Lviv clinical bulletin 2018, 3(23): 8-23

https://doi.org/10.25040/lkv2018.03.008

Clinical-pathagenetic, Age, Gender, Genetic Aspects of Non-alcoholic Fatty Liver Disease and Nonviral Chronic Hepatitis Without, and also with Comorbid Hypothyroidism; Improving of Their Treatment

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V. Prysyazhnyuk, O. Voloshyn

Higher State Educational Establishment of Ukraine “Bukovinian State Medical University”

Introduction. Non-alcoholic fatty liver disease (NAFLD) is the most common ailment among all liver lesions due to an increase in the number of people with obesity, dyslipidemia, increased incidence of type 2 diabetes and metabolic syndrome. The conditions that may be associated with NAFLD are also actively discussed, among which hypothyroidism plays an important role. In recent decades, chronic hepatitis (CH) has become widespread in Ukraine and in the world.

The aim of the study. To improve the diagnostic and treatment efficiency of patients with NAFLD and nonviral CH, taking into account clinical and pathogenic, age, gender, genetic factors and the presence of hypothyroidism.

Materials and methods. The observation of 311 patients with chronic diffuse liver diseases, including those 188 patients diagnosed with NAFLD (44 among them were diagnosed with hypothyroidism) and 123 nonviral CH patients formed the basis of the clinical research. The control group included 45 practically healthy individuals, representative by age and gender to the examined patients. A complex of modern clinical, biochemical, immune-enzyme, genetic, instrumental and statistical methods of the research were used to solve the tasks in the thesis.

Results. Clinical-pathogenic, age, gender peculiarities of clinical course of NAFLD and CH, biochemical blood parameters, lipid, adipokine and cytokine profiles were determined. The correlation between the cytokines plasma content and the biochemical markers of cytolytic, cholestatic, intoxication syndromes, lipid profile are indicative of their important role in pathogenesis of NAFLD and CH. Changes in the structural and functional parameters of the heart, increase of the left ventricle myocardium mass and its index, and ejection fraction reduction were determined with age among NAFLD patients and CH patients.

G-allele of glutathione-S-transferase (GST) P1 (A313G) gene occurred more freguently in NAFLD patients as compared to practically healthy individuals and was found to be associated with higher alanine aminotransferase activity and increased atrial natriuretic propeptide, leptin and lower adiponectin concentrations in the blood as compared to the corresponding indicators in patients with AA-genotype. Higher activity of cytolytic syndrome markers, as well as elevated leptin and atrial natriuretic propeptide contents in the blood were investigated in NAFLD patients with Ala-allele of the peroxisome proliferator-activated receptor-y (PPAR-y) gene in comparison with Pro/ Pro genotype carriers. G-allele of GSTP1 gene was found to be associated with a higher alanine aminotransferase activity in the blood in CH patients as compared to AA-genotype carriers. Higher interleukin 10 level in the blood was observed in patients with Ala-allele of PPAR-y gene as compared to Pro/Pro-genotype carriers.

NAFLD patients with subclinical and manifested hypothyroidism are characterized by torpid NAFLD clinical course, higher activity of markers of cholestasis, proatherogenic changes of the lipid profile, and adipokine imbalance. NAFLD patients are shown to develop insulin resistance syndrome. In particular, in NAFLD and concomitant subclinical and manifested hypothyroidism patients a significant decrease in J. F. Caro index was determined, and in patients with manifested hypothyroidism the growth of HOMA IR index comparable to respective indicators in NAFLD patients with normal thyroid function was found.

