Hyperthyroidism is a form of thyrotoxicosis due to inappropriately high synthesis and secretion of thyroid hormone(s) by the thyroid. The most common causes of hyperthyroidism include Graves’ disease (GD), toxic multinodular goiter (TMNG), and toxic adenoma (TA). Several varieties of thyroiditis can present with thyrotoxicosis, including postpartum thyroiditis, painless thyroiditis, drug-induced thyroiditis, subacute thyroiditis, traumatic thyroiditis, and acute thyroiditis.
GD is an autoimmune disorder in which thyrotropin receptor antibodies (TRAbs) stimulate the TSH receptor, increasing thyroid hormone production. TMNG is disease status in which there is excess production of thyroid hormones from functionally autonomous thyroid nodules, which do not require stimulation from thyroid stimulating hormone (TSH). In TAs, autonomous hormone production can be caused by somatic activating mutation of genes regulating thyroid hormone systhesis.
A thyroid adenoma (TA) is distinguished from a multinodular goiter (TMNG) of the thyroid in that an adenoma is typically solitary, and is a neoplasm resulting from a genetic mutation(or other genetic abnormality) in a single precursor cell.
Table 1 Causes of Thyrotoxicosis
Before initiating therapy, the disease should be evaluated including assessment of disease severity, biochemical evaluation, and the etiology of hyperthyroidism should be determined.
The assessment of disease severity comprises of thyrotoxic manifestations, cardiovascular complications, and neuromuscular complications. Goiter size, obstructive symptoms, and the severity of Graves’ ophthalmopathy (GO; the inflammatory disease that develops in the orbit in association with autoimmune thyroid disorders).
Serum TSH, free T4 and total T3 should be used for biochemical evaluation. Serum TSH should be used as an initial screening test. The relationship between free T4 and TSH (when the pituitary-thyroid axis is intact) is an inverse log-linear relationship;therefore, small changes in free T4 result in large changes in serum TSH concentrations.
In overt hyperthyroidism, usually both serum free T4 and T3 estimates are elevated, and serum TSH is undetectable. However, in milder hyperthyroidism, serum T4 and free T4 estimates can be normal, only serum T3 may be elevated, and serum TSH will be <0.01 mU/L (or undectable). These laboratory findings have been called “T3-toxicosis” and may represent the earliest stages of disease or that caused by an autonomously functioning thyroid nodule.
Subclincial hyperthyroidism is defined as a normal serum free T4 estimate and normal total T3 or free T3 estimate, with subnormal srum TSH concentration.
In the absence of a TSH-producing pituitary adenoma or thyroid hormone resistance, if the serum TSH is normal, the patient is almost never hyperthyroid. Euthyroid hyperthyroxinemia has been used to describe a disease status that total serum T4 level is elevated (and usually elevated total serum T3 level) in the absence of hyperthyroidism. Euthyroid hyperthyroxinemia usually is caused by thyroid hormone-binding protein disorders, or some specific drugs.
When free thyroid hormone concentrations are elevated and TSH is normal or elevated, further evaluation is necessary. After excluding euthyroid hyperthyroxinemia, TSH-producing pituitary adenoma or thyroid hormone resistance caused by genetic mutation may be the reason.
To determination the etiology of hyperthyroidism, a radioactive iodine uptake should be performed when the clinical presentation of thyrotoxicosis is not diagnostic of GD, a thyroid scan should be added in the presence of thyroid nodularity.
Thyroid hormone influences almost every tissue and organ system in the body. It increases tissue thermogenesis and basal metabolic rate (BMR) and reduces serum cholesterol levels and systemic vascular resistance. Some of the most profound effects of increased thyroid hormone levels are on the cardiovascular system.
The signs and symptoms of overt and mild, or subclinical thyrotoxicosis are similar, but differ in magnitude. Overt thyrotoxicosis, whether endogenous or exogenous, is characterized by excess thyroid hormones in serum and suppressed TSH (<0.01 mU/L). There are also measureable changes in basal metabolic rate, cardiovascular hemodynamics, and psychiatric and neuropsychological function. Symptoms and signs that result from increased adrenergic stimulation inculde tachycardia and anxiety.
