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 Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 11  |  Issue : 3  |  Page : 103-107

Thyroid functions and autoimmunity in Egyptian children with chronic hepatitis C virus infection before interferon treatment


1 Department of Pediatrics, Faculty of Medicine, Assiut University, Assiut, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt

Date of Web Publication13-Aug-2014

Correspondence Address:
Kotb Abbass Metwalley
Assistant Professor of Pediatrics, Pediatric Endocrinology Unit, Faculty of Medicine, Assiut University, Assiut
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-0354.138554

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  Abstract 

Background: The association of thyroid dysfunction with hepatitis C virus (HCV) infected children who are on interferon therapy is well established. But thyroid functions in untreated chronic HCV children is an aspect which the present study intended to explore. Settings and Design: Cross-sectional controlled study. Materials and Methods: The study included 30 children with chronic hepatitis C (Group 1; mean age 9.86 ± 2.22 years). Thirty healthy children age- and sex-matched were included as control group (Group 2; mean age 8.54 ± 2.31 years). Measurement of thyroid stimulating hormone (TSH), free thyroxine (FT 4 ), and free triiodothyronine (FT 3 ), as well as anti-thyroid peroxidase antibodies (TPO Ab) and anti-thyroglobulin (Tg Ab) were done. Results: Mean TSH levels were significantly higher in the group 1 as compared to control (P < 0.001). Subclinical hypothyroidism was detected in 13.3% in the study group vs 3.3% in the control group (P < 0.001). Positive levels of TPO Ab and Tg Ab were found to be 23.3% and 13.3% in Group 1 compared with 6.6% and 3.3% in controls, respectively. We also observed a significant positive correlation between TSH levels and age, HCV duration, viral load, anti-TPO Abs, antiTg Abs, and negative correlation with FT4. Conclusions: Both subclinical hypothyroidism and thyroid autoimmunity are common in Egyptian children with chronic hepatitis C before interferon treatment.

Keywords: Alanine aminotransferase, chronic hepatitis C, hypothyroidism


How to cite this article:
Metwalley KA, Sherif T. Thyroid functions and autoimmunity in Egyptian children with chronic hepatitis C virus infection before interferon treatment. Thyroid Res Pract 2014;11:103-7

How to cite this URL:
Metwalley KA, Sherif T. Thyroid functions and autoimmunity in Egyptian children with chronic hepatitis C virus infection before interferon treatment. Thyroid Res Pract [serial online] 2014 [cited 2019 Dec 8];11:103-7. Available from: http://www.thetrp.net/text.asp?2014/11/3/103/138554


  Introduction Top


Egypt is a country with a high load of hepatitis C virus (HCV). The prevalence of anti-HCV among Egyptian children ranged between 3% and 9%. [1] Chronic HCV infection has been associated with a wide range of extrahepatic manifestations. [2] In these patients, both autoimmune phenomena and autoimmune diseases have been reported. [3] Thyroid dysfunction has been described as an extrahepatic manifestation of chronic HCV infection. [4] The reported data on thyroid function and anti-thyroid autoantibodies in adults with untreated HCV infection are controversial. [5],[6] Few data are available regarding thyroid functions and thyroid autoimmune disease in children with untreated chronic HCV infection. [7],[8] Up to our best knowledge, this is the first study trying to estimate thyroid function and autoimmunity in children with chronic HCV infection in Upper Egypt before interferon treatment.

Aim of the study

To estimate thyroid function and the prevalence of anti-thyroid specific autoantibodies in a cohort of untreated Egyptian children with chronic HCV infection.


  Materials AND METHODS Top


Patients

This is a cross-sectional study, it included 30 children with chronic HCV infection (Group 1) They were 17 boys and 13 girls. Diagnosis of chronic hepatitis C was based on detection of HCV ribonucleic acid (RNA) in peripheral blood by reverse transcriptase polymerase chain reaction (RT-PCR) for 6 months or more. In addition, 30 apparently healthy age and sex matched healthy children of same local population were studied as a control (Group 2). They were 16 boys and 14 girls. Both patients and controls were recruited from Pediatric Outpatients Clinic in Assiut University Children Hospital, Egypt. The study protocol was approved by the ethical committees of Assiut University Children Hospital, Egypt. Written informed consents were obtained from the parents of both patients and controls.

