The association of hepatitis C virus infection and thyroid disease: A systematic review and meta-analysis

Abstract

Previous studies have reported that hepatitis C virus (HCV) infection may increase the risk of thyroid disease (TD) even thyroid cancer (TC), but quantitative assessments of risk were rare and the results were not consistent. The purpose of this study was to evaluate the impact of HCV infection on TD and TC, and provide clues to explore the relationship between HCV infection and TD and TC. The literature retrieval was performed up to August 20th, 2021 in the database of PubMed, Cochrane library, Web of Science, China National Knowledge Infrastructure and Wang Fang. The risk of HCV for TD or TC was expressed with odds ratio (OR) and 95% confidence intervals (CI). Subgroup analysis was used to explore the source of heterogeneity. Six articles (three studies published as article and three studies published as abstract) were included in this meta-analysis, with a total of 5398 controls and 1925 cases of hepatitis C. The results of meta-analysis found that HCV infection were significantly associated with an increased risk of TD (sum OR = 1.80, 95% CI = 1.54–2.10, P < 0.001, I² = 74.3%) and TC (sum OR = 16.36, 95% CI = 4.65-57.62, P < 0.001, I² = 0%). HCV infection may increase the risk of TD and TC. More work is needed in the future to establish a causal role, however an awareness of the possibility of increased risk of TD and TC may lead to earlier diagnosis and better outcomes in patients with hepatitis C.

Keywords

Thyroid cancer thyroid disease HCV infection meta-analysis

Introduction

Thyroid disease (TD) has a clinical manifestation of thyroid dysfunction, often accompanied by various autoimmune phenomena. Currently, TDs under medical treatment mainly include hyperthyroidism and thyroiditis, while TDs under surgical treatment mainly include goiter and thyroid tumors. The two types are not independent, but can be transformed into each other.¹ Thyroid cancer (TC) is the most common malignancy of the endocrine system, which accounts for approximately 1% of all types of human cancer.² Hepatitis C is caused by hepatitis C virus (HCV) infection, and 58 million people globally had chronic HCV infection in 2019, but only 21% of those were diagnosed.^3,4 Previous studies have reported that HCV infection can increase the risk of TD and even TC,^5–8 but the results were inconsistent. In addition, Scappaticcio et al.⁹ also found that liver blood test abnormalities were associated with newly diagnosed and untreated hyperthyroidism. In order to further understand the relationship between HCV and TD and even TC, we performed this systematic review and meta-analysis.

Materials and methods

This systematic review and meta-analysis were performed according to their preferred reporting items’ (PRISMA) statement¹⁰ (Supplementary Table 1).

Literature search

We conducted a systematic review and meta-analysis dated to August 20, 2021 in the databases of PubMed, Cochrane library, Web of Science, China National Knowledge Infrastructure, and Wang Fang. There were no restrictions on the language and year of publication. We searched the following keywords in the above database: “hepatitis C” or “chronic hepatitis C” or “HCV” or “CHC”) AND (“thyroid cancer” or “thyroid carcinoma” or “thyroid tumor” or “thyroid disease” or “thyroid diseases”) (Supplementary Table 2). All types of studies were initially included. The procedure is outlined in Figure 1.

Figure 1.

Preferred reporting items for the review flow diagram for identification of relevant studies.

Study selection and data extraction

The included studies met the following criteria: (a) patients with HCV infection (HCV RNA positive in blood)¹¹ and suffering from TD or TC; (b) patients gave informed consent. Studies were excluded if they had no relevant data.

The main information extracted from each study were: first author's name, online time, study design, study sites, sex, age, treatment history, number of cases, and number of controls. To avoid selection bias caused by one person, two reviewers (Dr. Wang and Dr. Liu) assessed all abstracts and chose the relevant literature for full-text reading. Any disagreement was resolved by discussion among all authors.

Quality assessment and statistical analysis

All studies included were assessed for methodological quality referring to the Newcastle Ottawa Scale (NOS) (http://www.ohri.ca/programs/clinical_epidemiology/nosgen.pdf). (Supplementary Table 3). A study can be awarded a maximum of one star for each numbered item within the Selection and Exposure categories. A maximum of two stars can be given for Comparability. Based on the scores, we graded the quality of each article into three levels: 0–3 stars indicated low quality, 4–6 stars indicated middle quality, and 7–9 stars indicated high quality. Two investigators independently determined the scores, and if there was any disagreement between the two investigators, it was resolved by consensus among all investigators.

