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Non-obese histologically confirmed NASH patients with abnormal liver biochemistry have more advanced fibrosis

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Abstract

Background and aims

Non-alcoholic fatty liver disease (NAFLD) commonly affects subjects with obesity, yet non-obese NAFLD is increasingly being recognized. We aimed to investigate the clinicopathological and genetic characteristics of non-obese NAFLD patients.

Methods

The clinical, histological and genetic data of 84 NAFLD patients with biopsy for abnormal liver function test were reviewed. Both NAS-CRN and SAF scoring systems were applied for histopathological evaluation. PNPLA3 and TMS6F2 genotyping were also performed.

Results

All of the 84 patients were histologically diagnosed with non-alcoholic steatohepatitis (NASH), with 36 of them (42.9%) being non-obese (BMI < 25 kg/m2). Compared with the obese group, non-obese group were predominantly females (88.9% vs 52.1%, p < 0.001), tended to have higher prevalence of diabetes (p = 0.068). More importantly non-obese patients had a significant higher prevalence of advanced fibrosis (F ≥ 3) (58.3% vs 29.2%, p = 0.013), and a trend of higher degree of ballooning (p = 0.061). In addition, values of liver stiffness measurement were also significantly higher in non-obese group (12.1 kPa vs 8.1 kPa, p = 0.032). There was also a trend of higher prevalence of TM6SF2 T allele in non-obese group (p = 0.085), while the prevalence of PNPLA3 risk allele did not differ between two groups. Multivariate analysis showed that higher fasting glucose (p = 0.038) and lower serum platelets (p = 0.040) were two independent predictors for advanced fibrosis in non-obese patients.

Conclusions

Non-obese NASH patients have a female predominance and more advanced fibrosis. Liver biopsy is crucial to evaluate the severity of disease in non-obese patients especially those with abnormal liver biochemistry.

Clinical trial number

NCT03386890.

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Abbreviations

NAFLD:

Non-alcoholic fatty liver disease

NASH:

Non-alcoholic steatohepatitis

MetS:

Metabolic syndrome

BMI:

Body mass index

PNPLA3 :

Polymorphisms of patatin-like-phospholipase domain-containing protein 3

TM6SF2 :

Transmembrane 6 superfamily antigen 2

WC:

Waist circumference

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

ALP:

Alkaline phosphatase

GGT:

γ-Glutamyltransferase

CHE:

Cholinesterase

LDL-C:

Low-density lipoprotein cholesterol

HDL-C:

High-density lipoprotein cholesterol

TG:

Triglycerides

UA:

Uric acid

PTA:

Prothrombin activity

HOMA-IR:

Homeostatic model assessment insulin resistance

SBP:

Systolic blood pressure

DBP:

Diastolic blood pressure

FPG:

Fasting plasma glucose

LSM:

Liver stiffness measurements

CAP:

Controlled attenuation parameter

H&E:

Hematoxylin and eosin

NASH CRN:

NASH Clinical Research Network

SD:

Standard deviation

IQR:

Interquartile range

TE:

Transient elastography

References

  1. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease—meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73–84.

    Article  Google Scholar 

  2. Kim D, Kim WR. Nonobese fatty liver disease. Clin Gastroenterol Hepatol. 2017;15:474–85.

    Article  CAS  Google Scholar 

  3. Assy N, Nasser G, Kamayse I, Nseir W, Beniashvili Z, Djibre A, et al. Soft drink consumption linked with fatty liver in the absence of traditional risk factors. Can J Gastroenterol. 2008;22:811–6.

    Article  Google Scholar 

  4. Enjoji M, Yasutake K, Kohjima M, Nakamuta M. Nutrition and nonalcoholic Fatty liver disease: the significance of cholesterol. Int J Hepatol. 2012;2012:925807.

    PubMed  PubMed Central  Google Scholar 

  5. Wei JL, Leung JC, Loong TC, Wong GL, Yeung DK, Chan RS, et al. Prevalence and severity of nonalcoholic fatty liver disease in non-obese patients: a population study using proton-magnetic resonance spectroscopy. Am J Gastroenterol. 2015;110:1306–14 (quiz 1315).

