Cytomegalovirus infection and the liver

Czech version

Authors: K. Chmelová; S. Fraňková; J. Šperl
Authors‘ workplace: Klinika hepatogastroenterologie, Transplantcentrum, IKEM, Praha
Published in: Gastroent Hepatol 2017; 71(6): 517-523
Category: Hepatology: Review article
doi: https://doi.org/10.14735/amgh2017517

Overview

Cytomegalovirus (CMV) is a DNA virus that belongs to the Herpesviridae family and the Betaherpesvirinae subfamily. Similar to other herpes viruses, CMV remains latent in myeloid cells for the entire lifespan of the host. The seroprevalence of CMV varies widely and negatively correlates with socioeconomic status, ranging from 40% of adults in Western European countries to almost 90% of adults in developing countries. CMV infection occurs via bodily fluids, especially saliva, and the virus can also be transmitted sexually and through transplanted organs. CMV replicates in many cells including hepatocytes, persists latently in bone marrow myeloid cells and can be reactivated upon immunosuppression. Primary CMV infection usually has an asymptomatic course, but can lead to life-threatening disease in immunocompromised individuals. However, a more common problem is reactivation of the latent virus. The clinical manifestation of CMV disease varies widely from asymptomatic viraemia (CMV infection sensu stricto) to CMV viral syndrome and CMV disease with organ involvement. CMV infection is a severe illness in solid-organ transplant patients and HIV-positive individuals. Anti-CMV prophylaxis and treatment of CMV infection are crucial in immunocompromised individuals. On the other hand, in healthy individuals, CMV hepatitis represents only 1% of all causes of liver function tests elevation. The 1-year incidence of CMV hepatitis is estimated to be 4/100,000 individuals. This disease mostly occurs in middle age and has a mild course that does not require antiviral therapy; a fulminant course is extremely rare. CMV never causes chronic hepatitis. Assessment of anti-CMV antibodies and CMV DNA are not part of the first-line differential diagnosis in patients with abnormal liver function tests. CMV hepatitis must be ruled out in middle-aged individuals presenting with viral syndrome and abnormal liver function tests.

Key words:
cytomegalovirus – hepatitis – seroprevalence – incidence – treatment – risk – immunosuppression

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

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

Submitted:
18. 9. 2017

Accepted:
26. 9. 2017

Sources

1. Stadler LP, Bernstein DI, Callahan ST et al. Seroprevalence of cytomegalovirus (CMV) and risk factors for infection in adolescent males. Clin Infect Dis 2010; 51 (10): e76–e81. doi: 10.1086/656918.

2. Cannon MJ, Schmid DS, Hyde TB. Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev Med Virol 2010; 20 (4): 202–213. doi: 10.1002/rmv.655.

3. Evans AS. Infectious mononucleosis and related syndromes. Am J Med Sci 1978; 276 (3): 325–339.

4. Sinzger C, Digel M, Jahn G. Cytomegalovirus cell tropism. Curr Top Microbiol Immunol 2008; 325: 63–83.

5. Sinclair J. Human cytomegalovirus: latency and reactivation in the myeloid lineage. J Clin Virol 2008; 41 (3): 180–185. doi: 10.1016/j.jcv.2007.11.014.

6. Stanier P, Taylor DL, Kitchen AD et al. Persistence of cytomegalovirus in mononuclear cells in peripheral blood from blood donors. BMJ 1989; 299 (6704): 897–898.

7. Leonardsson H, Hreinsson JP, Löve A et al. Hepatitis due to Epstein-Barr virus and cytomegalovirus: clinical features and outcomes. Scand J Gastroenterol 2017; 52 (8): 893–897. doi: 10.1080/00365521.2017.1319972.

8. Eddleston M, Peacock S, Juniper M et al. Severe cytomegalovirus infection in immunocompetent patients. Clin Infect Dis 1997; 24 (1): 52–56.

9. Bonnet F, Neau D, Viallard JF et al. Clinical and laboratory findings of cytomegalovirus infection in 115 hospitalized non-immunocompromised adults. Ann Med Interne (Paris) 2001; 152 (4): 227–235.

10. Kalil AC, Florescu DF. Prevalence and mortality associated with cytomegalovirus infection in nonimmunosuppressed patients in the intensive care unit. Crit Care Med 2009; 37 (8): 2350–2358. doi: 10.1097/CCM.0b013e3181a3aa43.

11. Reeves M, Sinclair J. Aspects of human cytomegalovirus latency and reactivation. Curr Top Microbiol Immunol 2008; 325: 297–313.

12. Björnsson HK, Olafsson S, Bergmann OM et al. A prospective study on the causes of notably raised alanine aminotransferase (ALT). Scand J Gastroenterol 2016; 51 (5): 594–600. doi: 10.3109/00365521.2015.1121516.

