such as type 2 diabetes, high blood pressure (≥130/85 mm Hg), elevated triglycerides (>150 mg/dL), low high-density lip protein (HDL) cholesterol (<40 mg/dL for men and <50 mg/dL for women), or prediabetes (fasting glucose 100–125 mg/dL or HbA1c 5.7–6.4%). In contrast, the 2023 MASLD criteria required hepatic steatosis and at least one metabolic abnormality, with different BMI cutoffs for Asians (BMI ≥ 23 kg/m²).¹⁵ The study collected data on demographics, such as age, gender, height, weight, BMI, and waist circumference. Laboratory profiles included various parameters like hemoglobin, ALT, AST, alkaline phosphatase, albumin, cholesterol levels, triglycerides, and uric acid HOMA-IR (cutoff of 2 for insulin resistance),²⁴ APRI, NAFLD fibrosis score, FIB-4 Index, CAP, and LSM (kPa) were compared between MASLD-MAFLD and MASLD alone, as well as between normal BMI by Asian criteria (BMI ≤ 23 kg/m²) and normal BMI by Western criteria but overweight by Asian BMI (≥ 23 kg/m² ≤ 25 kg/m²). Fibrosis was assessed via liver stiffness, and steatosis was evaluated using CAP. CAP values were categorized as follows: <247 dB/m (S0, normal liver, <5% fat), 247–280 dB/m (S1, mild fatty liver, 5–33% fat), 280–299 dB/m (S2, moderate fatty liver, 34–66% fat), and >299 dB/m (S3, severe fatty liver, >67% fat).¹⁶ Liver stiffness cutoffs were 6.3 kPa for stage F2, 8.3 kPa for F3, and 10.5 kPa for F4.²⁵

Continuous data presented as frequencies and percentages. To explore associations between categorical variables, we applied the Chi-square test. For comparisons of continuous variables between groups, the Student’s t-test (with appropriate adjustments) was used. Correlations between metabolic parameters) were analyzed using Spearman’s rank correlation for non-parametric data and Pearson’s correlation coefficient (PCC) for parametric data. A p-value of less than 0.05 was considered statistically significant across all analyses. All statistical analyses were conducted using SPSS software (version 26, IBM, Armonk, NY, USA).

RESULTS

The baseline features of 111 people diagnosed with NAFLD are presented in Table 1. Among the participants, the males were 92 (83%). Diagnosis modalities included ultrasonography for 37 (33%) and FibroScan for 74 (67%) individuals. The average age of the participants was 43.3 ± 13.2 years, and the mean waist circumference was 88.2 ± 8.4 cm). Among the males, 45 (40%) had a waist circumference greater than 90 cm, while among females, 13 (12%) exceeded 80 cm. Common comorbidities included diabetes mellitus 18 (16%), hypertension 12 (11%), and ischemic heart disease 2 (2%).

The laboratory profiles revealed an average hemoglobin of 13.2 ± 1.7, white blood cell count of 6.2 ± 2.1, and platelet count of 250.4 ± 82.6. Bilirubin levels averaged 0.71 ± 0.56, ALT levels averaged 55.0 ± 37.4, with 53% of patients exhibiting elevated ALT. Aspartate aminotransferase averaged 36.0 ± 20.0, gamma-glutamyl transferase (GGT) 56.6 ± 50.4), and ALP 103.2 ± 60.9. Albumin levels were on average 3.8 ± 0.43, cholesterol 182.4 ± 39.7 with 68% showing elevated levels, and triglycerides 180.0 ± 110.7 with half of the patients showing elevated levels. High-density lipoprotein averaged 36.6 ± 12.9 with 52% having low HDL levels, and low-density lipoprotein (LDL) averaged 101.6 ± 36.4. Very low-density lipoprotein (VLDL) levels averaged 39.6 ± 31.3. Fasting insulin were 17.5 ± 9.3 and fasting blood sugar (FBS) levels 105.3 mg/dL ± 37.4, with half of the patients having FBS above 100 mg/dL. The homeostatic model assessment for insulin resistance (HOMA-IR) averaged 3.5 ± 2.9, with 65% of patients showing a HOMA-IR of 2 or higher. The mean creatinine was 0.87 ± 0.19 and uric acid 5.4 ± 1.3. The NAFLD fibrosis score averaged 1.6 ± 0.87 and the FIB-4 Index 1.0 ± 0.71. The CAP was 274.8 ± 57.0, and liver stiffness averaged 11.5 ± 26.9, with 26% showing stiffness greater than 7.9 kPa. The aspartate aminotransferase to platelet ratio index (APRI) averaged 0.65 ± 0.55.

