Early diagnosis of non-alcoholic fatty liver disease: the role of biomarkers and complex indices of non-alcoholic fatty liver steatosis

Metabolic syndrome is a series of pathologies united by a similar pathogenesis, the end of which, most often, is cardiovascular accidents, which are leaders among the causes of death in the population around the world. Non-alcoholic fatty liver disease (NAFLD) is the hepatic equivalent of the metabolic syndrome, registered earlier than all other equivalents, on the rights of the liver as a first-line energy depot. At the same time, according to multicenter studies, 95% of people with NAFLD (any stage) are not diagnosed with the disease. Clarification of additional risk factors for NAFLD and the presence of a specific biomarker of non-alcoholic liver steatosis would make it possible to stop the vicious cascade of metabolic processes, which in the future can lead to a significant increase in the life expectancy of the population. The potentially high role of Secreted Frizzled Related Protein-4 (SFRP4) adipokine in the early diagnosis of NAFLD is known. The aim of the study was to optimize the early diagnosis of non-alcoholic fatty liver disease using modern indices and biomarkers. Materials and methods. The work was carried out at the Department of Faculty and Hospital Therapy of the Chuvash State University named after I. N. Ulyanov” in the period from 2016 to 2020. This study included several stages: first of all, a retrospective analysis of 1150 outpatient records of patients from several medical organizations of the Chuvash Republic for the period 2016-2018 was carried out. to form two study groups: experimental and control. At the second stage, as a result of applying the exclusion criteria, 162 people remained in the experiment: 110 from the experimental group, 52 from the control group. The subjects of both groups were compared by gender and age, the age range of the subjects varied from 18 to 80 years old with an average value of 48.3 years. Further, the patients undergo a detailed examination, according to the presented plan: Collection of complaints, medical history, objective examination. Laboratory studies (general and biochemical blood tests, lipidogram, assessment of the level of serum adipokine SFRP4). Instrumental studies (ultrasound of the OBP, TE (SAR), ESP with elastometry). Evaluation of the most informative complex indices for the early diagnosis of NAFLD: MI, IVO indices, HSI, FLD-I. Further, all the necessary statistical processing and analysis of the obtained data were performed (Microsoft Office Excel 2016, StatTech v. 2.8.8 (developer - Stattech LLC, Russia)). Results. Accessible (not requiring the use of additional time and material costs) NAFLD indices with the highest sensitivity rates (99.1% and 98.2%, respectively) were MI and IVO. A noticeable direct correlation was traced between MI (p=0.640), moderate - between the IVO (p=0.398) and the elastographically determined index of non-alcoholic liver steatosis. High sensitivity and specificity of skin manifestations (xanthoma, xanthelasma - 69.6% and 89.7% and seborrheic dermatitis - 82.0% and 71.4%) were found in relation to early manifestations of NAFLD. From anthropometric indicators: the CW/CF index has a pronounced (ρ=0.643), CW - moderate (ρ=0.238), and BMI - a weak direct (ρ=0.223) correlation with the elastographically determined index of non-alcoholic liver steatosis. Adipokine SFRP4 correlates (ρ=0.841) with early manifestations of hepatic steatosis in patients, as determined by TE in CAP mode.

early diagnosis of non-alcoholic fatty liver disease, non-alcoholic steatosis, biomarkers, steatosis index, adipokines, transient elastography

1. Younossi Z.M., Koenig A. B., 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 Jul;64(1):73-84. doi: 10.1002/hep.28431.

2. Kim N.H, Park J., Kim S. H., Kim Y. H., Kim D. H., Cho G. Y., Baik I., Lim H. E., Kim E. J., Na J. O., Lee J. B., Lee S. K., Shin C. Non-alcoholic fatty liver disease, metabolic syndrome and subclinical cardiovascular changes in the general population. Heart. 2014; 100: 938-943.

3. Babenko A. Yu., Laevskaya M. Yu. Non-alcoholic fatty liver disease - relationship with metabolic syndrome. RMJ. 2018; 1(I): 34-40. (in Russ.)@@ Бабенко А. Ю., Лаевская М. Ю. Неалкогольная жировая болезнь печени - взаимосвязи с метаболическим синдромом. РМЖ. 2018; 1 (I): 34-40.

