TRIPASS XR تري باس

 

MANAGEMENT OF EYE SYMPTOMS

CASE 52-21, QUESTION 2: Was previous treatment of H.R.’s hyperthyroidism appropriate? How should

his current ocular symptoms be managed?

The optimal treatment of hyperthyroidism and its effect on the course of

ophthalmopathy remain controversial.

237,238,242 Thioamides might improve eye

symptoms through an immunosuppressive mechanism of action and control of the

hyperthyroidism or exert a neutral effect.

237 Many clinicians believe that RAI ablation

or surgical removal is preferable because it removes the antigen source and prevents

progression of the ophthalmopathy.

180,237 However, several studies have confirmed

development or worsening of eye symptoms immediately after RAI therapy.

240,242

Concomitant use of 0.4 to 0.5 mg/kg of prednisone begun 1 to 3 days post-RAI

continued for one month and tapered over 2 months may be used in patients with mild

active eye disease to prevent progression of eye symptoms.

34,240,242 A recent study

showed lower dose, shorter duration prednisone therapy (0.2 mg/kg/day for 6 weeks)

to conventional doses as effective as conventionally used doses.

243 After 6 months

there was no difference in clinical activity score, exophthalmos, or lid retraction.

Patients with active moderate-to-severe or sight threatening ophthalmopathy at the

time of treatment should be treated with surgery or thioamides instead of RAI.

34

Regardless of the treatment used, control of the hyperthyroidism often improves most

eye findings, except for proptosis.

In H.R., prednisone 40 to 60 mg/day should have been started after his RAI

treatment and continued for 2 to 3 months

p. 1066

p. 1067

until the eye symptoms improved. Because the pathophysiology of the

ophthalmopathy is unclear, treatment is limited to symptomatic and empiric measures

once the patient is euthyroid.

237,238 H.R. should also be encouraged to stop smoking to

prevent progression of the ophthalmopathy.

212 His pioglitazone should be

discontinued, in case this is contributing to his ophthalmopathy.

Because periorbital edema and chemosis are worse in the morning after being in

the horizontal position, elevating the head of the bed, diuretics, and restricting salt

intake may be helpful. Protective glasses can relieve photophobia and external

irritation. Topical corticosteroid drops are effective in decreasing local irritation,

but they should be used cautiously because they increase the risk of infection. Ocular

irritants such as smoke and dust should be avoided. Bothersome symptoms (e.g., dry

eye, redness, tearing) caused by eyelid retraction can be relieved by artificial tears

and lubricants.

237

Incomplete lid closure predisposes to corneal scarring and

ulceration, so lubricant eyedrops should be applied several times daily and at night

to keep the bulbs moist. Taping the eyelids shut at night prevents drying and scarring.

Lateral surgical closure of the lids (tarsorrhaphy) may be required to improve lid

closure.

With severe and progressive ophthalmopathy, an aggressive approach is

necessary. Systemic corticosteroids can produce either dramatic or marginal results

in the emergency treatment of progressive exophthalmos associated with decreasing

visual acuity. Prednisone at dosages of 35 to 80 mg/day is often effective, although

dosages as high as 100 to 140 mg/day may be necessary.

237,238 Pain, irritation, tearing,

and other subjective complaints often respond within 24 hours of administration.

Therapy for about 3 months is necessary to improve eye muscle and optic nerve

function disturbances. Initial large doses should be tapered rapidly once the desired

response is obtained to minimize adverse effects. Subconjunctival and retrobulbar

injections of steroids are not as effective.

Orbital x-ray therapy also relieves congestive and inflammatory symptoms.

237 The

combination of orbital irradiation and systemic steroids may be required to achieve

maximal benefits. Plasmapheresis and immunosuppressive agents, such as

cyclophosphamide, azathioprine, cyclosporine, and methotrexate, combined with

steroids have also been used with limited success. Future investigations are focusing

on anti-TNF and anti-interleukin receptor antibodies agents that may neutralize some

of the inflammatory reactions in the eye.

237,239

When the previous measures and thyroid ablation fail to arrest the progression of

visual loss and exophthalmos, then surgical orbital decompression should be

considered.