    Article  CAS  Google Scholar 

  6. Vos B, Moreno C, Nagy N, Fery F, Cnop M, Vereerstraeten P, et al. Lean non-alcoholic fatty liver disease (Lean-NAFLD): a major cause of cryptogenic liver disease. Acta Gastroenterol Belg. 2011;74:389–94.

    PubMed  Google Scholar 

  7. Leung JC, Loong TC, Wei JL, Wong GL, Chan AW, Choi PC, et al. Histological severity and clinical outcomes of nonalcoholic fatty liver disease in nonobese patients. Hepatology. 2017;65:54–64.

    Article  CAS  Google Scholar 

  8. Margariti A, Deutsch M, Manolakopoulos S, Tiniakos D, Papatheodoridis GV. The severity of histologic liver lesions is independent of body mass index in patients with nonalcoholic fatty liver disease. J Clin Gastroenterol. 2013;47:280–6.

    PubMed  Google Scholar 

  9. Dela Cruz AC, Bugianesi E, George J, Day CP, Liaquat H, Charatcharoenwitthaya P, et al. Characteristics and long-term prognosis of lean patients with nonalcoholic fatty liver disease. Gastroenterology. 2014;146:S-909.

    Article  Google Scholar 

  10. WHO Expert Consultation. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet. 2004;363:157–63.

    Article  Google Scholar 

  11. Bonora E, Targher G, Alberiche M, Bonadonna RC, Saggiani F, Zenere MB, et al. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity. Diabetes Care. 2000;23:57–63.

    Article  CAS  Google Scholar 

  12. Heng D, Ma S, Lee JJ, Tai BC, Mak KH, Hughes K, et al. Modification of the NCEP ATP III definitions of the metabolic syndrome for use in Asians identifies individuals at risk of ischemic heart disease. Atherosclerosis. 2006;186:367–73.

    Article  CAS  Google Scholar 

  13. Sasso M, Beaugrand M, de Ledinghen V, Douvin C, Marcellin P, Poupon R, et al. Controlled attenuation parameter (CAP): a novel VCTE guided ultrasonic attenuation measurement for the evaluation of hepatic steatosis: preliminary study and validation in a cohort of patients with chronic liver disease from various causes. Ultrasound Med Biol. 2010;36:1825–35.

    Article  Google Scholar 

  14. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21.

    Article  Google Scholar 

  15. Bedossa P, Poitou C, Veyrie N, Bouillot JL, Basdevant A, Paradis V, et al. Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients. Hepatology. 2012;56:1751–9.

    Article  Google Scholar 

  16. Akyuz U, Yesil A, Yilmaz Y. Characterization of lean patients with nonalcoholic fatty liver disease: potential role of high hemoglobin levels. Scand J Gastroenterol. 2015;50:341–6.

    Article  CAS  Google Scholar 

  17. Honda Y, Yoneda M, Kessoku T, Ogawa Y, Tomeno W, Imajo K, et al. Characteristics of non-obese non-alcoholic fatty liver disease: effect of genetic and environmental factors. Hepatol Res. 2016;46:1011–8.

    Article  CAS  Google Scholar 

  18. Kumar R, Rastogi A, Sharma MK, Bhatia V, Garg H, Bihari C, et al. Clinicopathological characteristics and metabolic profiles of non-alcoholic fatty liver disease in Indian patients with normal body mass index: do they differ from obese or overweight non-alcoholic fatty liver disease? Indian J Endocrinol Metab. 2013;17:665–71.

    Article  Google Scholar 

  19. Hagstrom H, Nasr P, Ekstedt M, Hammar U, Stal P, Hultcrantz R, et al. Risk for development of severe liver disease in lean patients with nonalcoholic fatty liver disease: a long-term follow-up study. Hepatol Commun. 2018;2:48–57.

    Article  Google Scholar 

  20. Nishioji K, Sumida Y, Kamaguchi M, Mochizuki N, Kobayashi M, Nishimura T, et al. Prevalence of and risk factors for non-alcoholic fatty liver disease in a non-obese Japanese population, 2011–2012. J Gastroenterol. 2015;50:95–108.

    Article  CAS  Google Scholar 

  21. Das K, Das K, Mukherjee PS, Ghosh A, Ghosh S, Mridha AR, et al. Nonobese population in a developing country has a high prevalence of nonalcoholic fatty liver and significant liver disease. Hepatology. 2010;51:1593–602.

