Interferon-Induced Thyroid Disease Bader Al-Harbi March-2008.
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Transcript of Interferon-Induced Thyroid Disease Bader Al-Harbi March-2008.
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Interferon-Induced Thyroid Disease
Bader Al-Harbi
March-2008
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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
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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
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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
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What is next ?
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• Repeated TFT on Nov -2006 ( on day Clinic)
TSH = 3 (N 0.35-5)
FT4 = 16
FT3 = N
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March
2005
Feb
2006
Sept
2006
Nov
2006
Jan
2007
IFN and Ribavirin
TSH N 0.13 0.012 3 7
FT4 N 16.4 22.9 16 10(L)
FT3 N 4.5 8
Clinically E E E E E
Hypo-thyroidism
? -treat
- F/U
- TPO abs
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anti-TPO : negative
No LT 4 replacement
F/U TFT q 1-2 Months
What do you think the diagnosis ?
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• Feb-April 2007:
-No Blood work was done
- Changed her phone number
- Note was sent to GP
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May 2007
TSH 0.012
FT4 25
FT3 9Clinically Palpitation
( pulse 105/min)
Insomnia
Inability to gain weight
What is Next ?
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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
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Interferon
• Discovered 50 y ago
• 3 types : - INF-a
- INF-b
- INF-g
• has - antiviral action
- reduce tumor growth
- modulating immune response
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• Side effect :
• The most common indication for INF-a treatment is HCV
other : melanoma
renal cell carcinoma,
hairy cell leukemia,
Kaposi’s sarcoma
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Interferon-induced thyroid disease(IITD)
• Epidemiology
• Classification
• Spectrum of the IITD
• Risk factors
• The mechanism of IITD
• Diagnosis and management
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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
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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
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Autoimmune IITD
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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
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• 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
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• 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 )
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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”
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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
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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
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Non-Autoimmune IITD
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• 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
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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
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• 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
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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
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Risk Factors For IITD
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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
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• 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
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• 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)
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• Limitation of Old Study :
- use less sensitive TAbs assay
- Lack of control group
- iodine intake
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• 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
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• 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
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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
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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. )
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3. Therapeutic Regimen.
• Interferon dose and duration
• Ribavirin
- mixed result
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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. )
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Mechanisms of IITD
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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
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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
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Diagnosis and management
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• No defined guidelines
• Collaboration between hepatologists and endocrinologists
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Patient with HCV starting IFN-a therapy Patient with HCV starting IFN-a therapy
Check TSH and TAbsCheck TSH and TAbs
TSH=NormalTabs=-ve
TSH=NormalTabs=-ve
TSH=NormalTabs=+ve
TSH=NormalTabs=+ve
TSH=abnormalTabs=+ve/-ve
TSH=abnormalTabs=+ve/-ve
1. TFT q 3 months until IFN-a therapy is
Completed
2. Repeat TFT and Tabs once after
competitionof IFN-a therpy
1. TFT q 3 months until IFN-a therapy is
Completed
2. Repeat TFT and Tabs once after
competitionof IFN-a therpy
1. TFT q 2 months until IFN-a therapy is
Completed
2. Repeat TFT q yearafter competitionof IFN-a therpy
1. TFT q 2 months until IFN-a therapy is
Completed
2. Repeat TFT q yearafter competitionof IFN-a therpy
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Abnormal thyroid Function Abnormal thyroid Function
Hyperthyroidism Hyperthyroidism Hypothyroidism Hypothyroidism
Thyroid scan and uptakeTAbs
Thyroid scan and uptakeTAbs
GDGD DTDT
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