STATA version 13.0 was used for the meta-analysis. Pooled OR with 95% CI for TD or TC risk associated with HCV infection was summarized with fixed/random effect models. Statistical heterogeneity was calculated with the I2-method, and I² was calculated as follows: I² (%) = 100 × (Q-df)/Q, where Q was Cochrane's heterogeneity statistic and df indicated the degree of freedom. Negative values for I² were set to zero, and an I² ≥50% was considered to have substantial heterogeneity. If I² was more than 50%, we used the random effects model;¹² otherwise, we used the fixed-effects model.¹³ Publication bias was analyzed by Funnel plots. P < 0.05 was considered statistically significant.

Results

A total of 4657 studies were initially included for further screening in this study. There were 4256 studies screened with title and abstract after the removal of duplicates. Screening these abstracts eliminated 4069 studies as review, or they lacked relevant topics, but 9 studies were manually searched from related system reviews. A total of 196 studies were identified and reviewed in full text. Of these, 188 studies were excluded due to incomplete messages such as not providing the number of cases/controls or the subjects were co-infected with hepatitis B virus. In the end, there were 8 studies included in the meta-analysis, with a total of 7323 participants (Figure 1).

Main characteristics of studies and participants

Table 1 summarizes the characteristics of studies and participants. A total of eight studies were identified, of which five were from Italy,^14–18 one from Japan,¹⁹ one from the USA,⁷ and one from Canada.²⁰ All studies were of case control design, of which five were published as articles^{7,14,16,18,20} and three published as abstracts.^15,17,19 Two studies only described the number of TDs or TCs,^16,19 and six studies described both TDs and TCs. In addition, to avoid the bias caused by iodine, two studies set iodine intake sufficient and deficient as control groups simultaneously.^14,16 According to the quality criteria of NOS, five studies were ranked as high quality^{7,14,16,18,20} and three were middle quality^15,17,19 (Table 1).

Table 1.

Main characteristics of studies included in this meta-analysis.

Author/online time	Study design	Study sites	Male/Female*	Age*	Iodine intake ( + ) (case/sum)**	Iodine intake (−) (case/sum)**	HCV ( + ) (case/sum)**	Quality
Alessandro et al. 2007¹⁴	case control	Italy	224/392; 224/392; 112/196	57 ± 15; 56 ± 12; 57 ± 13	1/616; 67/616	0/616;49/616	6/308;73/308	7
Antonelli et al. 2000¹⁵	case control	Italy	334/501; 63/75	48 ± 16; 52 ± 13	-	0/835; 239/835	2/138; 58/138	6
Hassan et al. 2009⁷	case control	the USA	636/468; 299/121	60 ± 0.3; 63 ± 0.6	0/1104; 134/1104	-	0/420; 63/420	8
Ishibashi et al. 2000¹⁹	case control	Japan	382/107; 99/52	52 ± 4; 57 ± 6	1/489	-	3/151	5
Antonelli et al. 2004¹⁶	case control	Italy	102/166; 139/250; 195/435	60 ± 5; 61 ± 7; 61 ± 13	32/268	51/389	145/630	7
Alessandro 1999¹⁷	case control	Italy	334/501;63/76	48 ± 16; 52 ± 14	-	0/835; 147/835	3/139; 29/139	7
Giuseppe 2008¹⁸	case control	Italy	95/55; 20/16	8.6(13.9); 8.3(13.9)	17/150		11/36	8
Seguro Danilovic et al. 2013²⁰	case control	Canada	44/52; 40/63	35.6 ± 10.3; 46.4 ± 12.8	13/96		11/103	8

*Data for age and sex correspond one-to-one with the case group and control group on the right, and the data were presented as mean ± SD or median (IQR).

**The data refer to the incidence of thyroid cancer and thyroid disease in the corresponding groups, respectively.

HCV: hepatitis C virus; IQR: interquartile range.

Association between HCV infection and TD

Seven studies were eligible to these included criteria, with a total of 6683 participants and 1774 subjects with HCV infection.^7,14–18,20 Of these subjects with HCV infection, there were 390 (22.0%) suffered from TD. The result of the random-effects model showed that HCV infection was linked to an increased risk of TD (sum OR = 1.80, 95% CI = 1.54–2.10, P < 0.001). There was some heterogeneity among these studies (I² = 74.3%, P = 0.001) (Figure 2(a)) and no publication bias (Supplementary Figure 1(a)). A subgroup analysis of study sites showed that heterogeneity has minimal change (66.4% vs. 74.3%). (Supplementary Figure 2).

Figure 2.

Association between HCV infection and risk of TD and TC. (a) Subjects with TD. (b) Subjects with TC. The size of the square represents the weight of the study in the meta-analysis; the line width represents the 95% confidence interval of the study; the vertical line represents the “no effect line”; the diamond-shaped block represents the combined effect estimate of each study (fixed-effect model or random-effects model).