On the basis of the obtained data, the treatment process was improved by L-carnitine added to basic therapy in NAFLD and CH patients, resulting in more effective decrease in the activity of cytolytic and cholestatic syndromes markers, decrease of tumor necrosis factor-a content, as manifestations of reducing inflammation processes intensity. In NAFLD patients the above mentioned also contributed to decrease in leptin content together with increased adiponectin concentration in the blood, indicating the normalization of adipokine profile. Additional quercetin prescription to the baseline therapy in observed patients resulted in more effective correction of the indicators of cytolysis, cholestasis and optimization of lipid profile, decrease in tumor necrosis factor-a and atrial natriuretic propeptide contents in the blood. L-carnitine and quercetin administration in addition to the baseline therapy contributes to the reduction in the risk of recrudescent application for medical treatment for NAFLD patients for the following 12 and for CH patients – for the next 6 months, to longer period of compensation of liver disease, reduction of clinical manifestations of diseases in case of required repeated treatment.

Conclusions. As a result of the conducted studies, it became possible to improve the diagnostic and treatment effciency of patients with non-alcoholic fatty liver disease and nonviral chronic hepatitis, taking into account clinical and pathogenic, age, gender, genetic factors and the presence of hypothyroidism.

References

  1. Abrahamovych OO, Abrahamovych MO, Leshchuk YaL, Krystopchuk SA, Fedets AB. Hyperlipidemia: A Modern View of a Problem from the Position of Gastroenterology (Literature Review and Clinical Case Descriptions. Acta Medica Leopoliensia. 2014;1:95-103. (Ukrainian).
  2. Andreieva OO, Zupanets IA, Shalamai AS. Study of the gastroprotective effect of the combination of quercetin and glucosamine derivatives on the model of ethanol-prednisolone lesion of the stomach in rats. Clinical Pharmacy. 2009;3:32-34. (Ukrainian).
  3. Herush IV, Meshchyshen IF. The state of the glutathione system of blood under conditions of experimental ulcerous defeat of the gastroduodenal zone and the effect of tincture of Echinacea purpurea. Bulletin of Problems Biology and Medicine. 1998;7:10-15. (Ukrainian).
  4. Korolyuk MA, Ivanova LI, Mayorova IG, Tokarev VE. Method for determination of catalase activity. Laboratornoe delo. 1998;1:16-19. (Russian).
  5. Mishchuk VH, Skoropad KM. Prevalence of combined alcohol liver and pancreas damage: evaluation criteria for identification. Bukovinian Medical Herald. 2015;19(1):108-113 (Ukrainian).
  6. Order of the Ministry of Health of Ukraine № 826 from 06.11.2014 р. «On approval and implementation of medical-technological documents on standardization of medical care in chronic non-infectious hepatitis». Kyiv: Ministry of Health; 2014. (Normative document of the Ministry of Health of Ukraine) (Ukrainian).
  7. Order of the Ministry of Health of Ukraine № 1051 from 28.12.2009 р. «On the provision of medical care to patients of gastroenterological profile (as amended in accordance with the Order of the Ministry of Health № 794 dated September 21, 2010). ” Kyiv: Ministry of Health; 2009. (Normative document of the Ministry of Health of Ukraine) (Ukrainian).
  8. Pankiv VI, Yuzvenko TIu. Interconnection of subclinical dysfunction of the thyroid gland and metabolic syndrome. Clinical endocrinology and endocrine surgery. 2015;3:54-59 (Ukrainian).