4. Itskova E. A., Kryuchkova O. N., Lutai Yu. A., et al. The main provisions of the National clinical guidelines for the diagnosis, treatment, prevention of obesity and associated diseases. Crimean therapeutic journal. 2018; 4:5-11. (in Russ.)@@ Ицкова Е. А., Крючкова О. Н., Лутай Ю. А. и др. Основные положения Национальных клинических рекомендаций по диагностике, лечению, профилактике ожирения и ассоциированных с ним заболеваний. Крымский терапевтический журнал. 2018; 4: 5-11.

5. Maev I. V., Tsukanov V. V., Lukicheva E. V. et al. Prevalence, pathogenesis and principles of treatment of non-alcoholic fatty liver disease. Pharmateka. 2011; 12(225): 12-15. (in Russ.)@@ Маев И. В., Цуканов В. В., Лукичева Э. В. и др. Распространенность, патогенез и принципы лечения неалкогольной жировой болезни печени. Фарматека. 2011; 12(225): 12-15.

6. Trukhan D. I. Non-alcoholic fatty liver disease: topical aspects of diagnosis in real clinical practice. Clinical analysis in general medicine. 2021; 4:40-50. (in Russ.) doi 10.47407/kr2021.2.4.00059.@@ Трухан Д. И. Неалкогольная жировая болезнь печени: актуальные аспекты диагностики в реальной клинической практике. Клинический разбор в общей медицине. 2021; 4: 40-50. doi 10.47407/kr2021.2.4.00059.

7. Drapkina O., Ivashkin V. Prevalence and risk factors for non-alcogolic fatty liver disease in Russian Federation.International Liver Congress 2010. Abstract book. 2010: 138. (in Russ.)

8. Cherkashina E. A. Actual issues of diagnosis and treatment of non-alcoholic fatty liver disease. Medical advice. 2015; 34:67-71. (in Russ.)@@ Черкашина Е. А. Актуальные вопросы диагностики и лечения неалкогольной жировой болезни печени. Медицинский совет. 2015; 34: 67-71.

9. Voznesenskaya E. A. Analysis of the occurrence of clinical syndromes and functional tests in patients with chronic liver diseases. Smolensk medical almanac. 2017; 1:73-77. (in Russ.)@@ Вознесенская Е. А. Анализ встречаемости клинических синдромов и функциональных проб у больных с хроническими заболеваниями печени. Смоленский медицинский альманах. 2017; 1: 73-77.

10. Prilensky B. Yu., Vasilkova T. N., Bukhna A. G. Non-psychotic mental disorders and clinical and laboratory characteristics of patients with non-alcoholic fatty liver disease. Siberian Bulletin of Psychiatry and Narcology. 2016; 4 (93): 86-92. (in Russ.)@@ Приленский Б. Ю., Василькова Т. Н., Бухна А. Г. Непсихотические психические расстройства и клинико-лабораторная характеристика пациентов с неалкогольной жировой болезнью печени. Сибирский вестник психиатрии и наркологии. 2016; 4 (93): 86-92.

11. Yamamura S., Nakano D., Hashida R. et al. Patient-reported outcomes in patients with non-alcoholic fatty liver disease: A narrative review of Chronic Liver Disease Questionnaire-non-alcoholic fatty liver disease/non-alcoholic steatohepatitis. J Gastroenterol Hepatol. 2021 Mar;36(3):629-636. doi: 10.1111/jgh.15172.

12. Pulixi E.A., Tobaldini E., Battezzati P. M. et al. Risk of obstructive sleep apnea with daytime sleepiness is associated with liver damage in non-morbidly obese patients with nonalcoholic fatty liver disease. PLoS ONE. 2014; 9: e96349.

13. Wiscombe S., Newton J., Day C., Gibson J., West S. Obstructive sleep apnoea is common in adults with biopsy-proven non-alcoholic fatty liver disease. Sleep Med. 2015; 16: 1026.

14. Qi J.C., Huang J. C., Lin Q. C. et al. Relationship between obstructive sleep apnea and nonalcoholic fatty liver disease in nonobese adults. Sleep Breath. 2016; 20: 529-535.

15. Estep J.M., Avila L. D., Weinstein A. et al. Polymorphism for serotonin receptor 5HTR2C is associated with cognitive performance and non-alcoholic fatty liver disease (NAFLD). Hepatology. 2019; 70: 1324A.

16. Syndromes in diseases of the hepatobiliary system: textbook / edd. N. A. Vlasova, Yu. G. Aznabaeva, N. Sh. Zagidullin, Sh. Z. Zagidullin, U. R. Farkhutdinov. Ufa: Publishing House of GBOU VPO BSMU of the Ministry of Health of Russia, 2016: 52. (in Russ.)@@ Синдромы при заболеваниях гепатобилиарной системы: учебное пособие / Сост.: Н. А. Власова, Ю. Г. Азнабаева, Н. Ш. Загидуллин, Ш. З. Загидуллин, У. Р. Фархутдинов. Уфа: Изд-во ГБОУ ВПО БГМУ Минздрава России, 2016: 52.