Thyroid Storm

CLINICAL PRESENTATION

CASE 52-22

QUESTION 1: H.L., a 48-year-old woman, is admitted to the hospital with a 3-week history of fatigue,

weakness, dyspnea on exertion, SOB, palpitations, and inability to keep food and liquids down. One year before

admission, she began noticing a preference for cold weather and an increase in nervousness and emotional

liability. After her husband died a few days ago, she experienced increased nausea and vomiting, irritability,

insomnia, tremor, and a 104°F fever, which she attributed to an upper respiratory tract infection. She denies

taking any current medications. Her laboratory data obtained on admission included an FT4

of 4.65 ng/dL

(normal, 0.8–1.4) and an undetectable TSH level. Assess H.L.’s subjective and objective data.

The presentation is consistent with thyroid storm, a life-threatening medical

emergency that might have been precipitated by the stress associated with the death

of her husband. The clinical manifestations of thyroid storm192

include the acute onset

of high fever, tachycardia, and tachypnea, and involvement of the following organ

systems: cardiovascular (tachycardia, pulmonary edema, hypertension, shock), CNS

(tremor, emotional liability, confusion, psychosis, apathy, stupor, coma), and GI

(diarrhea, abdominal pain, nausea and vomiting, liver enlargement, jaundice,

nonspecific elevations of bilirubin and prothrombin time). Hyperglycemia is also a

common clinical finding in thyroid storm.

Thyroid storm develops in about 2% to 8% of hyperthyroid patients. The

pathogenesis of thyroid storm is not well understood, but the condition can be

described as an “exaggerated” or decompensated form of thyrotoxicosis. The term

decompensated implies failure of body systems to adequately resist the effects of

thyrotoxicosis. It is not attributed solely to the release of massive quantities of

hormones, which can occur after surgery or RAI therapy. Catecholamines also play

an important role; the increased quantities of thyroid hormone in conjunction with

increased sympathetic and adrenal output contribute to many of the manifestations of

thyroid storm. Although thyroid hormones exert an independent effect, many of the

symptoms of hyperthyroidism are ameliorated by catecholamine-blocking agents such

as β-blockers and calcium channel blockers (e.g., diltiazem, verapamil).

TREATMENT

CASE 52-22, QUESTION 2: What treatment plan (including route of administration) should be initiated

promptly in H.L.?

Intensive, continuous, and immediate treatment can significantly reduce the

mortality of thyroid storm. Mortality rates in thyroid storm are high, ranging between

20% and 30%.

192 Treatment of thyroid storm should be directed against four major

areas discussed in the following sections.

192

Decrease in Synthesis and Release of Hormones

High dosages of thioamides, preferably PTU 800 to 1,200 mg/day or methimazole 60

to 100 mg/day, should be given orally in four divided doses. If H.L. cannot take oral

doses, a rectal formulation of PTU (better bioavailability with enema than

suppository) or methimazole, which is as effective as the oral route, can be

administered.

177–179 No commercial parenteral preparation is available for either

drug, limiting their use by the IV route. PTU is the thioamide of choice because it acts

more rapidly than methimazole by blocking the peripheral conversion of T4

to T3

, a

dominant source of the hormone.

Iodides, which rapidly block further release of intraglandular stores of T4

, should

be given at least 1 hour after thioamide administration. Given in this way, the

substrate for hormone synthesis is not increased, and the therapeutic effect of

thioamide is not blocked. The addition of iodides (e.g., Lugol’s solution 15 to 30

drops/day orally in divided doses) to the thioamides often ameliorates symptoms

within 1 day.

Cholestyramine 4 g orally (PO) QID may assist in lowering hormone levels

rapidly but should be administered apart from other agents to prevent inhibiting their

absorption.

244 Other effective modalities include plasmapheresis, charcoal

hemoperfusion, and plasma exchange.

Reversal of the Peripheral Effects of Hormones and Catecholamines

β-Adrenergic blocking drugs are the preferred agents to decrease the tachycardia,

agitation, tremulousness, and other symptoms

p. 1067

p. 1068

of excessive adrenergic stimulation seen in thyroid storm. Propranolol is the βblocker of choice because its clinical efficacy in storm is well documented, and it

inhibits the peripheral conversion of T4

to T3

.

