Evolution of insulin resistance after liver transplantation – a prospective study

Czech version

Authors: Irena Míková ¹; Erhartová D. ¹; K. Dvořáková ¹; Šedivý P. ²; Drobný M. ²; M. Dezortová ²; M. Hájek ²; M. Cahová ³; H. Daňková ³; Sticová E. ⁴; V. Lánská ⁵; Pavel Trunečka ¹
Authors‘ workplace: Klinika hepatogastroenterologie, Transplantcentrum, IKEM, Praha ¹; Pracoviště radiodiagnostiky a intervenční radiologie, IKEM, Praha ²; Centrum experimentální medicíny, IKEM, Praha ³; Pracoviště klinické a experimentální patologie, IKEM, Praha ⁴; Oddělení lékařské statistiky, IKEM, Praha ⁵
Published in: Gastroent Hepatol 2019; 73(4): 287-295
Category: Clinical and Experimental Gastroenterology: Original Article
doi: https://doi.org/10.14735/amgh2019287

Overview

Introduction: Insulin resistance (IR) plays an important role in the pathogenesis of nonalcoholic fatty liver disease and other diseases. Data regarding the prevalence and evolution of IR in patients before and after liver transplantation (LT) are limited. This prospective study aimed to evaluate the prevalence and evolution of IR in patients before and within 2 years (Y) after LT.

Methods: In 77 patients listed for LT from May 2015 to April 2017, clinical, laboratory, and elastographic evaluations were performed before LT and 6 months (M), 1Y, and 2Y after LT. The liver fat content was also determined by ¹H magnetic resonance (¹H MR) spectroscopy. Liver graft biopsy was performed at 1Y and 2Y after LT.

Results: IR defined as HOMA-IR ≥ 3.0 was found in 26 patients (41.3%) before LT, 16 patients (25.4%) at 6M after LT, 22 patients (34.9%) at 1Y after LT, and 29 patients (46.0%) at 2Y after LT (P = 0.028 for 2Y vs. 6M). Pretransplant IR correlated with age, indication for LT, and the presence of metabolic syndrome. IR at 2Y after LT correlated with the presence of metabolic syndrome, hypertension, and diabetes mellitus, body mass index, the level of gamma-glutamyl transferase, the liver fat content estimated both histologically and by ¹H MR spectroscopy, the grade of ballooning in liver biopsy, and the fibrosis stage estimated by shear wave elastography.

Conclusion: The prevalence of IR is high in patients both before and after LT, and increases significantly with time after LT. Great attention should be paid to posttransplant IR and associated factors.

Submitted: 23. 7. 2019

Accepted: 13. 8. 2019

Conflict of Interest: The authors declare that the article/manuscript complies with ethical standards, patient anonymity has been respected, and they state that they have no financial, advisory or other commercial interests in relation to the subject matter.

Publication Ethics: This article/ manuscript has not been published or is currently being submitted for another review.

The authors agree to publish their name and e-mail in the published article/ manuscript.

Dedication: This work was fi nancially supported by grant No. 15-26906A of the Ministry of Health of the Czech Republic.

The Editorial Board declares that the manuscript met the ICMJE „uniform requirements“ for bio medical papers.

Keywords:

nsulin resistance – magnetic resonance – NAFLD

Sources

1. Muniyappa R, Lee S, Chen H et al. Current approaches for assessing inzulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage. Am J Physiol Endocrinol Metab 2008; 294 (1): E15–E26. doi: 10.1152/ajpendo.00645.2007.

2. Than NN, Newsome PN. A concise review of non-alcoholic fatty liver disease. Atherosclerosis 2015; 239 (1): 192–202. doi: 10.1016/j.atherosclerosis.2015.01.001.

3. Wallace TM, Matthews DR. The assessment of insulin resistance in man. Diabet Med 2002; 19 (7): 527–534.

4. Magri CJ, Fava S, Galea J. Prediction of insulin resistance in type 2 diabetes mellitus using routinely available clinical parameters. Diabetes Metab Syndr 2016; 10 (2 Suppl 1): S96–S101. doi: 10.1016/j.dsx.2016.03.002.

5. Anastácio LR, Lima AS, Toulson Davisson Correia MI. Metabolic syndrome and its components after liver transplantation: incidence, prevalence, risk factors, and implications. Clin Nutr 2010; 29 (2): 175–179. doi: 10.1016/j.clnu.2009.08.008.