  9. Pashkovska NV. Treatment of hypothyroidism according to modern clinical guidelines. International Journal of Endocrinology. 2016;6:48-58) (Ukrainian).
  10. Rogovskiy VS, Matyushin AI, Shimanovskiy NL. Prospects for the use of quercetin preparations for the prevention and treatment of atherosclerosis. International Medical Journal. 2011;3:114-118 (Ukrainian).
  11. Skliarov YeIa, Barnett OIu, Kurliak NV. Gender features of changes in the functional status of the liver in patients with coronary heart disease in combination with nonalcoholic fatty liver disease in the context of atorvastatin administration. Bukovinian Medical Herald. 2016;2:158-161 (Ukrainian).
  12. Skrypnyk IM, Maslova HS, Havlovskyi OD, Mandryka LIu. Antioxidant-prooxidant status in patients with non-alcoholic steatohepatitis in combination with type 2 diabetes in the dynamics of complex pathogenetic treatment. Bulletin of Problems Biology and Medicine. 2013;3(1):211-216 (Ukrainian).
  13. Stepanov YuM, Skyrda IIu. Gastroenterological assistance to the population of Ukraine: main indicators of health and resource provision in 2011. Gastroenterology. 2013;1:8-11 (Ukrainian).
  14. Travina OV. Guide to biochemical methods of research. Moscow: Medgiz; 1995. 256 p. (Russian).
  15. Tronko MD. Current state and prospects for the development of fundamental and clinical endocrinology for 2015-2020. Endokrynologia. 2015;1:373-380 (Ukrainian).
  16. Fadieienko HD, Nikiforova YaV. Prevention of progression of non-alcoholic fatty liver disease. Zdorovia Ukrainy. 2016;2:51-53 (Ukrainian).
  17. Kharchenko NV, Babak OIa, editors. Gastroenterology: textbook in 2 volumes. Kirovograd: Polium; 2017. Vol1. 488 p. (Ukrainian).
  18. Kharchenko NV. Chronic liver diseases: hepatoprotective pharmacotherapy in conditions of real clinical practice. Modern Gastroenterology. 2016;6:70-75 (Ukrainian).
  19. Cherenko SM, Larin OS, Pidaiev AV, Tovkai OA, Sichinava RM. Long-term results of the application of thyroid tissue autotransplantation in order to prevent postoperative hypothyroidism. Clinical Endocrinology and Endocrine Surgery. 2013;3:15-18 (Ukrainian)
  20. Albano E, Parola M, editors. Oxidative stress in applied basic research and clinical practice. Studies on hepatic disorders. Springer; 2015. 978 p.
  21. Altirriba J, Poher AL, Rohner-Jeanrenaud F. Chronic oxytocin administration as a treatment against impaired leptin signaling or leptin resistance in obesity. Front Endocrinol (Lausanne). 2015;6:119. https://doi.org/10.3389/fendo.2015.00119
  22. Asmi MN, Walsh MJ. A practical guide to echocardiograpthy. London: Chapman and Hall Medical; 1995. 260 p.
  23. Bae JC, Lee WY, Yoon KH, Park JY, Son HS, Han KA et al. Improvement of nonalcoholic fatty liver disease with carnitine-orotate complex in type 2 diabetes (CORONA): a randomized controlled trial. Diabetes Care. 2015;38(7):1245-1252. https://doi.org/10.2337/dc14-2852
  24. Basaranoglu M, Basaranoglu G, Sentürk H. From fatty liver to fibrosis: a tale of “second hit”. World J Gastroenterol. 2013;19(8):1158-1165. https://doi.org/10.3748/wjg.v19.i8.1158
  25. Bertolotti M, Lonardo A, Mussi C, Baldelli E, Pellegrini E, Ballestri S et al. Nonalcoholic fatty liver disease and aging: epidemiology to management. World J Gastroenterol. 2014;20(39):14185-14204. https://doi.org/10.3748/wjg.v20.i39.14185
