Werner & Ingbar's The Thyroid: A Fundamental & Clinical Text, 9th Edition

50.Primary Hypothyroidism Due to Other Causes

Peter A. Singer

Spontaneous primary hypothyroidism, which is nearly always due to chronic autoimmune (Hashimoto's) thyroiditis, is the most common cause of hypothyroidism in many countries. In the United States alone, cross-sectional studies of the elderly have demonstrated high serum thyrotropin (TSH) levels in from 6.7% to 19% of people, with a greater prevalence in women (1,2,3). Iodine deficiency is the principal cause of hypothyroidism in underdeveloped areas in the world, and may be present in as many as 1 billion people worldwide, although the actual prevalence of hypothyroidism in affected individuals is not known. (These disorders are discussed in detail in the section Iodine Deficiency in Chapter 11 and Chapter 49.)

This chapter will discuss other types of primary hypothyroidism, ranging from those encountered commonly, such as following radioactive iodine therapy (RAI) or thyroidectomy, and uncommon and even rare forms of hypothyroidism, including some due to infiltrative and inherited disorders (Table 50.1). Some types of hypothyroidism are so rare that they are unlikely to be encountered by a practicing physician, and are of academic interest only.


Thyroid ablation

   Radioactive iodine therapy or surgery for

      Graves' thyrotoxicosis

      Toxic nodular goiter

      Nontoxic nodular goiter

   External radiotherapy for

      Hodgkin's and non-Hodgkin's lymphoma

      Solid cancers of the head and neck

      Aplastic anemia


Pharmacologic agents

   Lithium carbonate

   Cytokines (interferon-α, interleukin-2)

   Other drugs (aminogluthamide, ethionamide, sulfonamides)

Infiltrative disorders

   Riedel's (invasive fibrous) thyroiditis





   AIDS (including Pneumocystis infection)

   Primary thyroid lymphoma

Toxic substances


   Industrial and environmental agents

Embryologic variants

   Lingual thyroid

For the purpose of this discussion, hypothyroidism is defined as a sustained elevation of serum TSH. Thus, subclinical hypothyroidism, which is characterized by normal serum levels of free thyroxine and high serum levels of TSH (see Chapter 78) will be included, along with overt hypothyroidism.


Treatment of Graves' Disease

Radioactive Iodine Therapy

Iodine 131 (131I) therapy for thyrotoxic Graves' disease is the most common cause of nonspontaneous hypothyroidism in the United States, probably because of physician preference for 131I, due to the relatively high relapse rate (~60) of thyrotoxicosis following withdrawal of antithyroid drug therapy (4). An international survey of thyroid specialists over a decade ago revealed that 131I was chosen by 69% of physicians in the United States as the primary form of treatment for a typical 43-year-old woman with Graves' thyrotoxicosis (5). In contrast, only 22% of physicians from Europe, 17% from Latin America, and 11% from Asia, selected 131I as the primary form of therapy (6,7). This therapy almost always results in hypothyroidism, necessitating othyroxine (T4) treatment. Indeed, most physicians in North America recommend a dose of 131I sufficient to ensure hypothyroidism, so that the need for T4 replacement will be predictable (8). Efforts to restore long-term euthyroidism with smaller doses of 131I have generally been unsuccessful, resulting in either persistent or recurrent thyrotoxicosis, or later onset of hypothyroidism. In one study of 187 patients in the United States treated with low doses of 131I, 12% become hypothyroid after 1 year, and 76% were hypothyroid at the end of 11 years of follow-up (9). A similar study in England yielded similar results, with 11% of patients becoming hypothyroid after 1 year, and 55% developing hypothyroidism after 15 years (10). Recently, high-dose 131I (128–155 µCi/g) was shown to result in cure of Graves' thyrotoxicosis in 90% of patients, and the development of hypothyroidism in approximately 80% (1,2,3). Because hypothyroidism develops so frequently, regardless of the dose used, the goal of long-term euthyroidism with 131I is not only difficult but is probably unwise, because patients treated with lower 131I doses require more careful long-term surveillance.