Association between HCV infection and TC

Five studies were eligible to these included criteria, with a total of 5035 participants and 1156 subjects with HCV infection.^{7,14,15,17,19} Of these subjects with HCV infection, there were 14 (1.21%) subjects suffered from TC. The results of the fixed-effect model showed that HCV infection might increase the risk of TC (sum OR = 16.74, 95% CI = 4.78–58.55, P < 0.001). There was no significant heterogeneity (I² = 0%, P = 0.843) (Figure 2(b)) and publication bias (Supplementary Figure 1(b)).

Discussion

Previous studies have reported that HCV infections might affect the risk of TD and TC, but their conclusions are inconsistent. Several studies found that there was no obvious statistically significant association between HCV infection and the risk of TC, and other studies have found the opposite.^8,21–24 In this meta-analysis, data were extracted from five literature databases (PubMed, Cochrane Library, Web of Science, China National Knowledge Infrastructure, and Wang Fang) that examined the influence of HCV on the occurrence of TD and TC. The combined data from five studies relevant to TD confirmed that subjects with HCV infection have a greater risk of TD (sum OR = 1.81, 95% CI = 1.28–2.56, P < 0.001). In addition, patients with HCV infection were more likely to have TC (sum OR = 16.36, 95% CI = 4.65–57.62, P < 0.001).

HCV belongs to the hepatitis virus genus of the Flaviviridae family. Its genome was a single plus-strand RNA with a size of approximately 9.6 kb.²⁵ HCV infection easily develops into chronic hepatitis C (CHC) due to the characteristic of high concealment and low awareness rate, subsequently becoming the potential cause of a variety of autoimmune diseases (e.g., AIDs) such as cryoglobulinaemia,²⁶ hypothyroidism,²⁷ autoimmune thyroid diseases (ATD),²⁸ and autoimmune liver disease.²⁹ As a result, research on the association between HCV infection and thyroid diseases—especially thyroid cancer—have always been a hot topic. Many previous studies have reported that HCV infection was associated with TD. Thyroid antibodies were observed by Pateron et al.³⁰ in 5 of 66 HCV patients; by Tran et al.³¹ in 9 of 72 HCV patients; by Baudin et al.³² in 8 of 68 HCV patients; and by Pawlotski et al.³³ in 5 of 61 HCV patients.

Currently, the mechanism of how HCV affects TD is not clear. Hadziyannis³⁴ found that the prevalence of anti-thyroid antibodies was repeatedly shown to increase under interferon-α treatment. Of course, with the advent of direct-acting antivirals, it is still unknown whether HCV patients, after interferon-free combined treatment, were more prone to TD, which will be the focus of future research.

Recent evidence in the literature analyzed critical points of the mechanisms of thyroid damage, with emphasis on the balance between the two sides of the interaction: (a) the environment (virus infection with potential cross-reaction); and (b) the host (susceptibility genes with consistent immune response).³⁵ Some studies have reported a genetic influence (the susceptibility genes) in the development of autoimmunity.^36,37 CD40 and HLA class Ⅱ have been clearly linked to TD by affecting the immune response of the host.^38–41 It is well known that stressful situations induce hormone secretion, leading to autoimmune thyroid disease (ATD), especially hyperthyroidism.⁴² A high number of drugs (lithium, amiodarone, interferons, anti-CD52 monoclonal antibody Campath1H) may induce ATD.^43–46 HCV may affect the functions and mechanisms of self-recognition both on the immune system and the thyroid cells, where HCV may directly destroy thyroid tissue or mimic the structure of some components of thyroid glands, starting the autoimmune disease.^47,48 Thus, people may suffer from increased risk of TD after HCV infection.

Our research has the following shortcomings. Above of all, only six studies were included in this meta-analysis although there was little heterogeneity among them. Moreover, the included studies were all case-control study designs, and more cohort studies will be needed in the future to further confirm the conclusions. Also, other factors (i.e., age, sex, and drugs used for HCV) may likely affect the incidence of TD or TC, but the related information was not clear in the original literature. Finally, although we searched multiple literature databases, there have been few relevant studies in recent years.

In conclusion, the results of our study showed that HCV infection may increase the risk of TD and TC. More work is needed in the future to establish a causal role; however, an awareness of the possibility of increased risk of TD and TC may lead to earlier diagnosis and better outcomes in patients with HCV.

