• Thyroid problems. Some patients develop changes in the function of their thyroid. Symptoms of thyroid changes include the inability to concentrate, feeling cold or hot all the time, a change in your weight and changes to your skin.

http://pegintron.com/pegintron/faqs.html#Q10

Thyroid Disorders in Chronic Hepatitis C

The objective of the current study was to explore the association of hepatitis C virus (HCV) infection with thyroid disorders. Italian researchers investigated the prevalence of thyroid disorders in 630 consecutive patients with chronic hepatitis due to HCV infection.

All patients were free of cirrhosis and hepatocellular carcinoma, and were not on interferon alfa treatment. Also included were a control group of 389 subjects from an iodine-deficient area, another control group of 268 persons living in an area of iodine sufficiency, and 86 patients >40 years of age with chronic hepatitis B.

Levels of thyroid-stimulating hormone (TSH), free thyroxine (T(4)), and triiodothyronine (T(3)), as well as anti-thyroglobulin and anti-thyroid peroxidase antibodies, were measured.

Results

Mean TSH levels were higher (P = 0.001), and free T(3) and free T(4) levels were lower (P <0.0001), in patients with chronic hepatitis C than in all other groups. 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.

Conclusions

Both hypothyroidism and thyroid autoimmunity are more common in patients with chronic hepatitis C, even in the absence of cirrhosis, hepatocellular carcinoma, or interferon treatment, than in normal controls or those with chronic hepatitis B infection.

Department of Internal Medicine and CNR Institute of Clinical Physiology, University of Pisa School of Medicine, Pisa, Italy. a.antonelli@med.unipi.it

06/30/04

Reference
A Antonelli and others. Thyroid disorders in chronic hepatitis C. American Journal of Medicine 117(1): 10-13. July 1, 2004.

http://www.hivandhepatitis.com/hep_c/news/2004/063004_b.html

THYROID DYSFUNCTION

WARNING:

Patients with pre-existing thyroid abnormalities whose thyroid function

cannot be maintained in the normal range by medication should not be treated with

interferon or peginterferon. Therapy should be discontinued for patients developing

thyroid abnormalities during treatment whose thyroid function cannot be normalized

by medication. Discontinuation of interferon-based therapy has not always reversed

thyroid dysfunction occurring during treatment.

PATHOPHYSIOLOGY

The thyroid is a bilobed gland located on either side of the trachea directly above the

larynx.1 It secretes the hormones thyroxine (T4) and triiodothyronine (T3). T4 represents

90% of secreted hormone and T3 represents 10%.2 Of T4, 99.97% is protein bound, with

T3 less strongly protein bound. T3 and T4 affect most body tissues by regulating protein,

fat, and carbohydrate catabolism as well as metabolism. T3 and T4 also regulate CNS

development, cardiac rate, and gastrointestinal tract functioning. Thyroid function is

regulated by the hypothalamic-pituitary axis. Thyrotropin-releasing hormone (TRH) is

released by the hypothalamus, which stimulates the pituitary to secrete TSH. TSH

stimulates the thyroid gland to produce T3 and T4. T3 and T4 circulating levels inhibit

release of TSH when sufficient synthesis has occurred. When T3 and T4 levels decrease,

the pituitary releases TSH.1 Hypothyroidism results from decreased thyroid gland

hormone production and secretion. Primary hypothyroidism results from lower levels of

T4 than T3. Increased TSH secretion increases T3 secretion. Secondary hypothyroidism

results in decreased synthesis of both hormones.2 Hyperthyroidism occurs when tissues

are exposed to excessive thyroid hormone concentrations. It has multiple causes, some of

which are transient and others of which are permanent, ie, Graves’ disease, thyroiditis.2