Surgery was the choice of treatment for the above-mentioned 43-year-old woman with Graves' thyrotoxicosis by only approximately 1% of physicians in the United States, whereas it was the preferred method of treatment by physicians in Latin America, Europe, and Asia (11). Although euthyroidism after surgery is desirable, hypothyroidism usually develops; 59% of 81 patients who underwent subtotal thyroidectomy in the United States, and 51% of 216 patients who underwent similar surgery in Japan, developed hypothyroidism within several years (11,12). In both studies, a thyroid remnant of less than 6 g was left in order to avoid recurrent thyrotoxicosis. Other studies have yielded similar findings, including two studies from Europe, in which nearly 50% of patients who underwent subtotal thyroidectomy eventually became hypothyroid (13,14). It is my practice to recommend near-total thyroidectomy for Graves' disease, so that the need for T4 therapy will be more predictable. Thus, both 131I and surgical treatment for thyrotoxic Graves' disease usually result in the need for T4 replacement.

Treatment of Toxic Nodular Goiter

Both 131I and surgery are commonly used for the treatment of patients with thyrotoxicosis due to either single or multiple autonomously functioning thyroid nodules. Because 131I is mainly concentrated in autonomously functioning tissue, extranodular thyroid tissue should theoretically be spared the effects of 131I. Between 6% and 36% of patients have been reported to become hypothyroid following 131I treatment, however, regardless of the dose of 131I administered (15,16). Patients who become hypothyroid are likely those in whom 131I uptake in nonnodular thyroid tissue was not completely suppressed (16). Radioactive iodine accumulation in the contralateral lobe assumes additional importance in younger patients, who may be subject to nodule formation many years following 131I therapy; hence the common recommendation that younger patients (perhaps < 30 years of age) be treated surgically (17,18). It has been suggested that administration of low doses of 131I (5–15 mCi) to patients with autonomous nodules minimizes the likelihood of posttreatment hypothyroidism (19).

Treatment of Nontoxic Nodular Goiter

Patients undergoing near-total thyroidectomy for nontoxic nodular goiter usually develop hypothyroidism, whereas partial thyroidectomy results in a lower incidence (20,21). Incomplete surgery, however, increases the possibility of recurrence, with regrowth reported to be as high as 10% to 20% of patients approximately 10 years after surgery, and 40% to 45% 30 years after surgery (22). Radioiodine treatment of nontoxic nodular goiter also appears to result in an appreciable incidence of hypothyroidism, with approximately 20% to 30% developing high serum TSH levels within 5 years after therapy (23). This form of treatment has been used in the United States less often than in Europe (24,25,26,27). Since the recent availability of recombinant TSH there has been more interest in the use of 131I for treatment of nontoxic goiter, because uptake of 131I can be increased with recombinant TSH administration, including previously nonfunctioning tissue, and lower doses of 131I may be required (28).

Euthyroid patients undergoing lobectomy for single nodules may develop hypothyroidism when exposed to pharmacologic doses of iodides, suggesting that patients with apparent uninodular disease may have a more diffuse underlying thyroid abnormality (29).

Radiation Exposure

Hypothyroidism is common after external radiotherapy with doses of 25 Gy (2,500 rad) or more to the head and neck area for malignant tumors, including Hodgkin's and non-Hodgkin's lymphoma, and solid cancers of the head and neck. Hypothyroidism may develop within the first year after radiotherapy, especially in patients under 20 years of age (30) but it typically develops within 3 to 5 years, and it may continue to develop many years later. In a review of 1,677 Hodgkin's lymphoma patients treated with external radiotherapy, the risk of hypothyroidism was 52% after 20 years, and 67% 26 years after therapy (31). This risk appears to be dose dependent (32).

When laryngectomy or partial thyroidectomy is done in addition to external radiotherapy, the likelihood of hypothyroidism increases to 65% to 70% (33,34). Hypothyroidism occurs in 30% to 40% of children and adolescents who receive whole-body irradiation for either aplastic anemia or leukemia, and in approximately 6% of children who receive craniospinal radiation for brain tumors (35,36). Hypothyroidism also occurs in 9% to 16% of adults who undergo total body irradiation following bone marrow transplantation (37).

