|Year : 2020 | Volume
| Issue : 2 | Page : 60-63
Thalassemia, hepatitis C and liver siderosis: Triple disease in children
Consultant Pediatric Gastro-Enterologist and Hepatologist, GI Kids Clinics and Imaging Center, Nagpur, Maharashtra, India
|Date of Submission||21-Oct-2020|
|Date of Decision||16-Nov-2020|
|Date of Acceptance||29-Nov-2020|
|Date of Web Publication||27-Apr-2021|
Dr. Yogesh Waikar
Superspeciality GI Kids Clinics and Imaging Center, Near Dhantoli Police Station, Dhantoli, Nagpur - 440 012, Maharashtra
Source of Support: None, Conflict of Interest: None
Thalassemia patients require multiple transfusions. Iron overload and hepatitis C are known complications due to transfusions. Iron overload is treated with iron chelators. Hepatitis C treatment is rapidly evolving in children. This review discusses the management of these patients in light of newly available direct-acting antiviral agents. Early diagnosis and treatment remains the cornerstone in the management of this triple disease.
Keywords: Direct-acting antiviral agents, hepatitis C, iron chelators, iron overload, thalassemia
|How to cite this article:|
Waikar Y. Thalassemia, hepatitis C and liver siderosis: Triple disease in children. J Pediatr Assoc India 2020;9:60-3
|How to cite this URL:|
Waikar Y. Thalassemia, hepatitis C and liver siderosis: Triple disease in children. J Pediatr Assoc India [serial online] 2020 [cited 2022 Aug 10];9:60-3. Available from: http://www.jpai.in//text.asp?2020/9/2/60/314812
| Introduction|| |
Thalassemia is an hemoglobinopathy. This condition requires repeated blood transfusions. The risk of transmission-associated hepatitis C is well known. Management of thalassemia with hepatitis C in the era of newer direct-acting antiviral agents (DAAs) has changed. Hepatic siderosis or liver iron overload is an added insult in this combined cohort of patients. Liver iron overload increases the probability of chronicity and liver fibrosis. The role of iron chelators and their drug interactions with antiviral agents are important. Triple disease, that is, thalassemia, hepatitis C, and hepatic siderosis, can be managed effectively if diagnosed and treated properly in children.
| Pediatric Hepatitis C|| |
Nearly 1% of the world's population have chronic hepatitis-C virus (HCV) infection. About 5 million children have active HCV infection. The National Health and Nutrition Evaluation Survey had noted that 0.2% of children between 6 and 11 years of age and 0.4% between 12 and 19 years of age in the USA suffer from HCV infection. In Asia, genotype 3 is prevalent. Genotype I b is more prevalent, among multiple transfused patients. Mother-to-child transmission is the main mode of transmission of HCV infection. Perinatally transmitted HCV infection is more likely to evolve to cirrhosis as compared to acquired.
Genotype 3 is more likely to get cleared spontaneously. Significant transaminitis, that is, deranged liver functions prior to virological clearance, is a known phenomenon. Unfortunately, levels of liver enzymes do not correlate with the disease severity. Newer guidelines for the treatment of HCV infection in children have been published recently with focus on DAAs. Ledipasvir/sofosbuvir and sofosbuvir and ribavirin have been recommended for genotypes 1 and 4 and genotypes 2 and 3, respectively. Liver biopsy is not required in every case. Recently completed trials even report the use of sofosbuvir and daclatasvir in children under 12 years of age with >95% of sustained virological response. Compared to interferon-based regimen, the superiority of DAA is now well established.
| Thalassemia and Hepatitis C|| |
HCV infection in thalassemia is a result of posttransfusion hepatitis. Recently, a study noted that 13.6% of beta-thalassemia patients have HCV infection. Another study noted that 49% of beta-thalassemia patients have HCV infection. Overall 9% of patients listed for bone marrow transplant (BMT) for thalassemia have pretransplant hepatitis. Hepatitis remains a common comorbid condition in thalassemia patients. This cohort of patients definitely needs special attention. Combined team approach of pediatric hematologists and hepatologists is essential. Each case needs individualized approach. The morbidity and mortality of the cohort gets increased if not properly managed. Liver disease is more severe in thalassemia and is augmented by hepatic siderosis. Liver iron overload is also the result of repeated blood transfusions. It progresses to hepatic inflammation and fibrosis. This triple-disease phenomenon needs early diagnosis. Reduced HCV treatment response with interferon-based regimen has been confirmed.
