Thyroid Syndromes

Does this patient have thyroid syndrome?

Thyroid disease can be accompanied by a variety of musculoskeletal manifestations ranging from early growth defects during infancy to adult manifestations including myalgias, arthralgias, myopathy, acropachy and frank arthritis.

Musculoskeletal manifestations are most pronounced in extreme states of thyroid dysfunction. A thorough history is essential in evaluating thyroid disease, including medical co-morbidities, radiation exposure, surgeries, family history and medications.

Hypothyroidism

In hypothyroidism, often other non-musculoskeletal manifestations dominate the clinical presentation including fatigue, cold intolerance, constipation, memory/concentration issues, menorrhagia, infertility, weight gain, coarse and brittle hair.

Cretinism, or congenital deficiency of thyroid hormone at birth, is a common treatable birth defect. At birth there rarely are any physical findings. This is due to partial placental transfer of maternal thyroid hormone. The physical exam findings are first seen after the first few weeks of infancy, when maternal hormones are lost. Without treatment; pallor, lethargy, slow movement, feeding problems, constipation, macroglossia, umbilical hernia, enlarged fontanels, hypotonia, dry skin, hypothermia and prolonged jaundice can occur. There is an increased risk of cardiac, renal, urinary tract, and gastrointestinal malformations in utero.

The musculoskeletal effects of cretinism include delays in ossification at the epiphyseal centers. Multiple foci of ossification occur causing growth stunting, bone deformity, and kyphosis predominantly at the thoraco-lumbar junction.

In adults, there are diverse musculoskeletal symptoms resulting from the hypothyroid state. Features include muscle weakness, arthralgias, arthritis, myalgias with and without elevations in creatinine phosphokinases, carpal tunnel syndrome, erosive osteoarthritis, and crystal induced arthritis.

Hypothyroid arthropathy most commonly affects the knees, metacarpophalangeal (MCP) joints, proximal interphalangeal (PIP) joints, metatarsal phalangeal (MTP) joints and wrists. On exam, tenderness, synovial thickening and joint effusions can be present. The joint effusions can be be large and characteristically lack erythema or warmth, unless secondary disease processes are present.

Synovial fluid analysis is characterized as non-inflammatory, with normal protein and cell counts. There is increased hyaluronic acid concentration in the synovial fluid producing the characteristic highly viscous synovium with a strongly positive “string test”.

Neuromuscular symptoms are common in hypothyroidism, estimated to occur in 30-80% with overt disease. The symptoms include weakness, cramping, myalgias, diminished reflexes and myoedema. Symptoms can occur any time during the course.

Weakness is the most common phenomena. Creatine kinase (CK) can be elevated and is associated with a prolonged ankle jerk reflex and muscle enlargement. Cramping can be severe, and myalgias worse after exertion. Electromyography (EMG) and muscle biopsy can be used for further characterization.

Myoedema is the phenomenon of mounding of the muscle tissue after light percussion lasting 30-60 seconds. It is not specific to hypothroidism and is thought to be due to sustained contraction due to decreased calcium uptake from sarcoplasmic reticulum. There is no EMG correlate for myoedema. Reflexes can have prolonged relaxation time, noted to be best seen at the Achilles tendon.

Hoffman’s syndrome, characterized by weakness, cramping and muscular enlargement is a rare complication, and often is accompanied by elevated creatinine phosphokinase. Similarly, in children with cretinism, Kocher-Debre-Semelainge syndrome can occur, characterized by diffuse muscle hypertrophy and proximal muscle weakness.

Carpal tunnel syndrome has been described in case reports to occur frequently in myxedema.

A polymyositis like syndrome due to hypothyroidism, with slowly progressive symmetric proximal muscle weakness at the shoulder and hip girdle has been frequently described, with elevated creatinine phosphokinase and modest elevations in erythrocyte sedimentation rate. The symptoms and myopathy respond rapidly to thyroid replacement.

Statin use can potentiate the musculoskeletal effects of hypothyroidism even in patients on thyroid replacement therapy. Complications include rhabdomyolysis as most statins (except for pravastatin and fluvastatin) are metabolized via the hepatic CYP3A4 system and can accelerate the catabolism of Levo-thyroxine, leading to unexpected hypothyroidism.

Sleep is affected in hypothyroidism and polysomnography performed in hypothyroid patients reveal decreased stage 3 and 4 sleep. This result is similar to findings seen in fibromyalgia.

