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

59.The Adrenal Cortex in Hypothyroidism

Robert G. Dluhy

Physicians and physiologists have long known of a connection between hypothyroidism and adrenocortical dysfunction. A potentially important interrelationship was recognized more than 50 years ago in patients with central (secondary) hypothyroidism resulting from pituitary insufficiency, when treatment of such patients with thyroxine (T4) without the simultaneous administration of cortisol was noted to exacerbate unrecognized secondary adrenocortical failure and result in adrenal crisis if a major stress such as surgery or sepsis supervened (1). This observation is best explained by thyroid hormone–induced stimulation of the metabolism of cortisol and other adrenocortical steroids (2,3) (see Chapter 37). If the cortisol pool is small and the hypothalamic–pituitary–adrenal system is atrophic, compensation may be inadequate.

EFFECTS OF HYPOTHYROIDISM ON CORTISOL PRODUCTION AND CLEARANCE

Cortisol secretion and metabolism are decreased in patients with both primary and secondary hypothyroidism. The magnitude of the changes in secretion and metabolism is similar; therefore, the patients' serum cortisol concentrations and urinary cortisol excretion are normal (4). In contrast, the urinary excretion of cortisol metabolites and of 17-ketosteroids is low, reflecting the decrease in cortisol secretion rate (2,3). Treatment with T4 increases the hepatic metabolism of cortisol and other steroids to normal. As cortisol metabolism increases and serum cortisol concentrations decline, corticotropin (ACTH) secretion increases, resulting in restoration of normal production of cortisol (and other ACTH-dependent steroids). The serum concentrations of these steroids therefore remain normal owing to the intact feedback relationship.

Thyroid hormone stimulates the activity of hepatic Δ4,5-steroid reductases, and it decreases the reductase activity of hepatic 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1, thereby decreasing conversion of cortisone, which is biologically inactive, to cortisol. Thus, the ratio of tetrahydrocortisone to tetrahydrocortisol provides an assessment of peripheral thyroid hormone action. For example, patients with thyrotoxicosis have a high ratio, and it is normal in patients with high serum T4 concentrations who have thyroid hormone resistance (5) (see Chapter 81). Conversely, in patients with overt hypothyroidism, 11β-HSD type 1 reductase activity is increased, and therefore cortisone conversion to cortisol is increased, with a consequent decrease in the ratio of tetrahydrocortisone to tetrahydrocortisol in urine (6). Measurement of urinary cortisol metabolites provides an index of peripheral thyroid hormone action. In one study the ratio of tetrahydrocortisone to tetrahydrocortisol was low in patients with overt hypothyroidism but normal in patients with subclinical hypothyroidism; although the mean ratios did not differ between the patients with subclinical hypothyroidism and normal subjects, half of the patients had ratios more than 1 standard deviation (SD) below the mean value in the normal subjects (7).

11β-HSD type 1 is active primarily as a reductase (cortisone to cortisol) in the liver, as noted above. 11β-HSD type 2 is active primarily as a dehydrogenase in the kidney (8). Normally, cortisol is metabolized to cortisone by 11β-HSD type 2 in the kidney, thus serving to “protect” the renal mineralocorticoid receptor from activation by cortisol. 11β-HSD type 2 deficiency states, such as licorice ingestion and possibly hypothyroidism, allow cortisol to act as a mineralocorticoid and activate mineralocorticoid receptors. As a result, sodium is retained and the renin–angiotensin–aldosterone system is suppressed.

EFFECTS OF HYPOTHYROIDISM ON PITUITARY–ADRENAL FUNCTION

Pituitary–adrenal responses to administration of metyrapone or insulin-induced hypoglycemia are normal or slightly decreased in patients with primary hypothyroidism (9); the responses tend to be more abnormal in patients with more severe hypothyroidism (10). Similarly, the adrenal response to exogenous ACTH is normal or decreased. In a study of the dynamics of 24-hour cortisol secretion in patients with primary hypothyroidism, the mean 24-hour serum cortisol concentration was slightly high, the circadian rhythmicity of serum cortisol was normal, and cortisol clearance was slowed; the calculated endogenous production rate of cortisol was normal (4). Serum corticosteroid-binding globulin (CBG) concentrations also were normal in these patients. Most of the abnormalities were not fully reversed after T4therapy for 6 months, but many of the patients still had high serum thyrotropin (TSH) concentrations at that time. The mild hypercortisolemia in these hypothyroid patients with a normal endogenous cortisol production rate is consistent with a decrease in the negative feedback effect of cortisol on corticotropin-releasing hormone (CRH) or ACTH secretion. Other evidence of hypothalamic dysfunction in hypothyroidism is the finding of an exaggerated ACTH response to ovine CRH (11).

