Phenotypes of interferon-α-induced thyroid dysfunction among patients treated for hepatitis C are associated with pretreatment serum TSH and female sex.
BACKGROUND
Thyroid dysfunction is a common complication of interferon-α (IFNα) therapy, with many phenotypic patterns and the potential for significant morbidity.


OBJECTIVE
Our objective was to gain mechanistic insight and predict clinical presentations by determining the risk factors for distinct subtypes of IFNα-induced thyroid dysfunction.


METHODS
ACHIEVE-1, a randomized trial conducted from 2005-2009, compared long-acting preparations of IFNα in 1323 patients with hepatitis C, genotype 1.


METHODS
A total of 149 outpatient clinics in North America, Europe, and Australia participated.


METHODS
We studied 1233 patients who were euthyroid at baseline. This population is 60% male and 82% Caucasian.


METHODS
Patients were treated with pegylated IFNα2a weekly or albumin-IFNα2b every 2 wk for 48 wk. Serum TSH and free T(4) were measured before therapy and 12 or more times over 60 weeks.


METHODS
Thyroid dysfunction was defined as a TSH outside the normal range during the course of therapy. Low serum TSH indicated thyrotoxicosis, elevated TSH indicated hypothyroidism, and both abnormalities occurred in biphasic thyroiditis.


RESULTS
Of previously euthyroid patients, 16.7% developed abnormal TSH values during therapy, including 24 with TSH below 0.1 mU/liter, 69 with TSH over 5.5 mU/liter, and 76 with biphasic thyroiditis. Biphasic thyroiditis was over 8-fold more common among women than men using multivariate logistic regression analysis [odds ratio (OR) = 8.4; 95% confidence interval (CI) = 4.5-15.8]. Thyrotoxicosis was most strongly associated with a lower pretreatment TSH (OR = 4.1 per -1 mU/liter decline; 95% CI = 1.9-9), whereas hypothyroidism was strongly associated with higher pretreatment TSH (OR = 3.9 per 1 mU/liter increase; 95% CI = 3-5.2).


CONCLUSIONS
Biphasic thyroiditis is common among women treated for hepatitis C with IFNα. Lower and higher pretreatment serum TSH are associated with greater likelihood of thyrotoxicosis and hypothyroidism, respectively. Antithyroid antibody levels were not available for the cohort, and thus we cannot clarify the role of pretreatment thyroid autoimmunity as a risk factor. Our results do show that readily identifiable patient characteristics are risk factors for specific patterns of IFN-induced thyroid dysfunction. These findings suggest that distinct mechanisms may underlie subtypes of thyroid dysfunction associated with immune-modulatory therapy for hepatitis C.
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, USA. jmammen1@jhmi.edu
Jennifer S
JS
Mammen
Sharon R
SR
Ghazarian
Erik
E
Pulkstenis
G Mani
GM
Subramanian
Antony
A
Rosen
Paul W
PW
Ladenson
D000328:Adult; D000998:Antiviral Agents / Q000009:adverse effects* / Q000627:therapeutic use; D015331:Cohort Studies; D003692:Delayed-Action Preparations; D005260:Female; D006526:Hepatitis C / Q000150:complications* / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D007037:Hypothyroidism / Q000139:chemically induced; D016898:Interferon-alpha / Q000009:adverse effects* / Q000627:therapeutic use; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010641:Phenotype; D018570:Risk Assessment; D012307:Risk Factors; D012727:Sex Characteristics; D013959:Thyroid Diseases / Q000139:chemically induced* / Q000453:epidemiology; D013966:Thyroiditis / Q000097:blood / Q000139:chemically induced; D013971:Thyrotoxicosis / Q000139:chemically induced; D013972:Thyrotropin / Q000097:blood* / Q000172:deficiency; D013974:Thyroxine / Q000097:blood; D016896:Treatment Outcome
D000998:Antiviral Agents; D003692:Delayed-Action Preparations; D016898:Interferon-alpha; D013972:Thyrotropin; D013974:Thyroxine