13. Shusterman NH, Frauenhoffer C, Kinsey MD. Fatal massive hepatic necrosis in cytomegalovirus mononucleosis. Ann Intern Med 1978; 88 (6): 810–812.

14. Yu YD, Park GC, Park PJ et al. Cytomegalovirus infection-associated fulminant hepatitis in an immunocompetent adult requiring emergency living-donor liver transplantation: report of a case. Surg Today 2013; 43 (4): 424–428. doi: 10.1007/s00595-012-0209-6.

15. Cebulla CM, Miller DM, Knight DA et al. Cytomegalovirus induces sialyl Lewis (x) and Lewis (x) on human endothelial cells. Transplantation 2000; 69 (6): 1202–1209.

16. Span AH, van Dam-Mieras MC, Mullers W et al. The effect of virus infection on the adherence of leukocytes or platelets to endothelial cells. Eur J Clin Invest 1991; 21 (3): 331–338.

17. Squizzato A, Gerdes VE, Buller HR. Effects of human cytomegalovirus infection on the coagulation system. Thromb Haemost 2005; 93 (3): 403–410.

18. Vercellotti GM. Effects of viral activation of the vessel wall on inflammation and thrombosis. Blood Coagul Fibrin 1998; 9: S3–S6.

19. Bonkowsky HL, Lee RV, Klatskin G. Acute granulomatous hepatitis. Occurrence in cytomegalovirus mononucleosis. JAMA 1975; 233 (12): 1284–1288.

20. Kenneson A, Cannon MJ. Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev Med Virol 2007; 17 (4): 253–276.

21. Stagno S, Whitley RJ. Herpesvirus infections of pregnancy. Part I: cytomegalovirus and Epstein-Barr virus infections. N Engl J Med 1985; 313 (20): 1270–1274.

22. Eggers M, Bader U, Enders G. Combination of microneutralization and avidity assays: improved diagnosis of recent primary human cytomegalovirus infection in single serum sample of second trimester pregnancy. J Med Virol 2000; 60 (3): 324–330.

23. Townsend CL, Forsgren M, Ahlfors K et al. Long-term outcomes of congenital cytomegalovirus infection in Sweden and the United Kingdom. Clin Infect Dis 2013; 56 (9): 1232–1239. doi: 10.1093/cid/ cit018.

24. Society for Maternal-Fetal M, Hughes BL et al. Diagnosis and antenatal management of congenital cytomegalovirus infection. Am J Obstet Gynecol 2016; 214 (6): B5–B11. doi: 10.1016/j.ajog.2016.02.042.

25. Picone O, Vauloup-Fellous C, Cordier AG et al. A series of 238 cytomegalovirus primary infections during pregnancy: description and outcome. Prenat Diagn 2013; 33 (8): 751–758. doi: 10.1002/pd.4118.

26. Gabrielli L, Bonasoni MP, Lazzarotto T et al. Histological findings in foetuses congenitally infected by cytomegalovirus. J Clin Virol 2009; 46 (Suppl 4): S16–S21. doi: 10.1016/j.jcv.2009.09.026.

27. Boppana SB, Fowler KB, Britt WJ et al. Symptomatic congenital cytomegalovirus infection in infants born to mothers with preexisting immunity to cytomegalovirus. Pediatrics 1999; 104 (1 Pt 1): 55–60.

28. Pass RF, Fowler KB, Boppana SB et al. Congenital cytomegalovirus infection following first trimester maternal infection: symptoms at birth and outcome. J Clin Virol 2006; 35 (2): 216–220.

29. Manicklal S, Emery VC, Lazzarotto T et al. The “silent” global burden of congenital cytomegalovirus. Clin Microbiol Rev 2013; 26 (1): 86–102. doi: 10.1128/CMR.00062-12.

30. Ozkan TB, Mistik R, Dikici B et al. Antiviral therapy in neonatal cholestatic cytomegalovirus hepatitis. BMC Gastroenterol 2007; 7: 9.

31. Simon DM, Levin S. Infectious complications of solid organ transplantations. Infect Dis Clin North Am 2001; 15 (2): 521–549.

32. Paya CV, Hermans PE, Wiesner RH et al. Cytomegalovirus hepatitis in liver transplantation: prospective analysis of 93 consecutive orthotopic liver transplantations. J Infect Dis 1989; 160 (5): 752–758.

33. Hibberd PL, Tolkoff-Rubin NE, Cosimi AB et al. Symptomatic cytomegalovirus disease in the cytomegalovirus antibody seropositive renal transplant recipient treated with OKT3. Transplantation 1992; 53 (1): 68–72.

34. Drouet E, Colimon R, Michelson S et al. Monitoring levels of human cytomegalovirus DNA in blood after liver transplantation. J Clin Microbiol 1995; 33 (2): 389–394.

35. Humar A, Snydman D, Practice ASTIDCo. Cytomegalovirus in solid organ transplant recipients. Am J Transplant 2009; 9 (Suppl 4): S78–S86. doi: 10.1111/ j.1600-6143.2009.02897.x.