Hyperthyroidism

In hyperthyroid states, non-musculoskeletal features often dominate the clinical presentation. The symptoms include heat intolerance, onycholysis, hair thinning, dermopathy, ophthalmopathy, tachycardia, dyspnea, urinary frequency, psychosis, depression, and in the elderly, apathy. Musculoskeletal symptoms include myopathy, adhesive capsulitis, myxedema, acropachy, and osteoporosis

In hyperthyroidism osteopenia and osteoporosis are the most common complications. Failure to recognize a declining need for thyroid replacement in the elderly is a preventable cause of iatrogenic hyperthyroidism. Bone density can improve after the correction of the hyperthyroid state, although often incompletely. In contrast, osteoporosis and osteopenia is not a complication of hypothyroidism.

In hyperthyroidism, mild proximal muscle stiffness and weakness including the bulbar muscles can occur. Myopathy and loss of muscle mass is a severe complication.

Thyrotoxic periodic paralysis is an extremely rare condition associated hyperthyroid myopathy, characterized by rapidly progressive paralysis of the proximal legs. It is due to intracellular potassium shifts.

Thyroid ophthalmopathy occurs in the setting of Graves’ disease, with symptoms of lid lag, lid retraction, proptosis, corneal irritation and diplopia. If severe, damage to the cornea and optic nerve can lead to permanent vision loss. It is due to an inflammatory infiltrate and enlargement of the ocular muscules is caused by mucopolysaccharide deposition.

Pretibial myxedema is a syndrome of painless nodules varying in size and color from pink to purple can occur in hyperthyroid states. The lesions can have a shiny, purple to pink appearance and can mimic erythema nodosum, scleroderma or morphea. It is due to increased hyaluronic acid in the skin.

Thyroid acropachy is a rare extreme complication of Graves’ disease characterized by insidious onset of swelling at the fingers and toes with digital clubbing. It is painful and can occur after the euthyroid state is achieved. Thyroid acropachy is strongly associated with Graves ophthalmopathy (1%) are pretibial myxedema (4%) and tobacco use.

Adhesive capsulitis is frequently described in the hyperthyroid state. It is often insidious in onset and responds poorly to standard therapy.

There is conflicting evidence that calcium pyrophosphate deposition disease (Pseudogout), is associated with hypothyroidism. Chondrocalcinosis on knee radiographs and calcium pyrophosphate crystals from synovial fluid samples have been reported to occur more frequently although the association with pseudogout has not been consistently reproduced.

Purine metabolism is impaired in thyroid disorders, with an increased incidence of hyperuricemia seen in both hypothyroid and hyperthyroid states. Uric acid levels have been shown to normalize after achievement of the euthyroid state. The incidence of gout is is higher in hypothyroid patients compared to age matched controls.

Differential diagnosis

The differential diagnosis is often case specific due the variety of musculoskeletal presentations. In hand arthropathy, erosive osteoarthritis, rheumatoid arthritis and all inflammatory small joint arthritides should be considered. At the larger joints, such as hips, osteoarthritis, aseptic necrosis, and inflammatory arthritides can mimic the presentation. Additionally, atypical infections such as tuberculosis, sarcoidosis, and malignancy should remain on the differential. The differential for the neuromuscular manifestations include polymyositis, rhabdomyolysis, carpal tunnel syndrome, polymyalgia rheumatica, muscular dystrophy, other causes of myopathy, myasthenia gravis, and motor neuron diseases.

What tests to perform?

Lab Testing

The initial step is to screen with thyroid-stimulating hormone (TSH) and free thyroxine (T4).

To evaluate the various differential diagnoses, Inflammatory markers should be ordered including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP).

Further evaluation based on history, exam and imaging results could include rheumatoid factor and antinuclear antibodies (ANA). Secondary causes for calcium pyrophosphate deposition disease (CPPD) should be investigated if present, including parathyroid hormone (hyperparathyroidism), calcium, magnesium, and hemochromatosis screening (liver function testing including AST, ALT, transferrin saturation and ferritin).

Imaging

Initial imaging includes radiographs of the affected joint. Small joints can show periarticular calcific deposits and central erosions of the articular surfaces, predominantly at the MCP and PIP which can mimic erosive osteoarthritis (EOA). Destructive lesions of the tibial plateau similar to compression fractures have been described, possibly due to epiphyseal dysgenesis or aseptic necrosis.

Wormian bones, named after Danish anatomist Ole Worm, are accessory sutures seen within the skull, most often at the lambdoid suture, and are associated with hypothyroidism. It is considered pathologic when there are greater than 10 accessory bones or if they become large. Wormian bones are a normal variant seen in the general population, more frequently in the Asian population.

Imaging findings with thyroid acropachy include periosteal bone formation, described as spiculated or lacy in appearance at the metacarpals, proximal, middle phalanges of the hand and the metatarsals and proximal phalanges of the toes.

Magnetic resonance imaging (MRI) can be further used to evaluate structural damage. Bone scans are useful in thyroid acropachy, showing increased uptake which may predate radiograph findings. Both MRI and bone scans are not routinely used in evaluation.

