Mineral disorders in patients with chronic liver disease. Part 1: epidemiology and pathophysiology
https://doi.org/10.14341/omet13124
Abstract
Chronic liver disease is a significant public health problem worldwide, and its consequences lead to the development of various mineral disorders, which occur in 75% of patients. Osteoporosis (up to 30% of patients) has the greatest clinical significance among the mineral disorders that develop in chronic liver disease. Fractures occur, according to different data, in 7-35% of patients. There are number of mechanisms influencing the state of mineral metabolism in chronic liver diseases: from the disturbance of vitamin D metabolism to the synthesis of pro-inflammatory cytokines and the function of intestinal microbiota. To date, these processes remain insufficiently studied: for example, aspects concerning the functioning of parathyroid glands in chronic liver diseases are not completely clear; there is no clear idea about the predominant processes in bone tissue (anti- or proresorptive). This determines the imperfection of prophylactic and therapeutic approaches in mineral disorders due to chronic liver diseases and the need for further research in this direction. The first part of this review focuses on the epidemiology and pathophysiology of mineral metabolism disorders in these conditions; the second part of the review will focus on current therapeutic approaches
About the Authors
A. M. GorbachevaRussian Federation
Anna M. Gorbacheva, MD, PhD
11 Dm.Ulyanova street, 115478, Moscow
ResearcherID: HKO-2637-2023
Scopus Author ID: 57190977461
Competing Interests:
None
E. E. Bibik
Russian Federation
Ekaterina E. Bibik, MD, PhD
11 Dm.Ulyanova street, 115478, Moscow
ResearcherID: AAY-3052-2020
Scopus Author ID: 57195679482
Competing Interests:
None
A. A. Lavreniuk
Russian Federation
Anastasia A. Lavreniuk, MD
11 Dm.Ulyanova street, 115478, Moscow
ResearcherID: ABF-4392-2022
Scopus Author ID: 7101843976
Competing Interests:
None
A. K. Eremkina
Russian Federation
Anna K. Eremkina, MD, PhD
11 Dm.Ulyanova street, 115478, Moscow
ResearcherID: R-8848-2019
Scopus Author ID: 57197775339
Competing Interests:
None
I. N. Tikhonov
Russian Federation
Igor N. Tikhonov, MD
ResearcherID: ABC-4408-2020
Scopus Author ID: 57200597669
Competing Interests:
None
N. G. Mokrysheva
Russian Federation
Natalia G. Mokrysheva, MD, PhD, Professor
11 Dm.Ulyanova street, 115478, Moscow
ResearcherID: AAY-3761-2020
Scopus Author ID: 35269746000
Competing Interests:
None
References
1. Cheemerla S, Balakrishnan M. Global Epidemiology of Chronic Liver Disease. Clin Liver Dis (Hoboken). 2021;17(5):365-370. doi: https://doi.org/10.1002/cld.1061
2. Sepanlou SG, Safiri S, Bisignano C, et al. The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. 2020;5(3). doi: https://doi.org/10.1016/S2468-1253(19)30349-8
3. Giouleme O, Vyzantiadis T, Nikolaidis N, et al. Pathogenesis of osteoporosis in liver cirrhosis. Hepatogastroenterology. 2006;53(72):938-943
4. Zheng JP, Miao HX, Zheng SW, et al. Risk factors for osteoporosis in liver cirrhosis patients measured by transient elastography. Medicine (United States). 2018;97(20). doi: https://doi.org/10.1097/MD.0000000000010645
5. Patel N, Muñoz SJ. Bone disease in cirrhosis. Clin Liver Dis (Hoboken). 2015;6(4). doi: https://doi.org/10.1002/cld.498
6. Nakchbandi IA. Osteoporosis and fractures in liver disease: Relevance, pathogenesis and therapeutic implications. World J Gastroenterol. 2014;20(28). doi: https://doi.org/10.3748/wjg.v20.i28.9427
7. Compston JE, McClung MR, Leslie WD. Osteoporosis. The Lancet. 2019;393(10169):364-376. doi: https://doi.org/10.1016/S0140-6736(18)32112-3
8. Merli M, Berzigotti A, Zelber-Sagi S, et al. EASL Clinical Practice Guidelines on nutrition in chronic liver disease. J Hepatol. 2019;70(1). doi: https://doi.org/10.1016/j.jhep.2018.06.024
9. Leidig-Bruckner G, Hosch S, Dodidou P, et al. Frequency and predictors of osteoporotic fractures after cardiac or liver transplantation: A follow-up study. Lancet. 2001;357(9253). doi: https://doi.org/10.1016/S0140-6736(00)03641-2
10. Navasa M, Monegal A, Guañabens N, et al. Bone fractures in liver transplant patients. Rheumatology. 1994;33(1). doi: https://doi.org/10.1093/rheumatology/33.1.52
11. Topcheeva ON, Drozdov VN, Embutnieks YV, Vyazhevich YV. Mineral’naya plotnost’ kostnoj tkani u bol’nyh cirrozom pecheni // Terapevticheskaya gastroenetrologiya. 2009;8:51-55 (In Russ.)
