The Prevalence of Advanced Liver Fibrosis among Patients with Type 2 Diabetes Mellitus: A Single-Centre Experience in Penang, Malaysia

Xe Hui Lee; Lisa Mohamed Nor; Choon Seong Ang; Toh Peng Yeow; Shueh Lin Lim

doi:10.15605/jafes.038.01.08

Authors

Xe Hui Lee Penang General Hospital, Penang, Malaysia https://orcid.org/0000-0002-9976-7505
Lisa Mohamed Nor Putrajaya Hospital, Wilayah Persekutuan Putrajaya, Malaysia
Choon Seong Ang Penang General Hospital, Penang, Malaysia
Toh Peng Yeow Penang General Hospital, Penang, Malaysia
Shueh Lin Lim Penang General Hospital, Penang, Malaysia https://orcid.org/0000-0003-0369-1954

DOI:

https://doi.org/10.15605/jafes.038.01.08

Keywords:

type 2 diabetes mellitus, Non-alcoholic Fatty Liver disease, Advanced Liver Fibrosis, transient elastography, FIB-4 Index

Abstract

Objectives. This study aimed to compare the severity of COVID-19, inflammatory parameters and clinical outcomes
among patients with normal and subnormal levels of Vitamin D.

Methodology. This is a retrospective cohort study of 135 patients admitted in a tertiary hospital for COVID-19. Patients
were grouped according to their Vitamin D level. Primary outcome measure was the composite of all-cause mortality and
morbidity. Other outcome measures determined were the comparison among the groups on the severity of COVID-19
infection, changes in inflammatory parameters, length of hospital stay and duration of respiratory support.

Results. There was a significant trend of higher ICU admission, mortality (p-value= 0.006) and poor clinical outcome
(p-value=0.009) among the Vitamin D deficient group. No significant difference was found for most of the inflammatory
parameters, duration of hospital stay and respiratory support. Overall, patients with deficient, but not insufficient Vitamin
D level had 6 times higher odds of composite poor outcome than those with normal Vitamin D (crude OR=5.18, p-value=
0.003; adjusted OR =6.3, p-value=0.043).

Conclusion. The inverse relationship between Vitamin D level and poor composite outcome observed in our study
suggests that low Vitamin D may be a risk factor for poor prognosis among patients admitted for COVID-19.

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Author Biographies

Xe Hui Lee, Penang General Hospital, Penang, Malaysia

Consultant Endocrinologist, Endocrinology Unit, Department of Medicine

Lisa Mohamed Nor, Putrajaya Hospital, Wilayah Persekutuan Putrajaya, Malaysia

Research Medical Officer, Clinical Research Centre

Choon Seong Ang, Penang General Hospital, Penang, Malaysia

Research Medical Officer, Clinical Research Centre

Toh Peng Yeow, Penang General Hospital, Penang, Malaysia

Senior Consultant Endocrinologist, Department of Medicine

Shueh Lin Lim, Penang General Hospital, Penang, Malaysia

Senior Consultant Endorinologist, Endocrinology Unit

References

Kuchay MS, Krishan S, Mishra SK, et al. Effect of empagliflozin on liver fat in patients with type 2 diabetes and nonalcoholic fatty liver disease: A randomized controlled trial (E-LIFT Trial). Diabetes Care. 2018;41(8):1801-8. https://pubmed.ncbi.nlm.nih.gov/29895557. https://doi.org/10.2337/dc18-0165.

Wong VW, Wong GL, Yeung DK, et al. Incidence of non-alcoholic fatty liver disease in Hong Kong: A population study with paired proton-magnetic resonance spectroscopy. J Hepatol. 2015;62(1):182-9. https://pubmed.ncbi.nlm.nih.gov/25195550. https://doi.org/10.1016/j.jhep.2014.08.041.

Wong VW, Wong GL, Choi PC, et al. Disease progression of non-alcoholic fatty liver disease: A prospective study with paired liver biopsies at 3 years. Gut. 2010;59(7):969-74. https://pubmed.ncbi.nlm.nih.gov/20581244. https://doi.org/10.1136/gut.2009.205088.

Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology. 2010;51(6):1972-8. https://pubmed.ncbi.nlm.nih.gov/20209604. https://doi.org/10.1002/hep.23527.

Bhala N, Angulo P, van der Poorten D, et al. The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: An international collaborative study. Hepatology. 2011;54(4):1208-16. https://pubmed.ncbi.nlm.nih.gov/21688282. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3238674. https://doi.org/10.1002/hep.24491.

Wong RJ, Aguilar M, Cheung R, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology. 2015;148(3):547-55. https://pubmed.ncbi.nlm.nih.gov/25461851. https://doi.org/10.1053/j.gastro.2014.11.039.

Wong RJ, Cheung R, Ahmed A. Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S. Hepatology. 2014;59(6):2188-95. https://pubmed.ncbi.nlm.nih.gov/25461851. https://doi.org/10.1053/j.gastro.2014.11.039.

Lai LL, Wan Yusoff WNI, Vethakkan SR, Nik Mustapha NR, Mahadeva S, Chan WK. Screening for non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus using transient elastography. J Gastroenterol Hepatol. 2019;34(8):1396-1403. https://pubmed.ncbi.nlm.nih.gov/30551263. https://doi.org/10.1111/jgh.14577.

Kwok R, Choi KC, Wong GL, et al. Screening diabetic patients for non-alcoholic fatty liver disease with controlled attenuation parameter and liver stiffness measurements: A prospective cohort study. Gut 2016;65(8):1359-68. https://pubmed.ncbi.nlm.nih.gov/25873639. https://doi.org/10.1136/gutjnl-2015-309265.

European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388-402. https://pubmed.ncbi.nlm.nih.gov/27062661. https://doi.org/10.1016/j.jhep.2015.11.004.

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):328-57. https://pubmed.ncbi.nlm.nih.gov/28714183. https://doi.org/10.1002/hep.29367.

Fallatah HI. Noninvasive biomarkers of liver fibrosis: An overview. Adv Hepatol. 2014:2014:Article ID 357287. https://doi.org/10.1155/2014/357287.

Machado MV, Cortez-Pinto H. Non-invasive diagnosis of non-alcoholic fatty liver disease. A critical appraisal. J Hepatol. 2013;58(5):1007-19. https://pubmed.ncbi.nlm.nih.gov/23183525. https://doi.org/10.1016/j.jhep.2012.11.021.

Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: Natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med. 2011;43(8):617-49. https://pubmed.ncbi.nlm.nih.gov/21039302. https://doi.org/10.3109/07853890.2010.518623.

Castera L. Non-invasive methods to assess liver disease in patients with hepatitis B or C. Gastroenterology. 2012;142(6):1293-302.e4. https://pubmed.ncbi.nlm.nih.gov/22537436. https://doi.org/10.1053/j.gastro.2012.02.017.

Shah AG, Lydecker A, Murray K, et al. Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2009;7(10):1104-12. https://pubmed.ncbi.nlm.nih.gov/19523535. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3079239. https://doi.org/10.1016/j.cgh.2009.05.033.

Boursier J, Zarski JP, de Ledinghen V, et al. Determination of reliability criteria for liver stiffness evaluation by transient elastography. Hepatology 2013;57(3):1182-91. https://pubmed.ncbi.nlm.nih.gov/22899556. https://doi.org/10.1002/hep.25993.

de Lédinghen V, Vergniol J. Transient elastography (FibroScan). Gastroenterol Clin Bio. 2008;32(6 Suppl 1):58-67. https://pubmed.ncbi.nlm.nih.gov/18973847. https://doi.org/10.1016/S0399-8320(08)73994-0.

Castéra L, Foucher J, Bernard PH, et al. Pitfalls of liver stiffness measurement: A 5-year prospective study of 13,369 examinations. Hepatology. 2010;51(3):828-35. https://pubmed.ncbi.nlm.nih.gov/20063276. https://doi.org/10.1002/hep.23425.