Interferon alfa stimulates production of various cytokines (eg, interferon-gamma [IFN-g],

interleukin-2 [IL-2]) that have direct effects on endocrine cells.3 As a result, cytokines

have been identified as important factors in the pathogenesis of autoimmune

endocrinopathies, particularly IFN-g and IL-2. It is postulated that interferon alfa

stimulates production of IFN-g and IL-2 from thyroid-infiltrating lymphocytes, hence

potentiating antithyroid autoimmunity. Specific antithyroid autoantibodies, antithyroid

peroxidase, and antithyroglobulin have also been observed in patients on interferon alfa,

resulting in an AI thyroiditis. This is generally reversible, but can take up to 18 months to

resolve. In some patients, hypothyroidism developed while on treatment may be

permanent.3 Hypothyroidism is more commonly manifested in patients undergoing

interferon therapy, with a ratio of hypothyroidism to hyperthyroidism of 2:1 or 3:1.4

Transient hyperthyroidism followed by persistent hypothyroidism has been reported.4

All patients should be counseled prior to initiation of interferon-based therapy that

irreversible thyroid disease can occur.

Side Effects Management Handbook • VI. Endocrine • p. 5

HIGH-RISK PATIENTS

· Women

· Age >40 years

· IL-2 and interferon concomitant therapy

· Pre-existing thyroid disease

· Family history

DIAGNOSTIC TESTS AND INTERPRETATION

1. TSH recommended initially (all patients)

2. If TSH is abnormal, complete thyroid panel including T4 and free T3.

a. High TSH, normal T4: compensated hypothyroidism

b. High TSH, low T4: clinical hypothyroidism

c. Low TSH, high T3: hyperthyroidism

3. Consider measuring antithyroid antibodies to rule out AI thyroid disease, such as

Hashimoto’s thyroiditis. Antithyroid antibodies: antithyroid peroxides,

antithyroglobulin, and antimicrosomal antibodies. Antithyroid autoantibodies are very

common in the general population, occurring in about 16% of women. Normal aging

increases the number of circulating antibodies; thus, the patient’s health and age must

be considered.

4. Note that measuring T4 alone could lead to missing a diagnosis of compensated

hypothyroidism, since the T4 level could be normal only because the TSH has

been stimulating the thyroid into additional production. Compensated hypothyroidism

cannot persist for long without progressing to overt hypothyroidism.

5. Note that T3 is measured, but is less meaningful; may be lower than normal in

up to 70% of all hospitalized patients.

SYMPTOMS OF HYPOTHYROIDISM1 SYMPTOMS OF HYPERTHYROIDISM2

SUBCLINICAL: · Restlessness

· Easily fatigued · Anxiety

· Mood alterations/mild depression · Heat intolerance

· Inability to lose weight · Palpitations

CLINICAL:

· Declining mental function · CHF

· Increased fatigue · Increased appetite

· Dry skin/myalgias · Emotional lability

· Constipation · Weight loss

· Irregular/heavy menses · Thyroid enlargement

· Pallor, yellow skin tone · Infertility

· Hoarseness · Gynecomastia in males

· Tremors in fingers/hands

Side Effects Management Handbook • VI. Endocrine • p. 6

TREATMENT FOR HYPOTHYROIDISM1

1. Check medical history for possible etiology. Two widely used drugs, lithium

carbonate (Eskalith®) and amiodarone (Cordarone®, Pacerone®), are known to cause

hypothyroidism.

2. Continue anti-HCV therapy while therapy for hypothyroidism is instituted.

3. Thyroid hormone replacement: levothyroxine (Levothroid®, Levoxyl®, Synthroid®,

Unithroid™) preferred. Age <50 years: 75–100 µg with 25–50 µg dose adjustment

every 2 to 3 weeks. Age >50 years: 25 to 50 µg, increases in 25 µg increments. Do

not interchange brands; bioequivalence problems between manufacturers. Peak

therapeutic effect: 4 to 6 weeks.

