Category Archives: Endocrinology.

DISEASES OF MANY GLANDS

Multiple gland failure

This is caused by autoimmune disease as detailed. Commonest are the associations of primary hypothyroidism and type 1 diabetes, and either of these with Addison’s disease or pernicious anaemia.

Multiple endocrine neoplasia

This is the name given to the simultaneous or metachronous recurrence of tumours involving a number of endocrine glands. They are inherited in an autosomal dominant manner and are thought to arise from the expression of a recessive oncogenic mutation, which has now been isolated.
Affected persons may pass on the mutation to their offspring in the germ cell, but for the disease to become evident a somatic mutation must also occur, e.g. deletion or loss of a normal homologous chromosome. The defect in MEN 1 is on the long arm of chromosome 11 near an area containing a number of oncogenes that encode for proteins with fibroblastic growth factor activity. The gene for MEN 2a is on chromosome 10 close to the retinol binding gene.
Screening unaffected members of a family shows that a significant number of affected individuals are unrecognized, especially with hypercalcaemia.

MANAGEMENT

Treatment is surgical.

TYPE 1. All four parathyroid glands are removed (as all may be involved) followed by vitamin D (1,25- dihydrocalciferol) replacement therapy. Pancreatic tumours are often multiple and recurrence after partial pancreatectomy is invariable. Other tumours are treated surgically if necessary.
TYPE 2. Tumours may also be recurrent or bilateral and a careful follow-up is necessary.

Symptoms

Anxiety or panic attacks
Palpitations
Tremor
Sweating
Headache
Flushing
Nausea and/or vomiting
Weight loss
Constipation or diarrhoea
Raynaud’s phenomenon
Chest pain
Polyuria/nocturia
Signs
Hypertension-intermittent or constant
Tachycardia plus arrhythmias
Bradycardia
Orthostatic hypotension
Pallor or flushing
Glycosuria
Fever
(Signs of hypertensive damage)

Screening

A careful family history should first be taken. If negative, it does not exclude involvement and it may need repeating at regular (1-5 year) intervals.
1 Type 1. Fasting calcium estimation (if elevated, look for other manifestations of MEN 1). 2 Type 2
(a) Medullary carcinoma of thyroid (MCT). Pentagastrin and calcium infusion test with measurement of calcitonin to pick up ‘C’ cell hyperplasia: doubling of the calcitonin level is abnormal.
(b) Phaeochromocytoma. VMA and metanephrine estimations.

ECTOPIC HORMONE SECRETION

This terminology refers to hormone synthesis, and normally secretion, from a neoplastic non-endocrine cell, most usually seen in tumours that have some degree of embryological resemblance to specialist endocrine cells. Multiple theories have been advanced to explain the occurrence. The clinical effects may be those of the hor- .mone produced, with or without manifestations of systemic malignancy.
The commonest situations seen are:
HYPERCALCAEMIA OF MALIGNANT DISEASE, often from squamous cell tumours of lung and breast, often with bone metastases. It is mediated by many different factors, but very rarely by PTH itself; a PTH-related protein (PTHrP) with considerable sequence homology has recently been isolated and appears to be the most frequent cause.
SIAD H. Again, this is commonest from a primary lung tumour. ECTOPIC ACTH SYNDROME. Small-cell carcinoma of the lung, carcinoid tumours and medullary thyroid carcinomas are the commonest causes.
PRODUCTION OF INSULIN-LIKE ACTIVITY may result in hypoglycaemia.

ENDOCRINE TREATMENT OF OTHER MALIGNANCIES

Endocrine forms of treatment for malignancy have been used for many years, for example oophorectomy for breast cancer and orchidectomy for prostatic malignancy. Newer more acceptable therapies include the antioestrogen tamoxifen for breast carcinoma and the LHRH analogues, buserelin and goserelin, for prostatic cancer.

The control of blood pressure (BP) is complex involving neural, cardiac, hormonal and many other mechanisms. BP is dependent upon cardiac output and peripheral resistance. Although cardiac output can be increased in endocrine disease (e.g. thyrotoxicosis), the main role of hormonal mechanisms is control of peripheral resistance  and of circulating blood volume. The oral contraceptive pill is a common endocrine cause of hypertension. When to investigate for secondary

Hypertension

Endocrine causes account for less than 5% of all hypertension (Table 16.39). It is impracticable and unnecessary to screen all hypertensive patients for secondary causes. The highest chances of detecting such causes are in:
• Subjects under 35 years old, especially those without a family history of hypertension
• Those with accelerated (mali nant) hypertension
• Those with indications of renal disease (proteinuria, unequal renal sizes)
• Those with hypokalaemia before diuretic therapy
• Those resistant to conventional antihypertensive therapy
• Those with unusual symptoms (e.g. sweating attacks or weakness)
Excessive renin, and thus angiotension II, production
Renal artery stenosis
Other local renal disease
Renin-secreting tumours
Excessive production of catecholamines
Phaeochromocytoma
Excessive GH production
Acromegaly
Excessive aldosterone production
Adrenal adenoma (Conn’s syndrome)
Idiopathic adrenal hyperplasia
Dexamethasone-suppressible hyperaldosteronism
Excessive production of other mineralocorticoids
Cushing’s syndrome (massive excess of cortisol, a weak mineralocorticoid)
Congenital adrenal hyperplasia (in some cases)
Tumours producing other mineralocorticoids, e.g. corticosterone
Exogenous ‘mineralocorticoids’
Liquorice ingestion
Abuse of mineralocorticoid preparations

The renin-angiotensin-aldosteroneaxis

Biochemistry and actions

The renin-angiotensin-aldosterone system is illustrated Angiotensinogen, an a2-globulin of hepatic origin, circulates in plasma. The enzyme, renin, is secreted by thekidney in response to decreased renal perfusion pressure  or flow; it cleaves the decapeptide angiotensin I from angiotensinogen. Angiotensin I is inactive but is further cleaved by converting enzyme (present in lung and vascular endothelium) into the active peptide, angiotensin II, which has two major actions:
1 It causes powerful vasoconstriction (within seconds).
2 It stimulates the adrenal zona glomerulosa to increase aldosterone production. Aldosterone causes sodium retention and urinary potassium loss (hours to days).
The vasoconstrictor action of angiotensin II is short term, while the sodium retention induced by aldosterone increases total body sodium and BP in the longer term. As BP increases and sodium is retained, the stimuli to renin secretion are reduced. Dietary sodium excess will tend to suppress renin secretion, whereas sodium deprivation or urinary sodium loss will increase it.

Atrial natriuretic factors/peptides (ANP)

These peptides are secreted from atrial granules. They produce marked effects on the kidney, increasing sodium and water excretion and glomerular filtration rate and lowering BP, plasma renin activity and plasma aldosterone. They appear to playa significant role in cardiovascular and fluid homeostasis but there is no evidence of primary defects in their secretion causing disease. Analogues that break down ANP as well as inhibiting the aminopeptidases are under development and might prove of value in producing a sodium diuresis.
RENIN (AND ANGIOTENSIN)

DEPENDENT HYPERTENSION

Many forms of unilateral and bilateral renal diseases are associated with hypertension. The classic example is renal artery stenosis: the major hypertensive effects of this and other situations such as renin-secreting tumours are directly or indirectly due to angiotensin II.
Renin inhibitors have  been produced and are under clinical trial. They appear to produce much the same effects as angiotensin-converting enzyme inhibitors and hold promise as antihypertensive agents, though none are yet available for clinical use.

Renal artery stenosis

DISORDERS OF ALDOSTERONE SECRETION

Primary hyperaldosteronism

PATHOPHYSIOLOGY

This rare condition « 1% of all hypertension) is causedby excess aldosterone production leading to sodium retention, potas sium loss and the combination of hypokalaemia and hypertension.

CAUSES

Adrenal adenomas (Conn’s syndrome) account for 60% of cases; 30% are due to bilateral adrenal hyperplasia, which may be secondary to excess of a pituitary aldosterone- stimulating factor that is as yet unidentified.

CLINICAL FEATURES

The usual presentation is with hypertension and hypokalaemia «3.5 mmol litre””), although 20% of patients have initial potassium levels of 3.5-4.2 mmollitre-I. The few symptoms are non-specific; muscle weakness, nocturia and tetany are rarely seen. The hypertension may be severe and associated with renal and retinal damage. Adenomas, often very small, are commoner in young females, while bilateral hyperplasia rarely occurs before age 40 years and is commoner in males.

INVESTIGATION

The characteristic features are:
HYPOKALAEMIA. A high-salt diet should be given for several days before testing and diuretics must be stopped 3 weeks before investigation; plasma samples must be separated quickly. Bethanidine or prazosin may be used for temporary control of blood pressure as they do not alter renin or aldosterone secretion.
URINARY POTASSIUM LOSS. Levels over 30 mmol daily during hypokalaemia are inappropriate.
ELEVATED PLASMA ALDOSTERONE LEVELS that are not suppressed with saline infusion (300 mmol over 4 hours) or fludrocortisone administration.
SUPPRESSED PLASMA RENIN ACTIvITy-l3-blockers and other drugs may interfere with renin activity. Once a diagnosis of aldosteronism is established, differentiation of adenoma from hyperplasia involves adrenal CT or MRI (not infallible as tumours may be very small), complex biochemical testing, adrenal scintillation scanning (now rarely needed) and venous catheterization.

TREATMENT

An adenoma should be surgically removed; BP falls in 70% of patients. Those with hyperplasia should be treated with the aldosterone antagonist spironolactone (100- 400 mg daily); side-effects include nausea, rashes and gynaecomastia. Amiloride (10-40 mg daily) is a less effective alternative, used especially as spironolactone in long term use has been linked with tumour development in animals. Calcium channel blockers are also effective.

