Hashimoto Thyroiditis

Etiology

The etiology of Hashimoto disease is very poorly understood. Most patients develop antibodies to a variety of thyroid antigens, the most common of which is anti-thyroid peroxidase (anti-TPO). Many also form antithyroglobulin (anti-Tg) and TSH receptor-blocking antibodies (TBII). These antibodies attack the thyroid tissue, eventually leading to inadequate production of thyroid hormone. There is a small subset of the population, no more than 10% to 15%, with clinically evident disease that are serum antibody-negative. Positive TPO antibodies presage the clinical syndrome.[3][4]

It can be part of the Polyglandular Autoimmune Syndrome type 2 with autoimmune adrenal deficiency and type-1 DM.[5] Hashimoto thyroiditis is also related to several other autoimmune diseases, such as pernicious anemia, adrenal insufficiency, and celiac disease.

Ruggeri et al. found that Hashimoto disease is associated with a variety of different nonthyroidal autoimmune diseases (NTADs), and diagnosis in adulthood made these even more prevalent.[6]

Epidemiology

After age six, Hashimoto is the most common cause of hypothyroidism in the United States and in those areas of the world where iodine intake is adequate. The incidence is estimated to be 0.8 per 1000 per year in men and 3.5 per 1000 per year in women. Twin studies have shown an increased concordance of autoimmune thyroiditis in monozygotic twins as compared with dizygotic twins. Danish studies have demonstrated concordance rates of 55% in monozygotic twins, compared with only 3% in dizygotic twins.[7] This data suggests that 79% of predisposition is due to genetic factors, allotting 21% for environmental and sex hormone influences. The prevalence of thyroid disease, in general, increases with age.

Pathophysiology

The development of Hashimoto disease is thought to be of autoimmune origin, with lymphocyte infiltration and fibrosis as typical features. The current diagnosis is based on clinical symptoms correlating with laboratory results of elevated TSH with normal to low thyroxine levels. It is interesting to note, however, that there is little evidence demonstrating the role of antithyroid peroxidase (anti-TPO) antibody in the pathogenesis of autoimmune thyroid disease (AITD). Anti-TPO antibodies can fix complement and, in vitro, have been shown to bind and kill thyrocytes. However, to date, there has been no correlation noted in human studies between the severity of disease and the level of anti-TPO antibody concentration in serum. We do, however, know that positive serum anti-TPO antibody concentration is correlated with the active phase of the disease.[8] Other theories implicated immune complexes, containing thyroid directed antibodies, as culprits of thyroid destruction.

Histopathology

On pathologic examination, there is a diffuse, symmetric enlargement of the thyroid. The capsule is often intact with a prominent pyramidal lobe. When cut, the surface is similar to that of lymph nodes, with a pale brown to yellow color. Interlobular fibrosis may or may not be present. Atrophy may also occur, and in some patients, the gland may become nodular or asymmetric. However, necrosis or calcification does not occur and would suggest a different diagnosis.

History and Physical

The organ system manifestations of Hashimoto thyroiditis are varied due to the nature of the disease. Initially, patients may have bouts of hyperthyroid symptoms, as the initial destruction of thyroid cells may lead to the increased release of thyroid hormone into the bloodstream. Eventually, when enough destruction has been caused by the antibody response, patients exhibit symptoms of hypothyroidism. These symptoms are insidious and variable and may affect almost any organ system in the body.

The classic skin characteristic associated with hypothyroidism is myxedema, which refers to the edema-like skin condition caused by increased glycosaminoglycan deposition. This, however, is uncommon and only occurs in severe cases. Skin can be scaly and dry, especially on the extensor surfaces, palms, and soles. Histologic examination reveals epidermal thinning. Increased dermal mucopolysaccharides cause water retention and, in turn, pale-colored skin.

The rate of hair growth slows, and hair can be dry, coarse, dull, and brittle. Diffuse or partial alopecia is not uncommon.

Decreased thyroid function can increase peripheral vascular resistance by as much as 50% to 60% and reduce cardiac output by as much as 30% to 50%. Bradycardia may result from a loss of chronotropic action of thyroid hormone directly on the sinoatrial cells. However, most patients have a few symptoms directly attributable to the cardiovascular system.