4. Adverse reactions of thyroid hormone replacement:

a. CNS: nervousness, insomnia, tremor

b. CV: tachycardia, angina

c. Gastrointestinal: diarrhea, vomiting

d. General: weight loss, fever, heat intolerance, menstrual irregularities

5. Recheck thyroid panel in 4 weeks. If there are persistent abnormalities, consider

referral to endocrinologist.

6. Be aware that antidiabetic agents may have to be increased when thyroid medications

are initiated, and patients taking estrogen (hormone replacement therapy) may need to

increase the amount when beginning thyroid medications.

Patients should be instructed to1:

1. Take medication at the same time every day to maintain hormone levels. A single

morning dose before breakfast decreases the chance of insomnia; tablets may be

crushed. Do not adjust the dose.

2. Take iron preparations, antacids, and cholesterol-lowering drugs 4 to 5 hours apart

from thyroxine.

3. Notify their healthcare provider of symptoms of intolerance: palpitations, chest pain,

anxiety, and sudden increase in size of thyroid gland.

4. Know that symptoms should begin to abate within 2 weeks of therapy initiation.

5. Be aware that thyroid hormone replacement is usually permanent, and they should tell

all healthcare providers that they are taking this therapy.

6. Store medications in cool, dark, dry place.

7. Avoid changing dose/brand or discontinuing treatment without physician approval.

8. Limit consumption of high iodine foods (especially kelp preparations), since thyroid

medications may increase toxicity to iodine.

9. Inform their radiologist about thyroid medication before any iodine contrast is given

for imaging studies.

TREATMENT FOR HYPERTHYROIDISM

1. Upon diagnosis of hyperthyroidism, strongly consider referral to the primary

physician and/or endocrinologist.

2. Antithyroid drugs: Methimazole (MMI; Tapazole®) and propylthiouracil (PTU).

Indications: Grave’s disease, hyperthyroidism in children and adolescents,

hyperthyroidism in pregnancy.

Side Effects Management Handbook • VI. Endocrine • p. 7

3. Iodide: Reserved for severe hyperthyroidism following iodine-131 (131I) therapy or as

preparation for surgery.2

4. Beta-adrenergic drugs: Propranolol (Inderal®, Inderide®). Indications: between

interval that 131I therapy becomes effective or prior to surgery.

5. Radioactive iodine. Indications: long-term antithyroid drug failures.

6. Surgery. Indications: hyperthyroid pregnant women who cannot tolerate antithyroid

drugs and those with large goiters to relieve symptoms locally.

Patients should be instructed:

1. That medications are generally taken for at least 2 years and should not be abruptly

discontinued

2. To contact healthcare professional with first signs of infection or fever

3. That the therapeutic effect of medication is not usually evident for about 3 weeks

THYROID DYSFUNCTION AND HCV INFECTION CONSIDERATIONS

The prevalence of antithyroid antibodies and autoimmune thyroid disease is higher in the

HCV-infected population than in control groups.5 A proportion of patients with

antithyroid antibodies will develop clinical thyroid dysfunction. Hypothyroidism is seen

more frequently than hyperthyroidism. Hyperthyroidism may transform over time into

hypothyroidism. The incidence of antithyroid antibodies and thyroid dysfunction is

enhanced by interferon alfa treatment. Thyroid dysfunction is reversible only in a

minority of patients following discontinuation of interferon alfa treatment. Antithyroid

autoantibodies have a 4.6% to 15% prevalence in untreated HCV-infected patients.

Latent AI thyroiditis is more frequent in untreated hepatitis C patients than in controls.

Risk factors for developing antithyroid antibodies include5:

• Age

• Female sex

• Increased TSH levels

• Hypoechogenic pattern of thyroid gland on ultrasound5

THYROID DYSFUNCTION IN HCV-INFECTED PATIENTS TREATED WITH

INTERFERON ALFA

• Study of 308 patients treated with interferon alfa therapy, including 211 with HCV

infection, who underwent thyroid function evaluation before and after interferon6

• 14% of patients had antithyroid peroxidase antibodies (ATPO); 3.7% had detectable

thyroid dysfunction prior to onset of therapy.6

• Interferon alfa led to increase in ATPO in 73% of patients with positive baseline

levels; 10.8% of patients developed de novo ATPO.