Secondary hyperaldosteronism

This situation arises when there is excess renin (and hence angiotensin II) stimulation of the zona glornerulosa. Common causes are accelerated hypertension and renal artery stenosis, when the patient will be hypertensive. Causes associated with normotension include congestive cardiac failure and cirrhosis, where excess aldosterone production contributes to sodium retention. Spironolactone is of value in both situations. Angiotensin-
converting enzyme (ACE) inhibitors, e.g. captopril, enalapril or lisinopril, are effective in heart failure, both symptomatically and in increasing life expectancy.

Hypoaldosteronism

Except as part of primary hypoadrenalism (Addison’s disease, see p.813), this is very uncommon. Causes include hyporeninaemic hypoaldosteronism, aldosterone biosynthetic defects and drugs (e.g. ACE inhibitors, heparin).

THE ADRENAL MEDULLA

The major catecholamines, noradrenaline and adrenaline, are produced in the adrenal medulla although most noradrenaline is derived from sympathetic neuronal release. While noradrenaline and adrenaline undoubtedly produce hypertension when infused, they probably play little part in BP regulation in normal humans.

Phaeochromocytoma

Phaeochromocytomas, tumours of the sympathetic nervous system, are very rare (less than 1 in 1000 cases of hypertension); 90% arise in the adrenal, while 10% occur elsewhere in the sympathetic chain; 25% are multiple and 10% are malignant, though this cannot be determined on simple histological examination. Some are associated with MEN syndromes (see below). Most tumours release both noradrenaline and adrenaline but large turn ours produce almost entirely noradrenaline.

CLINICAL FEATURES

The clinical features are those of catecholamine excess and are frequently, but not necessarily, intermittent. The diagnosis should particularly be considered when cardiovascular instability has been demonstrated and in severe hypertension in pregnancy.

DIAGNOSIS

The possibility needs to be considered quite frequently in patients with hypertension. Specific tests are:
MEASUREMENT OF URINARY METABOLITES (preferably metanephrines rather than vanillylmandelic acid (VMA) – Fig. 16.29) is a useful screening test;
normal levels on three 24-hour collections of metanephrines virtually exclude the diagnosis. Many drugs and dietary vanilla interfere with these tests.
IF HIGH METANEPHRINES OR VMAs ARE FOUND, plasma catecholamines are estimated.
URINARY CATECHOLAMINES are measured in some centres.
CT SCANS, initially of the abdomen, are helpful to localize the tumours which are often large. MR I usually shows the lesion clearly.
SCANNING WITH [131I] METAIODOBENZYLGUANIDINE  produces specific uptake in sites of sympathetic activity with about 90% success. It is particularly useful in extra-adrenal turn ours.

TREATMENT

Tumours should be removed if this is possible. Medical preoperative and perioperative treatment is vital and includes complete a- and f3-blockade with phenoxybenzamine (20-80 mg daily initially in divided doses), then propranolol (120-240 mg daily), plus transfusion of whole blood to re-expand the contracted plasma volume. The a-blockade must precede the f3-blockade. Labetolol is not recommended. Surgery in the unprepared patient is fraught with dangers of both hypertension and hypotension; expert anaesthetic help is vital and sodium nitroprusside should be available in case sudden severe hypertension develops.
When operation is not possible, combined a- and f3- blockade can be used long term. Patients should be kept under clinical and biochemical review after tumour resection as about 10% recur or
develop a fur ther tumour.

Thirst and water regulation is largely controlled by ADH (vasopressin), which is synthesized in the hypothalamus, and then migrates in neurosecretory granules along axonal pathways to the posterior pituitary. Pituitary damage alone without hypothalamic involvement does not therefore lead to ADH deficiency as the hormone can still ‘leak’ from the damaged end of the intact axon. Changes in plasma osmolality are sensed by osmoreceptors in the anterior hypothalamus. Vasopressin secretion is suppressed at levels below 280 mosmol kg “, thus allowing maximal water diuresis. Above this level, plasma vasopressin increases in direct proportion to plasma osmolality. At the upper limit of normal (295 mosmol kg-I) maximum antidiuresis is achieved and thirst is experienced at about 298 mosmol kg-I. Other factors affecting vasopressin release.

At normal concentrations the kidney is the predominant site of action. Via a cyclic AMP mechanism it allows the collecting tubule to become permeable to water, thus permitting reabsorption of hypotonic luminal fluid. At high concentrations vasopressin also causes vasoconstriction. Disorders of vasopressin secretion or activity include:
• Deficiency as a result of hypothalamic disease (diabetes insipidus)
• Inappropriate excess of the hormone
• ‘Nephrogenic’ diabetes insipidus-a condition in
which the renal tubules are insensitive to vasopressin, an example of a receptor abnormality While all these are uncommon, they need to be distinguished from the occasional patient with ‘hysterical water drinking’ and those whose renal tubular function has been impaired by electrolyte abnormalities, such as hypokalaemia or hypercalcaemia.

Increased by:
Increased osmolality
Hypovolaemia
Hypotension
Nausea
Hypothyroidism
Angiotensin II
Adrenaline
Cortisol
Nicotine
Antidepressants
Decreased by:
Decreased osmolality
Hypervolaemia
Hypertension
Ethanol
a-Adrenergic stimulation

Diabetes insipidus (01)

CLINICAL FEATURES

Deficiency of vasopressin leads to polyuria, nocturia and compensatory polydipsia. Daily urine output may reach as much as 10-15 litres, leading to dehydration that may be very severe if the thirst mechanisms are impaired or the patient is denied fluid.
Causes of Dr are listed. The commonest is hypothalamic-pituitary surgery, following which transient Dr is common, frequently remitting after a few days or weeks. Primary overdrinking (polydipsia) is a common differential diagnosis.
Dr may be masked by simultaneous cortisol deficiency- cortisol replacement allows a water diuresis and Dr then becomes apparent. DIDMOAD syndrome (Wolfram syndrome) is a rare recessive disorder comprising diabetes insipidus, diabetes mellitus, optic atrophy and deafness.

BIOCHEMISTRY

• High or high-normal plasma osmolality with low urine osmolality (in primary polydipsia plasma osmolality tends to be low)
• Resultant high or high-normal plasma sodium
• Failure of urinary concentration with fluid deprivation
• Restoration of urinary concentration with vasopressin or an analogue
The latter two points may be studied with a formal waterdeprivation
test (see Appendix). In normal subjects, plasma osmolality remains normal while urine osmolality rises above 700 mosmol kg-I. In Dr, plasma osmolality rises while the urine remains dilute, only concentrating after exogenous vasopressin is given (cranial Dr) or not concentrating after vasopressin if renal Dr is present. This test can give equivocal results and measurement of vasopressin during the test is helpful.

Cranial diabetes insipidus

Congenital
Idiopathic
Tumours
Craniopharyngioma
Pituitary with suprasellar extension
Hypothalamic tumour, e.g. glioma
Metastases, especially breast
Lymphoma/leukaemia
Infections
Tuberculosis
Meningitis
Cerebral abscess
Infiltrations
Sarcoidosis
Histiocytosis X
Post surgical
Transfrontal
Trans-sphenoidal
Trauma
Base of skull fracture
Post radiotherapy (to head)
Vascular
Haemorrhage/thrombosis
Sheehan’S syndrome
Nephrogenic diabetes insipidus
Idiopathic
Renal tubular acidosis
Hypokalaemia
Hypercalcaemia
Drugs, e.g.
Lithium
Demethylchlortetracycline (demeclocycline)
Glibenclamide

TREATMENT

Synthetic vasopressin (desmopressin, DDA VP) is the treatment of choice. It is given intranasally as a spray 10- 20 JLgonce to three times daily or intramuscularly 2-4 JLg daily. Response is variable and must be monitored carefully with fluid input/output charts and plasma osmolality measurements. An oral preparation, 0.1-D.2 mg daily, is now available with shorter action than the spray. Alternative agents in mild Dr, probably working by sensitizing the tubules to endogenous vasopressin, include thiazide diuretics, carbamazepine 200-400 mg daily or chlorpropamide (200-350 mg daily). These are rarely used, especially with the risk of hypoglycaemia from chlorpropamide.
Nephrogenic diabetes insipidus In this condition, renal tubules are resistant to normal or high levels of plasma vasopressin. It may be inherited as a sex-linked recessive or can be acquired as a result of renal disease, drug ingestion, hypercalcaemia or hypokalaemia. Wherever possible the cause should be reversed. Other causes of polyuria and polydipsia.
Diabetes mellitus, hypokalaemia and hypercalcaemia are diagnoses to be considered. In the case of diabetes mellitus the cause is an osmotic diuresis secondary to glycosuria and this leads to dehydration and an increased perception of thirst due to hypertonicity of the extracellular fluid.

Primary or hysterical polydipsia is a relatively common cause of thirst and polyuria. It is a psychiatric disturbance characterized by the excessive intake of water. Plasma sodium and osmolality fall as a result and the urine produced is appropriately dilute. Vasopressin levels become virtually undetectable. Prolonged primary polydipsia may lead to the phenomenon of ‘renal medullary washout’, with a fall in the concentrating ability of the kidney. Characteristically the diagnosis is made by a waterdeprivation test. A low plasma osmolality is usual at the start of the test, and since vasopressin secretion and action can be stimulated, the patient’s urine becomes concentrated (albeit ‘maximum’ concentrating ability may be impaired); the initially low urine osmolality gradually increases with the duration of the water deprivation.