    Article  CAS  Google Scholar 

  22. Cho HC. Prevalence and factors associated with nonalcoholic fatty liver disease in a nonobese Korean population. Gut Liver. 2016;10:117–25.

    Article  Google Scholar 

  23. Sinn DH, Gwak GY, Park HN, Kim JE, Min YW, Kim KM, et al. Ultrasonographically detected non-alcoholic fatty liver disease is an independent predictor for identifying patients with insulin resistance in non-obese, non-diabetic middle-aged Asian adults. Am J Gastroenterol. 2012;107:561–7.

    Article  Google Scholar 

  24. Kim D, Chung GE, Kwak MS, Seo HB, Kang JH, Kim W, et al. Body fat distribution and risk of incident and regressed nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2016;14(132–138):e134.

    Google Scholar 

  25. Yang JD, Abdelmalek MF, Pang H, Guy CD, Smith AD, Diehl AM, et al. Gender and menopause impact severity of fibrosis among patients with nonalcoholic steatohepatitis. Hepatology. 2014;59:1406–14.

    Article  CAS  Google Scholar 

  26. Liu YL, Reeves HL, Burt AD, Tiniakos D, McPherson S, Leathart JB, et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat Commun. 2014;5:4309.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was funded by Beijing Municipal Administration of Hospitals Clinical Medicine Development of special funding support (XMLX201606), The Digestive Medical Coordinated Development Center of Beijing Municipal Administration of Hospitals (XXZ03) and Research Foundation of Beijing Friendship Hospital, Capital Medical University (yyqdkt2017-8).

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Authors and Affiliations

  1. Liver Research Center, Beijing Friendship Hospital, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center of Digestive Diseases, Capital Medical University, 95 Yong-An Road, Xi-Cheng District, Beijing, 100050, China

    Qianyi Wang, Hong You, Xiaojuan Ou, Xinyan Zhao, Yameng Sun, Min Wang, Ping Wang, Yu Wang, Weijia Duan, Xiaoming Wang & Jidong Jia

  2. Clinical Epidemiology and EBM Unit, National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China

    Shanshan Wu & Yuanyuan Kong

  3. Indiana University Health Pathology Laboratory, Department of Pathology, Indiana University School of Medicine, 350 West 11th Street, #4014, Indianapolis, IN, 46202, USA

    Romil Saxena

  4. Department of Pathology and Medical Biology, University Medical Center Groningen, Hanzeplein 1, PO Box 30.001, 9700 RB, Groningen, The Netherlands

    Annette S. H. Gouw

Authors
  1. Qianyi Wang
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  2. Hong You
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  6. Min Wang
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  8. Yu Wang
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  14. Annette S. H. Gouw
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  15. Jidong Jia
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Contributions

Study design: JJ, RS, ASHG, HY. Data collection: QW, MW, XO, YW, WD, XW. Liver biopsy assessment: XZ, RS, ASHG. Statistical analysis: QW, YS, YK, SW. Manuscript writing: QW. Genotype analysis: PW, QW, MW. Critical revision of the manuscript: HY, JJ, RS, ASHG.

Corresponding authors

Correspondence to Romil Saxena, Annette S. H. Gouw or Jidong Jia.

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Conflict of interest

Qianyi Wang, Hong You, Xiaojuan Ou, Xinyan Zhao, Yameng Sun, Min Wang, Ping Wang, Yu Wang, Weijia Duan, Xiaoming Wang, Shanshan Wu, Yuanyuan Kong, Romil Saxena, Annette S. H. Gouw, Jidong Jia declare that they have no conflicts of interest.

Ethical approval

The study was conducted in accordance with the Declaration of Helsinki. The study protocol was approved by the institutional Ethics Committee (Ethical approval no. 2015-P2-070-01). All patients signed informed consent for liver biopsy and blood sample storage.

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Romil Saxena, Annette S. H. Gouw and Jidong Jia share co-corresponding authorship.

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Wang, Q., You, H., Ou, X. et al. Non-obese histologically confirmed NASH patients with abnormal liver biochemistry have more advanced fibrosis. Hepatol Int 13, 766–776 (2019). https://doi.org/10.1007/s12072-019-09982-z

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  • DOI: https://doi.org/10.1007/s12072-019-09982-z

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