Supplemental Material

sj-docx-1-jbm-10.1177_17246008211056959 - Supplemental material for The association of hepatitis C virus infection and thyroid disease: A systematic review and meta-analysis

Supplemental material, sj-docx-1-jbm-10.1177_17246008211056959 for The association of hepatitis C virus infection and thyroid disease: A systematic review and meta-analysis by Hongpeng Wang, Yixiu Liu and Yanguang Zhao in The International Journal of Biological Markers

Footnotes

Author contributions

HPW, YXL, and YGZ: Study design and protocol, searches, title, abstract and full text screening, data-abstraction. HPW and YXL: Data verification, statistical analyses and interpretation of the data.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Decision making consultation and management innovation grant of the science department of Shaping Ba District, Chongqing (grant number jcd202020, cstc2020jxjl0096).

ORCID iD

Yixiu Liu

Statement of ethics

An ethics statement is not applicable because this study is based exclusively on published literature.

Supplemental material

Supplemental material for this article is available online.

References

Walsh

. Managing thyroid disease in general practice. Med J Aust 2016; 205: 179–184.

Shirazi

Hedayati

Daneshpour

, et al. Analysis of loss of heterozygosity effect on thyroid tumor with oxyphilia cell locus in familial non medullary thyroid carcinoma in Iranian families. Indian J Hum Genet 2012; 18: 340–343.

WHO, et al., Recommendations and guidance on hepatitis C virus self-testing. WHO 2021. (https://www.who.int/publications/i/item/9789240031128)

WHO, et al., Global progress report on HIV, viral hepatitis and sexually transmitted infections. WHO 2021. (https://www.who.int/publications/i/item/9789240027077)

Antonelli

Ferri

Fallahi

, et al. Thyroid disorders in chronic hepatitis C virus infection. Thyroid 2006; 16: 563–572.

Fallahi

Ferrari

Giuggioli

, et al. Thyroid involvement in hepatitis C-associated mixed cryoglobulinemia. Hormones (Athens) 2014; 13: 16–23.

Hassan

Kaseb

, et al. Association between hypothyroidism and hepatocellular carcinoma: a case-control study in the United States. Hepatology 2009; 49: 1563–1570.

Montella

Pezzullo

Crispo

, et al. Risk of thyroid cancer and high prevalence of hepatitis C virus. Oncol Rep 2003; 10: 133–136.

Scappaticcio

Longo

Maiorino

, et al. Abnormal liver blood tests in patients with hyperthyroidism: systematic review and meta-analysis. Thyroid 2021; 31: 884–894.

10.

Corma-Gomez

Macias

Tellez

, et al. Liver stiffness at the time of sustained virological response predicts the clinical outcome in people living with human immunodeficiency virus and hepatitis C virus with advanced fibrosis treated with direct-acting antivirals. Clin Infect Dis 2020; 71: 2354–2362.

11.

WHO. Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C virus infection. Geneva. 2018.

12.

DerSimonian

Laird

. Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 177–188.

13.

Mantel

Haenszel

. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959; 22: 719–748.

14.

Alessandro

Clodoveo

Poupak

, et al. Thyroid cancer in HCV-related chronic hepatitis patients: a case-control study. Thyroid 2007; 17: 447–451.

15.

Antonelli

Porciello

Marccheroni

, et al. Thyroid cancer in patients with chronic hepatitis C virus infection. J Hepatol 2000; 32: 108–108.

16.

Antonelli

Ferri

Pampana

, et al. Thyroid disorders in chronic hepatitis C. Am J Med 2004; 117: 10–13.

17.

Antonelli

Ferri

Fallahi

. Thyroid cancer in patients with hepatitis C infection. JAMA 1999; 281: 1588–1588.

18.

Indolfi

Stagi

Bartolini

, et al. Thyroid function and anti-thyroid autoantibodies in untreated children with vertically acquired chronic hepatitis C virus infection. Clin Endocrinol (Oxf.) 2008; 68: 117–121.

19.

Ishibashi

Katayama

Shinzaki

, et al. The high prevalence of thyroid cancer in patients with hepatitis type C virus infection. Gastroenterology 2000; 118: A1450–A1450.

20.

Seguro Danilovic

Mendes-Correa

Chammas

, et al. Thyroid disturbance related to chronic hepatitis C infection: role of CXCL10. Endocr J 2013; 60: 583–590.

21.

Omland

Farkas

Jepsen

, et al. Hepatitis C virus infection and risk of cancer: a population-based cohort study. Clin Epidemiol 2010; 2: 179–186.

22.

Duberg

Nordström

Törner

, et al. Non-Hodgkin's lymphoma and other nonhepatic malignancies in Swedish patients with hepatitis C virus infection. Hepatology 2005; 41: 652–659.

23.