Syndrome of inappropriate

antidiuretic hormone (SIADH)

CLINICAL FEATURES

The presentation is usually vague, with confusion, nausea, irritability and, later, fits and coma. There is no oedema. Mild symptoms usually occur with plasma sodium levels below 125 mmol litre”! and serious manifestations are likely below ll5 mmol Iitre” ‘.
The syndrome must be distinguished from those causing similar dilutional hyponatraemia from excess infusion of dextrose/water solutions or diuretic administration (thiazides or amiloride.

DIAGNOSIS

The usual features are:
• Dilutional hyponatraemia due to excessive water retention
• Low plasma osmolality with higher ‘inappropriate’ urine osmolality
• Continued urinary sodium excretion >30 mmol litre:”
• Absence of hypokalaemia (or hypotension)
• Normal renal and adrenal and thyroid function

TREATMENT

The underlying cause should be corrected where possible. For symptomatic relief:
FLUID INTAKE should be restricted to 500-1000 ml daily.
PLASMA OSMOLALITY AND SODIUM AND BODY WEIGHT should be measured frequently.
IF WATER RESTRICTION IS POORLY TOLERATED OR INEFFECTIVE, demethylchIortetracycline (600- 1200 mg daily) may be given; this inhibits the action of vasopressin on the kidney causing a reversible form of nephrogenic diabetes insipidus. It may, however, cause photosensitive rashes.
WHEN THE SYNDROME IS VERY SEVERE, hypertonic saline (300 mmol litre ” slowly i.v.) is rarely given and frusemide may be used. These should be used with extreme caution by specialists.

Turnouts

 Small-cell carcinoma of lung
Prostate
Thymus
Pancreas
Lymphomas
Pulmonary lesions
Pneumonia
Tuberculosis
Lung abscess
CNS causes
Meningitis
Tumours
Head injury
Subdural
Cerebral abscess
SLE vasculitis
Metabolic causes
Alcohol withdrawal
Porphyria
Drugs
Chlorpropamide
Carbamazepine
Cyclophosphamide
Vincristine
SLE, systemic lupus erythematosus.

PATHOPHYSIOLOGY

This condition, comprising six major types, results from an autosomal recessive deficiency of an enzyme in the cortisol synthetic pathways, most commonly 21- hydroxylase which occurs in about 1 in 15000 births. The 21-hydroxylase deficiency has been shown to be due to defects on chromosome 6 near the HLA-region affecting a cytochrome P450 enzyme (P450C21)’
As a result, cortisol secretion is reduced and feedback leads to increased ACTH secretion to maintain adequate cortisol- this in turn leads to diversion of the steroid precursors into the androgenic steroid pathways.
Thus, 17-hydroxyprogesterone, androstenedione and testosterone levels are increased, leading to virilization. Rarely, aldosterone synthesis is impaired with resultant salt wasting. The other forms affect l ljl-hydroxylase, 17ahydroxylase, 3f3-hydroxysteroid dehydrogenase and a cholesterol side chain cleavage enzyme.

CLINICAL FEATURES

If severe, this presents at birth with sexual ambiguity oradrenal failure. In the female, clitoral hypertrophy, urogenital abnormalities and labioscrotal fusion are common, but the syndrome may be unrecognized in the male. Some cases include salt-losing states. Precocious puberty with hirsuties is a later presentation, while some milder cases only present in adult life, usually accompanied by primary amenorrhoea. Hirsutism developing before menarche is suggestive of CAH.

INVESTIGATION

Expert advice is essential in the confirmation and differential diagnosis of deficiency.
• 17-Hydroxyprogesterone levels are increased.
• Urinary pregnanetriol excretion is increased.
• Basal ACTH levels are raised.

TREATMENT

Replacement of glucocorticoid activity and mineralocorticoid activity if deficient is as for primary hypoadrenalism (see above). Correct dosage is often difficult to establish in the child but should ensure normal 17-hydroxyprogesterone and ACTH levels while allowing normal growth; excessive replacement leads to stunting of growth. Uses and problems of therapeutic steroid therapy Apart from their use as therapeutic replacement for endocrine deficiency states, synthetic glucocorticoids are widely used for many non-endocrine conditions.
Short-term use (e.g. for acute asthma) carries little risk of significant side-effects except for the simultaneous suppression of immune responses. The danger lies in their continuance, often through medical oversight or patient default.
Long-term therapy with synthetic or natural steroids will, in most respects, mimic endogenous Cushing’s syndrome. Exceptions are the relative absence of hirsuties, acne, hypertension and severe sodium retention, as the synthetic steroids have low androgenic and mineralocorticoid activity.
Excessive doses of steroids may also be absorbed from skin when strong dermatological preparations are used but inhaled steroids very rarely cause Cushing’s syndrome, although they may cause adrenal suppression. The major hazards are detailed in Information box 16.9; in the long term many are of such severity that the clinical need for high-dose steroids should be continually and critically assessed.

Supervision of steroid therapy

All patients receiving steroids should carry a steroid card and know that:
LONG-TERM STEROID THERAPY MUST NEVER BE STOPPED SUDDENLY. Doses should be reduced very gradually, with most being given in the morning at the time of withdrawal-this minimizes adrenal suppression. Many authorities believe that ‘alternate day therapy’ produces less suppression.
DOSES NEED TO BE INCREASED in times of serious intercurrent illness (defined as presence of a fever), accident and stress. Double doses should be taken during these times.
OTHER PHYSICIANS, ANAESTHETISTS AND DENTISTS must be told about steroid therapy.

accident and stress. Double doses should be taken during these times.
OTHER PHYSICIANS, ANAESTHETISTS AND DENTISTS must be told about steroid therapy.

Steroids and surgery

Any patient receiving steroids or who has recently received them and may still be suppressed requires careful control of steroid medication around the time of surgery.

This may arise from hypothalamic-pituitary disease or from long-term steroid therapy leading to hypothalamicpituitary- adrenal suppression.
Most patients with the former have panhypopituitarism and need T4 replacement as well as cortisol; in this case hydrocortisone must be started before T4. The commonest cause of hypoadrenalism is long-term corticosteroid medication for non-endocrine disease. The hypothalamic-pituitary axis and the adrenal may both be suppressed and the patient may have vague symptoms of feeling unwell. The long ACTH stimulation test should demonstrate a delayed cortisol response. Weaning off steroids is often a long and difficult business.

Cushing’s syndromes

Cushing’s syndrome is the term used to describe the clinical state of increased free circulating glucocorticoid. It occurs most often following the therapeutic administration of synthetic steroids; all the spontaneous forms of the syndrome are rare.

PATHOPHYSIOLOGY AND CAUSES

Causes of Cushing’s syndrome are usually subdivided into two groups:
1 Increased circulating ACTH from the pituitary (=60% of cases), known as Cushing’s disease, or an ectopic tumour (=15%) with consequential glucocorticoid excess
2 A primary excess of endogenous or exogenous glucocorticoid hormone alone, with subsequent (physiological) suppression of ACTH

CLINICAL FEATURES

The predominant clinical features of Cushing’s syndrome are those of glucocorticoid excess and are illustrated.

Particular points include:
PIGMENTATION only occurs with ACTH-dependent causes.
A CUSHINGOID APPEARANCE can be caused by excess alcohol consumption (pseudo-Cushing’s syndrome)- the pathophysiology is poorly understood.
IMPAIRED GLUCOSE TOLERANCE or frank diabetes are common, especially in the ectopic ACTH syndrome.
HYPOKALAEMIA due to the mineralocorticoid activity of cortisol is common with ectopic ACTH secretion.

ACTH-dependent disease

Pituitary-dependent (Cushing’s disease)
Ectopic ACTH-producing tumours
ACTH administration
Non-ACTH-dependent causes
Adrenal adenomas
Adrenal carcinomas
Glucocorticoid administration
Others
Alcohol-induced pseudo-Cushing’s syndrome

DIAGNOSIS

There are two phases to the investigation:
1 Confirmation of the presence or absence of Cushing’s syndrome
2 Differential diagnosis of its cause

Confirmation

Confirmation rests on demonstrating inappropriate cortisol secretion, not suppressed by exogenous glucocorticoids: difficulties occur with obesity and depression where cortisol dynamics are often abnormal. Random cortisol measurements are of no value. Investigations to confirm the diagnosis include:
24-HoUR URINARY FREE CORTISOL MEASUREMENTS. Repeatedly normal values (corrected for body mass) render the diagnosis most unlikely.
48-HoUR LOW-DOSE DEXAMETHASONE TEST. Patients with Cushing’s syndrome fail to suppress plasma or urinary cortisol levels. The overnight dexamethasone test is unreliable but has occasional value in excluding the diagnosis.
CIRCADIAN RHYTHM. After 48 hours in hospital, cortisol samples are taken at 0900 and 2400 hours (without warning the patient). Normal subjects show a pronounced circadian variation; those with Cushing’s syndrome have high evening cortisol levels, though the 0900 value may be normal.
INSULIN TOLERANCE TEST. This is useful in depression or obesity, when abnormal circadian and suppression responses are seen. The normal rise of cortisol with hypoglycaemia does not occur in patients with Cushing’s syndrome.