Fatigue, exertional dyspnea, and exercise intolerance are likely associated with a combination of limited pulmonary and cardiac reserve in addition to decreased muscle strength or increased muscle fatigue. Hypothyroid rats have been shown to have decreased endurance. Biochemical changes in this population have shown decreased muscle oxidation of pyruvate and palmitate, increased utilization of glycogen stores, and diminished fatty acid mobilization. Muscle weakness and myopathy are important features.

The presentation may also be subclinical. Early symptoms may include constipation, fatigue, dry skin, and weight gain. More advanced symptoms may include cold intolerance, decreased sweating, nerve deafness, peripheral neuropathy, decreased energy, depression, dementia, memory loss, muscle cramps, joint pain, hair loss, apnea, menorrhagia, and pressure symptoms in the neck from goiter enlargement such as voice hoarseness.

Physical findings may include:

• Cold and dry skin
• Facial edema, particularly periorbital, as well as nonpitting edema involving the hands and feet
• Brittle nails
• Bradycardia
• The delayed relaxation phase of tendon reflexes
• Elevated blood pressure
• Slow speech
• Ataxia
• Macroglossia

Furthermore, patients can have an accumulation of fluid in the pleural and pericardial cavities rarely. Myxoedema coma is the most severe clinical presentation and has to be managed as an endocrine emergency within patient care.

Evaluation

Hashimoto thyroiditis is an autoimmune disorder of inadequate thyroid hormone production. The biochemical picture indicates raised thyroid-stimulating hormone (TSH) in response to low free T4. A low total T4 or free T4 level in the presence of an elevated TSH level confirms the diagnosis of primary hypothyroidism.

Integrative and functional medicine practitioners may also assess free T3 and reverse T3 levels; however, Western medicine does not use this approach.

The presence of anti-thyroid peroxidase and anti-thyroglobulin antibodies suggests Hashimoto thyroiditis. However, 10%  of patients may be antibody negative.

Anemia is present in 30 to 40%.

There can be decreased glomerular filtration rate (GFR), renal plasma flow, and renal free water clearance with resultant hyponatremia.

Creatine kinase is frequently elevated.

Prolactin levels may be elevated.

Elevated total cholesterol, LDL, and triglyceride levels can occur.

A thyroid ultrasound assesses thyroid size, echotexture, and whether thyroid nodules are present; however, it is usually not necessary for diagnosing the condition in the majority.[9][10]

Treatment / Management

The mainstay of treatment for hypothyroidism is thyroid hormone replacement. The drug of choice is titrated levothyroxine sodium administered orally. It has a half-life of 7 days and can be given daily. It should not be given with iron or calcium supplements, aluminum hydroxide, and proton pump inhibitors to avoid suboptimal absorption. It is best taken early in the morning on an empty stomach for optimum absorption.

The standard dose is 1.6 - 1.8 mcg/kg per day, but it can vary from one patient to another. Patients less than 50 years old should be commenced on a standard full dose; however, lower doses should be used in patients with cardiovascular diseases and the elderly. In patients older than 50 years, the recommended starting dose is 25 mcg/day, with reevaluation in six to eight weeks. In contrast, in pregnancy, the dose of thyroxine needs to be increased by 30%, and in patients with short-bowel syndrome, increased doses of levothyroxine are needed to maintain a euthyroid state.

There is less evidence to support an autoimmune/anti-inflammatory diet. The theory behind the inflammation has to do with leaky gut syndrome, where there is an insult to the gut mucosa, which allows the penetrance of proteins that do not typically enter the bloodstream via transporters in the gut mucosa. It is theorized that a response similar to molecular mimicry occurs, and antibodies are produced against the antigens. Unfortunately, the antigen may be very structurally similar to thyroid peroxidase, leading to antibody formation against this enzyme. The concept of an autoimmune diet is based on healing the gut and decreasing the severity of the autoimmune response. More research is required on this topic before it becomes a part of the guidelines.

Differential Diagnosis

• Euthyroid sick syndrome
• Goiter
• Graves disease (diffuse toxic goiter)
• Hypopituitarism (panhypopituitarism)
• Lithium-induced goiter
• Nontoxic goiter
• Polyglandular autoimmune syndrome type 1
• Polyglandular autoimmune syndrome type 2
• Thyroid cancer (lymphoma)
• Toxic nodular goiter