Graves' disease

Graves' Disease

I. What every physician needs to know.

Graves’ disease is an autoimmune disorder caused by stimulating antibodies to the thyroid stimulating hormone (TSH) receptor on thyroid follicular cells. It is the most common cause of hyperthyroidism with 20-30 cases per 100,000 individuals each year. It affects women more than men with peak incidence in patients age 30-60 years. Recent studies suggest increased incidence among young African-Americans.

Patients present with hyperthyroidism, diffuse goiter and often exophthalmos. The thyroid-stimulating hormone (TSH) is suppressed with elevated T4 and T3. Graves’ can be confirmed by diffuse uptake and a radioiodine uptake scan.

II. Diagnostic Confirmation: Are you sure your patient has Graves' disease?

Graves’ disease can be confused with other disorders causing hyperthyroidism, but it is the most common cause. The diagnosis can be established on clinical features such as diffusely enlarged thyroid, exophthalmos, elevated T4 and T3 levels, and undetectable TSH. If the diagnosis is uncertain, TSH-receptor antibody (TRab) levels can be measured. In addition, radioactive iodine uptake (RAI) or thyroid ultrasound with Doppler can confirm the diagnosis of Graves’ disease.

Graves’ disease can be differentiated on the basis of a diffusely enlarged thyroid, exophthalmos and diffuse uptake on radioiodine uptake assay.

A. History Part I: Pattern Recognition:

Graves’ disease commonly presents in a 40-year-old African American woman who presents with general symptoms of hyperthyroidism, a diffusely enlarged thyroid, and exophthalmos. Much less commonly, she might also have a rash on her anterior shins, known as Graves’ dermopathy.

B. History Part 2: Prevalence:

Graves’ disease affects 0.5% of the population with female to male predominance of 8 to 1. Graves’ disease accounts for 50 to 80% of causes of hyperthyroidism.

C. History Part 3: Competing diagnoses that can mimic Grave's disease.

Other diagnoses that should be considered in a patient with thyrotoxicosis include the following:

Toxic multinodular goiter
Solitary toxic nodule
Thyroiditis (painless, subacute de Quervain, or drug-induced)
Struma ovarii
Molar pregnancy

D. Physical Examination Findings.

The common presenting exam findings are as follow:

Hyperthyroidism – (see general topic) including fatigue, weight loss, tachycardia (or tachyarrhythmia), tremor, irritability, heat/cold intolerance.

Tachycardia (80% prevalence)

Increased pulse pressure

Diffusely palpable goiter with audible bruit

Exophthalmos – proptosis, periorbital edema, eyelid retraction

Clubbing known as thyroid acropachy in Graves’

Graves’ dermopathy which is a thickening of the skin often on the anterior shins, also known as pretibial myxedema.

Note that some elderly patients may present less classically with depression and weight loss. This clinical presentation is called “apathetic” hypothyroidism”.

E. What diagnostic tests should be performed?

The diagnosis of Graves’ disease is suspected by an appropriate clinical history and examination. It can be confirmed with thyroid function studies and when necessary a radioactive iodine uptake study.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Thyroid stimulating hormone – suppressed or low
T4 – elevated
T3 – elevated (usually to greater degree than T4; 10% of Graves’ cases have isolated elevation of T3)

Thyroid receptor antibodies can be ordered to confirm the diagnosis, but their availability varies by site, and the results may not be available in a meaningful time to contribute to the patient’s care.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Radio-iodine uptake scan (RAIU) shows diffuse uptake in the thyroid gland. The study is most important when the diagnosis of thyroiditis is higher on the differential diagnoses due to an irregularly enlarged thyroid gland on exam.
A thyroid ultrasound can suggest Graves’ disease, but is not nearly as useful as the RAIU. It can be useful if a non-functioning nodule is found on the RAIU or can be palpated on exam.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

A thyroid ultrasound is a second-line test, unless there is an irregular enlargement of the thyroid gland or there is a probable thyroid nodule.
Thyroid receptor antibodies can be confirmatory of the diagnosis of Graves’, but are not routinely required.

III. Default Management.

The goals in immediate management are to recognize the clinical severity of the hyperthyroidism with attention to patient comorbidities that may impair their ability to tolerate the hyperthyroidism. In general, hyperthyroidism due to Graves’ disease is treated with one of the following approaches: (i) use of anti-thyroid drugs to normalize thyroid hormone production, (ii) destruction of the thyroid using radioactive iodine (RAI), or (iii) surgical removal of the thyroid. These will be discussed in detail later.

For most patients, beta-blocker should be initiated to blunt the symptoms of hyperthyroidism. Propranolol or atenolol are often used, but no beta-blocker has been proven to be superior.