All participants met the MASLD diagnostic criteria, yet 18 lean NAFLD patients did not meet the MAFLD criteria and were classified as MASLD-Alone. Comparisons between the MASLD-MAFLD and MASLD-Alone groups showed significant differences in elevated triglycerides and HOMA-IR, both with p-values less than 0.05 (Table 2).

Further comparisons between those with a normal BMI under Asia Pacific criteria (BMI ≤ 23) and those with a normal non-Asian BMI but considered overweight by Asia Pacific standards (BMI between 23 and ≤25) indicated significant differences in waist circumference and insulin resistance, also with p-values below 0.05, while fibrosis measurements via noninvasive tests such as CAP, FIB-4 Index, and NAFLD Fibrosis scores showed no significant differences (Table 3). Pearson correlation analysis conducted to explore the relationships among clinical and biochemical parameters in lean NAFLD patients highlighted significant positive correlations among cardiometabolic risk factors, HOMA-IR, CAP, FIB-4 Index, and NAFLD Fibrosis score, all with p-values less than 0.001.

DISCUSSION

This study underscores the prevalence and clinical characteristics of lean NAFLD, aligning with global observations. Predominantly affecting males, this condition manifests at an earlier age in our study population than typically seen in Western counterparts.²⁶ Non-alcoholic fatty liver disease is emerging as a significant contributor to liver disease mortality in Pakistan, although detailed national data remain unavailable. The incidence varies from 9 to 27% in rural regions to 21–42% in metropolitan areas.²⁷ Studies from Asia report the prevalence of NAFLD among those with a BMI below 25 kg/m² ranging from 7.0 to 20.0%.^28–31 When comparing MASLD-MAFLD and MASLD-Alone groups, individuals meeting MASLD-MAFLD criteria exhibited a broader spectrum of clinical and metabolic dysregulations, including a large proportion with low HDL, insulin resistance, and more than three cardiometabolic abnormalities. The MAFLD criteria identify individuals with higher metabolic risk profiles and more advanced disease since it requires at least two metabolic abnormalities, whereas MASLD requires only one risk abnormality.³² However, MASLD may lead to overdiagnosis in individuals with lower metabolic risks, and MAFLD may underdiagnose or misclassify cases, as noted by Ramírez-Mejía MM et al., who called for further research to validate both criteria globally.³³

Another study from India found that many lean individuals are missed under the MAFLD criteria, suggesting that MASLD criteria are more applicable to lean patients.³⁴ Our research did not uncover significant differences in hepatic fibrosis measures between the two criteria, showing none is better in diagnosing liver fibrosis in lean people. A substantial number of lean NAFLD patients had elevated ALT with most meeting the criteria for MASH. We included individuals who were overweight by Asian BMI criteria but normal by Western standards, with 61% of lean NAFLD patients having a BMI between 23 and ≤25 kg/m².³⁵ These patients exhibited significant metabolic dysregulation, notably elevated triglycerides and insulin resistance. Insulin insensitivity is a key factor in the development of lean fatty liver illness.³⁶ Our findings suggest that the MASLD criteria were more inclusive and effective in identifying lean NAFLD patients, while the MAFLD criteria captured a broader spectrum of metabolic dysfunctions. In the MASLD-MAFLD group, there were significantly higher levels of elevated triglycerides, HOMA-IR, and the presence of three or more cardiometabolic risk factors when compared to the MASLD-alone group (p < 0.05). The definitions of normal weight and obesity differ slightly between Asian and non-Asian populations.^5,10 Our findings suggest that adopting Western BMI criteria for Asian populations may better reflect metabolic health, as no significant statistical differences were observed in key parameters between classifications. Western BMI criteria appear to encompass metabolic dysregulation more comprehensively, which is crucial for the early identification and management of lean or mildly overweight NAFLD patients. Given the genetic similarities between South Asia and Europe due to migration over the past 8,000 years, we recommend using Western BMI classification for South Asian populations in Pakistan and Northern India to increase lean NAFLD identification.³⁷

Regular screening for NAFLD in lean individuals, particularly those with metabolic risk factors, is essential for early diagnosis and intervention. Enhancing healthcare provider awareness about lean NAFLD prevalence and its metabolic implications can improve patient outcomes through timely and appropriate management strategies. Our study has some limitations, such as its single-centered, a relatively small number of participants, and the lack of liver biopsies.