12. Topcheeva ON. Osobennosti narusheniya mineral’noj plotnosti kostnoj tkani u bol’nyh cirrozom pecheni razlichnoj etiologii: Diss. … med. nauk. M. 2010:115 (In Russ.)
13. Kirgueva OI. Sostoyanie kostnoj tkani u muzhchin, stradayushchih cirrozom pecheni: Diss. … med. nauk. Volgograd. 2017:124 (In Russ.)
14. Ehnert S, Aspera-Werz RH, Ruoß M, et al. Hepatic Osteodystrophy- Molecular Mechanisms Proposed to Favor Its Development. Int J Mol Sci. 2019;20(10). doi: https://doi.org/10.3390/ijms20102555
15. Wintermeyer E, Ihle C, Ehnert S, et al. Crucial role of vitamin D in the musculoskeletal system. Nutrients. 2016;8(6). doi: https://doi.org/10.3390/nu8060319
16. Holick MF. Vitamin D: A D-lightful solution for health. In: Journal of Investigative Medicine. 2011;59. doi: https://doi.org/10.2310/JIM.0b013e318214ea2d
17. Nussler AK, Wildemann B, Freude T, et al. Chronic CCl4 intoxication causes liver and bone damage similar to the human pathology of hepatic osteodystrophy: A mouse model to analyse the liver-bone axis. Arch Toxicol. 2014;88(4). doi: https://doi.org/10.1007/s00204-013-1191-5
18. Hochrath K, Ehnert S, Ackert-Bicknell CL, et al. Modeling hepatic osteodystrophy in Abcb4 deficient mice. Bone. 2013;55(2). doi: https://doi.org/10.1016/j.bone.2013.03.012
19. Chongthavornvasana S, Lertudomphonwanit C, Mahachoklertwattana P, Korwutthikulrangsri M. Determination of Optimal Vitamin D Dosage in Children with Cholestasis. BMC Pediatr. 2023;23(1). doi: https://doi.org/10.1186/s12887-023-04113-y
20. Abdel-Rahman N, Sharawy MH, Megahed N, El-Awady MS. Vitamin D3 abates BDL-induced cholestasis and fibrosis in rats via regulating Hedgehog pathway. Toxicol Appl Pharmacol. 2019;380. doi: https://doi.org/10.1016/j.taap.2019.114697
21. Zhao XY, Li J, Wang JH, et al. Vitamin D serum level is associated with Child-Pugh score and metabolic enzyme imbalances, but not viral load in chronic hepatitis B patients. Medicine (United States). 2016;95(27). doi: https://doi.org/10.1097/MD.0000000000003926
22. Arteh J, Narra S, Nair S. Prevalence of vitamin D deficiency in chronic liver disease. Dig Dis Sci. 2010;55(9). doi: https://doi.org/10.1007/s10620-009-1069-9
23. DeLuca HF. History of the discovery of vitamin D and its active metabolites. Bonekey Rep. 2014;3. doi: https://doi.org/10.1038/bonekey.2013.213
24. Shinchuk L, Holick MF. Vitamin D and rehabilitation: Improving functional outcomes. Nutrition in Clinical Practice. 2007;22(3). doi: https://doi.org/10.1177/0115426507022003297
25. Booth DR, Ding N, Parnell GP, et al. Cistromic and genetic evidence that the vitamin D receptor mediates susceptibility to latitudedependent autoimmune diseases. Genes Immun. 2016;17(4):213-219. doi: https://doi.org/10.1038/gene.2016.12
26. Christensen MHE, Apalset EM, Nordbø Y, Varhaug JE, Mellgren G, Lien EA. 1,25-Dihydroxyvitamin D and the Vitamin D Receptor Gene Polymorphism Apa1 Influence Bone Mineral Density in Primary Hyperparathyroidism. PLoS One. 2013;8(2). doi: https://doi.org/10.1371/journal.pone.0056019
27. Christakos S, Dhawan P, Porta A, Mady LJ, Seth T. Vitamin D and intestinal calcium absorption. Mol Cell Endocrinol. 2011;347(1-2). doi: https://doi.org/10.1016/j.mce.2011.05.038
