Interferon-Induced Thyroid Disease Bader Al-Harbi March-2008

Case Mrs. B. 44 y seen on Nov 2006 Re: abnormal TFT ( August -2006) TSH = FT4= 22.9 FT3 = 8 PMH : 1. HCV for 10 y – received IFN-a and Ribavirin for 48 wks ( March 2005 – Feb 2006) - at end of TTT : -ve viral load - 6 month after TTT : relapsed with high viral load

2. depression /anxiety 3. chronic back pain 4. Smoker 1 pack/day for 20 y Medication : - Ativan, celebrex, ventolin prn FH : - hypothyroidism in her mother and 2 sister

Re : hyperthyroidism ( Sept-Nov/2006): - clinically euthyroid ( why I am Here ? ) - no local symptoms at neck - no recent URTI or IV contrast -Exam : - euthyroid - thyroid :non-tender,normal size, soft, no bruit - eye: N - no pretibial myxedema

What is next ?

Repeated TFT on Nov ( on day Clinic) TSH = 3 (N ) FT4 = 16 FT3 = N

March 2005 Feb 2006 Sept 2006 Nov 2006 Jan 2007 IFN and Ribavirin TSHN FT4N (L) FT3N4.58 Clinically EEEEE Hypo- thyroidism ? -treat - F/U - TPO abs

 anti-TPO : negative  No LT 4 replacement  F/U TFT q 1-2 Months What do you think the diagnosis ?

Feb-April 2007: - No Blood work was done - Changed her phone number - Note was sent to GP

May 2007 TSH0.012 FT425 FT39 Clinically Palpitation ( pulse 105/min) Insomnia Inability to gain weight What is Next ?

 started on Diltiazem CD 120 mg OD  thyroid scan and uptake : - uptake : 34.3 % ( normal) - scan Graves Disease + some degree thyroiditis  anti-TPO abs :-ve anti-TBII : 21.8  Tapazole 10 mg po od was started

Interferon Discovered 50 y ago 3 types : - INF-a - INF-b - INF-g has - antiviral action - reduce tumor growth - modulating immune response

Side effect : The most common indication for INF-a treatment is HCV other : melanoma renal cell carcinoma, hairy cell leukemia, Kaposi’s sarcoma

Interferon-induced thyroid disease (IITD) Epidemiology Classification Spectrum of the IITD Risk factors The mechanism of IITD Diagnosis and management

Epidemiology of IITD First recognized case : patient treated with INF for carcinod tumer and breast Cancer The prevalence of TD during IFN treatment is 1-35 % Prospective studies have shown that up to 15% of patients with hepatitis C receiving IFN develop clinical thyroid disease and up to 40% developed thyroid antibodies

Classification of IITD Autoimmune IITD : 1. thyroid Abs 2. Hashimato’s thyroiditis (HT) 3. Graves’ disease (GD) Non-autoimmune IITD : 1. destructive thyroiditis 2. non-autoimmune hypothyroidism

Autoimmune IITD

1. TAbs without clinical disease The most common presentation TPO-AB and TG-AB The long term effect ( hypothyroidism ) : 5 % per year Production T Abs de novo or significant increase in TAbs level in individuals who were positive prior interferon therapy

The incidence of de novo development of thyroid Abs secondary to IFN therapy 1.9% to 40.0% - Different studies used different assays to test for thyroid Abs - the cutoffs used to define a serum as positive for TAb’s varied in different studies in individuals who had positive TAb’s prior to IFN therapy an increase in the level of antibodies during therapy

majority of individuals who develop “de novo” TAb’s on IFN therapy remain TAb positive after the end of treatment ( median follow up =6 y )

2. Hashimoto’s Thyroiditis Most clinical manifestation Present as Hypothyroidism + TPO abs the presence of TAbs before the initiation of IFNa therapy is a significant risk Hashimoto’s thyroiditis positive TPO antibodies before IFNa therapy had a positive predictive value of 67%  “screening for TAbs should be performed before the initiation of IFNa therapy to assess the risk of developing HT”

3. Graves’ Disease Less common Present : hyperthyroidism + TBII+TS Thyrotoxicosis induced by alpha-interferon therapy in chronic viral hepatitis. ( Clin Endocrinol (Oxf) 2002;56: Wong V, Fu AX, George J, Cheung NW ) - retrospective stuy of 321 patients with hepatitis B or C treated with IFN -10 patients who developed thyrotoxicosis (completely suppressed TSH) - 6 patients developed GD (diffusely increased uptake on thyroid scintigraphy as well as positiveTSI) - All GD patients had symptoms from their thyrotoxicosis - In all cases the thyrotoxicosis failed to resolve with cessation of IFN

Development of thyroid disease during therapy of chronic viral hepatitis with interferon alfa. (Gastroenterology 1992;102: Lisker-Melman M, Di Bisceglie AM, Usala SJ, Weintraub B, Murray LM, Hoofnagle JH) - retrospective stuy237 patients receiving IFN - 3 patient only develop GD, failed to resolve with cessation of IFN

Non-Autoimmune IITD

50% of patients who develop thyroid dysfunction during IFN therapy do not develop Tabs  suggests thyroid dysfunction may be mediated by a direct effect of interferon on thyroid cell function and not by immune mediated effects

1. Destructive Thyroiditis self-limited, only < 5 % will have permanent hypothyroidism characterized by three phases - hyperthyroidism ( Thyroid scan, negative TAbs ) - hypothyroidism - normalization of thyroid functions All patient who have hyperthyroidism - 50 %  DT - 50 %  GD