• Increased prevalence of ATPO following therapy was more frequent in women.6

• Patients with high baseline ATPO titers had a higher rate of thyroid dysfunction at

end of treatment.

• Six months posttherapy, an increased rate of thyroid dysfunction persisted in 8% of

patients.

• 5.8% of euthyroid patients with undetectable ATPO prior to therapy developed

thyroid dysfunction; 11/15 developed hypothyroidism and 4/15 hyperthyroidism.

Side Effects Management Handbook • VI. Endocrine • p. 8

• 15.2% of euthyroid patients with detectable ATPO prior to treatment developed

hypothyroidism.

• Six months posttherapy, normal thyroid function was observed in 3/15 patients (20%)

who developed hypothyroidism and 4/7 patients who developed hyperthyroidism.

• 3/7 remaining patients who developed hyperthyroidism during treatment progressed

to hypothyroidism during follow-up.

• Clinical recommendation: interferon-based therapy can continue unless the patient is

symptomatic or unstable.

Thyroid Autoimmunity Associated With Interferon-Alpha May Be Irreversible

A DGReview of :"Long-Term Outcome of Interferon-(alpha)-Induced Thyroid Autoimmunity and Prognostic Influence of Thyroid Autoantibody Pattern at the End of Treatment"
Journal of Clinical Endocrinology & Metabolism

06/14/2001
By Mark Greener
Thyroid autoimmunity associated with interferon-[a (INF-a) may be irreversible in some cases. Previous studies suggest that INF-a can cause thyroid autoimmunity and dysfunction. However, previous studies did not assess patients beyond six to 12 months following the end of therapy. As a result, researchers from the Seconda University of Naples and the Federico II University of Naples, Italy, performed the first study that assessed the natural history of IFN-related thyroid autoimmunity during long-term follow up. The authors enrolled 79 men and 35 women aged between 23 and 67 years. (The mean age was 48 years.) The patients, who did not suffer from pre-existing thyroid disease, received a 12-month course of recombinant IFN-a for chronic active hepatitis C. The authors assessed thyroid autoimmunity and function at the end of treatment with INF-a as well as after six months and a median of 6.2 years, although the latter ranged from 5.5 to 8.4 years. Following INF-a treatment, 78 patients were negative for thyroid autoantibodies. Only one of these patients expressed autoantibodies during follow up. Thirty-six patients expressed thyroid autoantibodies at the end of treatment. Of these, 16 patients continued to express thyroid autoantibodies throughout follow-up. The authors described these patients as suffering from persistent thyroiditis. Ten patients became negative for thyroid autoantibodies at the six month assessment, but showed antibodies again at the final evaluation. This pattern was described as remitting /relapsing thyroiditis. Finally, ten patients were negative for autoantibodies at different times - so called transient thyroiditis. No patients developed overt thyroid dysfunction. However, 12 patients, all of whom showed thyroid autoantibodies and eight of whom had persistent thyroiditis, showed subclinical hypothyroidism. Patients who did not express thyroid autoantibodies at the end of treatment were unlikely to develop either thyroiditis (odds ratio: 0.02) or thyroid dysfunction (odds ratio: 0.06). In contrast, patients who expressed high titres of the thyroid autoantibodies TgAb and TPOAb at the end of treatment were at increased risk of developing chronic thyroiditis and thyroid dysfunction. The odds ratios for chronic thyroiditis associated with TgAb levels and TPOAb levels over the 50th percentile were 17.3 and 7.3 respectively. Patients positive for both TgAb and TPOAb after IFN therapy showed an odds ratio of 38.7 of expressing subclinical hypothyroidism at the end of follow up. The authors drew four conclusions from the study. First, being negative for thyroid autoantibodies after IFN-a treatment for chronic hepatitis C protects against the subsequent development of thyroid autoimmunity and dysfunction. Second, the thyroid autoimmunity associated with INF-a is not completely reversible. Third, high autoantibody levels at the end of the INF-a course is associated with an increased risk of chronic thyroid autoimmunity. Finally, expressing both TgAb and TPOAb at the end of treatment predicts the risk of suffering from subclinical thyroid dysfunction many years later.