192,200

If rapid effects are necessary,

propranolol 1 mg by slow IV push can be given every 5 minutes to lower the heart

rate to approximately 90 beats/minute. A 5- to 10-mg/hour IV infusion can maintain

the desired heart rate. IV esmolol 50 to 100 mcg/kg/minute can also be given. If

perfusion is maintained, oral β-blockers (e.g., propranolol, 40 mg every 6 hours;

atenolol, 50–100 mg BID; metoprolol, 50–100 mg daily; nadolol, 40–80 mg daily),

titrated to response, can also be given.

Supportive Treatment of Vital Functions

This may include sedation, oxygen, IV glucose, vitamins, treatment of infections with

antibiotics, digitalization to maintain the cardiac status, rehydration, and treatment of

hyperpyrexia with cooling blankets, sponge baths, and the judicious use of

antipyretics. Because hypoadrenalism is often suspected, hydrocortisone 100 to 200

mg should empirically be given IV every 6 hours. Because pharmacologic doses of

steroids acutely depress serum T3

levels, a beneficial effect in storm, their routine

use is recommended.

Elimination of Precipitating Causes of Storm

Precipitating causes of thyroid storm include infection (most common), trauma,

inadequate preparation before thyroidectomy, surgical operations, stress, diabetic

ketoacidosis, pregnancy, emboli, discontinuation or withdrawal of antithyroid

medications, drug therapy, and RAI therapy.

192

DRUG-INDUCED THYROID DISEASE

Lithium

CASE 52-23

QUESTION 1: D.A., a 56-year-old man, complains of sluggishness, cold intolerance, fatigue, and a “rundown”

feeling, which doctors attribute to the depressive phase of his bipolar affective illness. He previously had been

well controlled with sertraline 100 mg/day, but lithium carbonate 900 mg/day was added 4 months ago because

of unreasonable mirthfulness and uncontrollable gift-buying tendencies. Physical examination reveals a puffy

face and a large goiter. What is a reasonable assessment of these subjective and objective data?

Thyroid function tests (i.e., TSH, FT4

) and a thyroid ultrasound should be obtained

to evaluate the possibility of lithium- and possibly sertraline-induced hypothyroidism

and goiter.

4,5,13,245

If the TSH is elevated, T4 should be initiated and lithium continued

if necessary. Although the incidence of goiter and hypothyroidism in the manicdepressive population is unknown, the 10% incidence of baseline-elevated TSH

appears higher than in the general population.

The exact mechanism of lithium’s antithyroid effect on the gland is unclear,

although it is highly concentrated by the gland. Similar to the iodides, chronic lithium

therapy inhibits the release of thyroid hormone from the gland. The fall in serum T4

and T3 hormone levels leads to a compensatory and transient increase in serum TSH

levels until a new steady state is achieved.

4,5,13

Elevated TSH levels are reported in approximately 19% of patients on chronic

lithium therapy.

13 Typically, the serum thyroid hormone levels decrease and the TSH

levels increase during the first few months of treatment, returning to pretreatment

levels after 1 year. In one study, TSH levels increased within 10 days after starting

therapy. Normalization of the TSH level is less likely to occur in patients with

preexisting positive thyroid antibodies before lithium therapy. Induction of thyroid

antibodies and increases in baseline antibody titers also occur after chronic lithium

therapy. Because abnormal thyroid function tests can be transient, a longer period of

observation is justified before starting thyroid therapy in patients with subclinical

hypothyroidism.

Overt hypothyroidism appears in a small percentage of the population after 5

months to 2 years of therapy; one 15-year study found an incidence of 1.5% but an 8.4

relative risk in females with antibody positivity compared to negative subjects.

4,5,13

Lithium-induced goiter with or without hypothyroidism is common after weeks to

months of therapy. Although incidences of less than 6% have been reported, higher

rates of 40% to 60% are observed if the goiter is diagnosed using more specific

imaging techniques (e.g. ultrasound).