In cretinism, long bone radiographs will reveal multiple foci of ossification resulting in a stippled appearance of bone referred to as epiphyseal dysgenesis.

In children, delayed bone age and delays in skeletal maturation can cause short stature and dwarfism. Secondary ossification centers are delayed and slipped femoral capital epiphysis is a common complication.

Electromyogram (EMG) can distinguish hypothyroid associated myopathy from other eitiologies, with EMG correlates including myopathic motor units with hyperirritability and increased polyphasic potentials.

Biopsy

Muscle biopsy is useful in long standing hypothyroidism to differentiate inflammatory myositis, showing Type 1 and 2 fiber atrophy, hypertrophy and myofiber necrosis.

How should patients with thyroid syndromes be managed?

• Treatment involves achieving the euthyroid state. In hypothyroidism, this is commonly achieved with hormone replacement therapy. Replacement levo-thyroxine should be taken on an empty stomach with water in the AM. It is recommended to wait at least 1/2 hour prior to eating.

• In primary hyperthyroidism, radioactive iodine ablation, medication therapy such as methimazole and propylthiouracil, or surgery are common modalities. Referral to an endocrinologist is recommended. Patients generally recover well with treatment at both extremes.

• Osteoporosis associated with hyperthyroidism requires treatment to achieve the euthyroid state. Additional treatment with bisphosphonates based on FRAX guidelines is recommended. Calcium and vitamin D supplementation when appropriate is recommended. Bone density should be checked every 2 years and often improves with the correction to the euthyroid state.

• Treatment of thyroid acropachy often requires systemic corticosteroids for joint manifestations. Tobacco cessation is recommended. In ophthalmopathy, corneal drying and ulceration must be prevented ocular lubricants. Orbital decompression can be used in severe cases.

• Beta-blockade in hyperthyroid myopathy may assist in muscle function.

What happens to patients with thyroid syndromes?

Natural history and epidemiology

The incidence and prevalence of thyroid related musculoskeletal disease has not been established.

Hypothyroidism

• It is estimated that 1/3 of the world’s population live in areas of iodine deficiency, defined as having a daily intake of iodine less than 50μg. When the intake falls to less than 25μg per day, congenital hypothyroidism is encountered. In the iodine replete countries, most thyroid disorders have an autoimmune basis, ranging from Hashimoto’s thyroiditis to thyrotoxicosis caused by Graves’ disease. The prevalence of thyroid disease is different between ethnic groups and estimated to be approximately 8% of the US population. Additionally, up to 5% of the population are estimated to have undiagnosed disease.

• Hypothyroidism, as defined solely by laboratory findings due to the variable clinical presentation, includes elevated serum TSH greater than 3.89mIU/L (controversial due to age discrepancies, accepted values range from 3-6 mIU/L) and low serum free Thyroxine (T4). In iodine replete communities, the prevalence of spontaneous hypothyroidism is estimated between 1-2%, and is 5-10 times more common in females than in men. The mean annual incidence is estimated at 3.6/1000 women and 0.6/1000 males. The most common cause of thyroid disease is due to goiter. The incidence of thyroid cancer, a less common cause of thyroid dysfunction, is estimated at 3.5/100,000 women and 1.3/100,000 men.

• Congenital hypothyroidism affects approximately 1/4000 births and is the most treatable cause of mental retardation. In iodine replete communities, congenital hypothyroidism is due to developmental defects of the gland. There is a higher incidence seen in Trisomy 21. Newborn thyroid screening is mandated in all US states.

• Subclinical hypothyroidism is defined as elevated TSH and normal free Thyroxine (T4). The estimated prevalence of subclinical hypothyroidism ranges from 4-10% of the population, with a higher frequency in elderly females.

• In hypothyroidism, 95% is considered primary, due to direct or antibody mediated destruction of the thyroid gland. There are two forms of destruction – goitrous and atrophic. These differ in the extent of lymphocytic infiltration, fibrosis, and follicular cell hyperplasia. Secondary and tertiary causes are due to pituitary and hypothalamic defects, respectively.

Hyperthyroidism

• Hyperthyroidism is defined as a serum TSH concentration less than 0.1mIU/L and a serum total of T4 greater than 170nmol/l. Hyperthyroidism is estimated to occur in 0.5-2% of the population and is estimated to be 10 times more common in women than men in iodine replete communities. Graves disease is the most common etiology, followed by toxic multinodular goiter.

