Basedow’s Disease: Symptoms, Diagnosis, and Treatment

Basedow’s disease, also known as Graves’ disease, is an autoimmune disease caused by the body’s immune system attacking the thyroid gland, leading to increased thyroid hormone production. This condition is most common in young women, but can occur in men and at any age.

1. Clinical Symptoms

Symptoms of Basedow’s disease vary and often depend on the severity of the condition. They include:

1.1 Goiter:

• Goiters are usually large, diffuse, uniform, elastic, and hypervascular (a systolic bruit is often heard over the goiter).

1.2 Eye Disease:

• This is a hallmark of Basedow’s disease, appearing in about 50% of cases, especially prevalent in smokers.

• Basedow’s eye disease is caused by inflammation of the muscles and tissues surrounding the eye, and the fat behind the eye socket, caused by autoantibodies against the TSH receptor.

• Basedow’s eye disease is not related to the severity of thyrotoxicosis.

• Eye disease can occur before, during, or after thyrotoxicosis.

• It can also occur in Hashimoto’s thyroiditis.

Manifestations of Basedow’s eye disease:

• Lid retraction and lack of eyelid synchronicity: Lid retraction causes the eyes to appear wide open, revealing the white of the eye.

• Inflammatory signs: Conjunctival congestion, lacrimation, stinging sensation, photophobia.

• Exophthalmos: Occurs on both sides, usually asymmetrically, and may regress in mild cases. Exophthalmos is measured using a Hertel exophthalmometer.

• Eyelid edema: May mask the actual exophthalmos.

• Restriction of eye movement: Due to the effects on the extraocular muscles, some patients may experience double vision.

• Compression of the optic nerve II: Leading to vision loss, requiring an ophthalmologist consult.

Basedow’s eye disease directly impacts visual prognosis. Cases with poor prognosis:

• Severe exophthalmos that does not improve with treatment.

• Paralysis of one or more extraocular muscles (differentiate from pseudo-paralysis with muscle contraction).

• Ocular compression (increased intraocular pressure).

Essential systemic ophthalmological examination:

• Visual acuity measurement.

• Conjunctival examination.

• Optic disc.

• Extraocular muscles, visual fields.

• Intraocular pressure measurement.

In severe cases, MRI should be performed to assess the degree of exophthalmos, determine muscle hypertrophy, the amount of retrobulbar fat, assess the risk of compression of the optic nerve II, and monitor disease progression (increased signal on MRI).

NOSPECT Classification of Exophthalmos by the American Thyroid Association (ATA):

• Grade 0: None.

• Grade 1: Upper eyelid retraction.

• Grade 2: Conjunctival involvement, lid edema, conjunctival edema, lacrimation, foreign body sensation, photophobia.

• Grade 3: Infiltration of extraocular muscles, causing restriction of upward and lateral gaze (double vision).

• Grade 4: Corneal involvement due to incomplete eyelid closure (corneal clouding, ulceration).

• Grade 5: Vision loss or impairment (optic nerve II involvement).

1.3 Other Manifestations:

• Pretibial myxedema: A characteristic of Basedow’s disease, similar to the eye disease. Firm, rubbery, raised skin lesions, appearing on the front of the shins or ankles.

2. Clinical Diagnosis (CLS)

2.1 Thyrotoxicosis with increased thyroid hormones in plasma:

• T3 (95-190 ng/dl = 1.5 – 2.9 nmol/l): Increased.

• FT3: (0.2-0.52 ng/dl = 3-8 pmol/l): Increased.

• T4: (5-12 µg/dl = 64-154 nmol/l): Increased.

• FT4: (0.9-2 ng/dl = 12-26 pmol/l): Increased.

2.2 T3/T4 ratio greater than 20: Evaluates disease progression.

2.3 Ultra-sensitive TSH (0.5-4.5 µIU/ml): Decreased.

When characteristic eye disease is present, the diagnosis of Basedow’s is almost certain.

For atypical cases, additional CLS may be performed:

• Evaluation of anti-TSH receptor antibodies:

• Autoantibody levels do not have prognostic significance.

• Monitoring autoantibodies during treatment is of no benefit.

• The presence of autoantibodies at the end of treatment is a prognostic factor for relapse; their disappearance does not confirm complete recovery.

• Thyroid ultrasound: Decreased echogenicity, increased tissue proliferation.

• Thyroid scintigraphy: Homogenous, diffuse iodine uptake on both sides. In typical cases (large, diffuse goiter, systolic bruit over the goiter with eye disease), thyroid scintigraphy is not necessary.

