Hypothyroidism

Definition

A clinical state defined as decreased production of thyroid hormone, by the thyroid gland resulting in deficiency of circulating hormone which regulates essential functions; such as heart rate, digestion, physical growth, and if left untreated, leads to multiple organs and tissues damage.

Thyroid hormone resistance: Mutation within thyroid hormone receptors (TRB) leads to poor hormone recognition by tissues and causes a condition similar to low thyroid production state.

Types

Primary hypothyroidism:

• Indicates decreased thyroidal secretion of thyroid hormone by factors affecting the thyroid gland itself

Secondary hypothyroidism:

• Decreased thyroidal secretion of thyroid hormone can also be caused by insufficient stimulation of the thyroid gland by thyroid-stimulating hormone (TSH), due to factors directly interfering with pituitary TSH release.

Tertiary hypothyroidism:

• Indicates decreased thyroidal secretions due to indirect reduction in thyroid releasing hormone (TRH) released from the hypothalamus.

Note: Clinically it is difficult to differentiate between the secondary and tertiary hypothyroidism so they are often collectively referred to as “central hypothyroidism”

Myxedema coma:

A severe state of hypothyroidism which, if left untreated, leads to severe stress and infections.

• Myxedema coma is a potentially lethal but rare condition, occurring with severe hypothyroidism

Etiology

Various functional or structural disorders are involved which may cause hypothyroidism, and are categorized as follows:

Primary hypothyroidism:

• Deficient thyroid hormone production by thyroid gland. Usually inherited. Accounts for approximately 90-95% of hypothyroidism

Central hypothyroidism:

• Inadequate stimulation of the normal gland from defect at the level of pituitary or hypothalamus

Peripheral (extrathyroidal) hypothyroidism:

• Symptoms exhibiting hypothyroid state, despite normal structure and function of the thyroid gland and due to peripheral tissue resistance to thyroid hormone

Epidemiology

Incidence

• Predominant age: >40 years
• Predominant gender: Female > Male, 5:1-10:1

Prevalence

• 5-10/1,000 in general population
• Common in elderly
• >65 years of age, increases to
  • 6-10% of women
  • 2-3% of men

Hashimoto’s thyroiditis:

• Annual incidence
  • Women: 400 per 100,000
  • Men: 100 per 100,000
• Mean age at diagnosis: 60 years
• Commonest cause of hypothyroidism

Pathophysiology

• Hypothyroidism results from dysfunction in the normal homeostasis in the formation and regulation of the active form of thyroid hormone T₃
• Thyroid hormone deficiency may stem from a variety of causes including destruction/atrophy of the thyroid gland (primary hypothyroidism), pituitary insufficiency (secondary hypothyroidism) or from abnormalities of the hypothalamic-pituitary axis (tertiary hypothyroidism)

In primary hypothyroidism, in response to a drop in T4 secretion from the thyroid gland, TSH secretion from the pituitary is increased. Thus, an elevated TSH is the primary marker of primary hypothyroidism.

Clinical Presentation

Clinically the disease varies from one patient to the other depending upon cause, duration, and severity of the hypothyroid state. Since thyroid hormones influence most organs, tissues, and cells of the body, there can be a wide spectrum of sign and symptoms in this disorder (see figure).

Note: An endocrinologist would most likely recognize the subtle manifestations and would be more skilled to do physical thyroid gland examination. Consultation is recommended for:

• Patients of age ≤18 years
• Patients who do not respond to treatment
• Pregnant patients
• Cardiac patients
• Structural changes in the thyroid gland
• Presence of other endocrine diseases

Differential Diagnosis

• Sick euthyroid syndrome
• Thyroiditis
• Depression
• Hypochondriasis
• Nephrotic syndrome
• Chronic nephritis
• Addison’s disease
• Hypopituitarism
• Neurasthenia
• Chronic fatigue syndrome
• Fibromyalgia
• Congestive heart failure (CHF)
• Primary amyloidosis
• Dementia from other causes
• Infertility
• Menopause
• Ovarian insufficiency
• Obesity
• Sleep disorders

Investigation and Workup

History and Physical:

History and physical examination will provide definitive information in severe cases, but the disease can often be asymptomatic or have non-specific signs and symptoms. However; biochemical proof of thyroid hormone deficiency is necessary for diagnosis.