Journal of Clinical Endocrinology & Metabolism 2001;86:1925-1929. "Long-Term Outcome of Interferon-(alpha)-Induced Thyroid Autoimmunity and Prognostic Influence of Thyroid Autoantibody Pattern at the End of Treatment"

Sex

Shortness of Breath

Shortness of breath is seen in up to 14% of patients:

Shortness of breath may be from anemia and this must be monitored for patients with normal Hgb, pulmonary function is usually normal in spite of symptoms,
a nonproductive cough may also occur,
chest pain is not usually a feature

Patients who have had their asthma under control, but have been taking interferon for the suppression of hepatitis C, have suffered enough to be hospitalized for the return of asthma symptoms. Hepatitis C therapy with interferon-alpha can lead to severe asthma exacerbation in patients with previously mild asthma. Interferon-alpha therapy has previously been associated with pulmonary complications, and now we have evidence of asthma exacerbation as well. (Mayo Clinic Proceedings 1999; 74:367-370)

Pulmonary and Renal

WARNING:

Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial

pneumonitis, and sarcoidosis, some resulting in respiratory failure and/or patient deaths,

may be induced or aggravated by peginterferon or interferon alfa therapy. Recurrence of

respiratory failure has been observed with interferon rechallenge. The etiology has yet to

be established.

Side Effects Management Handbook • XII. Pulmonary & Renal • p. 2

XII. Pulmonary and Renal

COUGH

Cough of unexplained etiology can occur in patients receiving interferon or peginterferon

alone or in combination with ribavirin. Nonproductive cough is sometimes seen in

association with throat irritation accompanying postnasal drip. The cough may be worse

at night or may become a nervous cough.

ASSESSMENT

Providers should perform physical examination, WBC, chest x-ray, etc, as needed to rule

out other possible etiologies before diagnosing cough secondary to peginterferon and/or

ribavirin.

MANAGEMENT STRATEGIES

Patients should be instructed to:

1. Maintain adequate hydration1 (consumption in fluid ounces = one half body weight in

pounds; eg, a 160-lb person should drink 80 fl oz/d).

2. Humidify air.

3. Use two pillows for sleep.

4. Use a saline nebulizer.

5. Suck on cough drops/hard candy/lozenges.

6. Try Cepacol® spray.

7. Take antihistamines at bedtime.

8. Try expectorants, especially during the day.

Providers should:

1. Follow absolute ANC and CBC with differential.

2. Perform chest x-ray as needed. If x-ray shows pulmonary infiltrates or there is

evidence of pulmonary function impairment, the patient should be closely monitored,

and, if appropriate, treatment should be discontinued. Patients who resume interferon

treatment should be closely monitored.

3. Administer flu/pneumonia vaccinations if not contraindicated. Administer other

vaccinations (eg, hepatitis A and B vaccinations if susceptible) in accordance with

Centers for Disease Control and Prevention (CDC) recommendations.

4. Recommend pharmacologic therapies. Consider prescription therapies if over-thecounter

agents are not helping.

a. Dextromethorphan hydrobromide – try before prescribing narcotics

b. Guaifenesin (Organidin®) with or without codeine; 30 cc as directed around the

clock for 2 to 3 days. Guaifenesin can be prescribed in capsule and extendedrelease

forms at 600 mg, 800 mg,1200 mg

REFERENCE

1. Rieger PT. Clinical Handbook for Biotherapy. Boston: Jones & Bartlett; 1999:60-90.