  26. Biondi B, Bartalena L, Cooper DS, Hegedüs L, Laurberg P, Kahaly GJ. The 2015 European thyroid association guidelines on diagnosis and treatment of endogenous subclinical hyperthyroidism. Eur Thyroid J. 2015;4(3):149-163. https://doi.org/10.1159/000438750
  27. Brenner C, Galluzzi L, Kepp O, Kroemer G. Decoding cell death signals in liver inflammation. J Hepatol. 2013;59(3):583-594. https://doi.org/10.1016/j.jhep.2013.03.033
  28. Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology. 1994;19(6):1513-1520. https://doi.org/10.1002/hep.1840190629
  29. Egert S, Bosy-Westphal A, Seiberl J, Kürbitz C, Settler U, Plachta-Danielzik S, et al. Quercetin reduces systolic blood pressure and plasma oxidised low-density lipoprotein concentrations in overweight subjects with a high-cardio-vascular disease risk phenotype: a double-blinded, placebo-controlled cross-over study. Br J Nutr. 2009;102(7):1065-1074. https://doi.org/10.1017/S0007114509359127
  30. Farooq MO, Bataller R. Pathogenesis and management of alcoholic liver disease. Dig Dis. 2016;34(4):347-355. https://doi.org/10.1159/000444545
  31. Foppa M, Duncan BB, Rohde LE. Echocardiography-based left ventricular mass estimation. How should we define hypertrophy? Cardiovasc Ultrasound. 2005;3:17. https://doi.org/10.1186/1476-7120-3-17
  32. Fung P, Pyrsopoulos N. Emerging concepts in alcoholic hepatitis. World J Hepatol. 2017;9(12):567-585. https://doi.org/10.4254/wjh.v9.i12.567
  33. Ganau A, Devereux RB, Roman MJ, de Simone G, Pickering TG, Saba PS et al. Patterns of left ventricular hypertrophy and geometric remodeling in essential hypertension. J Am Coll Cardiol. 1992;19(7):1550-1558. https://doi.org/10.1016/0735-1097(92)90617-V
  34. Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American association of clinical endocrinologists and the American thyroid association. Endocr Pract. 2012;18(6):988-1028. https://doi.org/10.4158/EP12280.GL
  35. Gharib H, Papini E, Paschke R, Duick DS, Valcavi R, Hegedüs L et al. American association of clinical endocrinologists, Associazione medici endocrinologi, and European thyroid association medical guidelines for clinical practice for the diagnosis and management of thyroid nodule. Endocr Pract. 2010;16(3):468-475. https://doi.org/10.4158/EP.16.3.468
  36. Grygiel-Górniak B. Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications – a review. Nutr J. 2014;13:17. https://doi.org/10.1186/1475-2891-13-17
  37. Habig HW, Pabst MJ, Jacoby WB. Glutathione-S-Transferasses. Journal of Biological Chemistry. 1974;249(22):7130-7139.
  38. Hammer O, Harper DAT, Ryan PD. PAST: Paleontological Statistics Software Package for Education and Data Analysis. Palaeontologia Electronica. 2001;4(1):4-9.
  39. Hashemi M, Eskandari-Nasab E, Fazaeli A, Bahari A, Hashemzehi NA, Shafieipour S et al. Association of genetic polymorphisms of glutathione-S-transferase genes (GSTT1, GSTM1, and GSTP1) and susceptibility to nonalcoholic fatty liver disease in Zahedan, Southeast Iran. DNA Cell Biol. 2012;31(5):672-677. https://doi.org/10.1089/dna.2011.1343
  40. Huang YS. Recent progress in genetic variation and risk of antituberculosis drug-induced liver injury. J Chin Med Assoc. 2014;77(4):169-173. https://doi.org/10.1016/j.jcma.2014.01.010
  41. Huang YY, Gusdon AM, Qu S. Cross-talk between the thyroid and liver: A new target for nonalcoholic fatty liver disease treatment. World J Gastroenterol. 2013;19(45):8238-8246. https://doi.org/10.3748/wjg.v19.i45.8238