3. Clinical Forms

3.1 Typical form: Young women with all of the above clinical signs.

3.2 Symptomatic form: Predominance of symptoms in certain organs:

• Cardiac manifestations: Tachycardia, supraventricular tachycardia, atrial flutter, atrial fibrillation. More common in older patients or those with prior cardiovascular disease.

• Neurological manifestations: Relating to the central nervous system with pyramidal syndrome, including increased tendon reflexes, Babinski (+), recovery after euthyroidism; extrapyramidal manifestations with chorea. Relating to the peripheral nervous system with reduced mobility, especially in the lower limbs.

• Muscle manifestations: Diverse with muscle atrophy, decreased reflexes, thyroid myopathy (Westpall), predominantly seen in men aged 30-50.

• Severe myasthenia gravis and Basedow’s: Incidence of severe myasthenia gravis/Basedow’s is 10-100 times higher than in the general population, usually an incidental finding.

• Thyrotoxic bone disease: Increased urinary calcium and urinary phosphate, normal/slightly increased serum calcium, serum phosphorus, and alkaline phosphatase.

• Gastrointestinal manifestations: Liver damage (15-20%) with jaundice, hepatomegaly, increased enzymes, increased bilirubin.

• Basedow’s and vomiting: Stable after euthyroidism.

• Hematologic manifestations:

• Complete blood count.

• Microcytic anemia, megaloblastic anemia of Biermer.

• Breast enlargement and Basedow’s: Breast enlargement is not a typical sign but may occur.

• Basedow’s and weight gain: Patients eat a lot due to an increased basal metabolic rate.

3.3 Forms related to the cause:

• Co-occurrence with other autoimmune diseases:

• Adrenal insufficiency and Basedow’s.

• Diabetes mellitus and Basedow’s.

3.4 Biological Forms:

• Predominantly increased T3: More common in iodine-deficient regions.

• Predominantly increased T4: Predominantly T4 secretion or inhibition of T4->T3 conversion.

3.5 Forms of Progression:

• Typical form: Returns to euthyroidism after treatment.

• Spontaneous regression form: 10-20%.

• Acute and subacute form:

• Subacute form typically includes signs of significant weight loss, diarrhea, rapid heart rate, fever, and mental symptoms.

• Acute form typically occurs due to treatment errors, especially with poor surgical preparation in patients with thyrotoxicosis.

• Apathetic form: Elderly patients, with the clinical picture dominated by muscle weakness, paralysis, anorexia, dysphagia. Difficult to diagnose.

4. Treatment

4.1 Non-specific Treatment:

• Rest, sedation.

• Beta-blockers (BBs) are used if indicated: Quickly reduce symptoms while awaiting the effects of specific treatment. Propranolol is often chosen for its non-selective effects (reduces tachycardia, tremor), inhibits T4->T3 conversion through inhibition of type 1 deiodinase: 60-160 mg/24h.

• Temporary oral contraceptives in young women.

4.2 Specific Treatment:

• Inhibition of thyroid hormone synthesis:

• Thioureylene derivatives:

• Carbimazole (Neomercazole) 5 mg, 20 mg tablets.

• Methimazole 5 mg, 10 mg, 20 mg tablets, more potent than Carbimazole.

• Thiouracils:

• Propylthiouracile (PTU) 50 mg tablets.

• Benzylthiouracile 25 mg tablets, twice as weak as PTU.

• Main effects of this drug group: Inhibit thyroid hormone synthesis by inhibiting thyroid peroxidase; they do not inhibit the release of hormones already synthesized and stored in the colloid. Therefore, the effects of the drug are only observed after 10-15 days of treatment. In addition, PTU also inhibits type 1 deiodinase and partially inhibits T4 -> T3 conversion.

• Usual dosage: Neomercazole loading dose 30-60 mg or 300-600 PTU (10 times less potent) for 4-6 weeks. -> Gradually reduce the dose and adjust according to clinical and CLS findings. (Combined with T4 therapy “inhibition and replacement,” can be applied to pregnant women (low-dose antithyroid drugs).

• Side effects:

• Skin allergy, varying by drug.

• Increased liver enzymes.

• Leukopenia and especially agranulocytosis (drug-induced agranulocytosis), accounting for only 0.1% of all cases using the drug for treatment.

• Monitoring:

• Evaluate free T4 (T3f in cases of T3-induced thyrotoxicosis) at week 4 (TSH remains low for a long time due to continued inhibition of the hypothalamic-pituitary-thyroid axis). After achieving euthyroidism, evaluate T4 TSH every 3-4 months throughout treatment.

