Phenotypes of interferon-α-induced thyroid dysfunction among patients treated for hepatitis C are associated with pretreatment serum TSH and female sex

Jennifer S Mammen, Sharon R. Ghazarian, Erik Pulkstenis, G. Mani Subramanian, Antony Rosen, Paul W Ladenson

Research output: Contribution to journalArticle

Abstract

Context: 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. Design: ACHIEVE-1, a randomized trial conducted from 2005-2009, compared long-acting preparations of IFNα in 1323 patients with hepatitis C, genotype 1. Setting: A total of 149 outpatient clinics in North America, Europe, and Australia participated. Patients: We studied 1233 patients who were euthyroid at baseline. This population is 60% male and 82% Caucasian. Interventions: Patients were treated with pegylated IFNα2a weekly or albumin-IFNα2b every 2wk for 48 wk. Serum TSH and free T4 were measured before therapy and 12 or more times over 60 weeks. Main Outcome Measures: 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.

Original languageEnglish (US)
Pages (from-to)3270-3276
Number of pages7
JournalJournal of Clinical Endocrinology and Metabolism
Volume97
Issue number9
DOIs
StatePublished - Sep 2012

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Hepatitis C
Interferons
Thyroiditis
Thyroid Gland
Phenotype
Thyrotoxicosis
Hypothyroidism
Serum
Odds Ratio
Confidence Intervals
Therapeutics
Regression analysis
Logistics
North America
Albumins
Ambulatory Care Facilities
Autoimmunity
Reference Values
Logistic Models
Genotype

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

@article{0e598b7f36d44dee98272bed012aad6d,
title = "Phenotypes of interferon-α-induced thyroid dysfunction among patients treated for hepatitis C are associated with pretreatment serum TSH and female sex",
abstract = "Context: 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. Design: ACHIEVE-1, a randomized trial conducted from 2005-2009, compared long-acting preparations of IFNα in 1323 patients with hepatitis C, genotype 1. Setting: A total of 149 outpatient clinics in North America, Europe, and Australia participated. Patients: We studied 1233 patients who were euthyroid at baseline. This population is 60{\%} male and 82{\%} Caucasian. Interventions: Patients were treated with pegylated IFNα2a weekly or albumin-IFNα2b every 2wk for 48 wk. Serum TSH and free T4 were measured before therapy and 12 or more times over 60 weeks. Main Outcome Measures: 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.",
author = "Mammen, {Jennifer S} and Ghazarian, {Sharon R.} and Erik Pulkstenis and Subramanian, {G. Mani} and Antony Rosen and Ladenson, {Paul W}",
year = "2012",
month = "9",
doi = "10.1210/jc.2012-1026",
language = "English (US)",
volume = "97",
pages = "3270--3276",
journal = "Journal of Clinical Endocrinology and Metabolism",
issn = "0021-972X",
publisher = "The Endocrine Society",
number = "9",

}

TY - JOUR

T1 - Phenotypes of interferon-α-induced thyroid dysfunction among patients treated for hepatitis C are associated with pretreatment serum TSH and female sex

AU - Mammen, Jennifer S

AU - Ghazarian, Sharon R.

AU - Pulkstenis, Erik

AU - Subramanian, G. Mani

AU - Rosen, Antony

AU - Ladenson, Paul W

PY - 2012/9

Y1 - 2012/9

N2 - Context: 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. Design: ACHIEVE-1, a randomized trial conducted from 2005-2009, compared long-acting preparations of IFNα in 1323 patients with hepatitis C, genotype 1. Setting: A total of 149 outpatient clinics in North America, Europe, and Australia participated. Patients: We studied 1233 patients who were euthyroid at baseline. This population is 60% male and 82% Caucasian. Interventions: Patients were treated with pegylated IFNα2a weekly or albumin-IFNα2b every 2wk for 48 wk. Serum TSH and free T4 were measured before therapy and 12 or more times over 60 weeks. Main Outcome Measures: 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.

AB - Context: 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. Design: ACHIEVE-1, a randomized trial conducted from 2005-2009, compared long-acting preparations of IFNα in 1323 patients with hepatitis C, genotype 1. Setting: A total of 149 outpatient clinics in North America, Europe, and Australia participated. Patients: We studied 1233 patients who were euthyroid at baseline. This population is 60% male and 82% Caucasian. Interventions: Patients were treated with pegylated IFNα2a weekly or albumin-IFNα2b every 2wk for 48 wk. Serum TSH and free T4 were measured before therapy and 12 or more times over 60 weeks. Main Outcome Measures: 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.

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