15 Endocrine disease
Pituitary disorders
• Anterior pituitary produces hormones necessary for growth, stress response, reproduction and metabolism.
Pituitary tumours
• Local compression effects of a pituitary tumour include:
• diplopia and III, IV and VI cranial nerve palsies secondary to tumour compression at the cavernous sinus
Treatment
Treatment (Table 15.1) options include surgery, radiotherapy and medical therapy, depending on the aetiology of the pituitary mass. Post-operative radiotherapy is used if significant tumour bulk remains after surgery or the underlying disease is still active. Radiotherapy results in a gradual decline of residual pituitary function over many years and must be monitored.
Table 15.1 Comparison of primary treatment for pituitary tumours
| Treatment method | Advantages | Disadvantages |
|---|---|---|
| Surgical | ||
| Trans-sphenoidal adenomectomy or hypophysectomy | Relatively minor procedure Potentially curative for micro- and smaller macro-adenomas |
Some extrasellar extensions may not be accessible Risk of CSF leakage and meningitis |
| Trans-frontal | Good access to suprasellar region | Major procedure; danger of frontal lobe damage High chance of subsequent hypopituitarism |
| Radiotherapy | ||
| External (40–50 Gy) | Non-invasive Reduces recurrence rate after surgery |
Slow action, often over many years Not always effective Possible late risk of tumour induction |
| Stereotactic | Precise administration of dose to lesion | Long-term follow-up data limited |
| Yttrium implantation | High local dose | Only used in few centres |
| Medical | ||
| Dopamine agonist (e.g. bromocriptine) | Non-invasive; reversible | Usually not curative; significant side-effects in minority |
| Somatostatin analogue (octreotide) | Non-invasive; reversible | Usually not curative; expensive |
| Growth hormone receptor antagonist (pegvisomant) | Highly selective | Usually not curative; very expensive |
Hypopituitarism
Clinical features
Secondary hypothyroidism (p. 571) and adrenal failure (p. 582) both lead to tiredness and general malaise:
• Hypoadrenalism causes mild hypotension, hyponatraemia and ultimately cardiovascular collapse during severe intercurrent stressful illness.
Examination
Investigation of pituitary function
• Basal serum investigations
• ACTH and 09:00 h cortisol. Individuals with normal diurnal rhythm (that is not disrupted by shift work or travel across time zones) show an early morning peak of cortisol > 500 nmol/L, which excludes ACTH deficiency. Cortisol values < 100 nmol/L at 09:00 h are strongly suggestive of hypothalamic–pituitary–adrenal (HPA) insufficiency. Levels lying between these values should be further investigated by dynamic testing of the HPA axis (see below).
• TSH, free T4, total T3. Low thyroid hormone values with a low TSH suggest secondary hypothyroidism.
• LH, FSH, oestrogen/testosterone, sex hormone-binding globulin (SHBG). Secondary hypogonadism is suggested by low LH and FSH, despite low levels of free circulating sex hormones (oestrogen and testosterone).
• Prolactin. Prolactin may be high, indicating stalk compression, or low due to compression of the normal pituitary. Very high levels (typically > 5000 mU/L) indicate a prolactinoma, which is likely to respond well to medical therapy (see p. 578).
• Insulin-like growth factor (IGF)-1. IGF-1 is produced by many tissues, including the liver, muscle and kidney, in response to growth hormone and is frequently used as a surrogate indicator of growth hormone levels. However, IGF-1 levels are also influenced by factors such as nutritional status, insulin resistance and age, complicating its interpretation.
• Dynamic tests
• Insulin tolerance test. 0.15 U/kg of short-acting insulin, administered intravenously to achieve a fall in plasma glucose to < 2.2mmol/L (confirmed by a laboratory measurement), initiates a classical stress response with release of cortisol and growth hormone. Glucose, cortisol and growth hormone levels are measured at baseline, 30, 45, 60, 90 and 120 mins. ACTH levels are also measured at baseline. A cortisol rise to > 550 nmol/L confirms an intact HPA axis; a growth hormone rise to > 20 mU/L (10 ng/L) confirms an intact growth hormone axis. The test should not be used if the 09:00 h cortisol has been shown to be < 100 nmol/L (this confirms that the patient has ACTH deficiency) or if the patient is hypothyroid. A similar response is seen after 1 mg glucagon SC. Contraindications: patients with epilepsy, unexplained losses of consciousness and ischaemic heart disease ideally should not have this test.
• Short tetracosactide test. This does not directly assess pituitary reserve and is more useful for evaluating adrenal function. Where dynamic pituitary stimulation tests are impossible, it may be used as a surrogate. Injection of 250 mcg synthetic ACTH is given intravenously, with measurement of ACTH at baseline, and cortisol at 0, 30 and 60 mins. An increase from baseline to cortisol levels > 550 nmol/L suggests normal adrenal function. A sluggish rise at 30 mins is indicative of reduced pituitary function.