Wong VW, Vergniol J, Wong GL, et al. Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease. Hepatology. 2010;51(2):454-62. https://pubmed.ncbi.nlm.nih.gov/20101745. https://doi.org/10.1002/hep.23312.

Wong VW, Vergniol J, Wong GL, et al. Liver stiffness measurement using XL probe in patients with nonalcoholic fatty liver disease. Am J Gastroenterol. 2012;107(12):1862-71. https://pubmed.ncbi.nlm.nih.gov/23032979. https://doi.org/10.1038/ajg.2012.331.

Castera L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography. J Hepatol 2008;48(5):835–47. https://pubmed.ncbi.nlm.nih.gov/18334275. https://doi.org/10.1016/j.jhep.2008.02.008.

Nahon P, Kettaneh A, Tengher-Barna I, et al. Assessment of liver fibrosis using transient elastography in patients with alcoholic liver disease. J Hepatol. 2008;49(6):1062-8. https://pubmed.ncbi.nlm.nih.gov/18930329. https://doi.org/10.1016/j.jhep.2008.08.011.

Nguyen-Khac E, Chatelain D, Tramier B, et al. Assessment of asymptomatic liver fibrosis in alcoholic patients using fibroscan: Prospective comparison with seven non-invasive laboratory tests. Aliment Pharmacol Ther. 2008;28(10):1188-98. https://pubmed.ncbi.nlm.nih.gov/18705692. https://doi.org/10.1111/j.1365-2036.2008.03831.x.

Sterling RK, Lissen E, Clumeck N, et al.; APRICOT Clinical Investigators. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43(6):1317-25. https://pubmed.ncbi.nlm.nih.gov/16729309. https://doi.org/10.1002/hep.21178.

de Lédinghen V, Vergniol J, Gonzalez C, et al. Screening for liver fibrosis by using FibroScan(®) and FibroTest in patients with diabetes. Dig Liver Dis. 2012;44(5):413-8. https://pubmed.ncbi.nlm.nih.gov/22285146. https://doi.org/10.1016/j.dld.2011.12.005.

Roulot D, Roudot-Thoraval F, NKontchou G, et al. Concomitant screening for liver fibrosis and steatosis in French type 2 diabetic patients using Fibroscan. Liver Int. 2017;37(12):1897-1906. https://pubmed.ncbi.nlm.nih.gov/28556413. https://doi.org/10.1111/liv.13481.

Sporea I, Mare R, Lupușoru R, et al. Liver stiffness evaluation by transient elastography in type 2 diabetes mellitus patients with ultrasound-proven steatosis. J Gastrointestin Liver Dis. 2016;25(2):167-74. https://pubmed.ncbi.nlm.nih.gov/27308647. https://doi.org/10.15403/jgld.2014.1121.252.lsf.

Zhao H, Song X, Li Z, Wang X. Risk factors associated with nonalcohol fatty liver disease and fibrosis among patients with type 2 diabetes mellitus. Medicine (Baltimore). 2018;97(37):e12356. https://pubmed.ncbi.nlm.nih.gov/30212992. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156034. https://doi.org/10.1097/MD.0000000000012356.

Metcalfe C. Biostatistics: A foundation for analysis in the health sciences, 7th ed. Wayne W. Daniel, Wiley. Stat Med. 2001;20(2):324-6. https://doi.org/10.1002/1097-0258(20010130)20:2<324::AID-SIM635>3.0.CO;2-O.

National Institutes of Health, Ministry of Health Malaysia. None-communicable diseases, healthcare demand, and health literacy. National Health and Morbidity Survey 2019. Accessed September 20, 2020. http://mpaeds.my/national-health-and-morbidity-survey-2019.

WHO Expert Consultation. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet. 2004;363(9403):157-63. https://pubmed.ncbi.nlm.nih.gov/4726171. https://doi.org/10.1016/S0140-6736(03)15268-3.

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):328-57. https://pubmed.ncbi.nlm.nih.gov/28714183. https://doi.org/10.1002/hep.29367.