Differential diagnosis of the cause

This can be extremely difficult. The classical ectopic ACTH syndrome is distinguished by a short history, pigmentation and weight loss, unprovoked hypokalaemia, clinical or chemical diabetes and plasma ACTH levels above 200 ng litre “. Severe hirsuties/virilization suggests an adrenal tumour.
Biochemical and radiological procedures for diagnosis include:
ADRENAL CT SCAN. Adrenal adenomas and carcinomas causing Cushing’s syndrome are relatively large and always detectable by CT scan. Carcinomas are distinguished by large size, irregular outline and signs of infiltration or metastases.
PITUITARY CT OR MRI. Of less value than the adrenal scan; only a minority of tumours of significant size are detected with confidence by CT, and indeed over 80% of skull X-rays are normal. MRI may be superior.
PLASMA POTASSIUM LEVELS. All diuretics must be stopped. Hypokalaemia is common with ectopic ACTH secretion.
HIGH-DOSE DEXAMETHASONE TEST

Failure of urinary or plasma cortisol suppression suggests an ectopic source of ACTH or an adrenal tumour. The metyrapone test has been shown to be of little value.
PLASMA ACTH levels. Low or undetectable ACTH levels «10 ng Iitre””) on two or more occasions are a reliable indicator of non-ACTH-dependent disease.
CRF TEST. Exaggerated ACTH responses to exogenous CRF suggest pituitary-dependent Cushing’s disease. CHEST X-RA y is mandatory to demonstrate a carcinoma of the bronchus or a bronchial carcinoid. Lesions may be very small; if ectopic ACTH is suspected, whole-lung and mediastinal CT scanning should be performed.
Further investigations may involve selective catheterization of the inferior petrosal sinus to measure ACTH for pituitary lesions, or blood samples taken throughout the body in a search for ectopic sources. Bronchoscopy, cytology and regional arteriograms are occasionally necessary.

TREATMENT

Untreated Cushing’s syndrome has a very bad prognosis, with death from hypertension, myocardial infarction, infection and heart failure. Whatever the underlying cause, cortisol hypersecretion should be controlled prior to surgery or radiotherapy. Considerable morbidity and mortality is otherwise associated with operating on unprepared patients. The usual drug is metyrapone, an l l-hydroxylase blocker, which is given in doses of 750 mg to 4 g daily in three to four divided doses. Plasma cortisol should be monitored, aiming to reduce the mean level during the day to 300-400 nmol litre-I, equivalent to normal production rates. Aminoglutethimide is sometimes used, but trilostane has been abandoned. Choice of treatment depends upon the cause. Cushing’s disease (pituitary-dependent hyperadrenalism)
Treatment options are surgery, radiotherapy and medical control; the choice remains controversial. Trans-sphenoidal removal of the tumour, by an experienced surgeon, is the treatment of choice. Selective surgery nearly always leaves the patient ACTH deficient immediately postoperatively, even after CRF, and this is considered a good prognostic sign. Transfrontal surgery is very rarely necessary because most tumours are small, though they are occasionally locally invasive. Yttrium implantation of radioactive needles in the fossa produces good results in some centres but it is not generally available.
External irradiation alone is very slow, only effective in 20-50% and of little value except in those unfit for, or unwilling, to have surgery. Children, however, respond much better to radiotherapy, 80% being cured. Medical therapy to reduce ACTH (e.g. bromocriptine, cyproheptadine) is rarely effective and bilateral adrenalectomy is now very little used, though remains an effective last resort.

Other causes

Adrenal adenomas should be resected after achievement of clinical remission with metyrapone. Contralateral adrenal suppression may last for years. Carcinomas are highly aggressive and the prognosis is
poor. In general, if there are no widespread metastases, tumour bulk should be reduced surgically and the adrenolytic drug op’DDD given; new preparations have reduced the side-effects of nausea/vomiting and ataxia. Some would also give radiotherapy to the tumour bed after surgery.
Ectopic tumour sources should be removed if possible. Otherwise chemotherapy/radiotherapy should be used, depending on the tumour. Control of the Cushing’s syndrome with metyrapone is beneficial for symptoms  If the source is not clear, cortisol hypersecretion should be controlled with medical therapy until a diagnosis can be made.

Nelson’s syndrome

This rare syndrome is of increased pigmentation associated with an enlarging pituitary tumour occurring after bilateral adrenalectomy. The tumour may be locally invasive but most physicians believe it can be prevented by pituitary radiotherapy soon after adrenalectomy, though the latter is now rarely used. Incidental adrenal tumours (‘Incidentalomas’) With the advent of abdominal CT scanning, unsuspected adrenal masses have been discovered in = 1% of scans. These obviously include the described adrenal tumours but cysts, myelolipomas and metastases are also seen. If found functional tests to exclude secretory activity should be performed; if none is found then most authorities recommend removal of large (>4-5 ern) and functional tumours but observation of smaller lesions.

ADRENAL ANATOMY AND FUNCTION

The human adrenals, weighing only 8-10 g together, comprise an outer cortex with three zones (reticularis, fasciculata and glomerulosa) producing steroids and an inner medulla that synthesizes, stores and secretes catecholamines (see Adrenal medulla). The adrenal steroids are grouped into three classes based on their predominant physiological effects:
GLUC0CORTICOIDS. These are named after their effects on carbohydrate metabolism; major actions.
MINERALOCORTICOIDS. Their predominant effect is on the extracellular balance of sodium and potassium in the distal tubule of the kidney: aldosterone is the predominant mineralocorticoid in humans (about 50%);
corticosterone makes a small contribution. The weak mineralocorticoid activity of cortisol is also important since it is present in considerable excess. Aldosterone is produced solely in the zona glomerulosa.
ANDROGENS. Although secreted in considerable quantities, most have only relatively weak intrinsic androgenic activity until metabolized peripherally to testosterone or dihydrotestosterone. The relative potency of common steroids.

Increased or stimulated

Gluconeogenesis
Glycogen deposition
Protein catabolism
Fat deposition
Sodium retention
Potassium loss
Free water clearance
Uric acid production
Circulating neutrophils
Decreased or inhibited
Protein synthesis
Host response to infection
Lymphocyte transformation
Delayed hypersensitivity
Circulating lymphocytes
Circulating eosinophils

BIOCHEMISTRY

All steroids have the same basic skeleton and the chemical differences between them are slight. The major biosynthetic pathways.

PHYSIOLOGY

Glucocorticoid production by the adrenal is under hypothalamic- pituitary control. Corticotrophin releasing factor (CRF) is secreted in the hypothalamus in response to circadian rhythm, stress and other stimuli. It travels down the portal system to stimulate ACTH release from the anterior pituitary corticotrophs. Circulating ACTH stimulates cortisol production in the adrenal. The cortisol secreted (or any other synthetic corticosteroid) feeds back on the hypothalamus and pituitary to inhibit further CRF/ ACTH release. The set-point of this system clearly varies through the day according to the circadian rhythm, and is usually overridden by severe stress. Following adrenalectomy or Addison’s disease, cortisol secretion will be absent or reduced; ACTH levels will therefore rise.
Mineralocorticoid secretion is mainly controlled by the renin-angiotensin system.

INVESTIGATION OF GLUCOCORTICOID ABNORMALITIES

Basal levels

ACTH and cortisol are released episodically. The following precautions are therefore necessary when taking a blood sample:
• Sampling time should be accurately recorded.
• Stress should be minimized.
• Sampling should be delayed for 48 hours after admission if Cushing’s syndrome is suspected.
• Appropriate reference ranges (for time and assay method) should be used.
Suppression and stimulation tests are used in instances of excess and deficient cortisol production respectively.

Dexamethasone suppression tests

Administration of synthetic glucocorticoid to a normal subject produces prompt feedback suppression of CRF and ACTH levels and thus of endogenous cortisol secretion (prednisolone and dexamethasone are not measured by most cortisol assays). Three forms of the test, used in the diagnosis and differential diagnosis of Cushing’s syndrome, are available.

ACTH stimulation tests

Synthetic ACTH (tetracosactrin, which consists of the first 24 amino acids of human ACTH) is given to stimulate adrenal cortisol production.

Addison’s disease-primary

hypoadrenalism

PATHOPHYSIOLOGY AND CAUSES

In this uncommon condition there is destruction of the entire adrenal cortex. Glucocorticoid, mineralocorticoid and sex steroid production are therefore all reduced. This differs from hypothalamic-pituitary disease, in which mineralocorticoid secretion remains largely intact, being predominantly stimulated by angiotensin II. Adrenal sex steroid production is also largely independent of pituitary action. In Addison’s disease reduced cortisol levels lead, through feedback, to increased CRF and ACTH production, the latter being responsible for the hyperpigmentation.

Autoimmune disease (= 80%)
Tuberculosis (=20%)
Surgical removal
Haemorrhage/infarction
Meningococcal septicaemia
Venography
Infiltration
Malignant destruction
Amyloid
Drugs, e.g. rifampicin
ketoconazole
AIDS
Schilder’s disease (adrenal leucodystrophy)

Primary hypoadrenalism shows a marked female preponderance and is now most often caused by autoimmune disease (=80%) rather than tuberculosis (=20%). All other causes are rare (Table 16.32). Autoimmune adrenalitis results from the destruction of the adrenal cortex by organ-specific autoantibodies. There is an association with other autoimmune conditions, e.g. pernicious anaemia, hypoparathyroidism, thyroiditis, premature ovarian failure, type 1 diabetes mellitus.

Primary hypoadrenalism shows a marked female preponderance and is now most often caused by autoimmune disease (=80%) rather than tuberculosis (=20%). All other causes are rare. Autoimmune adrenalitis results from the destruction of the adrenal cortex by organ-specific autoantibodies. There is an association with other autoimmune conditions, e.g. pernicious anaemia, hypoparathyroidism, thyroiditis, premature  ovarian failure, type 1 diabetes mellitus.

CLINICAL FEATURES

 The symptomatology of Addison’s disease is often vague-non-specific complaints of weakness, tiredness, weight loss and anorexia
predominate.