Laboratory studies:

• Common tests of thyroid function include TSH, free T4, anti-thyroid peroxidase (anti-TPO) antibodies (see figure)
• Serum thyrotropin hormone (TSH) measurement is the first-line diagnostic test
• An elevated TSH level should be confirmed by a repeated measurement, along with measurement of serum free T₄ estimates
• Many patients with primary hypothyroidism have normal circulating levels of T₃
• Free T₄ assays can be unreliable in the setting of severe illness

Interpretation of test results:

Although most laboratories report the upper range of normal for TSH is 4.5 mIU/L, evidence suggests that the true upper limit of normal may be as low as 2.5 mu/L.
Ref: Wartofsky, L. The evidence for a narrower thyrotropin reference range is compelling. The Journal of Clinical Endocrinology & Metabolism, 90:5483-5488, 2005.

Overt primary hypothyroidism:

• TSH: Increased
• Serum free thyroxine (T₄): Decreased

Subclinical hypothyroidism:

• TSH: Elevated (usually <10 mlU/L)
• Serum free T₄: Normal

Secondary or tertiary hypothyroidism:

• TSH: Low or normal
• Serum free T₄: Decreased
• Impaired TSH response to TRH

Antithyroid antibodies:

Anti-Thyroid peroxidase (TPO) antibodies

• Useful to establish an autoimmune etiology of hypothyroidism in selected cases
• Useful in predicting progression of subclinical to overt hypothyroidism

Imaging Studies

Ultrasound (thyroid):

• Detect nodules and infiltrative disease
• Useful in follow-up for the size of thyroid and nodules

MRI of the pituitary gland/hypothalamus:

• When central hypothyroidism is suspected

Treatment

Clinical Trials

• The starting dose of levothyroxine in primary hypothyroidism treatment: a prospective: randomized, double-blind trial
• The beneficial effect of L-thyroxine on cardiovascular risk factors, endothelial function, and quality of life in subclinical hypothyroidism: randomized, crossover trial
• Subclinical hypothyroidism is associated with increased risk for all-cause and cardiovascular mortality in adults

Pipeline Agents

Pending new data.

Physician Resources

1. Tips for patient care

Risk factor management:

• Advise patient to report signs of infection or potential heart problems (palpitations, dyspnea)
• Hypothyroidism could increase the risk of infertility and miscarriage
• If suspecting the presence of adrenal insufficiency, it should be confirmed or ruled out and should be treated prior to treatment of hypothyroidism
• Generally, routine surgery in a hypothyroid patient should be deferred until euthyroidism is restored
• Diabetic patients may need a readjustment of hypoglycemic agents with the institution of thyroxine
• High-bulk diet may help avoid constipation
• Educate patient about myxedema coma

Monitoring:

• Monitor TSH levels every 6 to 8 weeks until normalized, then at 6 months, followed by annual assessments
• An elevated TSH level should be confirmed by a repeated measurement, along with measurement of serum free T₄
• If treatment in subclinical hypothyroidism is not initiated, then monitor with annual TSH and free T₄ measurement
• Follow cardiac status closely in elderly patients

Medications:

• Advise patient to establish the prescribed routine for pill-taking
• Educate about the importance of drug therapy compliance
• Appreciate lower starting doses of drugs in elderly and debilitated patients
• Consider concurrent risk factors and disease states with the prescribed therapy
• Levothyroxine is usually the first choice of treatment
• Thyroid hormone has a narrow toxic-to-therapeutic ratio
  • Must be titrated on the basis of laboratory tests and clinical responses
• Avoid over-replacement with thyroid hormone