Management
Options for hormone replacement regimes are given in Table 15.2.
| Axis | Usual replacement therapies |
|---|---|
| Adrenal | Hydrocortisone 15–40 mg daily (starting dose 10 mg on rising/5 mg lunchtime/5 mg evening) (Normally no need for mineralocorticoid replacement) |
| Thyroid | Levothyroxine 100–150 mcg daily |
| Gonadal | |
| Male | Testosterone IM, orally, transdermally or implant |
| Female | Cyclical oestrogen/progestogen orally or as patch |
| Fertility | HCG plus FSH (purified or recombinant) or pulsatile GnRH to produce testicular development, spermatogenesis or ovulation |
| Growth | Recombinant human growth hormone used routinely to achieve normal growth in children Also advocated for replacement therapy in adults where growth hormone has effects on muscle mass and well-being |
| Thirst | Desmopressin 10–20 mcg 1–3 times daily by nasal spray or orally 100–200 mcg 3 times daily Carbamazepine, thiazides and chlorpropamide are very occasionally used in mild diabetes insipidus |
| Breast (prolactin inhibition) | Dopamine agonist (e.g. cabergoline 500 mcg weekly) |
FSH, follicle-stimulating hormone; GnRH, gonadotrophin-releasing hormone; HCG, human chorionic gonadotrophin.
Thyroid disorders
The thyroid hormones, T4 and T3, are produced within the thyroid gland. Synthesis and release are stimulated by TSH, which is released from the pituitary gland in response to the hypothalamic factor, TRH (thyrotrophin-releasing hormone) (Fig. 15.1). Predominantly, T4 is produced, but this is converted in the peripheral tissues (liver, kidney, muscle) to the more active T3. More than 99% of T4 and T3 circulate bound to plasma proteins, mainly thyroid-binding globulin (TBG).
Thyroid function tests
• Measurement of plasma TSH is the single most useful assessment of thyroid function, even for the detection of mild disease. Levels will increase in response to falling levels of circulating active thyroid hormones and fall with high levels of thyroid hormone. Exceptions include pituitary disease and ‘sick euthyroid syndrome’, in which TSH may be low without hyperthyroidism.
Problems in interpreting thyroid function tests
• Serious acute or chronic illness. Failure of conversion of T4 to T3 (in favour of reverse T3) causes a reduction in hypothalamic–pituitary production of TSH, resulting in low/normal measurements of all factors.
• Pregnancy or oral contraceptive use. Increased levels of TBG lead to higher levels of total T4 and T3. Levels of free hormone are unaffected. The TSH can be low.
• Heterophile antibodies. These interfere with assay measurements of hormone levels and lead to bizarre thyroid function tests that have no obvious clinical explanation. The laboratory should be able to confirm this with additional testing.
• Amiodarone. This prevents generation of T3 from T4, resulting in an increase in T4 levels. Tissue perception of this is of ‘reduced’ active T3 levels, and TSH levels may therefore increase. Amiodarone also provides a significant iodine load, up to 100 times the daily recommended amount. This can have two effects on thyroid function. The iodine load can:
• precipitate thyrotoxicosis by unmasking subclinical hyperthyroidism in an iodine-deplete individual (amiodarone-induced thyrotoxicosis type 1) or
Hypothyroidism
• Primary hypothyroidism is confirmed by high levels of TSH. ‘Compensated’ hypothyroidism comprises a slightly raised TSH (typically < 10 mU/L) with normal levels of T4 and T3. Further failure of the thyroid gland results in increasing TSH and falling levels of T4 and T3 below the normal range.
• Secondary hypothyroidism is due to pituitary–hypothalamic failure; there is no increase in TSH despite falling levels of thyroid hormone.
Investigations
Treatment
• Thyroxine (T4) replacement is lifelong, with the aim of reducing the TSH level to the lower half of the normal range. A typical replacement dose is levothyroxine between 100 and 150 mcg per day. Starting doses range between 25 mcg and 100 mcg, depending on existing co-morbidity.
• Patients with heart disease benefit from slow increments of thyroxine, and adjustments to anti-anginal therapy may be required. In severe cardiac disease treatment may be initiated with a small dose of T3 (liothyronine) 2.5 mcg every 8 hours, doubling the dose every 48 hours until a maximal dose of 10 mcg 3 times daily is achieved. T4 is then commenced at this point and the T3 discontinued 5 days later.