Beta-adrenergic blockade should be given to elderly patients with symptomatic thyrotoxicosis and to other thyrotoxic patients with resting heart rates in excess of 90 bpm or coexistent cardiovascular disease.
Thyroid Storm Management
Life-threatening thyrotoxicosis or thyroid storm is a rare, occasionally iatrogenic disorder characterized by multisystem involvement and a high mortality rate if not immediately recognized and treated aggressively. Precise criteria for thyroid storm have been defined and include tachycardia, arrhythmias, congestive heart failure, hypotension, hyperpyrexia, agitation, delirium, psychosis, stupor and coma, as well as nausea, vomiting, diarrhea, and hepatic failure.
Table 2 Point Scale for the Diagnosis of Thyroid Storm
Precipitants of thyroid storm in a patient with previously compensated thyrotoxicosis include abrupt cessation of antithyroid drugs, thyroid or nonthyroidal surgery in a patient with unrecognized or inadequately treated thyrotoxicosis, and a number of acute illnesses unrelated to thyroid disease. Thyroid storm also occurs rarely following radioactive iodine therapy.
Each pharmacologically accessible step in thyroid hormone production and action is targeted in the treatment of patients with thyroid storm, which includes beta-adrenergic blockade, antithyroid drug therapy, inorganic iodide, corticosteroid therapy, aggressive cooling with acetaminophen and cooling blankets, volume resuscitation, respiratory support and monitoring in an intensive care unit.
Management of Hyperthyroidism due to GD
There are three approaches to management hyperthyroidism due to GD. They are 131I therapy, antithyroid drugs (ATD) therapy, and thyroidectomy. Each approach has it benefits and disadvantages. In this post we discuss the antithyroid drugs approach.
Factors that favor antithyroid drug thearpy include patients with high likelihood of remission (patients, especially females, with mild disease, small goiters, and negative or low-titer TRAb);the elderly or others with comorbidities increasing surgical risk or with limited life expectancy;individuals in nursing homes or other facilities who may have limited longevity and are unable to follow radiation safety regulations;patients with previously operated or irradiated necks;patients with lack of access to a high-volume thyroid surgeon;and patients with moderate to severe active GO (Graves’ ophthalmopathy).
But if patients have definite contraindications to long-term ATD thearpy including previous known major adverse reactions to ATDs, this approach should be avoided. A baseline absolute neutrophil count <500/mm3 (0.5 ×109/L) or liver transaminase enzyme levels elevated more than fivefold the upper limit of normal are contraindications to initiating ATD therapy. With this approach, the possibility of disease recurrence exists and patients need continued monitoring. Although the possibility of remission is high, there might be the possibility of un-remission with this approach.
The goal of ATD therapy is to render the patient euthyroid as quickly and safely as possible. These medications do not cure Graves’ hyperthyroidism but if given in adequate doses, they are very effective in controlling the hyperthyroidism;when they fail to achieve euthyroidism the usual cause is nonadherence. The treatment might have a beneficial immunosuppressive role, but the major effect is to reduce the production of thyroid hormones and maintain a euthyroid state while awaiting a spontaneous remission.
Before initiating ATD therapy, baseline blood test including CBC, liver funtion, thyroid biochemical evaluation etc should be considered to aid in the interpretation of future laboratory values. Why? Because low white cell counts are common in patients with autoimmune diseases and abnormal liver enzymes are frequently seen in patients with thyrotoxicosis, and ATDs can cause agranulocytosis and hepatotoxicity, to distinguish whether these phenomenons is due to ATDs or the disease itself, baseline blood test is useful. In addition, a baseline blood test is useful to determined whether ATD therapy is contraindicated.
In China, there are only two antithyroid drugs, methimazole (MMI) and propylthiouracil (PTU). MMI should be used in virtually every patient who choose antithyroid drug theapy for GD, except during the first trimester of pregnancy when PTU is preferred, in the treatment of thyroid storm, and in patients with minor reaction to MMI who refuse radioactive iodine therapy or surgery. However, the pregnancy category of both MMI and PTU are D and MMI is able to cross the blood-placenta barrier.