Inclusion criteria

  • Age between 2 and 16 years
  • Documented chronic HCV infection
  • Not on interferon treatment
  • Hepatitis B negative.


Exclusion criteria

  • Family history of autoimmune disease
  • Children from iodine deficiency areas
  • Children with diseases or receiving drugs that may affect thyroid function
  • Children with endocrinal diseases
  • Children with acute or chronic illness
  • Chronic liver disease (schistosomiasis, Wilson's disease, hepatotoxic drugs, hemochromatosis, alpha1-antitrypsin deficiency, autoimmune chronic active hepatitis
  • Evidence of hepatic decompensation (hepatic encephalopathy or ascites).


Methods

All children were subjected to:

  1. A thorough history was taken including data about onset and course of the disease symptoms suggestive of hypothyroidism (puffy features, swelling in neck, cold intolerance, etc.) or hyperthyroidism (emotional lability, weight loss, restless sleep, some degree of exophthalmos, etc.)
  2. All patients and controls underwent a physical examination for signs of thyroid dysfunction and estimation of thyroid size by palpation.


Laboratory investigation

Routine general laboratory tests, if needed.

Liver biochemical profile: Bilirubin (total and direct), albumin, aspartate and alanine aminotransferases (AST and ALT). Liver biochemistry tests were done by routine methods. ALT (normal up to 40 U/L) and AST (normal up to 40 U/L) were considered elevated if any elevation above the upper limit was detected.

Thyroid stimulating hormone (TSH) serum level was determined by ultrasensitive immunometric assays (ImmuliteTM 2000 Third Generation, Diagnostic Products Corporation, Los Angeles, CA). Free thyroxine (FT4) and free triiodothyronine (FT3) were determined by radioimmunoassay (RIA) using an automated system (Roche Diagnostics) The reference range for TSH was 0.4-4.0 mU/L, for FT3 3.5-5.5 pmol/L, and for FT4 10.0-26.0 pmol/L. The coefficients of variations (CV) were 5.0 and 5.1% at TSH concentrations of 4.0 and 10.0 mU/L, respectively. For FT4, the CV was 6.5% at 10.0 pmol/L and FT3 8.9% at 3.5 pmol/L.

Serum anti-thyroid peroxidase antibodies (TPO Ab) and anti-thyroglobulin (Tg Ab) were measured by rapid enzyme linked immunosorbent assay (ELISA) Genesis Diagnostics, Littleport, UK). Anti-Tg Ab and anti-TPO Ab concentrations more than 100and 75 IU/ml, respectively, were considered positive. Positivity of at least one antibody was considered as having autoimmunity of thyroid (AIT).

Subclinical hypothyroidism was defined as an elevated TSH level (4.0 IU/ml) together with normal serum thyroid hormone levels. Hypothyroidism was defined as an elevated TSH together with a decreased serum thyroid hormone level. Subclinical hyperthyroidism was defined as a decreased TSH (0.3 IU/mL) together with normal thyroid hormone levels and hyperthyroidism was defined as a decreased TSH together with elevated thyroid hormone levels. [9]

Statistical methods

Analysis was carried out using Statistical Package for Social Sciences (SPSS, version 16). Simple statistics such as frequency, arithmetic mean, and standard deviation (SD) were used. For comparison of the two groups, Student's t-test was used for parametric data and the Mann-Whitney U-test was used for nonparametric data. Linear correlations were performed by Spearman's or Pearson's test. For all analyses, P < 0.05 provided statistical significance.