Myxoedema coma
• General management includes maintenance of airway and body warmth (but not active rewarming, which risks peripheral vasodilatation and cardiovascular collapse), restriction of free water and glucose supplementation.
• IV hydrocortisone replacement 100 mg every 8 hours should be initiated, after blood tests have been taken for ACTH and cortisol.
• Thyroid hormone should be given without waiting for biochemical confirmation of hypothyroidism. There is no consensus on method of thyroid hormone replacement. Some advocate the use of 300–500 mcg levothyroxine IV followed by 50–100 mcg daily (either orally or IV). Others advocate a lower-dose regimen of 25 mcg levothyroxine daily, increasing on a weekly basis.
Hyperthyroidism
Clinical features
• Graves’ disease. This autoimmune disease is the commonest form of thyrotoxicosis. In addition to symptoms and signs of hyperthyroidism, there may be ocular changes (exophthalmos and ophthalmoplegia), pretibial myxoedema and thyroid acropachy. Other autoimmune diseases, such as pernicious anaemia and myasthenia gravis, are also associated. The degree of thyrotoxicosis may fluctuate and the typical picture is of relapses and remissions. Ultimately many patients become hypothyroid.
• Toxic solitary nodule/toxic multinodular goitre. Although typical thyrotoxicosis can occur, autonomy within a nodule may not cause complete suppression of TSH.
• De Quervain’s thyroiditis. A transient episode of hyperthyroidism can occur with acute inflammation of the thyroid, secondary to viral infections such as mumps, Coxsackie, influenza, adenoviruses and echoviruses. Toxicosis may last for some weeks and may be followed by a period of hypothyroidism. In its acute phase it is accompanied by fever, malaise and local thyroid tenderness, and the ESR is often raised. Symptomatic treatment is with NSAIDs or aspirin, with the option of short-term prednisolone starting at 40 mg per day, reducing over 6 weeks.
Treatment (Table 15.3)
There are three main options and preference varies widely.
• Antithyroid medications. Carbimazole initially 20 mg 3 times daily is the drug most commonly used in the UK. Its active metabolite, methimazole, is used preferentially in the USA. These drugs inhibit the formation of thyroid hormone and the clinical benefits can take up to 2 weeks to become apparent. Propylthiouracil 300–600 mg daily is occasionally used as an alternative, particularly during pregnancy and breast feeding. It has additional theoretical benefits in that it prevents peripheral conversion of T4 to T3. The major side-effect of these medications is agranulocytosis, and prior to commencing treatment patients should be told to seek medical help should severe mouth ulcers, sore throat or febrile illness occur. A white blood cell count is then urgently required. Antithyroid medication also reduces the immune processes and thus a trial of therapy for up to 18–24 months may result in remission of autoimmune thyrotoxicosis. Initially doses of antithyroid medications are high. There is then the option of dose reduction as the thyroid tests normalize, or the option of adding thyroxine to high-dose anti-thyroid medication (‘block and replace regimen’). A fall of T4 and T3 in response to treatment guides initial dose reductions (gradually reduce dose to 5 mg over 6 to 24 months if hyperthyroidism is controlled), as the TSH may remain suppressed for some time. Antithyroid medications will never lead to remission in toxic nodular disease, and while long-term antithyroid medications are an option, more definitive treatment is required.
• Radioactive iodine. This is increasingly accepted as a safe treatment option in the management of adults with thyrotoxicosis. It provides definitive treatment for toxic nodular disease and can be used in Graves’ disease, although there are concerns that antibody levels rise following treatment and these can exacerbate dysthyroid eye disease. Patients should be made euthyroid prior to therapy but anti-thyroid medications should be discontinued at least 4 days before. A pregnancy test is performed in young females. Following treatment with 131iodine 200–550 MBq, patients must be monitored for a short-term ‘flare’ of thyrotoxicosis (transient hypothyroidism may also occur) and for longer-term development of hypothyroidism. The presence of a large goitre with potential for airway compromise is a contraindication. Radioactive iodine is contraindicated in pregnancy and lactation.
• Surgery. Subtotal thyroidectomy is performed when anti-thyroid medications are not tolerated, when radioactive iodine is contraindicated, or for cosmetic reasons. All patients must be rendered euthyroid, stopping the antithyroid drugs 1–2 weeks before surgery and giving 60 mg of potassium iodide 3 times daily to reduce the vascularity of the gland.
• Transient hypocalcaemia is relatively common following surgery due to trauma to the parathyroid glands and disruption to the blood supply. This resolves with oral or IV calcium supplementation. Long-term replacement with alfacalcidol 0.25–1 mcg/day is occasionally required. Damage to the recurrent nerve and permanent loss of parathyroid gland function can occur. Function from the residual gland may be sufficient to avoid thyroid hormone replacement.