4,5,13 A direct goitrogenic effect of lithium on

inducing cell proliferation might explain the occurrence of euthyroid goiter. The

goiters respond to discontinuation of lithium or to suppression with thyroid hormone

despite continuation of lithium therapy. Surgical removal of the goiter is required if

there are local obstructive symptoms. In D.A.’s case, sertraline could be exerting an

additive or synergistic antithyroid effect with lithium because antithyroid effects have

also been associated with this drug.

245

Most patients with lithium-induced thyroid abnormalities are women older than 50

years, have a prior history of compromised thyroid function (e.g., Hashimoto’s

thyroiditis), positive thyroid antibodies before lithium therapy, or a strong family

history of thyroid disease.

4,5,13 Therefore, baseline thyroid function tests (i.e., FT4

,

TSH), antibodies, and thyroid ultrasound should be obtained before starting lithium

therapy, and levels should be checked annually thereafter or more frequently if

clinically indicated. Patients should also be questioned about a positive history or

family history for thyroid disease and the concurrent use of other, potentially

goitrogenic medications (e.g., tricyclic antidepressants, iodides, iodinated

expectorants/herbals).

Iodides and Amiodarone

CASE 52-24

QUESTION 1: C.Y., a 54-year-old man with chronic atrial fibrillation presents with a 6-month history of

weakness, fatigue, tremor, heat intolerance, and increased palpitations, previously controlled for the last 2 years

on amiodarone 200 mg/day. Physical examination reveals a 50-g multinodular gland, which C.Y. says has “been

there forever.” He denies any family history of thyroid disease or ingestion of any thyroid medication. His

current complaints began after a magnetic resonance imaging (MRI) procedure with iodinated radiocontrast

media. What might be responsible for C.Y.’s hyperthyroid symptoms?

The iodine load from the MRI or the amiodarone could be responsible for C.Y.’s

hyperthyroid symptoms.

3,12,17,28,57,173

Iodide-induced hyperthyroidism, or Jod-Basedow

phenomenon, was first described in the 1800s when patients residing in iodidedeficient areas became toxic when given adequate iodide supplementation. Both T3

toxicosis and classic T4

toxicosis have been reported following iodide ingestion or

injection of roentgenographic contrast media.

Although it is presumed that both iodide deficiency and a multinodular goiter, as in

C.Y., are required to invoke the Jod-Basedow phenomenon, iodide-induced disease

has been reported in patients residing in iodide-sufficient areas, as well as in

euthyroid patients with normal glands and no apparent risk

p. 1068

p. 1069

factors (e.g., family history).

28,173

Amiodarone can cause hypo- or hyperthyroidism in susceptible patients because of

its high iodine content.

3,12,16,17,28,57,173 Twelve milligrams (37%) of free iodine is

released per 400-mg dose of amiodarone. Patients with multinodular goiters, who

lose the ability to turn off iodide organification from increased iodide loads (Wolff–

Chaikoff effect), are most likely to develop iodide-induced thyrotoxicosis.

Conversely, patients with positive antibodies or with underlying Hashimoto’s

thyroiditis, who cannot escape from the Wolff–Chaikoff block, are most likely to

develop hypothyroidism.

Amiodarone-induced hypothyroidism may occur at any time during therapy and

does not appear to be related to the cumulative dose. A low-normal or low FT4 and a

persistently elevated TSH (see Case 52-4) are consistent with amiodarone-induced

hypothyroidism, which occurs in 6% to 10% of long-term users. The hypothyroidism

responds readily to T4

therapy, even if the amiodarone is continued.

3,17,57

Amiodarone-induced hypothyroidism typically resolves after stopping the drug, but

resolution may be delayed because of its long half-life.

In contrast, amiodarone-induced thyrotoxicosis, which occurs in 1% to 5% of

long-term users, occurs early and suddenly during therapy, so that routine monitoring

of thyroid function tests is not useful. Elevated hormone levels, an undetectable TSH

level, and clinical symptoms consistent with hyperthyroidism are the best indicators

of amiodarone-induced thyrotoxicosis. Worsening of tachyarrhythmias may be the

first clinical clue to amiodarone-induced thyrotoxicosis.

Amiodarone-induced hyperthyroidism can be classified as either type I or type

II.