  Results Top


[Table 1] shows demographic and metabolic characteristics of the studied groups. TSH level was significantly higher in children with chronic hepatitis C (Group 1) than in controls (Group 2) (P < 0.001). No statistically significant difference was observed between the Groups 1 and2 regarding age, sex AST, ALT, FT3, and FT4.
Table 1: Demographic and metabolic characteristics of the studied groups


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[Table 2] shows thyroid function and antibodies in children with HCV infection compared to the controls. Four children (13.3%) were found to have subclinical hypothyroidism in children with chronic hepatitis C compared to one child (3.3%) in the control group (P < 0.001). The mean anti-TPO Ab and anti-Tg Ab in HCV children were significantly higher than those in the control. Children with chronic hepatitis C infection had significantly higher anti-TPO Ab positivity and anti-Tg Ab positivity in comparison with controls. Both nti-TPO Ab and nti-Tg Ab positivity was reported in10% children with HCV infection.

None of the children with chronic HCV infection had clinical hypothyroidism or hyperthyroidism.
Table 2: Thyroid function and antibodies in the studied groups


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[Table 3] shows correlation coefficient between serum TSH levels and thyroid antibodies and biochemical data of studied children with HCV infection. Serum levels of TSH have significant positive correlations with age, HCV duration, viral load, anti-TPO Ab, anti-Tg Ab; and negative correlation with FT4. No significant correlation between TSH and ALT was reported.
Table 3: Correlation coefficient between serum TSH level and thyroid antibodies and biochemical data of children with HCV infection


Click here to view



  Discussion Top


Egypt has one of the highest prevalence rates of HCV infection worldwide. High rates of HCV infection are observed in all age groups, suggesting that an ongoing risk of HCV acquisition still exists. [10] There are several schools of thought regarding the need for treatment of children with chronic hepatitis C. Because chronic hepatitis C generally has a slow progression to fibrosis and severe disease is rare in children, follow-up without treatment until adulthood may be a valid option for many children. Conversely, treatment may be justified because it allows definitive resolution in a subgroup of patients. [11] In Egypt, even when treatment was planned, long time waiting list to start treatment was recorded, this may be attributed to poor resources and financial factors. These observations prompted us to carry out a prospective study aimed at detecting abnormalities in the function of the thyroid gland and the presence of thyroid autoantibodies in untreated Egyptian children with chronic hepatitis C.

In the present study, both subclinical hypothyroidism and thyroid autoimmunity were more common in children with HCV compared to controls. This in agreement with Antonelli et al., 2004 [12] who reported that children with chronic hepatitis C were more likely to have hypothyroidism (13%), anti-thyroglobulin antibodies (17%), and anti-thyroid peroxidase antibodies (21%) compared to controls. It has been suggested that HCV, like other viruses, may trigger autoimmunity in genetically predisposed individuals. Data from experimental models and investigations of thyroid diseases clearly indicate that the ongoing expansion of autoreactive T cells with specificity to thyroid autoantigens is the main immunological event in the induction and continuation of thyroid damage. Thus, an infectious agent (e.g. HCV) could initiate autoimmune thyroid disease by mimicking the structure of some component of thyroid tissue. This infectious agent might be less immunogenic, but could cause production of thyroid autoantibodies. [13]

Our result revealed that four children (13.3%) were found to have subclinical hypothyroidism in children with chronic hepatitis C compared to one child (3.3%) in the control group (P < 0.001). Indolfi et al., 2008 [14] reported in their study that four out of 36 (11.1%) HCV-infected children and 4/150 controls (2.7%) showed subclinical hypothyroidism (P = 0.04). To decrease poor outcomes in children with chronic hepatitis C, subclinical hypothyroidism should be diagnosed early and treatment started promptly. Moreover, early treatment in these patients reduces the risk of hyperlipidemia and atherosclerotic heart disease in future. Thyroid dysfunction remained undiagnosed if the patient did not undergo routine periodic screening of thyroid dysfunction in all HCV patients. Moreover, antiviral therapy is contraindicated in patients with thyroid disease not controlled by hormone therapy. [15]