28. Veldurthy V, Wei R, Oz L, Dhawan P, Jeon YH, Christakos S. Vitamin D, calcium homeostasis and aging. Bone Res. 2016;4. doi: https://doi.org/10.1038/boneres.2016.41
29. Shymanskyi I, Lisakovska O, Mazanova A, Labudzynskyi D, Veliky M. Vitamin D3 modulates impaired crosstalk between RANK and glucocorticoid receptor signaling in bone marrow cells after chronic prednisolone administration. Front Endocrinol (Lausanne). 2018;9(JUN). doi: https://doi.org/10.3389/fendo.2018.00303
30. Wacker M, Holiack MF. Vitamin D-effects on skeletal and extraskeletal health and the need for supplementation. Nutrients. 2013;5(1). doi: https://doi.org/10.3390/nu5010111
31. Takahashi N, Udagawa N, Suda T. Vitamin D endocrine system and osteoclasts. Bonekey Rep. 2014;3. doi: https://doi.org/10.1038/bonekey.2014.17
32. Prié D, Forand A, Francoz C, et al. Plasma Fibroblast Growth Factor 23 Concentration Is Increased and Predicts Mortality in Patients on the Liver-Transplant Waiting List. PLoS One. 2013;8(6). doi: https://doi.org/10.1371/journal.pone.0066182
33. He X, Shen Y, Ma X, et al. The association of serum FGF23 and non-alcoholic fatty liver disease is independent of vitamin D in type 2 diabetes patients. Clin Exp Pharmacol Physiol. 2018;45(7). doi: https://doi.org/10.1111/1440-1681.12933
34. Bihari C, Lal D, Thakur M, et al. Suboptimal Level of Bone-Forming Cells in Advanced Cirrhosis are Associated with Hepatic Osteodystrophy. Hepatol Commun. 2018;2(9). doi: https://doi.org/10.1002/hep4.1234
35. Lavi-Moshayoff V, Wasserman G, Meir T, Silver J, Naveh- Many T. PTH increases FGF23 gene expression and mediates the high-FGF23 levels of experimental kidney failure: A bone parathyroid feedback loop. Am J Physiol Renal Physiol. 2010;299(4). doi: https://doi.org/10.1152/ajprenal.00360.2010
36. Silver J, Naveh-Many T. FGF23 and the parathyroid glands. Pediatric Nephrology. 2010;25(11). doi: https://doi.org/10.1007/s00467-010-1565-3
37. Fisher L, Fisher A. Vitamin D and Parathyroid Hormone in Outpatients With Noncholestatic Chronic Liver Disease. Clinical Gastroenterology and Hepatology. 2007;5(4). doi: https://doi.org/10.1016/j.cgh.2006.10.015
38. Islam MZ, Viljakainen HT, Kärkkäinen MUM, Saarnio E, Laitinen K, Lamberg-Allardt C. Prevalence of vitamin D deficiency and secondary hyperparathyroidism during winter in pre-menopausal Bangladeshi and Somali immigrant and ethnic Finnish women: associations with forearm bone mineral density. Br J Nutr. 2012;107(2):277-283. doi: https://doi.org/10.1017/S0007114511002893
39. Narayanasamy K, Karthick R, Raj AK. High Prevalent Hypovitaminosis D Is Associated with Dysregulation of Calcium-parathyroid Hormone-vitamin D Axis in Patients with Chronic Liver Diseases. J Clin Transl Hepatol. 2019;7(1):15-20. doi: https://doi.org/10.14218/JCTH.2018.00018
40. Duarte MP, Farias ML, Coelho HS, et al. Calcium-parathyroid hormone-vitamin D axis and metabolic bone disease in chronic viral liver disease. J Gastroenterol Hepatol. 2001;16(9):1022-1027. doi: https://doi.org/10.1046/j.1440-1746.2001.02561.x
41. Marek B, Kajdaniuk D, Niedziołka D, et al. Growth hormone/insulinlike growth factor-1 axis, calciotropic hormones and bone mineral density in young patients with chronic viral hepatitis. Endokrynol Pol. 2015;66(1):22-29. doi: https://doi.org/10.5603/EP.2015.0005