CONCLUSION

Lean NAFLD is a substantial health problem in Asian people. Our analysis underlines the necessity of a holistic strategy to detecting and addressing lean NAFLD. It proposes for adopting Western BMI criteria for the diagnosis of lean NAFLD in Asian populations may promote early identification of persons at risk for metabolic problems. While the MAFLD criteria better catch patients with a wider range of metabolic risk abnormalities. Additional multicenter investigations with larger sample size are necessary to confirm these findings for adopting adequate diagnostic criteria for lean NAFLD in our community.

REFERENCES

1. Younossi ZM, Golabi P, Paik JM, et al. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): A systematic review. Hepatology 2023;77(4):1335–1347. DOI: 10.1097/HEP.0000000000000004.

2. Le MH, Le DM, Baez TC, et al. Global incidence of non-alcoholic fatty liver disease: A systematic review and meta-analysis of 63 studies and 1,201,807 persons. Journal of Hepatology 2023;79(2):287–295. DOI: 10.1016/j.jhep.2023.03.040.

3. Younossi ZM, Stepanova M, Ong J, et al. Nonalcoholic steatohepatitis is the most rapidly increasing indication for liver transplantation in the United States. Clinical Gastroenterology and Hepatology 2021;19(3):580–589. DOI: 10.1016/j.cgh.2020.05.064.

4. Holmer M, Melum E, Isoniemi H, et al. Nonalcoholic fatty liver disease is an increasing indication for liver transplantation in the Nordic countries. Liver International 2018;38(11):2082–2090. DOI: 10.1111/liv.13751.

5. Ye Q, Zou B, Yeo YH, et al. Global prevalence, incidence, and outcomes of non-obese or lean non-alcoholic fatty liver disease: A systematic review and meta-analysis. The lancet Gastroenterology & Hepatology 2020;5(8):739–752. DOI: 10.1016/S2468-1253(20)30077-7.

6. Golabi P, Paik JM, AlQahtani S, et al. Burden of non-alcoholic fatty liver disease in Asia, the Middle East and North Africa: Data from Global Burden of Disease 2009-2019. Journal of hepatology. 2021;75(4):795–809. DOI: 10.1016/j.jhep.2021.05.022.

7. Leung JC, Loong TC, Wei JL, et al. Histological severity and clinical outcomes of nonalcoholic fatty liver disease in nonobese patients. Hepatology 2017;65(1):54–64. DOI: 10.1002/hep.28697.

8. Younes R, Bugianesi E. NASH in lean individuals. In Seminars in liver disease. New York: Thieme Medical Publishers. 2019;(39)1: pp. 86–95.

9. Lu FB, Zheng KI, Rios RS, et al. Global epidemiology of lean non‐alcoholic fatty liver disease: A systematic review and meta‐analysis. Journal of gastroenterology and hepatology. 2020;35(12):2041–2050. DOI: 10.1111/jgh.15156.

10. Weinberg EM, Trinh HN, Firpi RJ, et al. Lean Americans with nonalcoholic fatty liver disease have lower rates of cirrhosis and comorbid diseases. Clinical Gastroenterology and Hepatology. 2021;19(5):996–1008.

11. Cruz AC, Bugianesi E, George J, et al. 379 characteristics and long-term prognosis of lean patients with nonalcoholic fatty liver disease. Gastroenterology 2014;146(5):S-909. DOI: 10.1016/S0016-5085(14)63307-2.

12. Tan KC. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. The lancet. 2004;363(9403):157–163. DOI: 10.1016/S0140-6736(03)15268-3.

13. Garvey WT, Mechanick JI, Brett EM, et al. American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity. Endocr Prac 2016;22(Suppl 3):1–203. DOI: 10.4158/EP161365.GL.

14. Eslam M, Newsome PN, Sarin SK, et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. Journal of Hepatology 2020;73(1):202–209. DOI: 10.1016/j.jhep.2020.03.039.

15. Rinella ME, Lazarus JV, Ratziu V, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology 2023;78(6):1966–1986. DOI: 10.1097/HEP.0000000000000520.

16. Lee HW, Park SY, Kim SU, et al. Discrimination of nonalcoholic steatohepatitis using transient elastography in patients with nonalcoholic fatty liver disease. PloS one 2016;11(6):e0157358. DOI: 10.1371/journal.pone.0157358.

17. Charan J, Biswas T. How to calculate sample size for different study designs in medical research? Indian journal of psychological medicine 2013;35(2):121–126. PMID: 24049221.