• To detect leukopenia or agranulocytosis, monitor complete blood count every 10 days/2 months at the beginning of antithyroid drug use and test anytime with fever/sore throat.

• Drug-induced agranulocytosis:

• Moderate leukopenia < 1500/mm3 may be simply due to thyrotoxicosis (monitor complete blood count).

• Screen for agranulocytosis with regular complete blood counts in the first 2 months of antithyroid drug use and test anytime with fever/sore throat.

• Granulocytes < 1000/mm3: Stop the drug, monitor.

• Granulocytes < 500/mm3: High risk of opportunistic infection:

• Hospitalization.

• Stop the drug.

• Culture broad-spectrum bacteria from body fluids.

• G-CSF if needed.

• Monitor recovery process.

• Surgery: Total thyroidectomy after achieving euthyroidism with medical treatment. Antithyroid medication is used for 2-3 months before surgery to prevent thyroid storm after surgery. There are various methods: partial thyroidectomy, near-total thyroidectomy, total thyroidectomy.

• Partial thyroidectomy: High recurrence rate, still a risk of hypothyroidism, requires long-term follow-up.

• Near-total thyroidectomy (without involvement of the recurrent laryngeal nerve and parathyroid glands): Recently more widely used due to lower recurrence rates but higher hypothyroidism rates.

• Total thyroidectomy: Permanent hypothyroidism, eliminates risks.

• Post-operative complications: Parathyroid damage, recurrent laryngeal nerve damage. Rate is significantly reduced with trained surgeons.

• Radioactive iodine:

• Purpose: Destroy thyroid tissue/hyperactive thyroid areas with radioactive iodine. Simple treatment (no hospitalization required for low-dose therapy), no evidence of genotoxicity or secondary cancer due to radioactive iodine.

• Methimazole is used for 4-6 weeks and stopped 3 days before radioactive iodine therapy.

• Transient hypothyroidism usually occurs within the first 6 months, treated with Levothyroxine. Check TSH after 2-4 months; if still high, the risk of permanent hypothyroidism.

• SHORT-TERM adverse effects of treatment:

• Temporary worsening of mild-to-moderate eye disease, after a few months. (Short-term corticosteroid treatment).

• Acute thyroiditis due to radiation, with neck pain and swelling occurring 3-4 days after treatment. Self-limiting, (temporary anti-inflammatory treatment).

• Outbreak of thyrotoxicosis after a few weeks due to the release of stored thyroid hormones as tissue is destroyed. -> Thionamide treatment for a few months before and stopped 3-8 days before therapy.

• Time needed to achieve effectiveness after more than 1-2 months, therefore, antithyroid drugs can be used after 2 months of treatment and gradually reduced while awaiting effectiveness.

• Contraindicated in pregnant women (always assess hCG before planned treatment). Effective contraception is required for 6 months after iodine treatment in women of childbearing age.

4.3 Treatment Indications:

• There is no optimal approach for Basedow’s disease because no method addresses the underlying cause. In addition, the choice of method and effectiveness of treatment varies between medical teams and patients.

• After treatment with antithyroid drugs, relapse occurs in 40-60% of cases, especially in the first year.

• Total thyroidectomy surgery leads to permanent hypothyroidism.

• Radioactive iodine treatment also leads to hypothyroidism in more than 50% of cases in the first few years and can worsen eye disease (due to thyroid cell destruction and the release of autoantibodies), although it may be preventable with corticosteroid therapy.

Overall, the approach to treatment in uncomplicated cases is usually as follows:

• Antithyroid medication for 1-2 years: Initial loading dose, then 2 scenarios: either gradually reduce the dose depending on the results of thyroid function tests or maintain the loading dose and combine with thyroxine to avoid drug-induced hypothyroidism.

• Surgery is considered in patients with relapse and a large goiter.

• Radioactive iodine therapy is usually applied to elderly patients or those who relapse after thyroid surgery, however, it is now more widely indicated in all ages unless contraindicated.

Note: Follow-up of patients over the long term is necessary due to the risk of relapse or hypothyroidism, which may occur for many years afterwards.

5. Treatment of Certain Special Situations

5.1 Cardiac thyrotoxicosis:

• Symptomatic treatment:

• Hospitalize elderly patients with unstable general condition.

• Tachycardia – heart failure -> Propranolol. BBs are beneficial in this case, but can increase the risk of thromboembolism, anticoagulation is necessary.