The rare patient may present with such severe hyperthyroidism that it is referred to as thyroid storm. The Burch and Wartofsky score can be used to determine the pre-test probability of a patient having thyroid storm. It is important to recognize this as patients with thyroid storm have a significant increase in the risk of mortality and must be managed aggressively in the intensive care unit setting. The discussion of thyroid storm can be found in the general section on hyperthyroidism.

A. Immediate management.

As mentioned in the default management section, the key to the management of Graves’ disease is to recognize the clinical severity of the hyperthyroidism. Most patients will initially require a beta-blocker to blunt the symptoms from hyperthyroidism. Beta-blocking agents relieve many symptoms, especially palpitations, tremulousness, anxiety, and heat sensitivity.

Although some β-blockers including propranolol, atenolol, and metoprolol can decrease conversion of T4 to T3, this is only at high doses. Typical starting doses of propranolol range from 40-160 mg per day; both atenolol and metoprolol are effective treatments and higher doses may be required because drug clearance is increased in hyperthyroidism.

Special attention should be given to patients with asthma, heart failure with reduced ejection fraction, bradyarrhythmias, and Raynaud phenomenon. In these patients, calcium-channel blockers are an alternative therapy for heart rate control. In patients who are acutely ill, intravenous use of Esmolol is recommended because of rapid onset and short duration of therapy.

B. Physical Examination Tips to Guide Management.

The primary physical findings to track by physical examination in a patient with Graves’ disease are those of hyperthyroidism – primarily cardiovascular findings like tachycardia or tachyarrhythmia. It is also important to observe the degree of exophthalmos seen on exam that may necessitate an evaluation by an ophthalmologist.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Free T4, T3 and TSH are the main tests to monitor. The FT4 and T3 should decrease more quickly than the TSH begins to rise.

D. Long-term management.

Patients in the US are most commonly treated with radio ablation with or without pre-ablation anti-thyroid medications – based on the severity of their hyperthyroid symptoms and the patient’s underlying ability to tolerate the hyperthyroidism.

The two most common therapies for antithyroid medications are methimazole and propylthiouracil (PTU), which inhibit thyroid hormone synthesis by interfering with thyroid peroxidase (TPO). PTU also inhibits peripheral conversion of T4 to T3.

Methimazole is the anti-thyroid medication of choice for most patients. PTU is not used as primary treatment because of hepatotoxicity, but is indicated for patients intolerant to methimazole, first trimester of pregnancy (see below), and patients with thyroid storm.

Antithyroid medications can be primary treatment (12-18 months) and they can also be used as pre-treatment in selected patients prior to RAI therapy and in patients prior to surgery. The usual starting dose is 10-30 mg depending on severity of symptoms; it is a single daily dose. In severe hyperthyroidism a split dose may be effective initially.

Thyroid function tests are performed at 2-6 weeks after drug initiation for improvement. Testing serum free T4 and T3 or free T3 should be monitored. Testing for TSH is not usually helpful in the first 1-2 months because levels can be suppressed due to antecedent hyperthyroidism. Once euthyroid, patients should be evaluated every 3 months for the next 12-18 months with adjustment of drug to maintain a euthyroid state.

In patients in whom TRAb levels have normalized, the relapse rates are 20-30% over 3-5 years of follow-up. In patients who relapse, definitive treatment with RAI or surgery should be considered, though long-term medical therapy may be an option.

Radioactive Iodine therapy

With this approach, radioactive iodine is incorporated into thyroid hormone, releasing beta particles that cause ionizing radiation damage to thyroid follicular cells resulting in gradual destruction of the gland. The goal of RAI therapy is to render the patient hypothyroid. This develops most commonly 2-3 months after a single administration of RAI. Pre-treatment with antithyroid drugs prior to RAI is not required generally. Due to transient worsening of thyrotoxicosis, older patients or those having co-morbidities, such as coronary artery disease, may benefit from pre-treatment. If pre-treatment is done, antithyroid drugs should be stopped 2-3 days prior to RAI and then restarted 3-5 days later to permit RAI incorporation into the thyroid hormone. RAI is contraindicated in pregnant or breastfeeding women.

There is some caution to using RAIU in patients with Graves’ orbitopathy. A meta-analysis in 2008 showed that RAI therapy is associated with new or worsened exophthalmos compared to antithyroid drug or surgery. Corticosteroids at the time of RAI may help to prevent this. Some guidelines recommend prophylactic corticosteroids in patients with mild Graves’ orbitopathy and risk factors (e.g., tobacco smoking) and moderate Graves’ orbitopathy (proptosis >3 mm above upper limit of normal and periorbital soft tissue inflammation) and avoidance of RAIU in patients with active or moderate to severe vision-threatening orbitopathy. With regards to risk of cancer and use of RAI, a recent large cohort showed there was no increase in cancer death compared to background levels.