Various factors play their roles in successful management, for example, concurrent liver histopathological insults due to triple-disease phenomenon, variable response to treatment regimens, serum iron or ferritin levels, drug-to-drug interactions, iron chelators and DAA interactions, and pre-BMT modification of conditioning regimens. Multi-axial analysis is important while treating this triple cohort.
| Drug-Associated Issues in Triple Disease|| |
Ribavirin is used to treat HCV infection. It is preferred for genotypes 2 and 3 HCV infection. Ribavirin has the side effect of hemolysis. It increases transfusion requirement in the treated subgroup. Origa et al. noted that the combination of sofosbuvir and ribavirin for genotype 2 increases blood transfusion demand, but sustained virological response remains unaffected. Hence, hemoglobin monitoring is essential while using ribavirin.
Deferoxamine, deferiprone, and deferasirox are commonly used iron chelators in thalassemia patients. No significant drug–drug interactions are noted between DAAs and iron chelators. A pediatric trial noted no toxicity when sofosbuvir and ledipasvir were administered to patients in combination with either deferoxamine or deferasirox.,
Minor drug–drug interactions of DAAs are documented with proton pump inhibitors, histamine receptor blockers, antacids, alkalinizing agents, and colchicine. They commonly interfere with ledipasvir absorption. Other drugs affecting DAAs are statins, antihypertensives, thyroid hormones, antiarrhythmics, and anti-epileptics. One should be cautious irrespective of the presence or absence of hemoglobinopathies while using them together.
DAAs can safely be used in HCV management in patients with thalassemia and sickle cell disease. Synergistic action of DAAs and iron chelators leads to improvement, in liver parameters.
Hepatitis C in the Settings of Bone Marrow Transplant for Thalassemia
BMT is the only curative therapy for beta-thalassemia. The associated morbidity and mortality with coexisting chronic HCV infection is known. Sinusoidal obstruction syndrome, graft-versus-host disease, hepatic inflammation, and liver failures are are more common. The American Society for Blood and Marrow Transplant Task Force recommends completing the therapy of HCV prior to transplant. Reduced-intensity regimen for conditioning (prior to transplant) is used to reduce the risk of sinusoidal obstruction syndrome and regimen-related toxicity. Long-term follow-up of these patients post-BMT with treated hepatitis C is awaited. There is a possibility of increased risk of cirrhosis and hepatocellular carcinoma.
| Interactive Interpretation of Clinical Pathologies of Triple disease|| |
HCV antibodies are reported in 85% of transfused patients in Italy, 23% in the UK, and 35% in the USA.,, Approximately 75% of the infected patients do not recover from the viral infection by 6 months. About 60% of the hemophilic patients who are transfused remain HCV positive. The total number of transfusions in hemoglobinopathy is strongly correlated with the chances of HCV infection. A clinico-virologicial analysis of HCV infection in transfusion-dependent beta-thalassemia (100 children) noted a statistically significant correlation between HCV viremia and shorter intertransfusion interval. Hence, reduced different donor exposures and increased aliquot quantity are recommended.
Genetic variants in interleukin-28 B gene are associated with spontaneous clearance of HCV in patients with thalassemia. Nearly 20% of patients in the cohort of thalassemia with HCV infection already have cirrhosis before starting on DAAs. Patients with acute HCV and thalassemia have low rate of spontaneous resolution of HCV infection. Majority of them progress to chronicity. Patients with concomitant HCV and thalassemia have reduced hemoglobin level, low total iron-binding capacity, and raised serum iron and transferrin/ferritin levels in comparison with those of acute HCV patients without thalassemia. No significant elevation of serum ferritin is observed during and after the treatment of HCV infection when correlated with chelators. Serum ferritin levels in DAA-treated group at follow-up (12 weeks) are found not to be significantly different from that of control group of thalassemia without HCV who received chelators. Thus, concomitant usage of iron chelators helps in triple disease.
The degree of transaminitis has no correlation with the presence or absence of HCV viremia. Some studies have noted that ALT and aspartate aminotransferase levels are higher in patients with HCV and thalassemia compared to those without thalassemia. However, the relation was not statistically significant. Levels of serum glutamic oxaloacetic transaminase/serum glutamic pyruvic transaminase do not correlate with the HCV disease severity. If those levels are raised, after-treatment reduction in liver enzymes is also seen.
Liver iron is an important factor in the triple disease responsible for fibrosis. Liver iron chelation is must irrespective of the HCV status., In a study by Kamal et al., a significant correlation was noted between liver iron concentration and hepatitis fibrosis rate.
Earlier treatment of HCV in thalassemia patients with currently available DAAs is not only cost-effective, but also evidence based., Sustained virological response is more with DAAs as compared to interferon therapy., There are fewer side effects of newer DAAs.,, Thus, early diagnosis and treatment with DAAs, continued iron chelation, remains the cornerstone in the treatment of triple disease. Blood transfusion requirement is more with ribavirin but less after this treated sub-group.
| Conclusion|| |
DAAs have changed the outlook of treatable chronic HCV and thalassemia patients. DAAs can be given with iron chelators. Before BMT, HCV viral clearance is mandated. One can preferably use reduced-intensity conditioning regimen prior to BMT. Early diagnosis and treatment remains the cornerstone in management. Follow-up for long-term complications such as cirrhosis and hepatocellular carcinoma is must. Unfortunately, costing of DAAs is the main limiting factor in the management of triple disease.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Global Hepatitis Report 2017. Em Inglês | WH O IRIS | ID: who-255016. Geneva: World Health Organization; 2017. p. 83.