Majority have subclinical. - occurs more frequently than reported - Many cases could potentially be missed because symptoms may be interpreted as interferon side effects usually resolves spontaneously upon cessation of interferon therapy

2. Non-Autoimmune Hypothyroidism Clinical and subclinical hypothyroidism without TAb’s during IFN Majority are transient permanent hypothyroidism is usually seen when patients develop TAb’s

Risk Factors For IITD

1. HCV estimated that 250,000 people are currently infected with hepatitis C in Canada (Heath Canada) the data for hepatitis C as a possible factor in the development of AITD – mixed

Independent expression of serological markers of thyroid autoimmunityand hepatitis virus C infection in the general population: results of a community-based study in north- western Sardinia. ( J Endocrinol Invest1999;22: Loviselli A, Oppo A, Velluzzi F, Atzeni F, Mastinu GL, Farci P, et al) - N= 1233 (94%; 444 males and 789 females) - measured Tabs and anti-HCV Abs - No association was found between the presence of hepatitis C and TAb’s

High prevalence of thyroid autoantibodies in a prospective series of patients with chronic hepatitis C before interferon therapy. (HEPATOLOGY 1993;18: Tran A, Quaranta JF, Benzaken S, Thiers V, Chau HT, Hastier P, et al) - prospective study -72 chronic hepatitis C patients before interferon therapy (43 men and 29 women; mean age = 51 +/- 2.1 yr) - Control = 60 chronic HBsAg-positive patients (34 men and 26 women; mean age = 50 +/- 2.2 yr), -The association between chronic hepatitis C and presence of thyroid autoantibodies is clearly confirmed (p = 0.021)

Limitation of Old Study : - use less sensitive TAbs assay - Lack of control group - iodine intake

Thyroid disorders in chronic hepatitis C. (Am J Med 2004;117: Antonelli A, Ferri C, Pampana A, Fallahi P, Nesti C, Pasquini M, et al.) - 4 group : interferon-naı¨ve patients who had hepatitis C 2. control group :389 gender- and age-matched subjects from an iodine- sufficient region 3. control group :268 people from an iodine-deficient region patients who had hepatitis B virus infection -measured : - TSH,FT4,FT3 - anti-thyroglobulin and anti-thyroid peroxidase antibodies

Main result : Patients with chronic hepatitis C were more likely to have hypothyroidism (13% [n = 82]) anti-thyroglobulin antibodies (17% [n = 108]), and anti-thyroid peroxidase antibodies (21% [n = 132]) than were any of the other groups

Summery : 1.the association of hepatitis C infection and thyroid autoimmunity is not consistent, more recent data support such an association. 2. the incidence of IIT was found to be significantly higher in patients with hepatitis C than in patients receiving interferon for hepatitis B

2. Women women : 4.4 times higher risk of developing thyroid dysfunction secondary to interferon therapy compared to men. (95% confidence interval ) Interferon-alpha and autoimmune thyroid disease. (Thyroid 2003;13: Prummel MF, Laurberg P. )

3. Therapeutic Regimen. Interferon dose and duration Ribavirin - mixed result

4. Presence of Baseline TAb’s the incidence of thyroid diseases in patients with pretreatment TPO-Ab was much higher compared to patients with negative TPO-Ab levels (60% vs. 3.3) The risk factor for development of thyroid disease during interferon-alpha therapyfor chronic hepatitis C. (Am J Gastroenterol 1994;89: Watanabe U, Hashimoto E, Hisamitsu T, Obata H, Hayashi N. )

Mechanisms of IITD

1. Immune Mediated Efects of IFN Increase expression of Class I MHC antigens on thyrocytes Activation of cytotoxic T cells Enhanced expression of cellular adhesion molecules Increased activity of lymphocytes, macrophages, NK cells, neutrophils,monocytes Increased activity of IL-6 Modulation of immunoglobulin production Inhibition of T regulatory cells Th1 polarization

2. Direct Effects of IFN on the Thyroid Inhibition of TSH-induced gene expression of Tg, TPO, and NIS Decreased iodine organification Decreased thyroxine (T4) release

Diagnosis and management

No defined guidelines Collaboration between hepatologists and endocrinologists

Patient with HCV starting IFN-a therapy Check TSH and TAbs TSH=Normal Tabs=-ve TSH=Normal Tabs=-ve TSH=Normal Tabs=+ve TSH=Normal Tabs=+ve TSH=abnormal Tabs=+ve/-ve TSH=abnormal Tabs=+ve/-ve 1. TFT q 3 months until IFN-a therapy is Completed 2. Repeat TFT and Tabs once after competition of IFN-a therpy 1. TFT q 3 months until IFN-a therapy is Completed 2. Repeat TFT and Tabs once after competition of IFN-a therpy 1. TFT q 2 months until IFN-a therapy is Completed 2. Repeat TFT q year after competition of IFN-a therpy 1. TFT q 2 months until IFN-a therapy is Completed 2. Repeat TFT q year after competition of IFN-a therpy

Abnormal thyroid Function Hyperthyroidism Hypothyroidism Thyroid scan and uptake TAbs Thyroid scan and uptake TAbs GD DT 1.Thyroid hormone replacement 2. Continue IFN 3. Monitor TFT q 2 months 1.Thyroid hormone replacement 2. Continue IFN 3. Monitor TFT q 2 months 1.Standard ttt (ATD,RAI, Surgery) 2. Consider D/C IFN 1.Standard ttt (ATD,RAI, Surgery) 2. Consider D/C IFN 1.BB (+) 2. Consider D/C IFN 1.BB (+) 2. Consider D/C IFN