Following RAI, thyroid function tests should be done at 2-6 week intervals. Patients should be started on levothyroxine immediately if T4 levels fall below normal.

Surgery

Surgery can be used for patients with Graves’ but is reserved for patients who have a very large scale goiter, respiratory distress from the goiter, or cannot tolerate anti-thyroid medications or radio ablation for some reason. Surgery does provide expedient and definitive treatment of the Graves’ disease with the lowest relapse rate. Patients undergoing surgery are usually prepared with antithyroid therapy for 1-3 months until they are euthyroid. A recent Cochrane systematic review shows that total thyroidectomy is more effective than subtotal thyroidectomy at preventing recurrent hyperthyroidism in Graves’ disease though with an increased risk of hypoparathyroidism.

E. Pregnancy and Graves’ disease

Graves’ disease affects 1-2 per 1000 pregnancies. Untreated overt hyperthyroidism is associated with pre-eclampsia, heart failure, premature delivery, and fetal death. Because of risks of severe birth defects with methimazole in the first trimester it is recommended patients be switched to PTU for the first trimester. TRab should be measured in the third trimester as a predictor of neonatal Graves’ disease and monitored in the post-partum period.

F. Common Pitfalls and Side-Effects of Management

The side effects of antithyroid drugs include the following:

Minor effects: pruritic rash and arthralgias in about 1-5% of patients typically within the first few weeks of initiating therapy. Patients with unresolved or severe symptoms can be switched to PTU but 30-50% have a similar reaction with this medication.

Agranulocytosis: This occurs in 1/500 patients and is dose-elated and develops within the first 90 days of drug initiation. The typical presentation is high fever and severe pharyngitis. Because leukopenia can be a manifestation of Graves’ disease, a white blood cell count and differential should be performed prior to antithyroid drug therapy. Caution with therapy if the count is below 1.5×10⁹/L.

Hepatotoxicity: Methimazole-induced hepatotoxicity is usually cholestatic whereas PTU has been associated with hepatocellular necrosis. The incidence is less than 0.1% and occurs within the first few days to 3 months of starting therapy. Routine monitoring of liver function is not known to limit severity of hepatotoxicity but is routinely done by endocrinologists. Antithyroid drugs should be avoided in patients with pre-existing liver function abnormalities specifically if transaminases are 3-5 times the upper limit of normal.

ANCA vasculitis: Occurs much more with PTU than methimazole and can occur months to years after therapy. The typical presentation is polyarthritis, fever, and purpura and treatment is to stop the drug and possible use of glucocorticoids or other immunotherapies.

IV. Management with Co-Morbidities

N/A

A. Renal Insufficiency.

No change in standard management.

B. Liver Insufficiency.

Caution should be used in giving antithyroid drugs to patients with known liver insufficiency as they are hepatotoxic to begin with (see above in adverse effects section). Patients with transaminases 3-5 times the upper limit of normal should not receive antithyroid drugs. Liver enzymes can be followed during treatment but the incidence of hepatotoxicity is very low (<0.1%).

C. Systolic and Diastolic Heart Failure

Patients with heart failure (HF) syndrome will have less capacity to tolerate hyperthyroidism, so they will need timely correction of their symptoms with the beta-blocker and often anti-thyroid medications and diuresis. Caution should be used with beta blockers in acutely decompensated heart failure.

D. Coronary Artery Disease or Peripheral Vascular Disease

Hyperthyroidism can worsen ischemic symptoms and precipitate angina or even a myocardial infarction. These patients need timely correction of their symptoms with the beta-blocker and often anti-thyroid medications.

E. Diabetes or other Endocrine issues

No change in standard management. If the patient has known adrenal insufficiency the patient would need stress dose steroids. Patients with diabetes mellitus may have hyperglycemia that is difficult to control. Patients with diabetes may also rarely have hypoglycemia during Graves’ disease.

F. Malignancy

Patients living with malignancies may have a concomitant reduction in their functional status from their malignancy that may make them less able to tolerate the symptoms of hyperthyroidism. This may necessitate more timely correction of their symptoms with the beta-blocker and anti-thyroid medications. No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc).

Would use caution with antithyroid medications (which can cause agranulocytosis) as patients with HIV/AIDS often have baseline leukopenia.

Patients on chronic steroids may have relative adrenal insufficiency requiring stress dose steroids for severe hyperthyroidism or thyroid storm.

H. Primary Lung Disease (COPD, Asthma, ILD)

No change in standard management.