36. Lee SO, Razonable RR. Current concepts on cytomegalovirus infection after liver transplantation. World J Hepatol 2010; 2 (9): 325–336. doi: 10.4254/wjh.v2.i9.325.

37. Paya CV. Prevention of cytomegalovirus disease in recipients of solid-organ transplants. Clin Infect Dis 2001; 32 (4): 596–603.

38. Singh N, Wannstedt C, Keyes L et al. Who among cytomegalovirus-seropositive liver transplant recipients is at risk for cytomegalovirus infection? Liver Transpl 2005; 11 (6): 700–704.

39. Strippoli GF, Hodson EM, Jones CJ et al. Pre-emptive treatment for cytomegalovirus viraemia to prevent cytomegalovirus disease in solid organ transplant recipients. Cochrane Database Syst Rev 2006 (1): CD005133.

40. Singh N. Optimization of outcomes related to cytomegalovirus in organ transplant recipients. Transplantation 2006; 82 (1): 15–16.

41. Razonable RR, Paya CV. Valganciclovir for the prevention and treatment of cytomegalovirus disease in immunocompromised hosts. Expert Rev Anti Infect Ther 2004; 2 (1): 27–41.

42. Salzberger B, Hartmann P, Hanses F et al. Incidence and prognosis of CMV disease in HIV-infected patients before and after introduction of combination antiretroviral therapy. Infection 2005; 33 (5–6): 345–349.

43. Emery VC. Restimulating interest in cytomegalovirus as a cofactor for HIV infection. J Infect Dis 2015; 211 (2): 169–171. doi: 10.1093/infdis/jiu419.

44. Jabs DA, Van Natta ML, Kempen JH et al. Characteristics of patients with cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Am J Ophthalmol 2002; 133 (1): 48–61.

45. Jabs DA, Holbrook JT, Van Natta ML et al. Risk factors for mortality in patients with AIDS in the era of highly active antiretroviral therapy. Ophthalmology 2005; 112 (5): 771–779.

46. Chou S. Newer methods for diagnosis of cytomegalovirus infection. Rev Infect Dis 1990; 12 (Suppl 7): S727–S736.

47. Kraft CS, Armstrong WS, Caliendo AM. Interpreting quantitative cytomegalovirus DNA testing: understanding the laboratory perspective. Clin Infect Dis 2012; 54 (12): 1793–1797. doi: 10.1093/cid/cis212.

48. Bek B, Boeckh M, Lepenies J et al. High-level sensitivity of quantitative pp65 cytomegalovirus (CMV) antigenemia assay for diagnosis of CMV disease in AIDS patients and follow-up. J Clin Microbiol 1996; 34 (2): 457–459.

49. van den Berg AP, Klompmaker IJ, Haagsma EB et al. Antigenemia in the diagnosis and monitoring of active cytomegalovirus infection after liver transplantation. J Infect Dis 1991; 164 (2): 265–270.

50. Kotton CN, Kumar D, Caliendo AM et al. Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation 2013; 96 (4): 333–360. doi: 10.1097/TP.0b013e31829df29d.

51. Murray BM. Management of cytomegalovirus infection in solid-organ transplant recipients. Immunol Invest 1997; 26 (1–2): 243–255.

52. Crumpacker CS. Ganciclovir. N Engl J Med 1996; 335 (10): 721–729.

53. Limaye AP. Ganciclovir-resistant cytomegalovirus in organ transplant recipients. Clin Infect Dis 2002; 35 (7): 866–872.

54. Balfour HH Jr, Chace BA, Stapleton JT et al. A randomized, placebo-controlled trial of oral acyclovir for the prevention of cytomegalovirus disease in recipients of renal allografts. N Engl J Med 1989; 320 (21): 1381–1387.

55. Flechner SM, Avery RK, Fisher R et al. A randomized prospective controlled trial of oral acyclovir versus oral ganciclovir for cytomegalovirus prophylaxis in high-risk kidney transplant recipients. Transplantation 1998; 66 (12): 1682–1688.

56. Lowance D, Neumayer HH, Legendre CM et al. Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation. International Valacyclovir Cytomegalovirus Prophylaxis Transplantation Study Group. N Engl J Med 1999; 340 (19): 1462–1470.

57. Reischig T, Hribova P, Jindra P et al. Long-term outcomes of pre-emptive valganciclovir compared with valacyclovir prophylaxis for prevention of cytomegalovirus in renal transplantation. J Am Soc Nephrol 2012; 23 (9): 1588–1597. doi: 10.1681/ASN.2012010100.

58. Kwo PY, Cohen SM, Lim JK. ACG Clinical Guideline: evaluation of abnormal liver chemistries. Am J Gastroenterol 2017; 112 (1): 18–35. doi: 10.1038/ajg.2016.517.