Internal radiation to the thyroid from 131I may also induce the formation of thyroid antibodies. Children exposed to radioactive fallout following the 1986 Chernobyl disaster had an increased prevalence of both thyroglobulin and thyroid peroxidase antibodies 6 to 8 years later (19.5% in exposed children vs. 3.8% in unexposed controls) (33). Their thyroid function was normal at the time of study, but they are probably at greater risk for the development of hypothyroidism.

Chemotherapy also appears to be associated with the development of hypothyroidism in patients with lymphoma (30,38), and the combination of chemotherapy and external radiotherapy results in a greater incidence of hypothyroidism than occurs with either chemotherapy or external radiotherapy alone (31,39,40).

Because hypothyroidism may be either an early or late sequela of external radiotherapy, long-term surveillance of irradiated patients with serum TSH testing is indicated.


Iodides, thionamide drugs, and other agents used in the treatment of thyroid disorders are discussed in Chapter 45. This section will focus on agents not used primarily for the treatment of thyroid disease.

Lithium Carbonate

Lithium carbonate is usually prescribed for the treatment of manic-depressive disorders, and may be associated with the development of both goiter and hypothyroidism. Goiter has been reported in 4% to 60% of patients receiving lithium, and is due primarily to its inhibitory effect on thyroid hormone secretion, resulting in TSH stimulation of the thyroid (41,42,43,44). The goiter is typically diffuse. A review of 4,681 lithium-treated patients revealed the overall prevalence of hypothyroidism to be 3.4%, with a range of 0% to 23.3% (45). Risk factors for the development of hypothyroidism include female sex and the presence of thyroid antibodies; patients who develop hypothyroidism during lithium therapy likely have underlying chronic autoimmune (Hashimoto's) thyroiditis (46,47). Lithium-treated patients with no thyroid antibodies may have transient increases in serum TSH (48). Most lithium-treated patients who develop hypothyroidism have subclinical hypothyroidism, with only mild to moderate increases in serum TSH and normal serum thyroid hormone concentrations, although overt hypothyroidism may occur (49,50). Exogenous iodides act synergistically with lithium, resulting in greater serum TSH increases than with lithium alone (51). Because of lithium's effects on the thyroid, patients for whom the drug is prescribed should have a serum TSH determination at the time of initiation of therapy, and every 6 to 12 months thereafter, or more frequently, as the clinical situation dictates. Lithium therapy is also associated with a greater prevalence of painless thyroiditis than in the general population (52). Although the mechanism for this in unclear, it might be due to induction of an autoimmune process, or to a direct toxic effect on thyroid cells (52,53) (see Chapter 27).



Interferon-α (IFN-α) is used for the treatment of hepatitis B and C, as well as for various tumors, including malignant carcinoid, Kaposi's sarcoma, chronic myelogenous leukemia, and hairy cell leukemia (54). It is also used in combination with interleukin-2 (IL-2), a cytokine sometimes used in the treatment of tumors (55).

Hypothyroidism was initially described as a side effect of IFN-α therapy in patients receiving long-term IFN-α treatment for breast cancer (56). Thyroid dysfunction due to IFN-α is now more commonly associated with its use in the treatment of chronic hepatitis C virus (HCV) infection (57). IFN-α-associated abnormalities include both thyrotoxicosis and hypothyroidism, with the latter being much more common (57). A biphasic pattern of thyroid dysfunction, with thyrotoxicosis followed by hypothyroidism, is often seen, similar to that observed with silent thyroiditis (58). The observed incidence of IFN-α-associated hypothyroidism in patients with HCV has been reported to vary from 7% to 39% (54,57,58,59,60). The addition of ribavirin to IFN-α therapy may increase the risk of hypothyroidism (61).

Risk factors associated with the development of hypothyroidism include female sex, longer duration of IFN-α treatment, presence of HCV, older age, and the preexisting presence of thyroid antibodies, especially antithyroid peroxidase (anti-TPO) antibodies (57). A recent study suggested that Asian origin is an independent risk factor for IFN-α-induced hypothyroidism (62). The presence of anti-TPO antibodies may be the most important risk factor; in one study, thyroid dysfunction occurred in 60% of patients receiving IFN-α who had anti-TPO antibodies before therapy, compared with only 3.3% of patients who did not have anti-TPO antibodies at that time (63).