Gower E, Estes C, Blach S, Razavi-Shearer K, Razavi H. Global epidemiology and genotype distribution of the hepatitis C virus infection. J Hepatol. 2014;61 1 Suppl:S45-57.
Denniston MM, Jiles RB, Drobeniuc J, Klevens RM, Ward JW, McQuillan GM, et al
. Chronic hepatitis C virus infection in United States, national health and nutrition examination survey 2003 to 2010. Ann Intern Med 2014:160:293-300.
Modin L, Arshad A, Wilkes B, Benselin J, Lloyd C, Irving WL, et al
. Epidemiology and natural history of hepatitis C virus infection among children and young people. J. Hepatol 2019;70:371-8.
Christofidou M, Lambropoulou-Karatza C, Dimitracopoulos C, Dimitracopoulos G, Spiliopoulou I, et al
. Distribution of hepatitis C virus genotype in viremic patients with Beta- thalassemia. Eur J Clin Microbial Infect Dis 2000;19:728-30.
DiMarco V, Capra M, Angelucci E, Borgna-Pignatti C, Telfer P, Harmatz P, et al
. Management chronic viral hepatitis in patients with Thalassemia recommendations from an international panel. Blood 2010;116:2875-83.
El-Shabrawi MH, Kamal NM. Burden of paediatric hepatitis C. World J Gastroenterol 2013;28:7880-8.
Bortolotti F, Verucchi G, Cammà C, Cabibbo G, Zancan L, Indolfi G, et al
. Long term course of chronic hepatitis C in children: From viral clearance to end stage liver disease. Gastroenterology 2008:134:1900-7.
Resti M, Jara P, Hierro L, Azzari C, Giacchino R, Zuin G, et al
. Clinical features and progression of perinatally acquired Hepatitis C virus infection J Med Virol 2003;70:373-7.
Ragasa R, Simone Corsaro L, Frazzetto E, Bertino E, Bellia MA, Bertino G, et al
. Hepatitis C virus infection in children and pregnant women: An updated review of the literature on screening and treatment. Am J Perinatol 2020; 10:e121-7.
Ghany MG, Morgan TR. Hepatitis C guidance 2019 update: American association for the study of liver diseases–infectious diseases society of America recommendations for testing, managing, and treating hepatitis C virus infection. Hepatology 2020;71:686-721.
Abdel Ghaffar TY, EL Naghi S, Abdel Gawad M, Helmy S, Ghaffar AA, Yousef M, et al
. Safety and efficacy of combined sofosbuvir/Daclatasvir treatment of children and adolescents with chronic hepatitis C genotype 4. J Viral Hepat 2018; 26:263-70.
Karnsakul W, Schwarz KB. Management of hepatitis C infection in children in the era of direct acting antiviral agents. J Viral Hepat 2019;26:1034-9.
Peffault de Latour R, Asselah T, Lévy V, Scieux C, Devergie A, Ribaud P, et al
. Treatment of chronic hepatitis C virus in allogenic bone marrow transplant recipients. Bone Marrow Transplant 2005;36:709-13.
Jafroodi M, Davoudi-KiaKalayeh A, Mohtasham-Amiri Z, Pourfathollah AA, Haghbin A. Trend in prevalence of hepatitis C virus infection among B-Thalassemia patients: 10 years of experience in Iran. Int J Prev Med 2015;6:89.
] [Full text]
Chern JP, Su S, Lin KH, Chang SH, Lu MY, Jou ST, et al
. Survival, mortality and complications in patients with beta-thalassemia major in Northern Taiwan. Paediatric Blood Cancer 2007;48:550-4.
Sabloff M, Chandy M, Wang Z, Logan BR, Ghavamzadeh A, Li C, et al
. HLA matched sibling bone marrow transplantation for B thalassemia major. Blood 2011;117:1745-50.
Daber HB, Sharara AI. Treatment of chronic HCV infection in patients with thalassemia. Clin Liver Dis 2019;14:199-202.
Alavian SM, Tabatabaei SV. Treatment outcome of chronic hepatitis C in sickle cell disease and thalassemic patients with interferon and ribavirin. Eur J Gastro enterol Hepatol 2010;22:123-4.
Inati A, Taher A, Gharra S, Koussa S, Taha M, Aoun E, et al
. Efficacy and tolerability of peginterferon alpha 2a with or without ribavirin in thalassemia major patients with chronic hepatitis C virus infection. Br J Haematol 2005;130:644-6.