6. Petta S, Cammà C, Di Marco V et al. Insulin resistance and diabetes increase fibrosis in the liver of patients with genotype 1 HCV infection. Am J Gastroenterol 2008; 103 (5): 1136–1144. doi: 10.1111/j.1572-0241.2008.018 13.x.

7. Svegliati-Baroni G, Bugianesi E, Bouserhal T et al. Post-load insulin resistance is an independent predictor of hepatic fibrosis in virus C chronic hepatitis and in non-alcoholic fatty liver disease. Gut 2007; 56 (9): 1296–1301. doi: 10.1136/gut.2006.107946.

8. Bugianesi E, Marchesini G, Gentilcore E et al. Fibrosis in genotype 3 chronic hepatitis C and nonalcoholic fatty liver disease: role of insulin resistance and hepatic steatosis. Hepatology 2006; 44 (6): 1648–1655. doi: 10.1002/hep.21 429.

9. Pais R, Rusu E, Zilisteanu D et al. Prevalence of steatosis and insulin resistance in patients with chronic hepatitis B compared with chronic hepatitis C and non-alcoholic fatty liver disease. Eur J Intern Med 2015; 26 (1): 30–36. doi: 10.1016/j.ejim.2014.12.001.

10. Moucari R, Asselah T, Cazals-Hatem D et al. Insulin resistance in chronic hepatitis C: association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis. Gastroenterology 2008; 134 (2): 416–423. doi: 10.1053/j.gastro.2007.11.010.

11. Maruyama H, Kobayashi K, Kiyono S et al. Interrelationship between insulin resistance and portal haemodynamic abnormality in cirrhosis. Int J Med Sci 2017; 14 (3): 240–245. doi: 10.7150/ijms.17738.

12. Andrade AR, Bittencourt PL, Codes L et al. New Onset diabetes and non-alcoholic fatty liver disease after liver transplantation. Ann Hepatol 2017; 16 (6): 932–940. doi: 10.5604/01.3001.0010.5285.

13. Chitturi S, Abeygunasekera S, Farrell GC et al. NASH and insulin resistance: insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology 2002; 35 (2): 373–379. doi: 10.1053/jhep.2002.30 692.

14. Scalioni LP, da Silva AP, Miguel JC et al. Lack of association between hepatitis C virus core gene variation 70/91aa and insulin resistance. Int J Mol Sci 2017; 18 (7). doi: 10.3390/ijms18071 444.

15. Hrebicek J, Janout V, Malincikova J et al. Detection of insulin resistance by simple quantitative insulin sensitivity check index QUICKI for epidemiological assessment and prevention. J Clin Endocrinol Metab 2002; 87 (1): 144–147. doi: 10.1210/jcem.87.1.8292.

16. Perseghin G, Caumo A, Mazzaferro V et al. Assessment of insulin sensitivity based on a fasting blood sample in men with liver cirrhosis before and after liver transplantation. Transplantation 2003; 76 (4): 697–702. doi: 10.1097/ 01.TP.0000079252.94857.8D.

17. Bugianesi E, Manzini P, D’Antico S et al. Relative contribution of iron burden, HFE mutations, and insulin resistance to fibrosis in nonalcoholic fatty liver. Hepatology 2004; 39 (1): 179–187. doi: 10.1002/hep.20023.

18. Patel K, Thompson AJ, Chuang WL et al. Insulin resistance is independently associated with significant hepatic fibrosis in Asian chronic hepatitis C genotype 2 or 3 patients. J Gastroenterol Hepatol 2011; 26 (7): 1182–1188. doi: 10.1111/j.1440-1746.2011.06 722.x.

19. Eslam M, Ampuero J, Jover M et al. Predicting portal hypertension and variceal bleeding using non-invasive measurements of metabolic variables. Ann Hepatol 2013; 12 (4): 588–598.

20. Jeon HK, Kim MY, Baik SK et al. Hepatogenous diabetes in cirrhosis is related to portal pressure and variceal hemorrhage. Dig Dis Sci 2013; 58 (11): 3335–3341. doi: 10.1007/s10620-013-2802-y.

21. Cammà C, Petta S, Di Marco V et al. Insulin resistance is a risk factor for esophageal varices in hepatitis C virus cirrhosis. Hepatology 2009; 49 (1): 195–203. doi: 10.1002/hep.22 655.

22. Degré D, Gustot T, Gerkens A et al. Insulin resistance is associated with esophageal varices in alcoholic liver disease patients. Eur J Gastroenterol Hepatol 2016; 28 (7): 792–796. doi: 10.1097/MEG.0000000000000627.