Transient hypothyroidism occurs more commonly with IFN-α therapy than does persistent hypothyroidism, although pooled data from several series indicate that 30% to 44% of patients who develop hypothyroidism during IFN-α treatment have persistent thyroid failure (54,57). The presence of thyroid antibodies at the end of IFN-α treatment is a positive predictive factor for persistent hypothyroidism (64).

The precise mechanism of IFN-α-induced thyroid dysfunction is not known, although it is probably related to activation or enhancement of the autoimmune process, As mentioned, patients with HCV are more susceptible than patients with other types of hepatitis (e.g., HBV) to develop thyroid dysfunction during IFN-α treatment. They also have a higher baseline prevalence of anti-TPO antibodies, suggesting an association between HCV and underlying thyroid autoimmunity (60). In addition, IFN-α therapy induces the production of thyroid antibodies in patients with HCV who had no prior thyroid abnormalities (57).

In addition to affecting the autoimmune process, IFN-α may exert a direct effect on the thyroid gland. In one study, perchlorate discharge test results were positive in 7 of 32 patients who were being treated with IFN-α, all of whom had negative test results prior to IFN-α, suggesting an IFN-α-induced organification defect of iodine (58).


Patients treated with IL-2 for various tumors have an increased risk of hypothyroidism. In one series, 32% of 111 patients with cancer developed hypothyroidism during IL-2 treatment, and 14% had hypothyroidism posttherapy, persisting from 44 to more than 149 days (median 54 days) (65). As with IFN-α-treated patients, positive thyroid antibodies and female sex are risk factors for thyroid dysfunction, whereas the type of tumor is not a predisposing factor (66,67). Patients who developed persistent hypothyroidism had more severe biochemical hypothyroidism during IL-2 treatment than those who had transient hypothyroidism (68).

As with IFN-α, IL-2 treatment likely activates the autoimmune process. Administration of IL-2 is associated with both the development of thyroid antibodies and increased titers of thyroid antibodies in patients who had antibodies or baseline (55,66). Combination therapy with IFN-α and IL-2 leads to an even greater prevalence of thyroid dysfunction than with either alone (69,70).

Because thyroid dysfunction is so common in patients treated with IFN-α or IL-2, measurements of serum TSH and anti-TPO antibodies before initiation of therapy may be indicated, especially in patients with HCV. One group recommends thyroid antibody and TSH testing before and during IFN-α, and 6 months after its withdrawal (60). Several months after treatment with IFN-α or IL-2 has been completed, T4 should be withdrawn to determine whether or not hypothyroidism is persistent.

Other Drugs

Several other drugs have been occasionally associated with hypothyroidism, including aminoglutethimide (71), ethionamide (72), and sulfonamides and sulfonylureas (73), by interfering with thyroid hormone biosynthesis. Generally, these drugs result in only mild increases in serum TSH, and overt hypothyroidism is very rare (71). One study reported that 31% of 29 men with prostate cancer treated with aminoglutethamide developed clinical or biochemical findings of hypothyroidism (71). Recently, therapy with thalidomide associated with hypothyroidism, although the mechanism is not known (74).


Riedel's Thyroiditis (Invasive Fibrous Thyroiditis)

This rare disorder has a reported prevalence of 0.06% to 0.3% in surgical series (75,76,77). It is characterized pathologically by replacement of the thyroid gland with dense fibrous tissue, which often invades adjacent soft tissue and muscle, hence the term invasive fibrous thyroiditis. Significant thyroid destruction with resultant hypothyroidism occurs in approximately 30% to 40% of cases (75,78). Hypoparathyroidism has been reported in a few patients in whom the destructive process involved the parathyroid glands (79).

The signs and symptoms of Riedel's thyroiditis include the development of an enlarging, hard neck mass associated with tracheoesophageal compression, findings suggestive of the possibility of poorly differentiated thyroid cancer and thyroid lymphoma (78). Riedel's thyroiditis is often associated with extracervical fibrosis, and within 10 years of the diagnosis approximately 30% of patients develop retroperitoneal or mediastinal fibrosis (77).