Origa R, Ponti ML, Filoso A, Lanza AG, Piga A, Saracco GM, et al
. Treatment of hepatitis C virus infection with direct acting antiviral drugs is safe and effective in patient with hemoglobinopathies. Am J Hematol 2017;92:1349-55.
Sinakos E, Kountouras D, Koskinas J, Zachou K, Karatapanis S, Triantos C, et al
. Treatment of chronic hepatitis C with direct acting antivirals in patients with B thalassemia major and advanced liver disease. Br J Haematol 2017:178:130-6.
Biliotti E, Palazz OD, Serani M, Silvestri AM, Volpicelli L, Esvan R, et al
. Interferon free antiviral treatment of chronic hepatitis C in patients affected by B thalassemia major. Ann Hematol 2017;96:1043-5.
Abdullatif HM, Ramzi R, Mogahed EA, Ghobrial CM, Abd El Zaher BA, El Raziky MS, et al.
Drug–drug Interactions in children and adolescents receiving ledipasvir/sofosbuvir for the treatment of hepatitis C virus infection. Clin Drug Investig 2019;39:857-64.
Ponti ML, Comitini F, Murgia D, Ganga R, Canu R, Dessì C, et al
. Impact of the direct-acting antiviral agents on chronic hepatitis C in Sardinian patients with transfusion dependent Thalassemia major. Dig Liver Dis 2019;51:561-7.
Maffel L, Sorrentino F, Caprari P, Taliani G, Massimi S, Risoluti R, et al
. HCV infection in thalassemia syndrome and hemoglobinopathies: New perceptive. Front Mol Biosci 2020;7:1-6.
Ramgopal A, Lauko A, Rotz S, Hanna R. Safety of allogeneic hematopoietic stem cell transplantation in beta-thalassemia patients with chronic hepatitis C infections treated at a pediatric center. Pediatr Transplant 2019;23:e13520.
Torres HA, Chong PP, De Lima M, Friedman MS, Giralt S, Hammond SP, et al
. Hepatitis C virus infection among hematopoietic stem cell transplant donors and recipients. American society for Blood and Marrow Transplant Task force recommendations. Biol Blood Marrow Transplant 2015;21:1870-82.
Ljungman P, Locasciulli A, De soria VG, Békássy AN, Brinch L, Espigado I, et al
. Long term follow up of HCV infected hematopoietic SCT patients and effects of antiviral therapy. Bone Marrow Transplant 2012;47:1217-21.
Prati D. Benefits and complications of regular blood transfusions in patients with beta-thalassemia major. Vox Sang 2000;79:129-37.
Wonke B, Hoffbrand AV, Brown D, Dusheiko G. Antibody to hepatitis C virus in multiple transfused patients with thalassemia major. J Clin Pathol 1990;43:638-40.
Cunningham MJ, Macklin ER, Neufeld EJ, Cohen AR, Thalassemia Clinical Research Network. Complications of beta- thalassemia major in North America. Blood 2014;104;34-9.
Lai ME, Origa R, Danjou F, Leoni GB, Vacquer S, Anni F, et al
. Natural history of hepatitis C in thalassemia major: A long term prospective study. Eur J Haematol 2013;90:501-7.
Zhang M, Rosenberg PS, Brown DL, et al
. Second multicenter hemophilia cohort study. Correlates of spontaneous clearance of hepatitis C virus among people with hemophilia. Blood 2006;107:892-7.
Chakravarti A, Verma V, Kumaria R, Dubey AP. Anti HCV seropositivity among multiple transfused patients with beta thalassemia. J Indian Med Assoc 2005;103:64-6.
Ragab L, Helal S, Zaghloul N, El-Raziky M, Afifi R, Musallam KM, et al
. Clinicovirologic analysis of hepatitis C infection in transfusion dependent B thalassemia major children. Int Jnl Lab Hem 2010;32:184-90.
Zachou K, Arvaniti P, Gatselis NK, Azariadis K, Papadamou G, Rigopoulou E, et al
. Patients with Haemoglobinopathies and chronic hepatitis C: A real difficult to treat population in 2016? Mediterr J Hematol Infect Dis 2017;9:e2017003.
Kamal S, Abdelhakam S, Ghoraba D, Mohsen MA, Salam AA, Hassan H, et al
. The course of hepatitis C infection and response to anti-viral therapy in patients with thalassemia major and hepatitis C Infection: A longitudinal, prospective study. Mediterr J Hematol Infect Dis 2019;11:e2019060.
Nguyen J, Barritt AS 4th
, Jhaveri R. Cost effectiveness of early treatment with direct-acting antiviral therapy in adolescent patients with hepatitis C virus infection. J Pediatr 2019;207:90-6. doi: 10.1016/j.jpeds.2018.12.012. [Epub 2019 Feb 06].