Important features are:
PIGMENTATION (dull, slaty, grey-brown) in the mouth (opposite the molars), hand and all flexural regions is the predominant sign. It is particularly significant if it occurs in a recent scar. It is caused by the direct action of ACTH on melanocytes.
POSTURAL SYSTOLIC HYPOTENSION, due to hypovolaemia and sodium loss, is usually present even if supine blood pressure is normal.

INVESTIGATION

Once Addison’s disease is suspected, investigation is urgent. If the patient is seriously ill or very hypotensive, hydrocortisone 100 mg should be given intramuscularly, ideally after a blood sample is taken for later measurement of plasma cortisol, or an ACTH stimulation test can be performed immediately. Full investigation should be delayed until emergency treatment has improved the patient’s condition. Otherwise, tests are as follows:
SINGLE CORTISOL MEASUREMENTS are of virtually no value.
THE SHORT ACTH STIMULATION TEST should be performed (see Table 16.31). An absent or impaired cortisol response is seen, confirmed if necessary by a long ACTH stimulation test to exclude adrenal suppression by steroids.
A 0900 PLASMA ACTH LEVEL – a high level (>80 ng litre-I) with low or low-normal cortisol confirms primary hypoadrenalism.
ELECTROLYTES AND UREA: these classically show hyponatraemia, hyperkalaemia and a high urea but can be normal.
BLOOD GLUCOSE may be low, with symptomatic hypoglycaemia.
ADRENAL ANTIBODIES are present in many cases of autoimmune adrenalitis.
CHEST AND ABDOMINAL X-RA YS may show evidence of tuberculosis and/or calcified adrenals.
SERUM ALDOSTERONE is reduced with high plasma renin activity.
HYPERCALCAEMIA AND ANAEMIA (after rehydration) are sometimes seen. They resolve on treatment.

TREATMENT

Long-term treatment is with replacement glucocorticoid and mineralocorticoid; tuberculosis must be treated if present or suspected. Replacement dosage details.
Adequacy of glucocorticoid dose is judged by:
• Clinical well-being and restoration of normal, but not excessive, weight
• Normal cortisol levels during the day while on replacement hydrocortisone (this cannot be used for synthetic steroids)
Fludrocortisone replacement is assessed by:
• Restoration of serum electrolytes to normal
• Blood pressure response to posture (it should not fall >10 mmHg systolic after 2 min standing)
• Suppression of plasma renin activity to normal

Patient advice

All patients requiring replacement steroids should:
CARRY A STEROID CARD.

WEAR A MEDIc-ALERT BRACELET; this gives details of their condition so that emergency replacement therapy can be given if found unconscious.
KEEP AN (UP-TO-DATE) AMPOULE OF HYDROCORTISONE at home in case oral therapy is impossible, and the general practitioner has to be called.

Acute hypoadrenalism

The major deficiencies are of salt, steroid and glucose. ASSUMING NORMAL CARDIOVASCULAR FUNCTION, 1 litre of normal saline should be given over 30-60 min with 100 mg of intravenous hydrocortisone.

DEXTROSE should be infused if there is hypoglycaemia. SUBSEQUENT SALINE REQUIREMENTS may be for several litres within 24 hours (assessing with central venous pressure line if necessary) plus hydrocortisone, 100 mg i.m. 6-hourly, until the patient is clinically stable.
ORAL REPLACEMENT MEDICATION is then started, initially hydrocortisone about 20 mg 8-hourly or equivalent, reducing to 20 mg + 10 mg or equivalent over a few days.
FLUD~OCORTISONE is unnecessary acutely as the high cortisol doses provide sufficient mineralocorticoid activity-it should be introduced later.

Thyrotoxicosis is often clinically obvious but treatment should never be instituted without biochemical confirmation. Differentiation of the mild case from anxiety states may be difficult; useful positive clinical markers are eye signs, proximal myopathy and wasting. The hyperdynamic circulation with warm peripheries seen with thyrotoxicosis can be compared with the clammy hands of anxiety.

INVESTIGATION

Serum TSH is suppressed «0.1 mU litre'”) though most physicians also like to confirm the diagnosis with a raised serum T, or T4; the former is more sensitive as there are occasional cases of ‘T, toxicosis’. Microsomal (directed against thyroid peroxidase) and thyroglobulin antibodies are present in most cases of Graves’ disease. TSH receptor antibodies are not measured routinely, but are present: TSI 80% positive, TBII 60–90% in Graves’ disease.
The TRH test is now very rarely necessary. A normal TSH rise excludes the diagnosis; a flat response is characteristic but not diagnostic.

TREATMENT

Three possibilities are available: antithyroid drugs, surgery and radioiodine. Practices and beliefs differ widely within and between countries; it also depends on patient preference and local expertise. Some general guidelines are:
PATIENTS WITH LARGE GOITRES, SINGLE OR MULTIPLE NODULAR GOITRES are unlikely to remit after a course of antithyroid drugs.
RADIOIODINE is now more widely used in the UK for those under the age of 40 years as has previously happened elsewhere; theoretical risks of carcinogenesis were not proven.
PATIENTS WITH DYSTHYROID EYE DISEASE may show worsening of eye problems after radioiodine, though this can often be prevented by steroid or early T4 administration.
PATIENTS WHO DEMONSTRATE POOR COMPLIANCE with drug therapy should probably undergo surgery.
PATIENT PREFERENCE, with informed discussion of the alternatives, must be given great weight.

Antithyroid drugs

Carbimazole is most often used in the UK. Occasionally propylthiouracil is also used. Methimazole, the active metabolite of carbimazole, is used in the USA. These drugs inhibit the formation of thyroid hormones and also have minor other actions; carbimazole/ methimazole is also an immunosuppressive agent. Initial doses and side-effects are detailed. Though thyroid hormone synthesis is reduced very quickly, the long half-life of T. (7 days) means that clinical benefit is not apparent for 10–20 days. As many of the manifestations of hyperthyroidism are mediated via the sympathetic system, f3-blockers are used to provide rapid partial symptomatic control; they also decrease peripheral conversion of T. to T,. Drugs preferred are those without intrinsic sympathomimetic activity. They should not be used alone for hyperthyroidism except when the condition is self-limiting, e.g. subacute thyroiditis.
Subsequent management is either by gradual dose titration or a ‘block and replace’ regimen.

GRADUAL DOSE TITRATION

Review after 4-6 weeks and reduce dose of carbimazol depending on clinical state and T./T3Ievels. TSH levels may remain suppressed for long periods. 2 When clinically and biochemically euthyroid, stop 13- blockers.
3 Review after 2-3 months and, if controlled, reduce carbimazole. Once-daily dosage is now possible.
4 Gradually reduce dose to 5 mg daily over 12-18 months if thyrotoxicosis remains controlled.
5 When euthyroid on 5 mg daily carbirnazole, discontinue.
6 About 50% of patients will relapse, mostly within the following 2 years. Long-term antithyroid therapy is then used or surgery or radiotherapy is considered (see below).
7 Propylthiouracil is used in similar fashion but doses required are tenfold higher (50-500 mg daily).
‘BLOCK AND REPLACE’ REGIMEN. With this policy, full doses of antithyroid drugs, usually carbimazole 30-45 mg daily, are given to suppress the thyroid completely while replacing thyroid activity with T. 0.1 mg daily. This is continued usually for 18 months, the claimed advantages being the avoidance of over- or under-treatment and the better use of the immunosuppressive action. Against this there is no ‘feel’ for whether the patient is likely to relapse as with the titration method.
TOXICITY. The major side-effect is agranulocytosis that occurs in approximately 1 in 1000 patients within 3 months of treatment. All patients must be warned to seek immediate medical attention if they develop unexplained fever or sore throat; this is best done with a written sheet. If toxicity occurs on carbimazole, propylthiouracil may be used and vice versa; side-effects are only occasionally repeated on the other drug. Surgery – subtotal thyroidectomy Thyroidectomy should only be performed in patients who have previously been rendered euthyroid. Conventional practice is to stop the antithyroid drug 10-14 days before operation and to give potassium iodide (60 mg three times daily), which reduces the vascularity of the gland. Particular indications for surgery are:
• Patient choice.
• A large goitre is unlikely to respond to antithyroid medication.
Indications for either surgery or radioiodine are:
• Persistent drug side-effects (also suitable for radioiodine)
• Poor compliance with drug therapy
• Recurrent hyperthyroidism after drugs
The operation should only be performed by experienced surgeons to reduce the chance of complications:
EARLY POSTOPERATIVE BLEEDING causing tracheal compression and asphyxia is a rare emergency requiring immediate removal of all clips/sutures to allow escape of the bloodlhaematoma.
LARYNGEAL NERVE PALSY (1%); vocal chord movement should be checked preoperatively. Mild hoarseness is more common and thyroidectomy is best avoided in serious singers!
TRANSIENT HYPOCALCAEMIA in up to 10% but with permanent hypoparathyroidism in less than 1%.
RECURRENT HYPERTHYROIDISM (less than 5%).
HYPOTHYROIDISM- about 10% of patients are hypothyroid within 1 year and this percentage increases with time. It is likeliest if microsomal antibodies are positive. Automated computer thyroid registers with annual TSH screening are used in some regions.

Radioactive iodine

Iodine-131 in an empirical dose (usually 18-40 x 1010Bq) accumulates in the thyroid and destroys the gland by local radiation. Early discomfort in the neck and immediate worsening of hyperthyroidism are sometimes seen; again patients must be rendered euthyroid before treatment though they have to stop antithyroid drugs about 5 days before radioiodine.
If worsening occurs, the patient should not receive carbimazole for 2-3 days after radioiodine, as it will prevent radioiodine uptake by the gland. They should receive propranolol until carbimazole can be restarted if necessary; euthyroidism normally returns in 2-3 months.
Apart from the immediate problems above, a major complication is the progressive incidence in subsequent hypothyroidism affecting the majority of subjects over the following 20 years. Though 75% of patients are rendered euthyroid in the short term, a small proportion remain hyperthyroid; increasing the radioiodine dose reduces recurrence but increases the rate of hypothyroidism. Again, long-term surveillance of thyroid function is necessary with frequent tests in the first year after therapy. Special situations in hyperthyroidism.