23. Ramos-Prol A, Hervás-Marin D, Rodríguez-Medina B et al. Alterations in carbohydrate metabolism in cirrhotic patients before and after liver transplant. Diabetes Res Clin Pract 2015; 110 (2): 123–128. doi: 10.1016/j.diabres.2015.10.002.

24. Merli M, Leonetti F, Riggio O et al. Glucose intolerance and insulin resistance in cirrhosis are normalized after liver transplantation. Hepatology 1999; 30 (3): 649–654. doi: 10.1002/hep.510300306.

25. Peláez-Jaramillo MJ, Cárdenas-Mojica AA, Gaete PV et al. Post-liver transplantation diabetes mellitus: a review of relevance and approach to treatment. Diabetes Ther 2018; 9 (2): 521–543. doi: 10.1007/s13300-018-0374-8.

26. Seo S, Maganti K, Khehra M et al. De novo nonalcoholic fatty liver disease after liver transplantation. Liver Transpl 2007; 13 (6): 844–847. doi: 10.1002/lt.20932.

27. Lim LG, Cheng CL, Wee A et al. Prevalence and clinical associations of posttransplant fatty liver disease. Liver Int 2007; 27 (1): 76–80. doi: 10.1111/j.1478-3231.2006.0 1396.x.

28. Dumortier J, Giostra E, Belbouab S et al. Non-alcoholic fatty liver disease in liver transplant recipients: another story of seed and soil. Am J Gastroenterol 2010; 105 (3): 613–620. doi: 10.1038/ajg.2009.717.

29. Hejlova I, Honsova E, Sticova E et al. Prevalence and risk factors of steatosis after liver transplantation and patient outcomes. Liver Transplant 2016; 22 (5): 644–655. doi: 10.1002/lt.24393.

30. Kleiner DE, Brunt EM, Van Natta M et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005; 41 (6): 1313–1321. doi: 10.1002/hep.20701.

31. Calzadilla-Bertot L, Vilar-Gomez E, Torres-Gonzalez A et al. Impaired glucose metabolism increases risk of hepatic decompensation and death in patients with compensated hepatitis C virus-related cirrhosis. Dig Liver Dis 2016; 48 (3): 283–290. doi: 10.1016/j.dld.2015.12. 002.

32. Petrides AS, Stanley T, Matthews DE et al. Insulin resistance in cirrhosis: prolonged reduction of hyperinzulinemia normalizes insulin sensitivity. Hepatology 1998; 28 (1): 141–149. doi: 10.1002/hep.510280119.

33. Orsi E, Grancini V, Menini S et al. Hepatogenous diabetes: is it time to separate it from type 2 diabetes? Liver Int 2017; 37 (7): 950–962. doi: 10.1111/liv.13337.

34. Kruszynska YT, Meyer-Alber A, Darakhshan F et al. Metabolic handling of orally administered glucose in cirrhosis. J Clin Invest 1993; 91 (3): 1057–1066. doi: 10.1172/JCI116263.

35. Tietge UJ, Selberg O, Kreter A et al. Alterations in glucose metabolism associated with liver cirrhosis persist in the clinically stable long-term course after liver transplantation. Liver Transp 2004; 10 (8): 1030–1040. doi: 10.1002/lt.20147.

36. Cabré E, Gassull MA. Nutritional and metabolic issues in cirrhosis and liver transplantation. Curr Opin Clin Nutr Metab Care 2000; 3 (5): 345–354.

37. Hui JM, Sud A, Farrell GC et al. Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression [corrected]. Gastroenterology 2003; 125 (6): 1695–1704. doi: 10.1053/j.gastro.2003.08.032.

38. Veldt BJ, Poterucha JJ, Watt KD et al. Insulin resistance, serum adipokines and risk of fibrosis progression in patients trans-planted for hepatitis C. Am J Transplant 2009; 9 (6): 1406–1413. doi: 10.1111/j.1600-6143.2009.026 42.x.

39. Narayanan P, Mara K, Izzy M et al. Recurrent or de novo allograft steatosis and long-term outcomes after liver transplantation. Transplantation 2019; 103 (1): 14–21. doi: 10.1097/TP.0000000000002317.

40. Gitto S, De Maria N, di Benedetto F et al. De-novo nonalcoholic steatohepatitis is associated with long-term increased mortality in liver transplant recipients. Eur J Gastroenterol Hepatol 2018; 30 (7): 766–773. doi: 10.1097/MEG.0000000000001105.