18. Ebrahimi F, Hagström H, Sun J, et al. Familial coaggregation of MASLD with hepatocellular carcinoma and adverse liver outcomes: Nationwide multigenerational cohort study. Journal of Hepatology 2023;79(6):1374–1384. DOI: 10.1016/j.jhep.2023.08.018.

19. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non‐alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012;55(6):2005–2023. DOI: 10.1002/hep.25762.

20. Siddiqui MS, Harrison SA, Abdelmalek MF, et al. Case definitions for inclusion and analysis of endpoints in clinical trials for nonalcoholic steatohepatitis through the lens of regulatory science. Hepatology 2018;67(5):2001-2012. DOI: 10.1002/hep.29607.

21. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018;67(1):328–357. DOI: 10.1002/hep.29367.

22. Kwo PY, Cohen SM, Lim JK. ACG clinical guideline: evaluation of abnormal liver chemistries. Am J Gastroenterol 2017;112(1):18–35. DOI: DOI.10.1038/ajg.2016.517.

23. Eslam M, Sanyal AJ, George J, et al. MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology 2020;158(7):1999–2014. DOI: 10.1053/j.gastro.2019.11.312.

24. Ghasemi A, Tohidi M, Derakhshan A, et al. Cut-off points of homeostasis model assessment of insulin resistance, beta-cell function, and fasting serum insulin to identify future type 2 diabetes: Tehran Lipid and Glucose Study. Acta diabetologica 2015;52(5):905–915. DOI: 10.1007/s00592-015-0730-3.

25. Cassinotto C, Boursier J, de Lédinghen V, et al. Liver stiffness in nonalcoholic fatty liver disease: A comparison of supersonic shear imaging, FibroScan, and ARFI with liver biopsy. Hepatology. 2016;63(6):1817–1827. DOI: 10.1002/hep.28394.

26. Singh S, Kuftinec GN, Sarkar S. Non-alcoholic fatty liver disease in South Asians: A review of the literature. Journal of Clinical and Translational Hepatology 2017;5(1):76–81. PMID: 28507930.

27. Pati GK, Singh SP. Nonalcoholic fatty liver disease in South Asia. Euroasian Journal of Hepato-gastroenterology 2016;6(2):154. DOI: 10.5005/jp-journals-10018-1189.

28. Fan JG, Kim SU, Wong VW. New trends on obesity and NAFLD in Asia. Journal of Hepatology 2017;67(4):862–873. DOI: 10.1016/j.jhep.2017.06.003.

29. Seto WK, Yuen MF. Nonalcoholic fatty liver disease in Asia: Emerging perspectives. Journal of Gastroenterology 2017;52:164–174. DOI: 10.1007/s00535-016-1264-3.

30. VanWagner LB, Armstrong MJ. Lean NAFLD: A not so benign condition? Hepatology communications 2018;2(1):5–8. DOI: 10.1002/hep4.1143.

31. Wei JL, Leung JC, Loong TC, et al. Prevalence and severity of nonalcoholic fatty liver disease in non-obese patients: a population study using proton-magnetic resonance spectroscopy. Official journal of the American College of Gastroenterology ACG. 2015;110(9):1306–1314. DOI: 10.1038/ajg.2015.235.

32. Lin SU, Huang J, Wang M, et al. Comparison of MAFLD and NAFLD diagnostic criteria in real world. Liver international. 2020;40(9):2082–2089. DOI: 10.1111/liv.14548.

33. Ramírez-Mejía MM, Jiménez-Gutiérrez C, Eslam M, et al. Breaking new ground: MASLD vs. MAFLD—which holds the key for risk stratification? Hepatology International 2024;18(1):168–178. DOI: 10.1007/s12072-023-10620-y.

34. De A, Bhagat N, Mehta M, et al. Metabolic dysfunction-associated steatotic liver disease (MASLD) definition is better than MAFLD criteria for lean patients with NAFLD. Journal of hepatology. 2024;80(2):e61–e62. DOI: 10.1016/j.jhep.2023.07.031.

35. Young S, Tariq R, Provenza J, et al. Prevalence and profile of nonalcoholic fatty liver disease in lean adults: systematic review and meta‐analysis. Hepatology communications 2020;4(7):953–972. DOI: 10.1002/hep4.1519.

36. Hill MA, Yang Y, Zhang L, et al. Insulin resistance, cardiovascular stiffening and cardiovascular disease. Metabolism 2021;119:154766. DOI: 10.1016/j.metabol.2021.154766.

37. Narasimhan VM, Patterson N, Moorjani P, et al. The formation of human populations in South and Central Asia. Science 2019;365(6457): eaat7487. DOI: 10.1126/science.aat7487.