Boursier J, Calès P. Controlled attenuation parameter (CAP): A new device for fast evaluation of liver fat? Liver Int. 2012;32(6):875-7. https://pubmed.ncbi.nlm.nih.gov/22672640. https://doi.org/10.1111/j.1478-3231.2012.02824.x.

Wong VW, Chan WK, Chitturi S, et al. Asia-Pacific working party on non-alcoholic fatty liver disease guidelines 2017-part 1: Definition, risk factors and assessment. J Gastroenterol Hepatol. 2018;33(1):70-85. https://pubmed.ncbi.nlm.nih.gov/28670712. https://doi.org/10.1111/jgh.13857.

Ekstedt M, Hagström H, Nasr P, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology. 2015;61(5):1547-54. https://pubmed.ncbi.nlm.nih.gov/25125077. https://doi.org/10.1002/hep.27368.

Angulo P, Machado MV, Diehl AM. Fibrosis in nonalcoholic Fatty liver disease: Mechanisms and clinical implications. Semin Liver Dis. 2015;35(2):132-45. https://pubmed.ncbi.nlm.nih.gov/25974899. https://doi.org/10.1055/s-0035-1550065.

Stål P. Liver fibrosis in non-alcoholic fatty liver disease - diagnostic challenge with prognostic significance. World J Gastroenterol. 2015;21(39):11077-87. https://pubmed.ncbi.nlm.nih.gov/26494963. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4607906. https://doi.org/10.3748/wjg.v21.i39.11077.

Hagström H, Nasr P, Ekstedt M, et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J Hepatol. 2017;67(6):1265-73. https://pubmed.ncbi.nlm.nih.gov/28803953. https://doi.org/10.1016/j.jhep.2017.07.027.

AURORA: Phase 3 study for the efficacy and safety of Cenicriviroc (CVC) for the treatment of liver fibrosis in adults with nonalcoholic steatohepatitis (NASH) (AURORA). Accessed October 15, 2020. http:// clinicaltrials.gov/ct2/show/NCT03028740.

Phase 3 study to evaluate the efficacy and safety of elafibranor versus placebo in patients with nonalcoholic steatohepatitis (NASH) (RESOLVE-IT). Accessed October 15, 2020. http://clinicaltrials.gov/ct2/show/NCT02704403.

Younossi ZM, Ratziu V, Loomba R, et al.; REGENERATE Study Investigators. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: Interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2019;394(10215):2184-96. https://pubmed.ncbi.nlm.nih.gov/31813633. https://doi.org/10.1016/S0140-6736(19)33041-7.

Study evaluating the efficacy and safety of obeticholic acid in subjects with compensated cirrhosis due to nonalcoholic steatohepatitis (REVERSE). Accessed October 15, 2020. http:// clinicaltrials.gov/ct2/show/NCT03439254.

A phase 3 study to evaluate the efficacy and safety of mgl-3196 (resmetirom) in patients with NASH and fibrosis (MAESTRO-NASH). Accessed October 15, 2020. http:// clinicaltrials.gov/ct2/show/NCT03900429.

A phase ¾ clinical study to evaluate the efficacy and safety of aramchol versus placebo in subjects with NASH (ARMOR). Accessed October 15, 2020. http:// clinicaltrials.gov/ct2/show/NCT04104321.

Wong VW, Wong GL, Tsang SW, et al. Metabolic and histological features of non-alcoholic fatty liver disease patients with different serum alanine aminotransferase levels. Aliment Pharmacol Ther. 2009;29(4):387-96. https://pubmed.ncbi.nlm.nih.gov/19035982. https://doi.org/10.1111/j.1365-2036.2008.03896.x.

Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. Geneva: World Health Organization; 2015. http://apps.who.int/iris/bitstream/handle/10665/154590/9789241549059_eng.pdf.

Prati D, Taioli E, Zanella A, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med. 2002;137(1):1-10. https://pubmed.ncbi.nlm.nih.gov/12093239. https://doi.org/10.7326/0003-4819-137-1-200207020-00006.