The etiology of Riedel's thyroiditis is not known; debate continues as to whether or not it is an autoimmune or a fibrotic disorder (80,81). An autoimmune etiology has been suggested because of the presence of thyroid antibodies, as well as histologic findings of lymphocytes and plasma cells (79).

Riedel's thyroiditis is usually slowly progressive, but it may also regress spontaneously. Treatment is focused on relief of obstruction; surgery may be necessary to relieve tracheal or esophageal compression, but the results may be unsatisfactory (82). Treatment with glucocorticoids has been used successfully (83), and the antiestrogen tamoxifen also has been used with some success (82,84). Although the mechanism for tamoxifen's beneficial effect is not known, it may be related to its stimulatory effect on production of transforming growth factor-β, a potent growth inhibitor (85,86).


Amyloid deposition in the thyroid is relatively common, reported to occur in 1.9% of 376 thyroidectomy specimens in one surgical series (87). Thyroid amyloid may occur in the context of either primary or secondary amyloidosis, with the latter being much more common, usually in patients with rheumatoid arthritis, although it occurs in patients with other chronic diseases as well, including tuberculosis, multiple myeloma, and inflammatory bowel disease (88,89,90,91). Clinically, asymptomatic diffuse or nodular thyroid enlargement is frequent, having been reported in 63% of 30 patients in one retrospective series (88). Thyroid function was abnormal in 10 of 30 patients with biopsy-proven amyloid deposits, including hypothyroidism in 5, thyrotoxicosis in 1, and painless thyroiditis in 1 patient (88). However, other reports suggest that thyroid dysfunction is rare in patients with amyloidosis (89,92).


Approximately 4% of patients with sarcoidosis have histologic changes of sarcoid in the thyroid (93). Hypothyroidism is the fact that thyroid autoantibodies are relatively common. In one report, 17 of 62 patients with pulmonary sarcoidosis had positive thyroid autoantibodies (94), with a higher prevalence of antibodies in men (54.5%) than in women (32.4%) over 40 years of age, in contrast to the usually greater prevalence of antibodies in women. Only one of the 17 patients had hypothyroidism, however (94).


Hemochromatosis may be associated with either secondary or primary hypothyroidism. Primary hypothyroidism in patients with hereditary hemochromatosis is associated with iron deposition in the thyroid gland, as well as in other tissues. The thyroid gland shows histologic evidence of fibrosis and lymphocytic infiltration (95,96). In one report, primary hypothyroidism was present in 3 of 17 adolescents who required multiple blood transfusions because of thalassemia major (97). These patients also are susceptible to hypothyroidism when given excess quantities of iodide (98). A study of 34 men with hemochromatosis revealed hypothyroidism in 3 patients, all of whom had high serum titers of anti-TPO antibodies, and histologic examination of one patient's thyroid revealed lymphocytic infiltration as well as iron deposition. The risk for hypothyroidism in men with hereditary hemochromatosis is about 80 times that of men in the general population (95).


Nephropathic cystinosis is a rare autosomal-dominant cystine storage disease resulting from deficiency of the normal carrier-mediated system that transports cystine out of lysosomes (99,100). As a result, there is an accumulation of cystine in various tissues, especially the kidneys, resulting in severe renal damage (99). The thyroid glands in these patients also commonly contain cystine deposits, and in one review of eight children with cystinosis, six had elevations in serum TSH (100). Among 36 adult patients who had undergone renal transplantation due to cystinosis revealed that 31 had hypothyroidism (96). The availability of renal transplantation fortunately allows for survival into adulthood of patients with cystinosis, and most of them develop hypothyroidism.

Other Infiltrative or Infectious Disorders

Hypothyroidism may occur as a result of opportunistic infections. Hypothyroidism due to Pneumocystis carinii involvement of the thyroid has been reported in several patients with acquired immunodeficiency syndrome (AIDS) (101,102,103). We reported three patients with Pneumocystis carinii thyroiditis, two of whom developed persistent hypothyroidism (103). Destruction of the thyroid gland by Kaposi's sarcoma, with resultant hypothyroidism, also has been reported in a patient with AIDS (104).