I. Gastrointestinal or Nutrition Issues

In a recent meta-analysis there was an association between low vitamin D levels and risk of Graves’ disease though there was significant heterogeneity. Otherwise, no change in standard management is required.

J. Hematologic or Coagulation Issues

Would likely avoid antithyroid medications (which can cause agranulocytosis), choosing radioablation or surgery for patients with pre-existing leukopenia.

K. Dementia or Psychiatric Illness/Treatment

Men present with more subtle signs of hyperthyroidism, so called “apathetic thyrotoxicosis”. Elderly patients may not tolerate the cardiovascular consequences of hyperthyroidism. It is important to consider that symptoms such as depression, mania, and psychosis may be presentations of hyperthyroidism and Graves’ disease in younger patients. Atypical antipsychotics such as olanzapine can be helpful in patients whose psychiatric symptoms are severe. Some psychiatric medications can worsen the physiologic effects of hyperthyroidism.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

Most patients with Graves’ can be managed as outpatients. In the event a patient is admitted for severe hyperthyroidism resulting in heart failure or an acute coronary syndrome (ACS), communication about the thyroid’s precipitating role in this may be beneficial.

B. Anticipated Length of Stay.

Most patients with Graves’ can be managed as outpatients. If patients are admitted it is usually for the cardiovascular complications – HF exacerbation or ACS – which can be managed as usual, with an eye to correcting the hyperthyroidism with antithyroid medications as soon as possible.

C. When is the Patient Ready for Discharge

D. Arranging for Clinic Follow-up

Most patients with Graves’ are diagnosed by a generalist, but may benefit from seeing an endocrinologist, especially if they have more severe signs of hyperthyroidism. Follow-up is generally every 4-6 weeks for monitoring of the T4 and T3, but an earlier initial appointment may be prudent.

In the event of clinically significant Graves’ orbitopathy, referral to an ophthalmologist may also be warranted.

1. When should clinic follow up be arranged and with whom.

Most patients with Graves’ are diagnosed by a generalist, but may benefit from seeing an endocrinologist, especially if they have more severe signs of hyperthyroidism. Follow-up is generally every 4-6 weeks for monitoring of the Free T4 and T3, but an earlier initial appointment may be prudent.

In the event of clinically significant Graves’ orbitopathy referral to an ophthalmologist may also be warranted.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

No additional labs needed other than a free T4, T3 or TSH that was ordered at diagnosis.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

Free T4, T3 or TSH are monitored every 4-6 weeks while on antithyroid medication or after an ablation (see long-term treatment section).

E. Placement Considerations.

None.

F. Prognosis and Patient Counseling.

Patients with Graves’ disease generally do well. In the rare case of thyroid storm there can be mortality rates as high as 20-50%, likely a factor of other comorbidities present and worsened by the hyperthyroidism.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

Not applicable.

What's the Evidence?

Burch, H, Cooper, DS. Management of Graves Disease: A Review. vol. 314. 2015. pp. 2544-2554.

Sundaresh, V, Brito, JP, Wang, Z, Prokop, LJ. “Comparative effectiveness of therapies for Graves’ hyperthyroidism: A systematic review and network meta-analysis”. J Clin Endocrinol Metab. vol. 98. 2013. pp. 3671-3677.

Ren, Z, Quin, L, Want, JQ, Zhang, R-G. “Comparative efficacy of four treatments in patients with Graves’ Disease: A network meta-analysis”. Exp Clin Endocrinol Diabetes. vol. 123. 2015. pp. 317-322.

Xu, M-Y, Cao, B, Yi, J, Wang, D-F. “Vitamin D and Graves’ Disease: A meta-analysis update”. Nutrients. vol. 7. 2015. pp. 3813-3827.

Klein, I, Danzi, S. “Thyroid Disease and the Heart”. Circulation. vol. 116. 2007. pp. 1725-1735.

Hazen, E, Sherry, NA, Parangi, S, Rabito, CA, Sadow, PM. “Case 10-2015: A 15-year-old girl with Graves’ Disease and psychotic symptoms”. NEJM. vol. 372. 2015. pp. 1250-1258.

Brent, GA. “Clinical practice. Graves’ disease”. The New England journal of medicine. vol. 358. 2008. pp. 2594-605.

Ginsberg, J. “Diagnosis and management of Graves’ disease”. Canadian Medical Association journal = journal de l’Association medicale canadienne. vol. 168. 2003. pp. 575-85.

Bahn, RS, Burch, HB, Cooper, DS, Garber, JR. “Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists”. Thyroid. vol. 21. 2011 Jun. pp. 593-646.

Bahn, RS. “Graves’ ophthalmopathy”. The New England journal of medicine. vol. 362. 2010. pp. 726-38.

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