Pathophysiology

• Autoimmune thyroid disease can be caused by multiple autoantibodies. All thyroid antibodies can be seen in all forms of autoimmune thyroid disease, in varying degrees of specificity. This includes anti-thyrotropin receptor antibodies, which are seen in 80-95% of Graves’ disease and 10-20% of autoimmune thyroiditis. Anti-thryroglobulinantibodies, seen in 5-20% of the healthy population, and found in 50-70% of Graves’ disease, and 80-90% of autoimmune thyroiditis. Anti-thyroid peroxidase antibodies are estimated to occur in 8-27% of the healthy population, 50-80% of Graves’ disease, and 90-100% of the autoimmune thyroiditis. Both anti-thyroglobulin and anti-thyroitropin antibodies are seen in varying degrees in relatives with autoimmune thyroiditis, reinforcing a genetic predisposition for antibody development.

• Bone remodeling consists of cycles of activation and resorption lasting approximately 210 days. In hypothyroidism there is a lengthened bone remodeling cycle, of up to 700 days. Osteoporosis is rare due to prolonged bone formation and decreased active resorption. This can be estimated by measuring bone markers including alkaline phosphatase, osteocalcin activity, and urinary excretion of calcium, all of which would be reduced..

• In hyperthyroidism, osteopenia and osteoporosis is common, due to the shortened bone remodeling phase, with excessive bone remodeling and subsequent reduced bone density. Histological changes include increased turnover in trabecular bone, increased remodeling and porosity in cortical bone with increased osteoclastic activity.

• There is debate whether exogenous levothyroxine or low circulating thyroid stimulating hormone is an independent risk factor for development of osteoporosis. When thyroid supplementation is given in suppressive doses (i.e.. during thyroid cancer treatment) with a target thyroid stimulating hormone less than 0.4mU/L, there is an increased risk of osteoporosis and fracture. When given at doses for physiological maintenance, there has not been an observed increase of risk for bone disease.

• Associated rheumatic conditions include an increased incidence of positive ANAs in patients with autoimmune thyroid disease. Many have Anti-DS DNA Ab. In cross sectional analysis, there is an increased prevalence and relative risk in developing systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in patients with Graves’ disease and/or Hashimoto’s thyroiditis.

• Psoriatic arthritis and limited scleroderma both have an observed increased incidence with thyroid peroxidase Ab positivity.

• Scleroderma can directly induce hypothyroidism due to fibrosis of the gland.

• SLE patients with thyroid disease have an increased risk of preterm delivery.

• TNF-alpha receptors are found in thyroid follicular cells. In Graves’ disease serum levels of TNF-alpha are elevated. In a small study of hyperthyroid patients, achievement of the euthyroid state led to normalization of TNF-alpha levels. The same was not observed in hypothyroid patients.

Pharmacologic considerations

• There are numerous medications used in thyroid and rheumatic diseases that have unintentional adverse crossover effects. Propylthiouracil has been shown to be the culprit for ANCA-positive drug-induced vasculitis. Methimazole can cause SLE-like syndromes. Aspirin and non steroidal anti-inflammatory drugs (NSAIDS ) lower serum total thyroid hormone by interfering with binding proteins. Glucocorticoids inhibit TSH secretion and reduces serum thyroid hormone concentrations.

What is the evidence?

Bland, JH, Frymoyer, JW, Newberg, AH. “Rheumatic Syndromes of Endocrine Disease”. Seminars in Arthritis and Rheumatism. vol. 9. 1979. (A review of rheumatologic diseases associated with the endocrinopathies)

McLean, RM, Podell, DN. “Bone and Joint Manifestations of Hypothyroidism”. Seminars in Arthritis and Rheumatism. vol. 24. 1995. pp. 282-290. (In depth review of the rheumatic manifestations of thyroid disease)

Vanderpump, MP. “The Epidemiology of Thyroid Disease”. British Medical Bulletin. vol. 99. 2011. pp. 39-51. (A review on the epidemiology of thyroid disorders including incidence and prevalence, from data taken from multiple studies from the US and Europe)

Horak, HA, Pourmand, R. “Endocrine Myopathies”. Neurologic Clinics. vol. 18. 2000. pp. 203-213. (A review on the neuromuscular findings in thyroid disorders)

Boelaert, K, Newby, PR, Simmonds, MJ. “Prevalence and relative risk of other autoimmune disease in subjects with autoimmune thyroid disease”. The American Journal of Medicine. vol. 123. 2010. pp. 183.e1-183.e9. (A cross sectional multicenter study of patients with Graves' disease or Hashimoto's thyroiditis and the prevalence of coexisting autoimmune disorders)

Schumacher, RH, Dorwart, BB. “Joint effusions, chondrocalcinosis and other rheumatic manifestations in hypothyroidism”. The American Journal of Medicine. vol. 59. 1975. pp. 780-798. (Small study of 12 patients evaluating the clinical and histological findings of joint effusions)

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