Primary thyroid lymphoma is associated with hypothyroidism. In one study 119 patients with primary thyroid lymphoma, overt hypothyroidism was present in 27% and subclinical hypothyroidism in 14% (105). Thyroid lymphoma occurs almost exclusively in patients with underlying chronic autoimmune (Hashimoto's) thyroiditis, which probably explains the high prevalence of hypothyroidism; thyroid antibodies are present in the serum in the majority of patients who have thyroid lymphoma (105,106,107).


Cigarette Smoking

Cigarette smoking increases the risk of hypothyroidism in patients who have underlying Hashimoto's thyroiditis. In a study from Japan of 380 women with Hashimoto's thyroiditis, 76% of 110 women who were smokers had hypothyroidism, in contrast to 35% of 256 nonsmokers (108). Also, 62% of 21 ex-smokers with Hashimoto's had hypothyroidism, suggesting that cessation of smoking does not result in restoration of normal thyroid function. In a study from Switzerland, 23% of 135 women with hypothyroidism were smokers. Those with subclinical hypothyroidism who smoked had higher serum TSH concentrations than nonsmokers, higher ratios of serum T3 to serum T4, and higher total and low-density lipoprotein cholesterol levels. Smoking had no effect on serum TSH, T4, or T3 levels in patients with overt hypothyroidism (109). A recent Danish study, on the other hand, found that mean serum TSH levels were lower among smokers than nonsmokers, although there was no association between smoking and either thyrotoxicosis or hypothyroidism (110). Another study from Denmark, however, did show a relationship between smoking and autoimmune thyrotoxicosis (111). A recent metaanalysis described an association between cigarette smoking and Graves' thyrotoxicosis and ophthalmopathy, Hashimoto's disease, and postpartum thyroiditis, but not hypthyroidism (112).

The mechanism for the effects of smoking on the thyroid is not entirely clear, but it may be related to higher concentrations of thiocyanate (113,114), which decreases iodide transport into the thyroid (115,116). In addition, other elements of tobacco smoke, including hydroxypyridine metabolites and benzopyrenes, may interfere with thyroid function (117,118). High concentrations of nicotine in rats do not affect thyroid function, the metabolism of thyroid hormones, or thyroid hormone action (119).

Industrial and Environmental Agents

Numerous synthetic and natural chemicals have been reported to cause goiter or hypothyroidism, including various pesticides, herbicides, industrial chemicals, and naturally occurring environmental chemicals. This topic has been discussed in comprehensive reviews (120,121).

The clinical importance of industrial agents on thyroid function is not clear, although there appears to be an increased incidence of autoimmune hypothyroidism in people exposed to polybrominated biphenyls (122). Resorcinol, which occurs in relatively high concentrations in watershed areas of coal-rich regions, has been associated with a higher prevalence of goiter (123).

Among naturally occurring substances, cassava has an antithyroid affect, probably by releasing thiocyanate, and is associated with a higher prevalence of goiter in areas of iodine deficiency (124). Pearlmilate, a fruit staple in iodinedeficient areas of sub-Saharan Africa, is rich in flavonites, which have an antithyroid effect (125). It is not clear whether hypothyroidism results from ingesting cassava and pearlmilate, although such substances enhance goitrogenesis in iodine-deficient areas (124).


Lingual Thyroid

Thyroid tissue restricted to the lingual region is rare, occurring in 1 in 100,000 persons, with a female predominance of 3:1 to 7:1 (126,127,128,129). Approximately one third of the patients have hypothyroidism at the time of the diagnosis, and in more than two thirds there is no other thyroid tissue (129).

Lingual thyroid is characterized by the presence of thyroid tissue at the base of the tongue in the midline and results from failure of the normal migration of thyroid tissue from its origin at the base of the tongue to the normal pretracheal location.

Symptoms of lingual thyroid, in addition to those associated with hypothyroidism, include the sensation of a foreign body in the posterior pharynx. If the mass is sufficiently large, signs and symptoms of obstruction of the throat especially when recumbent, may occur (130).

The diagnosis of lingual thyroid is usually made clinically, and radionuclide scanning may be used to confirm the diagnosis. Small asymptomatic lingual thyroid masses may be treated with T4 to decrease their size or prevent further growth. In patients with symptomatic lesions, surgery is preferred, although radioactive iodine also has been used (131,132,133).


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