Thyroid crisis

This rare condition, with a mortality of 10%, is a rapid deterioration of thyrotoxicosis with hyperpyrexia, severe tachycardia and extreme restlessness. It is usually precipitated by stress, infection, surgery in an unprepared patient or radioiodine therapy. With careful management it should no longer occur.
Treatment is urgent. Propranolol in full doses is started immediately together with potassium iodide, antithyroid drugs, corticosteroids (which suppress many of the manifestations of hyperthyroidism) and full supportive measures.
Hyperthyroidism in pregnancy and neonatal life Maternal hyperthyroidism during pregnancy is uncommon and usually mild. Diagnosis can be difficult because of misleading thyroid function tests, although TSH is largely reliable. The pathogenesis is almost always Graves’ disease. TSI crosses the placenta to stimulate the fetal thyroid. Carbimazole also crosses the placenta, but T. does so poorly. The smallest dose of carbimazole necessary is used and the fetus must be monitored (see below). The paediatrician should be informed and the infant checked immediately after birth -overtreatment with carbimazole can cause fetal goitre.
If necessary (high doses needed, poor patient compliance or drug side-effects), surgery can be performed, preferably in the second trimester. Radioactive iodine is absolutely contraindicated.
The fetus and maternal Graves’ disease Any mother with a history of Graves’ disease may have circulating TSr. Even if she has been treated (e.g. by surgery), the immunoglobulin may still be present to
stimulate the fetal thyroid, and the fetus can thus become hyperthyroid, while the mother remains euthyroid.
Any such patient should therefore be monitored during pregnancy. Fetal heart rate provides a direct biological assay of thyroid status, and monitoring should be performed at least monthly. Rates above 160 min ” are strongly suggestive of fetal hyperthyroidism and maternal treatment with carbimazole and/or propranolol may be used. To prevent the mother becoming hypothyroid, T. may be given as this does not easily cross the placenta. Sympathomimetics, used to prevent premature labour, are contraindicated as they may provoke fatal tachycardia in the fetus.
Thyrotoxicosis may also develop in the neonatal period as TSI has a half-life of approximately 3 weeks. Manifestations in the newborn include irritability, failure to thrive and persisting weight loss, diarrhoea and eye signs. Thyroid function tests are difficult to interpret as neonatal normal ranges vary with age.
Untreated neonatal thyrotoxicosis is probably associated with hyperactivity in later childhood.

THYROID EYE DISEASE

This is also known as dysthyroid eye disease or ophthalmic Graves’ disease.

PATHOPHYSIOLOGY

The evidence suggests that the exophthalmos of Graves’ disease is due to specific antibodies that cause retroorbital inflammation with swelling and oedema of the extraocular muscles leading to limitation of movement. This leads to proptosis which can sometimes be unilateral, and increased pressure on the optic nerve may cause optic atrophy. Histology shows a focal oedema and glycosaminoglycan deposition followed by fibrosis. While often associated with Graves’ hyperthyroidism, it need not be so and patients may be hyperthyroid, euthyroid or hypothyroid. TSH receptor antibodies are almost invariably found in the serum but their role in the pathogenesis in unclear.

CLINICAL FEATURES

The clinical appearances are characteristic. Proptosis and limitation of eye movements (by ‘tight’ muscles) are direct effects of the inflammation, while conjunctival oedema, lid lag and corneal scarring are secondary to the proptosis and lack of eye cover. The ability to close the eyes completely is important, as otherwise corneal damage may occur. Visual impairment from optic nerve pressure may occur. Eye manifestations often do not parallel the clinical course of Graves’ disease- in particular the degree of toxicosis. Only 5-10% threaten sight, but the discomfort and cosmetic problems cause great patient anxiety. There is a grading system.

INVESTIGATIONS

Few investigations are necessary if the appearances are characteristic and bilateral. TSH and T3 or T. should be measured.
The exophthalmos should be measured to allow progress to be monitored. If appearances or measurements are markedly discrepant in the two eyes, other retroorbital space-occupying lesions should be considered: CT or MRI of the orbits will exclude other causes and show enlarged muscles and oedema.

TREATMENT

If patients are thyrotoxic this should be normalized, but hypothyroidism must be avoided as this may exacerbate the eye problem: an increased incidence of eye problems after radioiodine treatment reflects this. Direct treatment may be either local or systemic:
METHYLCELLULOSE EYEDROPS are given to aid lubrication. Some patients gain relief by sleeping upright.SYSTEMIC STEROIDS (prednisolone 30-120 mg daily) usually  reduce inflammation if more severe symptomsare present. Pulse intravenous methylprednisolone may  be more rapidly effective in severe cases.
IRRADIATION OF THE ORBITS (20 Gy in divided doses) is also used in severe instances, with steroid cover. LATERAL TARSORRHAPHY will protect the cornea iflids cannot be closed.
SURGICAL DECOMPRESSION of the orbit(s) is occasionally needed.
CORRECTIVE EYE MUSCLE SURGERY may improve diplopia due to muscle changes, but should be deferred till the situation has been stable for 6 months. Plastic surgery around the eyes may also be of value.

Grade 0   No signs or symptoms
Grade 1   Only signs, no symptoms
Grade 2   Soft tissue involvement
Grade 3   Proptosis (measured with exophthalmometer)
Grade 4   Extraocular muscle involvement
Grade 5   Corneal involvement
Grade 6   Sight loss with optic nerve involvement

Goitre is more common in women than in men and may be either physiological or pathological.

CLINICAL FEATURES

Most commonly a goitre is noticed as a cosmetic defect by the patient or by friends or relatives. The majority are painless but pain or discomfort can occur in acute varieties. Goitres can produce dysphagia and difficulty in breathing, implying oesophageal or tracheal compression. Clinical examination should record the size, shape, consistency and mobility of the gland as well as whether its lower margin can be demarcated (thus implying the absence of retrosternal extension). A bruit may be present. Associated lymph nodes should be sought and the tracheal position determined if possible. Examination should never omit an assessment of the patient’s clinical thyroid status.
There is a WHO grading of goitre:

GRADE 0  No palpable or visible goitre
GRADE 1  Palpable goitre
1A Goitre  detectable only on palpation
1B Goitre  palpable and visible with neck extended
GRADE 2  Goitre visible with neck in normal position
GRADE 3  Large goitre visible from a distance

Specific enquiry should be made about any medication, especially iodine-containing preparations, and possible exposure to radiation.

ASSESSMENT

Two facts are essential about any goitre: its pathological nature and the patient’s thyroid status. The nature can often be judged clinically. Goitres are usually separable into diffuse and nodular types, the causes of which differ.
Particular points of note are:
PUBERTY AND PREGNANCY may produce a diffuse increase in size of the thyroid.
IN GRAVES’ DISEASE (autoimmune hyperthyroidism) the gland is again diffusely enlarged, often somewhat firm and frequently associated with a bruit.
ACUTE TENDERNESS in a diffuse swelling, sometimes with severe pain, is suggestive of an acute viral thyroiditis (de Quervain’s). This is usually associated with a systemic viral illness and may produce transient clinical hyperthyroidism with an increase in serum T. PAIN in a goitre may be caused by thyroiditis, bleeding into a cyst or (rarely) a thyroid tumour.
SIMPLE GOITRE: in this instance no clear cause is found for enlargement of the thyroid, which is usually smooth and soft. It may be associated with thyroid growthstimulating antibodies.
NODULAR GOITRES may have multiple or solitary nodules. Commonest is the multinodular goitre, especially in older patients. The patient is usually euthyroid but may be hyperthyroid. Multinodular goitre is the commonest cause of tracheal and/or oesophageal compression and may cause laryngeal nerve palsy. It may also extend retrosternally.
SOLITARY NODULES present a difficult problem. A history of pain, rapid enlargement or associated lymph nodes in such a situation suggests the possibility of thyroid carcinoma. The majority of such nodules are, however, cystic or benign and, indeed, may simply be the largest solitary nodule of a multinodular goitre. Risk factors for malignancy include previous irradiation, long-standing iodine deficiency and occasional familial cases. Solitary toxic nodules (Plummer’s syndrome) are quite uncommon and may be associated with TJ production.
FIBROTIC GOITRE (Riedel’s thyroiditis): this rare condition, usually producing a ‘woody’ gland, is associated with other midline fibrosis and is often difficult to distinguish from carcinoma, being irregular and hard.
EXCESSIVE DOSES OF CARBIMAZOLE OR PROPYLTHIOURACIL will induce goitre.
IODINE DEFICIENCY AND DYSHORMONOGENESIS can also cause goitre.
MALIGNANCY. Rarely the thyroid is the site of a metastatic deposit or the site of origin of a lymphoma.

Physiological

Puberty
Pregnancy
Autoimmune
Graves’ disease
Hashimoto’s disease
Thyroiditis
Acute (de Quervain’s thyroiditis)
Chronic fibrotic (Riedel’s thyroiditis)
Iodine deficiency (endemic goitre)
Dyshormonogenesis
Goitrogens (e.g. sulphonylureas)
Multinodular goitre
Diffuse goitre
Colloid
Simple
Cysts
Tumours
Adenomas
Carcinoma
Lymphoma
Miscellaneous
Sarcoidosis
Tuberculosis

INVESTIGATION

Clinical findings will dictate appropriate initial tests: THYROID FUNCTION TESTS-TSH plus T. or TJ
CHEST AND THORACIC INLET X-RAYS where appropriate to detect tracheal compression and large retrosternal extensions.