42. Corey RL, Whitaker MD, Crowell MD, et al. Vitamin D deficiency, parathyroid hormone levels, and bone disease among patients with end-stage liver disease and normal serum creatinine awaiting liver transplantation. Clin Transplant. 2014;28(5). doi: https://doi.org/10.1111/ctr.12351
43. Dibble JB, Sheridan P, Hampshire R, Hardy GJ, Losowsky MS. Evidence for secondary hyperparathyroidism in the osteomalacia associated with chronic liver disease. Clin Endocrinol (Oxf ). 1981;15(4):373-383. doi: https://doi.org/10.1111/j.1365-2265.1981.tb00677.x
44. Gerhardt A, Greenberg A, Reilly JJ, Van Thiel DH. Hypercalcemia. A complication of advanced chronic liver disease. Arch Intern Med. 1987;147(2):274-277. doi: https://doi.org/10.1001/archinte.147.2.274
45. Compston JE, Greer S, Skingle SJ, et al. Early increase in plasma parathyroid hormone levels following liver transplantation. J Hepatol. 1996;25(5):715-718. doi: https://doi.org/10.1016/s0168-8278(96)80243-1
46. Prytuła A, Walle J Vande, Van Vlierberghe H, et al. Factors associated with 1,25-dihydroxyvitamin D3 concentrations in liver transplant recipients: a prospective observational longitudinal study. Endocrine. 2016;52(1):93-102. doi: https://doi.org/10.1007/s12020-015-0757-9
47. Klein GL, Soriano H, Shulman RJ, Levy M, Jones G, Langman CB. Hepatic osteodystrophy in chronic cholestasis: evidence for a multifactorial etiology. Pediatr Transplant. 2002;6(2):136-140. doi: https://doi.org/10.1034/j.1399-3046.2002.01060.x
48. Marie PJ, Kassem M. Osteoblasts in osteoporosis: Past, emerging, and future anabolic targets. Eur J Endocrinol. 2011;165(1). doi: https://doi.org/10.1530/EJE-11-0132
49. Ruiz-Gaspà S, Martinez-Ferrer A, Guañabens N, et al. Effects of bilirubin and sera from jaundiced patients on osteoblasts: Contribution to the development of osteoporosis in liver diseases. Hepatology. 2011;54(6). doi: https://doi.org/10.1002/hep.24605
50. Nuti R, Brandi ML, Checchia G, et al. Guidelines for the management of osteoporosis and fragility fractures. Intern Emerg Med. 2019;14(1). doi: https://doi.org/10.1007/s11739-018-1874-2
51. Delgado-Calle J, Sato AY, Bellido T. Role and mechanism of action of sclerostin in bone. Bone. 2017;96. doi: https://doi.org/10.1016/j.bone.2016.10.007
52. Rhee Y, Kim WJ, Han KJ, Lim SK, Kim SH. Effect of liver dysfunction on circulating sclerostin. J Bone Miner Metab. 2014;32(5). doi: https://doi.org/10.1007/s00774-013-0524-z
53. Reid IR. Targeting Sclerostin in Postmenopausal Osteoporosis: Focus on Romosozumab and Blosozumab. BioDrugs. 2017;31(4). doi: https://doi.org/10.1007/s40259-017-0229-2
54. Guañabens N, Parés A. Osteoporosis in chronic liver disease. Liver International. 2018;38(5). doi: https://doi.org/10.1111/liv.13730
55. Kimura K, Terasaka T, Iwata N, et al. Combined effects of androgen and growth hormone on osteoblast marker expression in mouse C2C12 and MC3T3-E1 cells induced by bone morphogenetic protein. J Clin Med. 2017;6(1). doi: https://doi.org/10.3390/jcm6010006
56. Qiu T, Crane JL, Xie L, Xian L, Xie H, Cao X. IGF-I induced phosphorylation of PTH receptor enhances osteoblast to osteocyte transition. Bone Res. 2018;6(1). doi: https://doi.org/10.1038/s41413-017-0002-7