In the present study, antiTPO Abswas detected in 23.3% (n = 30), and antiTg Abs in 13% (n = 30). In previous reports in adults, the prevalence of abnormal concentrations of antithyroid antibodies in patients with chronic HCV varied markedly, ranging from 2 to 48%. [16] Differences in geographical distribution, genetic variability in the populations studied, [17] and even environmental factors such as iodine intake or virus infection, [18] could play a major role in the development of clinically recognizable autoimmune thyroid disease. Early detection of thyroid autoimmunity or disease in children is important, because of its progression to subclinical hypothyroidism in 11% and overt hypothyroidism in 3% of them. [19]

In this study, TSH levels (the most sensitive marker of thyroid function) correlated positively with anti-TPO Ab and anti-TG Ab among children with chronic HCV infection. This suggests that both antibodies directly involved in thyroid injury with subsequent thyroid dysfunction and elevated TSH levels. In addition, it has been shown that thyroid autoantibodies indicate an underlying autoimmune process and are useful indicators of present or future thyroid dysfunction. [20]

In the present study, TSH level correlated positively with the duration and viral load of HCV infection. Longer duration and higher vial load of HCV infection would give the altered immune system a greater chance to react against different organs including thyroid gland with subsequent organ dysfunction in variable severity ranging from subtle biochemical disturbance to overt clinical disease. [13]


  Conclusions Top


Both subclinical hypothyroidism and thyroid autoimmunity are common in Egyptian children with chronic hepatitis C before interferon treatment.

Recommendations

  1. Routine screening of thyroid function in Egyptian children with chronic HCV is mandatory before starting interferon treatment.
  2. Further studies are needed to delineate the long-term effects of subclinical hypothyroidism among children with chronic HCV infection and hence to evaluate thyroxine replacement therapy in the treatment of subclinical hypothyroidism.


Limitations of the study

  1. Liver biopsy was not done due to different policy and refusal by parent. The use of liver biopsy to assess the degree of fibrosis in children with chronic hepatitis C infection has been discussed in many aspects; whether is mandatory or not or the existence of other alternatives for this invasive procedure.
  2. Genotypes were not detected among hepatitis C infection. Although genotype 4 is the most prevalent in Egyptian children.


 
  References Top

1.Habib M, Mohamed MK, Abdel-Aziz F, Magder LS, Abdel-Hamid M, Gamil F, et al. Hepatitis C virus infection in a community in the Nile Delta: Risk factors for seropositivity. Hepatology 2001;33:248-53.  Back to cited text no. 1
    
2.Zignego AL, Ferri C, Pileri SA, Caini P, Bianchi FB. Italian Association of the Study of Liver Commission on Extrahepatic Manifestations of HCV infection. Extrahepatic manifestations of Hepatitis C Virus infection: A general overview and guidelines for a clinical approach. Dig Liver Dis 2007;39:2-17.  Back to cited text no. 2
    
3.Stroffolini T, Colloredo G, Gaeta GB, Sonzogni A, Angeletti S, Marignani M, et al. Does an 'autoimmune' profile affect the clinical profile of chronic hepatitis C? An Italian multicenter survey. J Viral Hepat 2007;11:257-62.  Back to cited text no. 3
    
4.Cacoub P, Renou C, Rosenthal E, Cohen P, Loury I, Loustaud-Ratti V, et al. Extrahepatic manifestations associated with hepatitis C virus infection: A prospective multicenter study of 321 patients. Medicine (Baltimore) 2000;79:47-6.  Back to cited text no. 4
    
5.Tran A, Quaranta JF, Benzaken S, Thiers V, Chau HT, Hastier P, et al. High prevalence of thyroid autoantibodies in a prospective series of patients with chronic hepatitis C before interferon therapy Hepatology 1993;18253-7.  Back to cited text no. 5
    
6.Marazuela M, García-Buey L, González-Fernández B, García-Monzón C, Arranz A, Borque MJ, et al. Thyroid autoimmune disorders in patients with chronic hepatitis C before and during interferon-alpha therapy. Clin Endocrinol (Oxf) 1996;44:635-42.  Back to cited text no. 6
    