Additional investigations

FINE NEEDLE ASPIRATION (FNA). In patients with a solitary nodule or a dominant nodule in a multinodular goitre, there is a 5% chance of malignancy; in view of this, FNA should be performed. This can be done in the outpatient clinic. Cytology in expert hands can usually differentiate the suspicious or definitely malignant nodule.
ULTRASOUND with high resolution is a sensitive method for delineating nodules and can demonstrate whether they are cystic or solid. Unfortunately, even cystic lesions can be malignant and therefore FNA is the preferred technique.
THYROI D SCAN (1251 or 1311) is useful to distinguish between functioning (hot) or non-functioning (cold) nodules. A hot nodule is virtually never malignant; however a cold nodule is malignant in 10% of cases. FNA has therefore reduced the need for imaging and will reduce the necessity for surgery.

TREATMENT

During puberty and pregnancy a goitre associated with euthyroidism rarely requires intervention. If euthyroid, the patient should be reassured that spontaneous resolution is likely. In other situations the patient should be rendered euthyroid.
Indications for surgical intervention are:
THE POSSIBILITY OF MALIGNANCY. A history of rapid growth, pain, cervical lymphadenopathy or previous irradiation to the neck are worrying features. FNA should be performed. Surgery may be necessary.
PRESSURE SYMPTOMS on the trachea or, more rarely, oesophagus. The possibility of retrostemal extension should be excluded.
COSMETIC REASONS. A large goitre is often a considerable anxiety to the patient even though functionally and anatomically benign.

THYROID CARCINOMA

The different types of thyroid carcinoma, their characteristics and treatment are listed. The tumour is relatively uncommon, being responsible for 400 deaths annually in the UK. Particular points are:
PAPILLARY AND FOLLICULAR CARCINOMAS may take up iodine, shown by scanning. Such patients after total thyroidectomy may be given a therapeutic radioiodine dose, which will be taken up by remaining thyroid tissue or metastatic lesions. Replacement T. will subsequently be needed and should suppress TSH, which may otherwise stimulate any residual differentiated carcinoma. Lungs and bone are the commonest sites of metastases, while local invasion is often a problem. The measurement of thyroglobulin in plasma has been used as a tumour marker for the presence of neoplastic tissue.
ANAPLASTIC CARCINOMAS AND LYMPHOMA do not respond to radioactive iodine.
MEDULLARY CARCINOMA, often associated with MEN, is usually treated by total thyroidectomy. The patient’s family should be screened for this and other endocrine neoplastic conditions.

HYPERTHYROIDISM

Hyperthyroidism is common, affecting perhaps 2-5% of all females at some time and with a sex ratio of 5 : 1, most often between ages 20 and 40 years. Nearly all cases are caused by intrinsic thyroid disease; a pituitary cause is extremely rare.

Graves’ disease

ATHOGENESIS. This is the commonest cause of hyperthyroidism and is due to an autoimmune process. Serum IgG antibodies bind to the thyroid TSH receptor stimulating thyroid hormone production, behaving like TSH. These TSH receptor antibodies can be measured in serum. There is an association with HLA-B8, Dw3 and 50% concordance is seen amongst monozygotic twins with a 5% concordance rate in dizygotic twins. Yersinia enterocolitica as well as Escherichia coli and other Gram-negative organisms contain TSH binding sites. This raises the possibility that the initiating event in the pathogenesis may be an infection in a geneticallysusceptible individual.
Associated with the thyroid disease in many cases are eye changes (see below) and other signs such as vitiligo and pretibial myxoedema. Rarely lymphadenopathy and splenomegaly may occur. Graves’ disease is also associated with other autoimmune disorders such as pernicious anaemia and myasthenia gravis.

The natural history is one of fluctuation, many patients showing a pattern of alternating relapse and remission; perhaps only 40% of subjects have a single episode. Many patients eventually become hypothyroid.

Graves’ disease

Solitary toxic nodule/adenoma
Toxic multinodular goitre
Acute thyroiditis
Viral
Autoimmune
Post irradiation
Thyrotoxicosis factitia (secret T4 consumption)
Exogenous iodine
Drugs-amiodarone
Metastatic differentiated thyroid carcinoma
TSH-secreting tumours (e.g. pituitary)
HCG-producing tumours
Hyperfunctioning ovarian teratoma (struma ovarii)
Only the first three are common.
HCG, human chorionic gonadotrophin

Toxic solitary adenoma/nodule (Plummers disease) This is the cause of about 5% of cases of hyperthyroidism. It does not usually remit after a course of antithyroid drugs.

Toxic multinodular goitre

This commonly occurs in older women; again antithyroid drugs are rarely successful in inducing a remission.

De Quervain’s thyroiditis

This is transient thyrotoxicosis from an acute inflammatory process, probably viral in origin. Apart from the toxicosis there is usually fever, malaise and pain in the neck with tachycardia and local thyroid tenderness. Thyroid function tests show initial thyrotoxicosis, the erythrocyte sedimentation rate (ESR) is raised and thyroid scans show suppression of uptake in the acute phase, though hypothyroidism, usually transient, may then follow after a few weeks. Treatment of the acute phase is with aspirin, using short-term prednisolone in severely symptomatic cases.
CLINICAL FEATURES OF HYPERTHYROIDISM
The symptoms of hyperthyroidism affect many systems; they and relevant signs. Symptomatology and signs vary with age and with the underlying aetiology. Important points are:
THE EYE SIGNS, PRETIBIAL MYXOEDEMA AND
THYROID ACROPACHY only occur in Graves’ disease.
Pretibial myxoedema is an infiltration on the shin, essentially only occurring with eye disease. Thyroid acropachy is very rare and consists of clubbing, swollen fingers and periosteal new bone formation.
IN THE ELDERLY a frequent presentation is with atrial fibrillation, other tachycardias and/or heart failure, often with few other signs. Thyroid function tests are mandatory in any patient with unexplained atrial fibrillation.
CHILDREN frequently present with excessive height or excessive growth rate, or with behavioural problems such as hyperactivity. They may also show weight gain rather than loss.
SO-CALLED ‘APATHETIC THYROTOXICOSIS’ in some elderly patients presents with a clinical picture more like hypothyroidism. There may be very few signs and a high degree of clinical suspicion is essential.

Hypothyroidism may produce many symptoms. The classical picture of the slow, dry-haired, thick-skinned, deep-voiced patient with weight gain, cold intolerance, bradycardia and constipation makes the diagnosis easy; the term ‘myxoedema’ refers to the accumulation of mucopolysaccharide in subcutaneous tissues. Milder symptoms are, however, more common. Special difficulties in diagnosis may arise:
CHILDREN WITH HYPOTHYROIDISM may not show classical features but often have a slow growth velocity, poor school performance and sometimes arrest of pubertal development.
YOUNG WOMEN WITH HYPOTHYROIDISM may not show obvious signs. Hypothyroidism should be excluded in all patients with oligomenorrhoea/ amenorrhoea, menorrhagia, infertility and hyperprolactinaemia.
AMONG THE ELDERLY, many of the clinical features are difficult to differentiate from normal ageing.

INVESTIGATION OF PRIMARY

HYPOTHYROIDISM

TSH is now the investigation of choice; a high TSH level confirms primary hypothyroidism. A low total or free T. level confirms the hypothyroid state and is especially important if there is any evidence of hypothalamic and pituitary disease, when TSH may be low or normal. Thyroid and other organ-specific antibodies may be
present. Other abnormalities include: ANAEMIA. This is usually normochromic and normocytic in type but it may be macrocytic (sometimes this is due to associated pernicious anaemia) or microcytic (in women, due to menorrhagia).
INCREASED ASPARTATE TRANSFERASE LEVELS, from muscle and/or liver.

INCREASED CREATINE KINASE LEVELS.

HYPERCHOLESTEROLAEMIA.

HYPONATRAEMIA due to an increase ill ADH and impaired free water clearance.

Symptoms

Tiredness/malaise
Weight gain
Anorexia
Cold intolerance
Poor memory
Change in appearance
Depression
Psychosis
Coma
Deafness
Poor libido
Goitre
Puffy eyes
Dry, brittle, unmanageable hair
Dry, coarse skin
Arthralgia
Myalgia
Constipation
Menorrhagia or oligomenorrhoea in women
A history from a relative is often revealing
Symptoms of other autoimmune disease may be present

TREATMENT

Replacement therapy with T. is given for life. The starting dose will depend upon the age and fitness of the patient, especially cardiac performance. In the young and fit, 100 ILgdaily is suitable, while 50 ILgdaily is more appropriate for the old or frail. T3 offers no significant advantage over T.

Patients with ischaemic heart disease require even lower initial doses, especially if the hypothyroidism is severe and long-standing. Most physicians would then begin with 25 ILgdaily and perform serial ECGs, increasing the dose at 2–{j week intervals if angina does not occur or worsen and the ECG does not deteriorate. Some, however, would use T3 beginning with 2.5 ILg8-hourly, doubling the dose every 48 hours up to 10 ILgthree times daily. If progress is satisfactory, T. (l00 ILgdaily) is then started and T3 is discontinued 5 days later. Adequacy of replacement should be assessed clinically and by thyroid function tests (TSH and possibly T.) after at least 6 weeks on a steady dose; the aim is to restore TSH to within the normal range. If serum TSH remains high, the dose of T. should be increased in 25-ILg increments and the tests repeated 6 weeks later. This stepwise progression should be continued until TSH becomes normal. The usual maintenance dose is 10G-200 ILggiven as a single daily dose; excessive replacement is probably dangerous.
Clinical improvement on T. may not begin for 2 weeks, though is quicker on T3′ and full resolution of symptoms may take 6 months. The importance of lifelong therapy must be emphasized and the possibility of other autoimmune endocrine disease developing, especially Addison’s disease, should be considered.