57. Guerra-Menéndez L, Sádaba MC, Puche JE, et al. IGF-I increases markers of osteoblastic activity and reduces bone resorption via osteoprotegerin and RANK-ligand. J Transl Med. 2013;11(1). doi: https://doi.org/10.1186/1479-5876-11-271
58. Krishnan V. Regulation of bone mass by Wnt signaling. Journal of Clinical Investigation. 2006;116(5):1202-1209. doi: https://doi.org/10.1172/JCI28551
59. Nasu M, Sugimoto T, Chihara M, Hiraumi M, Kurimoto F, Chihara K. Effect of natural menopause on serum levels of IGF-I and IGFbinding proteins: Relationship with bone mineral density and lipid metabolism in perimenopausal women. Eur J Endocrinol. 1997;136(6). doi: https://doi.org/10.1530/eje.0.1360608
60. de la Garza RG, Morales-Garza LA, Martin-Estal I, Castilla-Cortazar I. Insulin-Like Growth Factor-1 Deficiency and Cirrhosis Establishment. J Clin Med Res. 2017;9(4). doi: https://doi.org/10.14740/jocmr2761w
61. Cemborain A, Castilla-Cortázar I, García M, et al. Osteopenia in rats with liver cirrhosis: Beneficial effects of IGF-I treatment. J Hepatol. 1998;28(1). doi: https://doi.org/10.1016/S0168-8278(98)80211-0
62. Adamek A, Kasprzak A. Insulin-like growth factor (IGF) system in liver diseases. Int J Mol Sci. 2018;19(5). doi: https://doi.org/10.3390/ijms19051308
63. Golds G, Houdek D, Arnason T. Male Hypogonadism and Osteoporosis: The Effects, Clinical Consequences, and Treatment of Testosterone Deficiency in Bone Health. Int J Endocrinol. 2017;2017. doi: https://doi.org/10.1155/2017/4602129
64. Seeman E. The structural and biomechanical basis of the gain and loss of bone strength in women and men. Endocrinol Metab Clin North Am. 2003;32(1). doi: https://doi.org/10.1016/S0889-8529(02)00078-6
65. Naseem S, Hussain T, Manzoor S. Interleukin-6: A promising cytokine to support liver regeneration and adaptive immunity in liver pathologies. Cytokine Growth Factor Rev. 2018;39. doi: https://doi.org/10.1016/j.cytogfr.2018.01.002
66. Wu Q, Zhou X, Huang D, Ji Y, Kang F. IL-6 enhances osteocytemediated osteoclastogenesis by promoting JAK2 and RANKL activity in vitro. Cellular Physiology and Biochemistry. 2017;41(4). doi: https://doi.org/10.1159/000465455
67. Nakchbandi IA, Mitnick MA, Lang R, Gundberg C, Kinder B, Insogna K. Circulating levels of interleukin-6 soluble receptor predict rates of bone loss in patients with primary hyperparathyroidism. Journal of Clinical Endocrinology and Metabolism. 2002;87(11). doi: https://doi.org/10.1210/jc.2001-011814
68. Blaschke M, Koepp R, Cortis J, et al. IL-6, IL-1β, and TNF-α only in combination influence the osteoporotic phenotype in Crohn’s patients via bone formation and bone resorption. Advances in Clinical and Experimental Medicine. 2018;27(1). doi: https://doi.org/10.17219/acem/67561
69. Norris CA, He M, Kang LI, et al. Synthesis of IL-6 by hepatocytes is a normal response to common hepatic stimuli. PLoS One. 2014;9(4). doi: https://doi.org/10.1371/journal.pone.0096053
70. Shimada M, Matsumata T, Taketomi A, et al. The role of interleukin-6, interleukin-16, tumor necrosis factor-alpha and endotoxin in hepatic resection. Hepatogastroenterology. 1995;42(5):691-697
71. Hernandez-Barragan A, Montes-de-Oca-Angeles D, Lemus- Peña M, et al. Serum determination of IL-1β and IL-1RA in patients with chronic liver diseases. Ann Hepatol. 2022;27. doi: https://doi.org/10.1016/j.aohep.2022.100864
