title: Patterns of interferon-alpha-induced thyroid dysfunction vary with ethnicity, sex, smoking status, and pretreatment thyrotropin in an international cohort of patients treated for hepatitis C.
abstract: BACKGROUND
  Interferon-alpha (IFNα)-induced thyroid dysfunction occurs in up to 20% of patients undergoing therapy for hepatitis C. The diversity of thyroid disease presentations suggests that several different pathological mechanisms are involved, such as autoimmunity and direct toxicity. Elucidating the relationships between risk factors and disease phenotype provides insight into the mechanisms of disease pathophysiology.
  
  
  METHODS
  We studied 869 euthyroid patients from the ACHIEVE 2/3 trial, a randomized international clinical trial comparing pegylated-IFNα2a weekly or albumin-IFNα2b every 2 weeks for up to 24 weeks in patients with hepatitis C, genotype 2 or 3, from 136 centers. The study population was 60% male and 55% white. Serum thyrotropin (TSH) and free thyroxine were measured before therapy, monthly during treatment from week 8, and at 4- and 12-week follow-up visits.
  
  
  RESULTS
  Overall, 181 (20.8%) participants had at least one abnormal TSH during the study. Low TSH occurred in 71 (8.2%), of whom 30 (3.5%) had a suppressed TSH below 0.1 mU/L. Hypothyroidism occurred in 53 patients (6.1%), with peak TSH above 10 mU/L in 12 patients (1.4%). Fifty-seven patients had a biphasic thyroiditis (6.6%), with extreme values for the nadir and/or peak TSH in all but one. Medical therapy was given to one thyrotoxic patient, four hypothyroid patients, and 26 biphasic thyroiditis patients. Multivariate logistic regression analysis demonstrated that biphasic thyroiditis is associated with being female and higher pretreatment serum TSH, whereas being Asian or a current smoker decreased the risk of thyroiditis. Hypo- and hyperthyroidism are most strongly predicted by the pretreatment TSH.
  
  
  CONCLUSIONS
  Biphasic thyroiditis accounted for the majority (58%) of clinically relevant IFNα-induced thyroid dysfunction. We confirmed our recent findings in a related cohort that female sex is a risk factor for thyroiditis but not hypothyroidism. Further, in this large multiethnic study, the risk of thyroiditis is dramatically increased, specifically for white women. Smoking was found to be protective of thyroiditis. These results support closer monitoring of women and those with a serum TSH at the extremes of the normal range during therapy so that prompt intervention can mitigate the consequences of thyroid dysfunction associated with IFNα treatment.
authors.affiliation: 1 Division of Endocrinology and Metabolism, Johns Hopkins University School of Medicine , Baltimore, Maryland.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Mammen
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Ghazarian
authors.forename: Antony
authors.initials: A
authors.lastname: Rosen
authors.forename: Paul W
authors.initials: PW
authors.lastname: Ladenson
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000009:adverse effects*; D001208:Asia / Q000453:epidemiology; D015415:Biomarkers / Q000097:blood; D016009:Chi-Square Distribution; D005060:Europe / Q000453:epidemiology; D005260:Female; D006526:Hepatitis C / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000208:ethnology; D006801:Humans; D007037:Hypothyroidism / Q000097:blood / Q000139:chemically induced* / Q000208:ethnology / Q000628:therapy; D016898:Interferon-alpha / Q000009:adverse effects*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009656:North America / Q000453:epidemiology; D016017:Odds Ratio; D011092:Polyethylene Glycols / Q000009:adverse effects*; D044469:Racial Groups; D011993:Recombinant Fusion Proteins / Q000009:adverse effects; D011994:Recombinant Proteins / Q000009:adverse effects; D012307:Risk Factors; D012709:Serum Albumin / Q000009:adverse effects*; D000075462:Serum Albumin, Human; D012737:Sex Factors; D012907:Smoking / Q000009:adverse effects*; D013020:South America / Q000453:epidemiology; D013966:Thyroiditis / Q000097:blood / Q000139:chemically induced* / Q000208:ethnology / Q000628:therapy; D013972:Thyrotropin / Q000097:blood*; D013974:Thyroxine / Q000097:blood; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D015415:Biomarkers; D016898:Interferon-alpha; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D012709:Serum Albumin; C543152:human serum albumin-interferon-alpha-2b fusion protein; D011092:Polyethylene Glycols; D013972:Thyrotropin; C100416:peginterferon alfa-2a; D013974:Thyroxine; D000075462:Serum Albumin, Human