3,12,55,57 Type I occurs in patients with underlying risk factors for thyroid disease

(e.g., multinodular goiter) and is related to the iodine load. The formation of large

amounts of preformed hormone from the massive iodine load produces a protracted

course of hyperthyroidism, which is challenging to manage. Type II amiodaroneinduced hyperthyroidism is because of a destructive thyroiditis, with excessive

release of thyroid hormone into the systemic circulation. This occurs most often in

patients with normal thyroid glands. Unique laboratory findings include a low RAIU

and elevated interleukin-6 levels.

The management of amiodarone-induced thyrotoxicosis is complicated because it

is not always possible to identify the type of hyperthyroidism and a mixture of the

two types can occur. Stopping amiodarone alone does not immediately improve the

hyperthyroidism because of the drug’s long half-life (22–55 days) and its

sequestration in fat. RAI ablation is never effective because the high iodine load from

amiodarone will suppress RAI uptake. The combination of methimazole and

potassium perchlorate is the treatment of choice for type I

hyperthyroidism.

3,12,17,28,57,173 The addition of corticosteroids to block T4

to T3

conversion is less effective because of the already potent inhibitory effects of

amiodarone on T4

to T3 conversion. However, in patients with type II

hyperthyroidism, agents that block T4

to T3 conversion (e.g., β-blockers,

corticosteroids, and iodinated contrast media if available), rather than the

aforementioned agents, are the most appropriate choices.

3,17,28,57,246 A total

thyroidectomy can rapidly control the thyrotoxicosis, permitting continued therapy

with amiodarone if necessary. Despite underlying cardiac disease in these patients,

uneventful surgery and a low complication rate have been observed if patients are

treated before surgery with a short course of an oral cholecystographic agent.

246

Changing amiodarone to dronedarone which is devoid of iodine and lacks the

undesirable thyroid effects should be strongly considered in C.Y.

Large doses of iodides should be avoided in patients with nontoxic multinodular

goiters, who are predisposed to thyrotoxicosis (see Case 52-4 and Case 52-15,

Question 2).

Thyrotropin-α and Thyroid Suppression Therapy for

Thyroid Cancer

CASE 52-25

QUESTION 1: J.R., a 28-year-old man, had a total thyroidectomy last year for papillary cancer followed by

RAI therapy. He is clinically euthyroid on 200 mcg L-thyroxine daily with a TSH level of <0.2 microunits/mL

(normal, 0.45–4.1). He is hesitant to discontinue his L-thyroxine, so that an RAIU scan and thyroglobulin testing

can be done to evaluate for tumor recurrence. His doctor is concerned about his suppressed TSH level and is

also worried about taking J.R. off his L-thyroxine because the patient says he “feels incapacitated” while

carrying out these tests. What can you tell his physician about the TSH level and the need to stop L-thyroxine

during these tests?

In patients with thyroid cancers, total thyroidectomy, followed by RAI and Lthyroxine therapy to suppress the TSH to subnormal levels, were associated with

improved overall survival.

247 The actual degree of thyroid suppression required is

complex and depends upon the severity and extent of the thyroid cancer and the

likelihood of a disease-free prognosis. The benefits of prolonged thyrotropin

suppression to prevent cancer recurrence need to be balanced against the risks and

adverse effects (e.g. osteoporosis, cardiac toxicity) of lifelong T4 suppression.

Lifelong TSH suppression to a level of <0.1 microunits/mL is preferred for patients

with high-to-intermediate risk of recurrent cancer or metastastes.

29 A low normal

TSH of 0.3 to 2 microunits/mL can be considered for disease-free patients. It is

important to annually assess recurrence of the malignancy by determining whether

any residual cancerous or normal thyroid tissue remains. This is done either by

withdrawing suppressive T4

therapy and allowing endogenous TSH concentrations to

rise or by administering recombinant human TSH (thyrotropin-α). If any functioning

follicular cells remain, the rise in TSH will cause a rise in thyroglobulin and/or

positive RAIU, indicating a need for further RAI therapy. Thyrotropin-α (Thryogen)

may be preferred because it allows screening without the troublesome hypothyroid

symptoms caused by withdrawal of T4