At the start of MMI therapy, higher initial doses are advised, usually 10-20 mg daily, to restore euthyroidism, following which the dose can be titrated to maintenance level (generally 5-10 mg daily). The ATA and AACE guideline recommended once daily administration of MMI, however the latest FDA label of MMI recommend higher initial doses and to divide the total drug dosage into three doses at 8-hour intervals. PTU should be started with 50-150 mg three times daily, depending on the severity of the hyperthyroidism.
There is a need for periodic clinical and biochemical evaluation of thyroid status in patients taking ATDs, if needed blood tests such as CBC and liver function should be monitored. An assessment of serum free T4 should be obtained about 4 weeks after initiation of thearpy, and the dose of medication adjusted accordingly. Serum T3 also may be monitored, since the estimated serum free T4 levels may normalize with persistent elevation of serum T3 (See “T3-toxicosis” aforementioned). Appropriate monitoring intervals are every 4-8 weeks until euthyroid levels are achieved with the minimal dose of medication. Once the patient is euthyroid, biochemical testing and clinical evaluation can be undertaken at intervals of 2-3 months.
Serum TSH may remain suppressed for several months after starting therapy and is therefore not a good parameter to monitor therapy early in the course. This may be confounded with subclinical hyperthyroidism, which the level of T3 and T4 are normal but serum TSH is suppressed or subnormal.
A differential white blood cell count should be obtained during febrile illness and at the onset of pharyngitis in all patients taking ATDs. Routine monitoring of white blood counts is not recommended. I had met a case of severe agranulocytosis, in which the patient had both febrile and pharyngitis. Routine monitoring of white blood cell counts is not likely to identify cases, as the frequency is quite low (0.2%-0.5%) and the condition sudden in onset. Because patients are typically symptomatic, measuring white blood cell counts during febrile illness and at the onset of pharyngitis has been the standard approach to monitoring. If patients develop agranulocytosis due to ATDs, the ATD therapy is contraindicated.
Liver functnion and hepatocellular integrity should be assessed in patients taking PTU who experience pruritic rash, jaundice, light-colored stool or dark urine, joint pain, abdominal pain or bloating, anorexia, nausea, or fatigue. Hyperthyroidism can itself cause mildly abnormal liver function tests, and PTU may cause transient elevations of serum transaminases in up to one-third of patients. Significant elevations to threefold above the upper limit of normal are seen in up to 4% of patients taking PTU.
In patients with improving thyrotoxicosis, a rising alkaline phosphatase with normalization of other liver function does not indicate worsening hepatic toxicity. The onset of PTU-induced hepatotoxicity may be acute, difficult to appreciate clinically, and rapidly progressive. If not recognized, it can lead to liver failure and death. Routine monitoring of liver function in all patients taking ATDs has not been found to prevent severe hepatotoxicity. PTU should be discontinued if transaminase levels (either elevated at onset of therapy, found incidentally or measured as clinically indicated) reach 2-3 times the upper limit of normal and fail to improve within 1 week with repeat testing. After discontinuing the drug, liver function tests should be monitored weekly until there is evidence of resolution.
When ATDs are discontinued, thyroid function testing should continude to be monitored at 1-3 month intervals for 6-12 months to diagnose relapse early.
Duration of antithyroid drug therapy for GD
If MMI is chosen as the primary therapy for GD, the medication should be continued for approximately 12-18 months, then tapered or discontinued if the TSH is normal at that time. A patient is considered to be in remission if they have had a normal serum TSH, FT4, and T3 for 1 year after discontinuation of ATD therapy. Pay attention that a meta-analysis shows the remission rate in adults is not improved by a course of ATDs longer than 18 months.
Measurement of TRAb levels prior to stopping ATD therapy is suggested, as it aids in predicting which patients can be weaned from the medication, with normal levels indicating greater chance for remission. Persistently high levels of TRAb and high thyroid blood flow identified by color Doppler ultrasound are also associated with higher relapse rates, and these patients should be assessed more frequently and at shorter intervals after ATDs are discontinued.
If a patient with GD becomes hyperthyroid after completing a course of methimazole, consideration should be given to treatment with radioactive iodine or thyroidectomy. However, low-dose of methimazole treatment for longer than 12-18 months may be considered in patients not in remission who prefer the ATD approach.