Social and Stress factors:

• Ensure patient and family are well informed about the disease and its treatment
• Individuals with hypothyroid should be regularly screened for subclinical psychological distress and psychiatric disorders

Alerts:

• Iron supplements frequently decrease levothyroxine absorption; caution required especially when iron supplements are prescribed due to increased demand for iron during pregnancy
• Thyroid hormone replacement can precipitate adrenal crises in patients with untreated adrenal insufficiency
• Relapses will occur if treatment is interrupted

Activities (physical, mental, others):

• Stress on the importance of staying active and having a regular exercise routine
• Advise patients to keep themselves mentally active

Myxedema coma:

• Myxedema coma is a medical emergency
• Untreated hypothyroidism may progress to myxedema coma
• Identify and treat the precipitating factors of myxedema coma, such as hypoglycemia, infection, medications, cold exposure
• A random cortisol level should be drawn prior to therapy
• Administer hydrocortisone until coexisting adrenal insufficiency is ruled out
• Deterioration of the patient’s mental status is one of the key manifestations of myxedema coma

Hypothyroidism and Pregnancy:

• Hypothyroidism in pregnancy is safely and easily treated with synthetic thyroid hormone
• Uncontrolled hypothyroidism during pregnancy can lead to, e.g.
  • Congestive heart failure, preeclampsia, miscarriage, low birth weight
  • Cognitive and developmental disabilities in the newborn
• Levothyroxine requirements will likely increase during pregnancy. Monitor TSH level every 4-6 weeks during the first half of pregnancy and at least once between 26 and 32 weeks gestation
• Women with hypothyroidism should achieve good control prior to conception (TSH not more than 2.5mlU/L)
• After delivery, most patients need to decrease the thyroxine dosage they received during pregnancy
• There is an increased risk of developing permanent primary hypothyroidism in women with a history of postpartum thyroiditis

2. Scales and Table

• Signs and symptoms of hypothyroidism
• Common tests of thyroid function
• Levothyroxine dosing in hypothyroidism and mild thyroid failure

References

Core Resources:

• Allan GM, Morros MP, Young J. Subclinical hypothyroidism and TSH screening. Canadian Family Physician 2020; 66:188
• American Association of clinical endocrinologist Medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism, 2006 amended version. Endocrine practice Vol 8 No.6
• Bekkering G, Agoritsas T, Lytvyn L, et al. Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline. BMJ. 2019;14;365:l2006. doi: 10.1136/bmj.l2006
• Birtwhistle R, Morissette K, Dickinson JA, et al. Recommendation on screening adults for asymptomatic thyroid dysfunction in primary care. CMAJ 2019; 191:E1274-E1280; doi: https://doi.org/10.1503/cmaj.190395
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Online Pharmacological Resources:

• e-Therapeutics
• Lexicomp
• RxList
• Epocrates

Journals/Clinical Trials:

• Abalovich M, et al: Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2007;92:S1-S47
• American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract. 2002;8:457-469
• American College of Physicians. Clinical guideline, part 1. Screening for thyroid disease. Ann Intern Med. 1998;129:141-3
• Alexander EK, Marqusee E, Lawrence J, et al. Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med. 2004;351:241-9
• Assessment of iodine deficiency disorders and monitoring their elimination. A guide for programme managers. (3^rd edition). World Health Organization 2007
• Aoki Y, Belin RM, Clickner R, et al. Serum TSH and total T4 in the United States population and their association with participant characteristics: National Health and Nutrition Examination Survey (NHANES 1999-2002). Thyroid. 2007;17:1211-23
• Bunevicius R, Kazanavicius G, Zalinkevicius R, et al. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med. 1999;340:424-429
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• Cinemre H, Bilir C, Gokosmanoglu F, et al. Hematologic effects of levothyroxine in iron-deficient subclinical hypothyroid patients: a randomized, double-blind, controlled study. J Clin Endocrinol Metab. Jan 2009;94:151-6
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