17. Ding J.H., Jin Z, Yang X. X., Lou J., Shan W.X,. Hu Y. X., Du Q., Liao Q. S., Xie R., Xu J. Y. Role of gut microbiota via the gut-liver-brain axis in digestive diseases. World J Gastroenterol. 2020; 26(40): 6141-6162. doi: 10.3748/wjg.v26.i40.6141.

18. Sowa J.P., Atmaca Ö., Kahraman A. et al. Non-invasive separation of alcoholic and non-alcoholic liver disease with predictive modeling. PLoS One. 2014 Jul 2;9(7): e101444. doi: 10.1371/journal.pone.0101444.

19. Singal A.K., Bataller R., Ahn J., Kamath P. S., Shah V. H. ACG Clinical Guideline: Alcoholic Liver Disease. The American Journal of Gastroenterology. 2018; 113(2): 175-194. doi:10.1038/ajg.2017.469.

20. Polyzos S.A., Kountouras J., Polymerou V. et al. Vaspin, resistin, retinol-binding protein-4, interleukin-1α and interleukin-6 in patients with nonalcoholic fatty liver disease. Ann Hepatol. 2016 Sep-Oct;15(5):705-14. doi: 10.5604/16652681.1212429.

21. Yang M., Xu D., Liu Y., Guo X., Li W., Guo C., Zhang H., Gao Y., Mao Y., Zhao J.Combined Serum Biomarkers in Non-Invasive Diagnosis of Non-Alcoholic Steatohepatitis. PLoS One. 2015 Jun 29;10(6): e0131664. doi: 10.1371/journal.pone.0131664.

22. Su W., Wang Y, Jia X., Wu W. et al.Comparative proteomic study reveals 17β-HSD13 as a pathogenic protein in nonalcoholic fatty liver disease. Proc Natl Acad Sci U S A. 2014 Aug 5;111(31):11437-42. doi: 10.1073/pnas.1410741111.

23. Wang C., Zhao Y., Gao X., Li L. et al. Perilipin 5 improves hepatic lipotoxicity by inhibiting lipolysis. Hepatology. 2015 Mar;61(3):870-82. doi: 10.1002/hep.27409.

24. Szendroedi J., Roden M. Perilipin 5: from fatty liver to hepatic lipodystrophy? Hepatology. 2015; 61: 751-753. doi: 10.1002/hep.27618.

25. Wruck W., Adjaye J. Meta-analysis reveals up-regulation of cholesterol processes in non-alcoholic and down-regulation in alcoholic fatty liver disease. World J Hepatol. 2017 Mar 18;9(8):443-454. doi: 10.4254/wjh.v9.i8.443.

26. Zvenigorodskaia L.A., Shinkin M. V. Alcoholic liver disease and non-alcoholic fatty liver disease. Similarities and differences. Peculiarities of treatment. Consilium Medicum. 2017; 19 (8): 97-102. (in Russ.) doi: 10.26442/2075-1753_19.8.97-102.@@ Звенигородская Л. А., Шинкин М. В. Алкогольная болезнь печени и неалкогольная жировая болезнь печени. Сходства и различия. Особенности лечения. Consilium Medicum. 2017; 19 (8): 97-102. doi: 10.26442/2075-1753_19.8.97-102.

27. Bi W.R., Yang C. Q., Shi Q., Xu Y., Cao C. P., Ling J., Wang X. Y. Large-scale analysis of factors influencing nonalcoholic fatty liver disease and its relationship with liver enzymes. Genet Mol Res. 2014 Aug 7;13(3):5880-91. doi: 10.4238/2014.August.7.3.

28. Ivashkin V.T., Maevskaya M. V., Pavlov Ch.S. et al. Clinical guidelines for the diagnosis and treatment of non-alcoholic fatty liver disease of the Russian Society for the Study of the Liver and the Russian Gastroenterological Association.Russian journal of gastroenterology, hepatology, coloproctology. 2016; 26(2): 24-42. (in Russ.)@@ Ивашкин В. Т., Маевская М. В., Павлов Ч. С. и др. Клинические рекомендации по диагностике и лечению неалкогольной жировой болезни печени Российского общества по изучению печени и Российской гастроэнтерологической ассоциации. Российский журнал гастроэнтерологии, гепатологии, колопроктологии. 2016; 26(2): 24-42.