  42. Ittermann T, Haring R, Wallaschofski H, Baumeister SE, Nauck M, Dörr M et al. Inverse association between serum free thyroxine levels and hepatic steatosis: results from the Study of Health in Pomerania. Thyroid. 2012;22(6):568-574. https://doi.org/10.1089/thy.2011.0279
  43. Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS et al. Guidelines for the treatment of hypothyroidism: prepared by the American thyroid association task force on thyroid hormone replacement. Thyroid. 2014;24(12):1670-1751. https://doi.org/10.1089/thy.2014.0028
  44. Kawaratani H, Tsujimoto T, Douhara A, Takaya H, Moriya K, Namisaki T et al. The effect of inflammatory cytokines in alcoholic liver disease. Mediators Inflamm. 2013;2013:495156. https://doi.org/10.1155/2013/495156
  45. Kitade H, Chen G, Ni Y, Ota T. Nonalcoholic fatty liver disease and insulin resistance: new insights and potential new treatments. Nutrients. 2017;9(4):E387. https://doi.org/10.3390/nu9040387
  46. Kotronen A, Peltonen M, Hakkarainen A, Sevastianova K, Bergholm R, Johansson LM et al. Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors. Gastroenterology. 2009;137(3):865-872. https://doi.org/10.1053/j.gastro.2009.06.005
  47. Lee JH, Kim D, Kim HJ, Lee CH, Yang JI, Kim W et al. Hepatic steatosis index: a simple screening tool reflecting nonalcoholic fatty liver disease. Dig Liver Dis. 2010;42(7):503-508. https://doi.org/10.1016/j.dld.2009.08.002
  48. Li G, Hu H, Shi W, Li Y, Liu L, Chen Y et al. Elevated hematocrit in nonalcoholic fatty liver disease: a potential cause for the increased risk of cardiovascular disease? Clin Hemorheol Microcirc. 2012;51(1):59-68.
  49. Li X, Jiang X, Sun J, Zhu C, Li X, Tian L et al. Cytoprotective effects of dietary flavonoids against cadmium-induced toxicity. Ann NY Acad Sci. 2017;1398(1):5-19. https://doi.org/10.1111/nyas.13344
  50. Li XL, Sui JQ, Lu LL, Zhang NN, Xu X, Dong QY et al. Gene polymorphisms associated with non-alcoholic fatty liver disease and coronary artery disease: a concise review. Lipids Health Dis. 2016;15:53. https://doi.org/10.1186/s12944-016-0221-8
  51. Liu L, Yu Y, Zhao M, Zheng D, Zhang X, Guan Q et al. Benefits of levothyroxine replacement therapy on nonalcoholic fatty liver disease in subclinical hypothyroidism patients. Int J Endocrinol. 2017;2017:5753039. https://doi.org/10.1155/2017/5753039
  52. Lonardo A, Sookoian S, Pirola CJ, Targher G. Non-alcoholic fatty liver disease and risk of cardiovascular disease. Metabolism. 2016;65(8):1136-1150. https://doi.org/10.1016/j.metabol.2015.09.017
  53. Loomba R, Cortez-Pinto H. Exercise and improvement of NAFLD: Practical recommendations. J Hepatol. 2015;63(1):10-12. https://doi.org/10.1016/j.jhep.2015.03.009
  54. Maisch B. Alcoholic cardiomyopathy: The result of dosage and individual predisposition. Herz. 2016;41(6):484-493. https://doi.org/10.1007/s00059-016-4469-6
  55. Malaguarnera M, Gargante MP, Russo C, Antic T, Vacante M, Malaguarnera M et al. L-carnitine supplementation to diet: a new tool in treatment of nonalcoholic steatohepatitis – a randomized and controlled clinical trial. Am J Gastroenterol. 2010;105(6):1338-1345. https://doi.org/10.1038/ajg.2009.719
  56. Marchesini G, Day ChP, Dufour JF, Canbay A, Nobili V, Ratziu V et al. EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388-1402. https://doi.org/10.1016/j.jhep.2015.11.004
  57. Navarro VJ, Khan I, Björnsson E, Seeff LB, Serrano J, Hoofnagle JH. Liver injury from herbal and dietary supplements. Hepatology. 2017;65(1):363-373. https://doi.org/10.1002/hep.28813
