Pathogenesis of graves disease

A combination of environmental as well as genetic factors contribute to an individuals susceptility to Graves' disease.

The hyperthyroidism of Graves' disease is caused by TSI (thyroid stimulating immunoglobulin), TSI are synthesized in the 

1. Thyroid gland
2. Bone marrow
3. Lymph nodes. 

Other thyroid autoimmune responses are also seen concurrently in patients with Graves' disease. Especially TPO (thyroperoxidase) antibodies occur in up to 80% of Graves disease and serve as a readily measurable marker of autoimmunity.

There is no direct correlation between the level of TSI and thyroid hormone levels in Graves' disease as the coexisting thyroiditis can also affect thyroid function.

Cytokines play major role in thyroid ophthalmopathy. 

There is infiltration of the extraocular muscles by activated T cells,there is  release of cytokines such as IFN-, TNF, and IL-1 which in turn  results in fibroblast activation and increased synthesis of glycosaminoglycans.These glycosaminoglycans trap water, there by leading to characteristic muscle swelling.In the later stages of the disease, there is irreversible fibrosis of the muscles.

Why there is more ocular involvement ?

Orbital fibroblasts may be more sensitive to cytokines, perhaps explaining the ophthalmic localization of the immune response. 

An additional cause of retrobulbar tissue expansion is increased fat deposition.

All these will increase the intraorbital pressure which will lead to proptosis, diplopia, and optic neuropathy.

Drug treatment of Graves'disease

The hyperthyroidism of Graves' disease is treated either by 

1.Reducing the synthesis of thyroid hormone using antithyroid drugs or   

2.Reducing the amount of thyroid tissue with radioiodine (Iodine131) treatment or by thyroidectomy

Antithyroid drugs include

Thionamides such as propylthiouracil, carbimazole and the active metabolite of the carbimazole that is methimazole. 

Effects of these drugs are following

1.Inhibit the function of TPO(thyroperoxidase) 

2.Reduce oxidation and organification of iodide. 

3.These drugs also reduce thyroid antibody levels 

4.They enhance rate of remission. 

Drug dosage

The initial dose of carbimazole or methimazole is usually 10–20 mg given every 8 or 12 h, but after euthyroidism is restored once-daily dosing is possible. 

Propylthiouracil is given at a dose of 100–200 mg every 6–8 h, this drug is given in divided doses are usually throughout the course. 

Lower doses of each drug may suffice in areas of low iodine intake as thyrotoxicosis improves.

Ttitration regimen 

In titration regimen the starting dose of antithyroid drugs can be gradually reduced once euthyroidism is achieved.The titration regimen is often preferred beause of the following

1.To minimize the dose of antithyroid drug 

2.It provides an index of treatment response

Block-replace regimen

Alternatively, high doses may be given combined with levothyroxine supplementation .

The advantage of this regimen is this will avoid drug-induced hypothyroidism. 

Monitoring treatment response

Thyroid function tests and clinical manifestations are reviewed every 3–4 weeks after starting drugs and the dose is titrated based on unbound T4 levels in blood. Most patients do not achieve euthyroidism until 6–8 weeks after initiation of treatment. 

TSH levels often remain suppressed for several months and therefore it do not provide a sensitive index of treatment response

The usual daily maintenance doses of antithyroid drugs in the titration regimen are

2.5mg –10 mg of carbimazole or methimazole

50–100 mg of propylthiouracil

Time taken for remission

Maximum remission rates are achieved by 18–24 months for the titration regimen 

6 months for the block-replace regimen. 

Patients with severe hyperthyroidism and large goiters are most likely to relapse once treatment stops, close follow up is required  in all patients for relapse during the first year after treatment and at least annually thereafter.

The common side effects of antithyroid drugs

Rash, urticaria, fever, and arthralgia (seen in 1–5% of patients).These side effect may resolve spontaneously or after substituting an alternative drug. 

Rare but major side effects include

Hepatitis, an SLE-like syndrome; and,the most important agranulocytosis (seen in <1%).

Antithyroid drug should be stopped and not to be restarted if a patient develops major side effects

Written instructions should be provided regarding the symptoms of possible agranulocytosis (sore throat, fever, mouth ulcers) and the patients should be advised to stop treatment and a complete blood count shoud be checked to confirm that agranulocytosis is not present

Betablockers

Propranolol (20–40 mg every 6 h) or longer-acting beta blockers such as atenolol is given  to control adrenergic symptoms, especially in the early stages of disease.

Beta blockers are especially useful in patients with thyrotoxic periodic paralysis

Anticoagulation should be considered in all patients with atrial fibrillation.Digoxin doses need to be increased in the thyrotoxic state