29. Xu C. Hyperuricemia and nonalcoholic fatty liver disease: from bedside to bench and back. Hepatol Int. 2016; 10:286-93.

30. Polyzos S.A., Kountouras J., Anastasilakis A. D., Geladari E. V., Mantzoros C. S. Irisin in patients with nonalcoholic fatty liver disease. Metabolism. 2014 Feb;63(2):207-17. doi: 10.1016/j.metabol.2013.09.013.

31. Tomizawa M., Kawanabe Y., Shinozaki F., Sato S., Motoyoshi Y., Sugiyama T., Yamamoto S., Sueishi M. Triglyceride is strongly associated with nonalcoholic fatty liver disease among markers of hyperlipidemia and diabetes. Biomed Rep. 2014 Sep;2(5):633-636. doi: 10.3892/br.2014.309.

32. Guan H., Zhang Y., Gao S., Bai L., Zhao S., Cheng X. W., Fan J., Liu E. Differential Patterns of Secreted Frizzled-Related Protein 4 (SFRP4) in Adipocyte Differentiation: Adipose Depot Specificity. Cell Physiol Biochem. 2018;46(5):2149-2164. doi: 10.1159/000489545.

33. Stewart K.E., Haller D. L., Sargeant C., Levenson J. L., Puri P., Sanyal A. J. Readiness for behaviour change in non-alcoholic fatty liver disease: implications for multidisciplinary care models. Liver Int. 2015 Mar;35(3):936-43. doi: 10.1111/liv.12483.

34. Hörbelt T., Knebel B., Fahlbusch P. et al. The adipokine sFRP4 induces insulin resistance and lipogenesis in the liver. Biochim Biophys Acta Mol Basis Dis. 2019 Oct 1;1865(10):2671-2684. doi: 10.1016/j.bbadis.2019.07.008.

35. Tarasova L.V., Diomidova V. N., Tsyganova Yu. V. Secreted frizzled related protein-4 as one of the indicators of differential diagnosis of fatty liver diseases. Bulletin of SurSU. Medicine. 2019; 1(39): 73-77. (in Russ.)@@ Тарасова Л. В, Диомидова В. Н., Цыганова Ю. В. Secreted frizzled related protein-4 как один из показателей дифференциальной диагностики жировых болезней печени. Вестник СурГУ. Медицина. 2019; 1(39): 73-77.

36. Lonardo A., Ballestri S., Marchesini G. et al. Nonalcoholic fatty liver disease: a precursor of the metabolic syndrome. Dig Liver Dis. 2015; 47: 181-190. doi: 10.1016/j.dld.2014.09.020.

37. Kowdley K., Wilson L., Van Natta M., Pai R. K., Sanyal A. J. Efficacy and safety of vitamin E for nonalcoholic steatohepatitis: Combined analysis of three controlled trials. Journal of Hepatology. 2015; 62(264A-A). doi: 10.1016/S0168-8278(15)30164-1.

38. Tarasyuk B.A., Shadrin V. O. The state of the hepatobiliary system in children with Epstein-Barr virus infection according to ultrasound diagnostics. Perinatology and Pediatrics. 2014; 3(59): 60. (in Russ.)@@ Тарасюк Б. А., Шадрин В. О. Состояние гепатобилиарной системы у детей с Эпштейна - Барр вирусной инфекцией по данным ультразвуковой диагностики. Перинатология и педиатрия. 2014; 3(59): 60.

39. Roitberg G.E., Dorosh Zh.V., Sharhun O. O. et al. Possibilities of using a new metabolic index in assessing insulin resistance in clinical practice. Rational pharmacotherapy in cardiology. 2014; 10(3): 264-274. (in Russ.)@@ Ройтберг Г. Е., Дорош Ж. В., Шархун О. О. и др. Возможности применения нового метаболического индекса при оценке инсулинорезистентности в клинической практике. Рациональная фармакотерапия в кардиологии. 2014; 10(3): 264-274.

40. Betrapally N.S., Gillevet P. M., Bajaj J. S. Gut microbiome and liver disease. Transl Res. 2017 Jan;179:49-59. doi: 10.1016/j.trsl.2016.07.005.

41. Scalera A., Tarantino G. Could metabolic syndrome lead to hepatocarcinoma via non-alcoholic fatty liver disease? World J Gastroenterol 2014; 20: 9217-9228. doi: 10.3748/wjg.v20.i28.9217.