In sum, patients with primary hypothyroidism have abnormalities of pituitary–adrenal function that may be correlated with the severity and duration of their hypothyroidism. Although cortisol is secreted and disposed of at a rate that is slower than normal, however, the quantity available to peripheral tissues is normal. Thus, basal pituitary–adrenal function is normal or reduced. The theoretic possibility has been raised that vigorous T4 treatment in patients with severe hypothyroidism might induce adrenocortical insufficiency (2,3). In practice, this does not occur except in patients with severe concomitant adrenal deficiency (1).

On the other hand, the hypothalamic–pituitary–adrenal system is hypofunctioning in patients with severe, long-standing primary hypothyroidism, probably as a result of the chronically reduced requirements for glucocorticoid (10,12). The association of hypothyroidism and hypoadrenalism always should be kept in mind, however, because of the possibility of concurrent thyroid insufficiency and primary adrenal insufficiency or autoimmune pituitary destruction (lymphocytic hypophysitis). Therefore, acutely ill patients with severe hypothyroidism or myxedema coma should be treated presumptively with cortisol, unless or until their adrenal function is determined to be normal (see Chapter 65).

EFFECTS OF HYPOTHYROIDISM ON THE RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM

Hypothyroidism is accompanied by decreases in many components of the renin–angiotensin–aldosterone system, including the secretion of renin (13,14), the hepatic production of angiotensinogen (15), serum angiotensin-converting enzyme activity (15), and the adrenal production and metabolism of aldosterone (16,17). The dominant effect is to decrease the hepatic degradation of aldosterone, similar to that described for cortisol; this decrease in the hepatic clearance of aldosterone results in an increase in its plasma half-life (2,18). The reduced rate of clearance of aldosterone is balanced by a lower secretion rate, and so serum aldosterone concentrations are usually normal. Independently, angiotensinogen production by the liver is decreased (15), as are serum angiotensin-converting enzyme concentrations (19) and plasma renin activity (14). Despite these multiple effects of hypothyroidism, its overall effects on the renin–angiotensin–aldosterone system are minimal, and they are not responsible for alterations in sodium and potassium homeostasis (13) or for the hypertension that occurs in some patients with hypothyroidism (see Chapters 53 and 55). As described above, changes in hepatic 11β-HSD type 1 activity and renal 11β-HSD type 2 activity in severe hypothyroidism may result in an increase in cortisol sufficient to activate renal mineralocorticoid receptors; this could contribute to hypertension, sodium retention, and lower serum aldosterone concentrations (20).

POLYGLANDULAR AUTOIMMUNE SYNDROMES

Schmidt's Syndrome

In 1926, Schmidt reported two patients who died of Addison's disease and were found at autopsy to have bilateral nontuberculous atrophy of the adrenal cortex, lymphocytic infiltration of the thyroid, and a normal pituitary gland (21). Neither patient was deemed hypothyroid, but Schmidt believed that both would have become hypothyroid had they survived. He based this speculation on what he thought to be the progressive character of the thyroid lesion, which resembled what is now known as chronic autoimmune thyroiditis, and his article emphasized his conviction that the pathologic lesions in the thyroid and adrenal were similar.

Many reports subsequently documented the coincidence of primary adrenal insufficiency and primary hypothyroidism, and the combination has come to be known as Schmidt's syndrome (22,23). This syndrome is more common in women, most of whom are in the age range of 20 to 50 years; there is strong evidence for a genetic predisposition to and an autoimmune basis for this syndrome (22,23,24,25,26). For example, thyroid involvement occurs nine times more often in patients with idiopathic (autoimmune) Addison's disease than in those with tuberculous Addison's disease (24), and the histopathologic features of the thyroid and adrenal lesions in Schmidt's syndrome resemble those of experimental autoimmune thyroiditis and adrenalitis. Because the syndrome often occurs with other autoimmune endocrine disorders, such as type 1 diabetes mellitus and primary ovarian failure (25,26), it probably should be viewed as one phenotype within the type 2 polyglandular failure syndrome (see later).