  58. Paniagua JA, Escandell-Morales JM, Gil-Contreras D, Berral de la Rosa FJ, Romero-Jimenez M, Gómez-Urbano A et al. Central obesity and altered peripheral adipose tissue gene expression characterize the NAFLD patient with insulin resistance: Role of nutrition and insulin challenge. Nutrition. 2014;30(2):177-185. https://doi.org/10.1016/j.nut.2013.07.017
  59. Perazzo H, Dufour JF. The therapeutic landscape of non-alcoholic steatohepatitis. Liver International. 2017;37:634-647. https://doi.org/10.1111/liv.13270
  60. Perumpail RB, Liu A, Wong RJ, Ahmed A, Harrison SA. Pathogenesis of hepatocarcinogenesis in non-cirrhotic nonalcoholic fatty liver disease: Potential mechanistic pathways. World J Hepatol. 2015;7(22):2384-2388. https://doi.org/10.4254/wjh.v7.i22.2384
  61. Resl M, Vila G, Grimm G, Heinisch B, Riedl M, Dieplinger B et al. Effects of B-type natriuretic peptide on cardiovascular biomarkers in healthy volunteers. J Appl Physiol. 2015;118(4):395-399. https://doi.org/10.1152/japplphysiol.00101.2014
  62. Roy N, Dasgupta D, Mukhopadhyay I, Chatterjee A, Das K, Bhowmik P et al. genetic association and gene-gene interaction reveal genetic variations in ADH1B, GSTM1 and MnSOD independently confer risk to alcoholic liver diseases in India. PLoS One. 2016;11(3):e0149843. https://doi.org/10.1371/journal.pone.0149843
  63. Sahebkar A. Does PPARγ2 gene Pro12Ala polymorphism affect nonalcoholic fatty liver disease risk? Evidence from a meta-analysis. DNA and Cell Biology. 2013;32(4):188-198. https://doi.org/10.1089/dna.2012.1947
  64. Sayiner M, Koenig A, Henry L, Younossi ZM. Epidemiology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in the united states and the rest of the world. Clin Liver Dis. 2016;20(2):205-214. https://doi.org/10.1016/j.cld.2015.10.001
  65. Sydorchuk L, Fediv O, Kohaniuk J, Sydorchuk A, Sydorchuk R, Fedoniuk L. Association of glutathione S-transferase gene CLASS T1 (GSTT1) AND M1 (GSTM1) with gastroesophageal reflux disease severity and diabetes mellitus. Immunogastroenterology 2013;2:109-113. https://doi.org/10.7178/ig.42
  66. Umoh NA, Walker RK, Al-Rubaiee M, Jeffress MA, Haddad GE. Acute alcohol modulates cardiac function as PI3K/Akt regulates oxidative stress. Alcohol Clin Exp Res. 2014;38(7):1847-1864. https://doi.org/10.1111/acer.12459
  67. Wang H, Yan T, Xie Y, Zhao M, Che Y, Zhang J et al. Mechanism-based inhibitory and peroxisome proliferator-activated receptor α-dependent modulating effects of silybin on principal hepatic drug-metabolizing enzymes. Drug Metab Dispos. 2015;43(4):444-454. https://doi.org/10.1124/dmd.114.061622
  68. Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology. 2011;140(1):124-131. https://doi.org/10.1053/j.gastro.2010.09.038
  69. Wu S, Wang YJ, Tang X, Wang Y, Wu J, Ji G et al. Genetic polymorphisms of glutathione S-transferase p1 (GSTP1) and the incidence of anti-tuberculosis drug-induced hepatotoxicity. PLoS One. 2016;11(6):e0157478. https://doi.org/10.1371/journal.pone.0157478
  70. Yan F, Wang Q, Lu M, Chen W, Song Y, Jing F et al. Thyrotropin increases hepatic triglyceride content through upregulation of SREBP-1c activity. J Hepatol. 2014;61(6):1358-1364. https://doi.org/10.1016/j.jhep.2014.06.037
  71. Zhao ZH, Fan YC, Zhao Q, Dou CY, Ji XF, Zhao J et al. Promoter methylation status and expression of PPAR-γ gene are associated with prognosis of acute-on-chronic hepatitis B liver failure. Clin Epigenetics. 2015;7:115. https://doi.org/10.1186/s13148-015-0149-2