• Avoid cardioversion before achieving euthyroidism (high risk of recurrence).

• If heart failure is present:

• Cardiac support, diuretics, vasodilators may be effective.

• BBs are still a beneficial indication because cardiac output often increases in hyperthyroidism. Monitor drug tolerance and choose the appropriate BB for cardiac function.

• Anticoagulation therapy is used for patients with tachycardia and/or total heart failure.

• Always coordinate with a cardiologist for monitoring and treatment.

• Treatment of thyrotoxicosis:

• High-dose antithyroid medication -> euthyroidism.

• Permanent treatment with surgery or radioactive iodine, depending on the individual case and co-morbidities.

5.2 Thyroid storm:

• Hospitalize in a specialized intensive care unit.

• Life support (pay attention to treatment of hyperthermia, fluid loss prevention).

• High-dose antithyroid medication via intravenous infusion.

• Intravenous propranolol.

• Intravenous corticosteroids, plasmapheresis in some cases.

• High-dose iodine after 24 hours of antithyroid drug use (effective in inhibiting thyroid hormone release by Lugol’s iodine type).

5.3 Basedow’s eye disease:

• Antithyroid medication has no direct effect. Euthyroidism helps improve the progression of eye disease (etiology is not due to thyrotoxicosis).

• Iodine can worsen eye disease.

• Mild cases, basic treatment: Eye drops for protection, sunglasses, elevate the head while sleeping, prisms if there is double vision.

• Malignant eye disease: Specialist follow-up and treatment.

• High-dose corticosteroid therapy (1-2 mg/kg) -> reduce dosage. (Can be applied as a bolus).

• Radiation therapy.

• Orbital decompression surgery.

• Eyelid plastic surgery in cases of prolonged severe inflammation.

5.4 Basedow’s and pregnancy:

• Coordinate with obstetric and endocrine specialists. Consider hyperthyroidism in the mother, fetal hypothyroidism due to medication, and the risk of fetal hyperthyroidism.

• Note that antithyroid drugs cross the placenta and the fetal thyroid is active from week 20.

• Mild cases, follow-up with rest, the disease regresses in the second trimester.

• Severe cases, low-dose antithyroid therapy to maintain normal free T4 levels. In this case, PTU is preferred over Neomercazole because, although both drugs cross the placenta, there is no evidence of birth defects from PTU, while Neomercazole, although rare, has been observed to cause birth defects: scalp aplasia, systemic abnormalities, deep nostrils.

• (Propranolol)

• Severe Basedow’s, surgery if indicated may be started in the second trimester after pre-surgical medical treatment.

• In all cases:

• Mother: Evaluate thyroid hormones every 3 weeks.

• Fetus: Monitor ultrasound screening for fetal hyperthyroidism.

• After birth:

• Mother: Risk of hyperthyroidism relapse.

• Fetus: Risk of early thyrotoxicosis, hypothyroidism due to antithyroid medication.

• Breast milk is considered safe for the baby because antithyroid drugs only pass into breast milk at low levels that are not significant. (PTU in breast milk is lower than Neomercazole).

Differential diagnosis:

• Transient thyrotoxicosis of pregnancy:

• Common context: Accounts for 2% of pregnancies, due to the stimulation of TSH receptors by hCG hormone. Appears in the first trimester of pregnancy.

• Restlessness, anxiety.

• Tachycardia.

• No normal weight gain.

• Severe cases may have + vomiting (rare), spontaneous regression in the second trimester.

• Thyrotoxicosis of pregnancy is often undetected. Some rare cases with clinical manifestations of thyrotoxicosis require treatment, distinguishing Basedow’s disease (no autoantibodies against the TSH receptor).

• Treatment: Rest, quiet. BBs for symptomatic treatment while awaiting spontaneous regression of the thyrotoxicosis condition.

Note:

• This article provides general information about Basedow’s disease, and does not substitute for diagnosis and treatment by a specialist.

• Consult a doctor for appropriate advice and treatment.

Additional information to note:

• Regular health check-ups: Women of childbearing age, especially those with a family history of Basedow’s disease, should have regular health check-ups to detect the disease early.

• Control risk factors: Smoking can worsen Basedow’s eye disease. Limit or quit smoking.

• Treatment of co-morbidities: Basedow’s disease can co-occur with other conditions such as cardiovascular disease, diabetes mellitus, so treat co-morbidities effectively to improve the effectiveness of Basedow’s disease treatment.

• Careful follow-up: After treatment for Basedow’s disease, patients should be carefully monitored to detect early signs of relapse or complications.