Some patients with idiopathic Addison's disease have slightly high serum TSH concentrations and serologic evidence of chronic autoimmune thyroiditis. In these patients, glucocorticoid replacement therapy results in normalization of TSH secretion (27,28), probably because even normal amounts of glucocorticoid reduce the intensity of chronic autoimmune thyroiditis and allow an increase in thyroid secretion. The clinical importance of this phenomenon is that a patient presenting with idiopathic Addison's disease and a slightly high serum TSH concentration should be treated with adrenal replacement therapy alone, with subsequent reassessment of thyroid function before T4 therapy is begun. If the patient has symptoms and signs of hypothyroidism, a higher serum TSH concentration (>20 mU/L), and a low serum T4 concentration, however, a diagnosis of Schmidt's syndrome is presumed, and both thyroid and adrenal replacement therapy should be instituted at the outset.

Type 1 and Type 2 Polyglandular Autoimmune Syndromes

Two distinct polyglandular autoimmune syndromes have been described (29,30,31,32,33). The type 1 syndrome consists of at least two of the triad of Addison's disease, hypoparathyroidism, and chronic mucocutaneous candidiasis; associated autoimmune disorders, such as chronic autoimmune thyroiditis, pernicious anemia, malabsorption, and alopecia universalis, also may be present. This rare syndrome usually presents with persistent candidiasis during infancy, with the associated autoimmune disorders usually appearing before puberty. The more common type 2 syndrome consists of Addison's disease with chronic autoimmune thyroiditis (Schmidt's syndrome), type 1 (autoimmune) diabetes mellitus, primary hypogonadism (especially in women), and several other autoimmune diseases, but not hypoparathyroidism or candidiasis. In contrast to the type 1 syndrome, the type 2 syndrome usually occurs in young or middle-aged women.

The range of autoimmune disorders that have been reported in association with Addison's disease is shown in Table 59.1, and the differences between the type 1 and type 2 forms of polyglandular autoimmune disease are shown in Table 59.2. There is considerable genetic heterogeneity in both disorders. The type 1 syndrome is inherited as an autosomal-recessive disorder (only siblings are affected). It is caused by loss-of-function mutations in the AIRE (autoimmune regulator) gene, which encodes a transcription factor (34). The type 2 syndrome is most often familial (autosomal dominant) and has distinct HLA associations (Table 59.2).

TABLE 59.1. ASSOCIATED AUTOIMMUNE DISORDERS IN 295 PATIENTSa WITH TYPE 1 OR TYPE 2 POLYGLANDULAR AUTOIMMUNE SYNDROME WHO HAD ADDISON'S DISEASE


Associated Entity

No. (%)

Females

Males

Female:Male Ratio


Chronic autoimmune thyroiditis

162 (55)

112

50

2.2

Type 1 (autoimmune) diabetes mellitus

118 (40)

66

52

1.3

Hypoparathyroidism

54 (18)

33

21

1.6

Chronic mucocutaneous candidiasis

52 (15)

29

23

1.3

Alopecia

24 (8)

14

10

1.4

Primary hypogonadism

20 (7)

15

5

3.0

Vitiligo

16 (5)

8

8

1.0

Intestinal malabsorption

16 (5)

6

10

0.6

Pernicious anemia

10 (3)

4

6

0.7

Chronic active hepatitis

9 (3)

6

3

2.0


a 183 females and 112 males

From Neufeld M, Maclaren NK, Blizzard RM. Two types of autoimmune Addison's disease associated with different polyglanddular autoimmune (PGA) autoimmune syndromes. Medicine 1981;60:355, with permission.

TABLE 59.2. CLINICAL CHARACTERISTICS OF PATIENTS WITH TYPE 1 AND TYPE 2 POLYGLANDULAR AUTOIMMUNE SYNDROMES


 Type 1

Type 2


Age at onset

Childhood

Adult life

Female:male ratio

1.0

Female preponderance

HLA associations

None

HLA-DR3, HLA-DR4

Gene (inheritance)

AIRE (recessive)

Polygenic

Disease components (% of patients)

 

 

   Addison's disease

100

60–67

   Chronic autoimmune thyroiditis, Grave's disease

10–12

70

   Diabets mellitus

2–4

50–52

   Hypoparathyoidism

82–89

None

   Chronic mucocutaneous candidiasis

73–78

None

   Primary hypogonadism

5–50

12–45

   Pernicious anemia

1

12–16

   Vitiligo

4–9

4–5

   Alopecia

20–32

Undetermined

   Chronic active hepatitis

11–13

None

   Malabsorption syndrome

22–25

None

   Myasthenia gravis

None

Undetermined


HLA, human leukocyte antigen.