7.Gehring S, Kullmer U, Koeppelmann S, Gerner P, Wintermeyer P, Wirth S. Prevalence of autoantibodies and the risk of autoimmune thyroid disease in children with chronic hepatitis C virus infection treated with interferon-alpha. World J Gastroenterol 2006;125787-92.  Back to cited text no. 7
    
8.Gregorio GV, Pensati P, Iorio R, Vegnente A, Mieli-Vergani G, Vergani D. Autoantibody prevalence in children with liver disease due to chronic hepatitis C virus infection. Clin Exp Immunol 1998;112:471-6.  Back to cited text no. 8
    
9.Wu T, Flowers JW, Tudiver F, Wilson JL, Punyasavatsut N. Subclinical thyroid disorders and cognitive performance among adolescents in the United States. BMC Pediatr 2006;6:12.  Back to cited text no. 9
    
10.El-Raziky MS, El-Hawary M, Esmat G, Abouzied AM, El-Koofy N, Mohsen N, et al. Prevalence and risk factors of asymptomatic hepatitis C virus infection in Egyptian children. World J Gastroenterol 2007;13:1828-32.  Back to cited text no. 10
    
11.Mack CL, Gonzalez-Peralta RP, Gupta N, Leung D, Narkewicz MR, Roberts EA, et al. North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. NASPGHAN practice guidelines: Diagnosis and management of hepatitis C infection in infants, children, and adolescents. Pediatr Gastroenterol Nutr2012;54:838-55.  Back to cited text no. 11
    
12.Antonelli A, Ferri C, Pampana A, Fallahi P, Nesti C, Pasquini M, et al. Thyroid disorders in chronic hepatitis C. Am JMed 2004;117:10-3.  Back to cited text no. 12
    
13.Del Prete GF, Tiri A, Mariotti S, Parronchi P, Pinchera A, Romagnani S, et al. Thyroiditis as a model of organ specific autoimmune disease. Clin Exp Rheumatol 1989;7 Suppl 3:S41-6.  Back to cited text no. 13
    
14.Indolfi G, Stagi S, Bartolini E, Salti R, de Martino M, Azzari C, et al. Thyroid function and anti-thyroid autoantibodies in untreated children with vertically acquired chronic hepatitis C virus infection. Clin Endocrinol (Oxf) 2008;68:117-21.  Back to cited text no. 14
    
15.Dalgard O, Bjøro K, Hellum K, Myrvang B, Bjøro T, Haug E, et al. Thyroid dysfunction during treatment of chronic hepatitis C with interferon alpha: No association with either interferon dosage or efficacy of therapy. J Intern Med 2002;251:400-6.  Back to cited text no. 15
    
16.Pateron D, Hartmann DJ, Duclos-Vallée JC, Jouanolle H, Beaugrand M. Latent autoimmune thyroid disease in patients with chronic HCV hepatitis. J Hepatol 1993;17417-9.  Back to cited text no. 16
    
17.Lenzi M, Johnson PJ, McFarlane IG, Ballardini G, Smith HM, McFarlane BM, et al. Antibodies to hepatitis C virus in autoimmune liver disease: Evidence for geographical heterogeneity. Lancet 1991;338:277-80.  Back to cited text no. 17
    
18.Prentice LM, Phillips DI, Sarsero D, Beever K, McLachlan SM, Smith BR. Geographical distribution of subclinical autoimmune thyroid disease in Britain: A study using highly sensitive direct assays for autoantibodies to thyroglobulin and thyroid peroxidase. Acta Endocrinol (Copenh) 1990;123:493-8.  Back to cited text no. 18
    
19.Pearce EN, Farwell AP, Braverman. Thyroiditis. N Engl J Med 2003;348:2646-55.  Back to cited text no. 19
    
20.Tomer Y, Davies TF. Searching for the autoimmune thyroid disease susceptibility genes: From gene mapping to gene function. Endocr Rev 2003;24:694-717.  Back to cited text no. 20
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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