42. Keskinler V.M., Mutlu H. H., Sirin A. et al. Visceral Adiposity Index As a Practical Tool in Patients with Biopsy-Proven Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis. Metab Syndr Relat Disord. 2021; 19(1): 26-31. doi 10.1089/met.2020.0054.

43. Statsenko M.E., Turkina S. V., Kosivtsova M. A., Shilina N. N. Non-invasive diagnosis of non-alcoholic fatty liver disease: simple “tools” are already in the hands of a practitioner. Bulletin of the Volgograd State Medical University. 2019; 2(70): 134-139. (in Russ.) doi: 10.19163/1994-9480-2019-2(70)-134-139.@@ Стаценко М. Е., Туркина С. В., Косивцова М. А., Шилина Н. Н. Неинвазивная диагностика неалкогольной жировой болезни печени: простые «инструменты» уже в руках практического врача. Вестник Волгоградского государственного медицинского университета. 2019; 2(70): 134-139. doi: 10.19163/1994-9480-2019-2(70)-134-139.

44. Zhirkov I.I., Gordienko A. V., Serdyukov D. Yu. Strategy for the diagnosis of non-alcoholic fatty liver disease. Bulletin of the Russian Military Medical Academy. 2019; 3(67): 195-200. (in Russ.)@@ Жирков И. И., Гордиенко А. В., Сердюков Д. Ю. Стратегия диагностики неалкогольной жировой болезни печени Вестник Российской Военно-медицинской академии. 2019; 3(67): 195-200.

45. Ahn Y., Yun S. C., Lee S. S., Son J. H., Jo S., Byun J., Sung Y. S., Kim H. S., Yu E. S. Development and Validation of a Simple Index Based on Non-Enhanced CT and Clinical Factors for Prediction of Non-Alcoholic Fatty Liver Disease. Korean J Radiol. 2020 Apr;21(4):413-421. doi: 10.3348/kjr.2019.0703.

46. Fuyan S., Jing L., Wenjun C., Zhijun T., Weijing M., Suzhen W., Yongyong X. Fatty liver disease index: a simple screening tool to facilitate diagnosis of nonalcoholic fatty liver disease in the Chinese population. Dig Dis Sci. 2013 Nov;58(11):3326-34. doi: 10.1007/s10620-013-2774-y.

47. Diomidova V.N., Tarasova L. V., Trukhan D. I., Tsyganova Yu. V., Vinogradova V. S. Ultrasound liver elastography with fading signal technology makes it possible to assess the degree of steatosis and to dynamically monitor the effectiveness of NAFLD treatment. Experimental and clinical gastroenterology. 2020; 9(181): 45-54. (in Russ.) doi 10.31146/1682-8658-ecg-181-9-45-54.@@ Диомидова В. Н., Тарасова Л. В., Трухан Д. И., Цыганова Ю. В., Виноградова В. С. Ультразвуковая эластография печени с технологией затухающего сигнала позволяет оценить степень стеатоза и осуществлять динамическое наблюдение эффективности лечения НАЖБП. Экспериментальная и клиническая гастроэнтерология. 2020; 9(181): 45-54. doi 10.31146/1682-8658-ecg-181-9-45-54.

48. Postnova N.A., Borsukov A. V., Morozova T. G., Ilyasov B. B., Andreev B. V. The use of compression elastography for non-invasive evaluation of liver fibrosis: results from a multicenter study. Ultrasonic and functional diagnostics. 2016; 6:10-21.@@ Постнова Н. А., Борсуков А. В., Морозова Т. Г., Ильясов Б. Б., Андреев Б. В. Использование компрессионной эластографии для неинвазивной оценки фиброза печени: результаты многоцентрового исследования. Ультразвуковая и функциональная диагностика. 2016; 6: 10-21.

49. Tsyganova Yu. V. The role of indices and biomarkers of liver steatosis in the early diagnosis of non-alcoholic fatty liver disease: specialty 3.1.18.Internal diseases: diss… candid. of medical sciences. Chuvash State University named after I. N. Ulyanov. Cheboksary, 2022: 144, 50-54. (in Russ.)@@ Цыганова Ю. В. Роль индексов и биомаркёров стеатоза печени в ранней диагностике неалкогольной жировой болезни печени: специальность 3.1.18. Внутренние болезни: диссертация на соискание ученой степени кандидата медицинских наук. Чувашский государственный университет имени И. Н. Ульянова. Чебоксары, 2022: 144 (50-54).