Interferon-Induced Thyroid Disease

Bader Al-Harbi March-2008

Case

• • Mrs. B. 44 y seen on Nov 2006 • Re: abnormal TFT ( August -2006) TSH = 0.012

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 -2006 ( on day Clinic)

TSH = 3 (N 0.35-5) FT4 = 16 FT3 = N

March 2005 Feb 2006

IFN and Ribavirin

TSH N 0.13

FT4 FT3 Clinically N N E 16.4

4.5

E Sept 2006 Nov 2006 0.012

22.9

8 E 3 16 E Jan 2007 7 10(L) E

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

TSH FT4 FT3 Clinically May 2007 0.012

25 9

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

• Discovered 50 y ago

Interferon

• 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 : 1985 - 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;56:793-798. 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: 2155-2160. 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;22:660-665. 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;18:253-257 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;117:10-13. Antonelli A, Ferri C, Pampana A, Fallahi P, Nesti C, Pasquini M, et al .) 4 group : 1. 630 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 4. 86 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

1.

Summery : 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 3.2-5.9)

Interferon-alpha and autoimmune thyroid disease.

(Thyroid 2003;13:547-551. 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;89:399-403 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

1. TFT

q 3 months

until IFN-a therapy is Completed 2. Repeat TFT and Tabs

once

after competition of IFN-a therpy

TSH=Normal Tabs=+ve

1. TFT

q 2 months

until IFN-a therapy is Completed 2. Repeat TFT q

year

after competition of IFN-a therpy

TSH=abnormal Tabs=+ve/-ve

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