72. Ruscitti P, Cipriani P, Carubbi F, et al. The role of IL-1β in the bone loss during rheumatic diseases. Mediators Inflamm. 2015;2015. doi: https://doi.org/10.1155/2015/782382
73. Dinarello CA. Overview of the IL-1 family in innate inflammation and acquired immunity. Immunol Rev. 2018;281(1). doi: https://doi.org/10.1111/imr.12621
74. Nakamura I, Jimi E. Regulation of Osteoclast Differentiation and Function by Interleukin-1. Vitam Horm. 2006;74. doi: https://doi.org/10.1016/S0083-6729(06)74015-8
75. Lorenzo J, Horowitz M, Choi Y. Osteoimmunology: Interactions of the bone and immune system. Endocr Rev. 2008;29(4). doi: https://doi.org/10.1210/er.2007-0038
76. Zhao S, Jiang J, Jing Y, et al. The concentration of tumor necrosis factor-α determines its protective or damaging effect on liver injury by regulating Yap activity. Cell Death Dis. 2020;11(1). doi: https://doi.org/10.1038/s41419-020-2264-z
77. Zhao B, Grimes SN, Li S, Hu X, Ivashkiv LB. TNF-induced osteoclastogenesis and inflammatory bone resorption are inhibited by transcription factor RBP-J. Journal of Experimental Medicine. 2012;209(2). doi: https://doi.org/10.1084/jem.20111566
78. Boyce BF, Li P, Yao Z, et al. TNFα and pathologic bone resorption. Keio Journal of Medicine. 2005;54(3). doi: https://doi.org/10.2302/kjm.54.127
79. Stojic J, Kukla M, Grgurevic I. The Intestinal Microbiota in the Development of Chronic Liver Disease: Current Status. Diagnostics. 2023;13(18). doi: https://doi.org/10.3390/diagnostics13182960
80. Liu J, Yang D, Wang X, et al. Gut Microbiota Targeted Approach in the Management of Chronic Liver Diseases. Front Cell Infect Microbiol. 2022;12. doi: https://doi.org/10.3389/fcimb.2022.774335
81. Jeong H, Kim D. Bone Diseases in Patients with Chronic Liver Disease. Int J Mol Sci. 2019;20(17):4270. doi: https://doi.org/10.3390/ijms20174270
82. Yang YJ, Kim DJ. An overview of the molecular mechanisms contributing to musculoskeletal disorders in chronic liver disease: Osteoporosis, sarcopenia, and osteoporotic sarcopenia. Int J Mol Sci. 2021;22(5):1-33. doi: https://doi.org/10.3390/ijms22052604
83. Sumida K, Shrestha P, Mallisetty Y, et al. Incident Diuretic Use and Subsequent Risk of Bone Fractures: A Large Nationwide Observational Study of US Veterans. Mayo Clin Proc. 2024;99(6):913-926. doi: https://doi.org/10.1016/j.mayocp.2023.09.018
84. van der Burgh AC, Oliai Araghi S, Zillikens MC, et al. The impact of thiazide diuretics on bone mineral density and the trabecular bone score: the Rotterdam Study. Bone. 2020;138. doi: https://doi.org/10.1016/j.bone.2020.115475
Supplementary files
|
1. Figure 1: Vitamin D metabolism in normal state and in chronic liver disease. Explanations in the text. | |
Subject | ||
Type | Исследовательские инструменты | |
View
(781KB)
|
Indexing metadata ▾ |
Review
For citations:
Gorbacheva A.M., Bibik E.E., Lavreniuk A.A., Eremkina A.K., Tikhonov I.N., Mokrysheva N.G. Mineral disorders in patients with chronic liver disease. Part 1: epidemiology and pathophysiology. Obesity and metabolism. 2024;21(4):373-381. (In Russ.) https://doi.org/10.14341/omet13124

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0).