Antonelli

Ferri

Fallahi

, et al. Thyroid cancer in HCV-related chronic hepatitis patients: a case-control study. Thyroid 2007; 17: 447–451.

24.

Giordano

Henderson

Landgren

, et al. Risk of non-Hodgkin lymphoma and lymphoproliferative precursor diseases in US veterans with hepatitis C virus. Jama 2007; 297: 2010–2017.

25.

Wei

Duan

Wang

. Guidelines for prevention and treatment of hepatitis C (2019 version). J Clin Hepatol 2020; 01: 33–52.

26.

Roccatello

Saadoun

Ramos-Casals

, et al. Cryoglobulinaemia. Nat Rev Dis Primers 2018; 4: 1–15.

27.

Molleston

Mellman

Narkewicz

, et al. Autoantibodies and autoimmune disease during treatment of children with chronic hepatitis C. J Pediatr Gastroenterol Nutr 2013; 56: 304–310.

28.

Obermayer-Straub

Manns

. Hepatitis C and D, retroviruses and autoimmune manifestations. J Autoimmun 2001; 16: 275–285.

29.

Rowan

Smith

Gleeson

, et al.

Hepatitis C virus in autoimmune liver disease in the UK: aetiological agent or artefact?

Gut 1994; 35: 542–546.

30.

Pateron

Hartmann

Duclos-Vallée

, et al. Latent autoimmune thyroid disease in patients with chronic HCV hepatitis. J Hepatol 1993; 17: 417–419.

31.

Tran

Quaranta

Benzaken

, et al. High prevalence of thyroid autoantibodies in a prospective series of patients with chronic hepatitis C before interferon therapy. Hepatology 1993; 18: 253–257.

32.

Baudin

Marcellin

Pouteau

, et al. Reversibility of thyroid dysfunction induced by recombinant alpha interferon in chronic hepatitis C. Clin Endocrinol (Oxf.) 1993; 39: 657–661.

33.

Pawlotsky

Ben Yahia

Andre

, et al. Immunological disorders in C virus chronic active hepatitis: a prospective case-control study. Hepatology 1994; 19: 841–848.

34.

Hadziyannis

. Nonhepatic manifestations and combined diseases in HCV infection. Dig Dis Sci 1996; 41: 63s–74s.

35.

Pastore

Martocchia

Stefanelli

, et al. Hepatitis C virus infection and thyroid autoimmune disorders: a model of interactions between the host and the environment. World J Hepatol 2016; 8: 83–91.

36.

Tomer

Davies

. Searching for the autoimmune thyroid disease susceptibility genes: from gene mapping to gene function. Endocr Rev 2003; 24: 694–717.

37.

Weetman

. Autoimmune thyroid disease: propagation and progression. Eur J Endocrinol 2003; 148: 1–9.

38.

Roederer

Quaye

Mangino

, et al. The genetic architecture of the human immune system: a bioresource for autoimmunity and disease pathogenesis. Cell 2015; 161: 387–403.

39.

Bech

Lumholtz

Nerup

, et al. HLA Antigens in Graves’ disease. Acta Endocrinol (Copenh.) 1977; 86: 510–516.

40.

Jacobson

Huber

Akeno

, et al. A CD40 Kozak sequence polymorphism and susceptibility to antibody-mediated autoimmune conditions: the role of CD40 tissue-specific expression. Genes Immun 2007; 8: 205–214.

41.

Kakizaki

Takagi

Murakami

, et al. HLA Antigens in patients with interferon-alpha-induced autoimmune thyroid disorders in chronic hepatitis C. J Hepatol 1999; 30: 794–800.

42.

Winsa

Adami

Bergström

, et al. Stressful life events and Graves’ disease. Lancet 1991; 338: 1475–1479.

43.

Chiovato

Pinchera

. Stressful life events and Graves’ disease. Eur J Endocrinol 1996; 134: 680–682.

44.

Coles

Wing

Smith

, et al. Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet 1999; 354: 1691–1695.

45.

Ruwhof

Drexhage

. Iodine and thyroid autoimmune disease in animal models. Thyroid 2001; 11: 427–436.

46.

Weetman

McGregor

. Autoimmune thyroid disease: further developments in our understanding. Endocr Rev 1994; 15: 788–830.

47.

Hsieh

Chuang

, et al. Virologic factors related to interferon-alpha-induced thyroid dysfunction in patients with chronic hepatitis C. Eur J Endocrinol 2000; 142: 431–437.

48.

Lunel

. Hepatitis C virus and autoimmunity: fortuitous association or reality? Gastroenterology 1994; 107: 1550–1555.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

1.19 MB