Adapted from Strakosch CR, Wenzel BE, Row vv et al. Immunology of autoimmune thyroid diseases. N Engl j Med 1982;307:1499, with permission.

These polyglandular autoimmune disorders are primarily the result of T cell–mediated glandular destruction. The serum antibodies found in many patients with either syndrome also may be pathogenic, having cytotoxic properties or inhibiting tropic hormone actions on their target glands (30,31,33,34,35,36). Tests for antibodies reacting with steroid 21-hydroxylase (CYP21) have excellent sensitivity and specificity for diagnosing incipient or overt adrenal insufficiency (37). In contrast to serum antithyroid antibodies, which may be present in high concentrations for long periods without progression to hormonal insufficiency, high serum antiadrenal antibody concentrations often signal more rapid progression to adrenal insufficiency. Among patients with high serum 21-hydroxylase antibody concentrations, specific genotypes (DR and DQ) greatly increase the risk for progression to adrenal insufficiency (38).

The clinical importance of these findings is clear. If a single autoimmune endocrine disease is discovered, another may appear later. High serum antibody concentrations often precede the onset of clinical disease. Thus, patients with hypothyroidism caused by chronic autoimmune thyroiditis should be monitored for these other disorders, especially if there is a family history of endocrine deficiency.

Glucocorticoids, Thyroid Disease, and Thyroid Function

When replacement doses of a glucocorticoid are given to patients with primary or secondary hypothyroidism, signs of Cushing's syndrome may appear (39,40) because of the hypothyroidism-induced decrease in cortisol clearance (2). This decrease also explains why patients with hypothyroidism are more susceptible than normal subjects to the undesirable effects of glucocorticoid therapy. This clinical state of relative hyperadrenocorticism abates when thyroid hormone is given and the normal rate of metabolism of not only cortisol but also synthetic glucocorticoids is restored (2,39,40).

Hyperadrenocorticism

Patients with either endogenous or exogenous Cushing's syndrome have multiple abnormalities in pituitary–thyroid function. These changes are more biochemically evident than clinically important, and they disappear after the Cushing's syndrome is treated or the exogenous glucocorticoid is discontinued. Glucocorticoid excess also may suppress chronic autoimmune thyroiditis, and it may become evident as hypothyroidism or goiter after reversal of the glucocorticoid excess (41). In addition, high doses of glucocorticoids ameliorate thyrotoxicosis in patients with silent thyroiditis or Graves' disease. In summary, the anti-inflammatory or immunosuppressive actions of glucocorticoids can ameliorate both thyrotoxicosis and hypothyroidism when the underlying cause is thyroid autoimmune disease.

Effects of Glucocorticoids on Thyroid Function

High doses of glucocorticoids have multiple reversible effects on pituitary–thyroid function, including inhibition of TSH secretion (42), decreased serum thyroxine-binding globulin (TBG) concentrations (43), inhibition of extrathyroidal conversion of T4 to triiodothyronine (T3) (44,45), and an increase in the renal clearance of iodide (46) (Table 59.3). Thus, serum TSH, TBG, T4, and T3 concentrations are slightly decreased, albeit usually within their respective ranges of normal; serum free T4 values are normal. With respect to TSH secretion, the effect of glucocorticoids is to decrease the amplitude of TSH pulses, probably by inhibiting the secretion of thyrotropin-releasing hormone (TRH) (47) (see Chapter 12). There is, in time, escape from glucocorticoid-induced suppression of TSH secretion, which is why patients with either exogenous or endogenous Cushing's syndrome have serum-free T4 concentrations within the normal range. The increase in renal clearance of iodide is modest and does not materially affect iodide availability unless dietary intake is limited.

TABLE 59.3. EFFECTS OF GLUCOCORTICOIDS ON PITUITARY-THYROID FUNCTION


Inhibition of TSH sescretion (transient)

Decrease in serum thyroxine-binding globulin concentrations

Inhibition of extrathyrodal conversion of T4 to T3

Increase in renal iodide clearance


T3, triiodothyronine; T4, thyroxine; TSH, thyrotropin.

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