Borderline hypothyroidism or compensated euthyroidism

Patients are frequently seen with low normal serum T. levels and slightly raised TSH levels. Sometimes this follows surgery or radioiodine therapy when it can reasonably be seen as ‘compensatory’. Most physicians would now treat with T. where the TSH is above twice normal, or when possible symptoms are present, but would simply repeat the tests (and measure thyroid antibodies) 3–{j months later where TSH is only marginally raised.

Myxoedema coma

Though very rare, severe hypothyroidism, especially in the elderly, may present with confusion or even coma. Hypothermia is often present and the patient may have severe cardiac failure, hypoventilation, hypoglycaemia and hyponatraernia.
The mortality was previously at least 50% and patients require full intensive care. Optimal treatment is controversial and data lacking; most physicians would advise T3 orally or intravenously in doses of 2.5-5 ILgevery 8 hours, then increasing as above. Large intravenous doses should not be used.
Additional measures, though unproven, should include:
• Oxygen (by ventilation if necessary)
• Monitoring of cardiac output and pressures via Swan- Ganz catheter
• Gradual rewarming
• Hydrocortisone 100 mg i.v, 8-hourly
• Dextrose infusion to prevent hypoglycaemia

‘Myxoedema madness’

Depression is common but occasionally with severe hypothyroidism in the elderly the patient may become frankly demented or psychotic, sometimes with striking delusions. This may occur shortly after starting T. replacement.

Screening for hypothyroidism

The incidence of congenital hypothyroidism is approximately 1 : 3500 births. Untreated, severe hypothyroidism leads to permanent neurological and intellectual damage (‘cretinism’). Routine screening of the newborn using a blood-spot, as in the Guthrie test, to detect a high TSH level as an indicator of primary hypothyroidism is efficient; cretinism is prevented if T. is started within the first few months of life.
Screening of elderly patients is controversial but there is little doubt that the incidence of unsuspected thyroid disease in those over 65 years is 1-3%. With this and undiagnosed hyperthyroidism many physicians believe in screening of all elderly hospital attenders.

The metabolic rate of many tissues is controlled by the thyroid hormones, and overactivity and underactivity of the gland pose the commonest of all endocrine problems.

Anatomy

The gland consists of two lateral lobes connected by an isthmus. It is closely attached to the thyroid cartilages and to the upper end of the trachea, and thus moves on swallowing. It is often palpable in normal women. Embryologically it originates from the base of the tongue and descends to the middle of the neck. Remnants of thyroid tissue can sometimes be found at the base of the tongue (lingual thyroid) and along the line of descent. The gland has a rich blood supply from superior and inferior thyroid arteries. The thyroid consists of follicles lined by cuboidal epithelioid cells. Inside is the colloid, which is an iodinated glycoprotein, thyroglobulin, synthesized by the follicular cells. Each follicle is surrounded by basement membrane, between which are parafollicular cells containing calcitonin- secreting C cells.

Biochemistry

The thyroid hormones, T. and T, are synthesized within the gland . More T. than T, is produced but T. is converted in some peripheral tissues (liver, kidney and muscle) to the more active T, by 5′-monodeiodination; an alternative 3′- monodeiodination yields the inactive reverse T, (rT,). The latter step occurs particularly in severe non-thyroidal illness (see below).

In plasma, more than 99% of all T. and T3 is bound to hormone-binding proteins (thyroxine-binding globulin, TBG; thyroid-binding prealbumin, TBP A; and albumin). Only free hormone is available for tissue action, where T3 binds to specific nuclear receptors within the cell. Factors affecting TBG.

Increased TBG
Hereditary
Pregnancy
Oestrogen therapy
Oral contraceptive use
Hypothyroid ism
Phenothiazines
Acute viral hepatitis
Decreased TBG
Hereditary
Androgens
Corticosteroid excess
Thyrotoxicosis
Nephrotic syndrome
Major illness
Malnutrition
Chronic liver disease
Drugs causing altered binding
Non-steroidal anti-inflammatory drugs
Phenytoin

Deficiency

Globally dietary iodine deficiency is an important cause of thyroid disease as it is an essential requirement for thyroid hormone synthesis. The recommended daily intake of iodine should be at least 140 f.Lgand dietary supplementation of salt and bread has reduced the number of areas where ‘endemic goitre’ still occurs.

Increased TBG

Hereditary
Pregnancy
Oestrogen therapy
Oral contraceptive use
Hypothyroid ism
Phenothiazines
Acute viral hepatitis
Decreased TBG
Hereditary
Androgens
Corticosteroid excess
Thyrotoxicosis
Nephrotic syndrome
Major illness
Malnutrition
Chronic liver disease
Physiology of the hypothalamicpituitary thyroid axis
TRH is released in the hypothalamus and stimulates release of TSH from the pituitary.
2 TSH stimulates the TSH receptor in the thyroid to increase synthesis of both T. and T3 and also to release stored hormone, producing increased plasma levels of T. and T3.
3 T. and T3 feed back on the pituitary and perhaps hypothalamus to reduce TRH and TSH secretion.

Thyroid function tests

RIAs for total T., free T., total T3, free T3 and IRMAs for TSH are widely available. There are only minor significant circadian rhythms, and measurements may be made at any time. Particular uses of the tests are summarized.
Tests include:
TSH MEASUREMENT. IRMAs for TSH now differentiate between normal and low levels and ISH levels now thus discriminate between hyperthyroidism, hypothyroidism and euthyroidism. There are pitfalls, however. These are mainly with hypopituitarism, with the ‘sick euthyroid’ syndrome and with dysthyroid eye disease, all of which may give ‘false’ (i.e. misleading, not incorrect) low results implying hyperthyroidism. As a single test of thyroid function it is the most sensitive in most circumstances but many laboratories prefer to perform at least two tests-serum T3 or free T3 where hyperthyroidism is suspected, serum T4 or free T4 where hypothyroidism is likely.
THYROID HORMONE UPTAKE TESTS (IHUI) are now used much less. There are many forms of this measurement of free protein-binding sites, used to calculate the ‘free thyroxine index’ (FT!). Depending on the method of calculation, high values may imply hypothyroidism or hyperthyroidism; check with your laboratory. IBG is sometimes measured directly.
‘FREE’ T4 TESTS attempt to measure only the unbound active hormone. They thus avoid the need for IHUI and calculation of the FI!. Though not perfect, many of them are adequate for clinical use.
IRH TEST. This has been rendered almost obsolete xcept for investigation of hypothalamic-pituitary dysfunction.
Primary hypothyroid patients show a high basal ISH level with an excessive rise; hyperthyroid subjects show suppression with a minimal increment of ISH. Flat responses are also seen in pituitary disease, with solitary autonomous nodules, Graves’ eye disease and excessive thyroxine replacement, and in patients on steroids or with Cushing’s syndrome.

Problems in interpretation of thyroid function tests There are three major areas of difficulty.
SERIOUS ACUTE OR CHRONIC ILLNESS. Thyroid function is affected in several ways, with reduced concentration and affinity of binding proteins, decreased peripheral conversion of T4 to T3, with more rT3 and reduced hypothalamic-pituitary ISH production. Systemically ill patients can therefore have an apparently low total and free T4 and T3 with a normal or low basal ISH (the ‘sick euthyroid’ syndrome). Levels are usually only mildly below normal and the tests should be repeated after resolution of the underlying illness.
PREGNANCY AND ORAL CONTRACEPTIVES. These lead to greatly increased IBG and thus to high or high-normal total T4 and high IHUI levels. The normal physiological changes during pregnancy are not fully understood but . rarely cause clinical problems.
DRUGs. Many drugs affect thyroid function tests by interfering with protein binding. The commonest are listed in Table 16.22. Basal TSH should be measured.

Antithyroid antibodies

Serum antibodies to the thyroid are common and may be either destructive or stimulating; both occasionally coexist in the same patient.
1 Destructive antibodies may be directed against the microsomes or against thyroglobulin; the antigen for thyroid microsomal antibodies is the peroxidase enzyme. They may be detected by haemagglutination techniques and are found in up to 20% of the normal population, especially older women, but only 10-20% of these develop overt hypothyroidism.
2 ISH receptor antibodies (TRAb). These IgG antibodies can be measured in two ways:
(a) By the inhibition of binding of ISH to its receptors (ISH-binding inhibitory immunoglobulin, TBII).
(b) By demonstrating that they stimulate the release of cyclic AMP (thyroid-stimulating immunoglobulin/antibody TSI, TSAb). These antibodies are seen in Graves’ disease. Long-acting thyroid stimulator (LATS) assay and LATSprotector (LATS-P) assay also demonstrate TSH antibodies but bear little correlation to clinical thyroid disease. These latter tests have been superseded by the above.

HYPOTHYROIDISM

PATHOPHYSIOLOGY

Underactivity of the thyroid may be primary, from disease of the thyroid, or secondary to hypothalamicpituitary disease (reduced TSH drive).

Causes of primary hypothyroidism

ATROPHIC (AUTOIMMUNE) HYPOTHYROIDISM. This is the commonest cause of hypothyroidism and is associated with microsomal autoantibodies leading to lymphoid infiltration of the gland and eventual atrophy and fibrosis. It is six times more common in females and the incidence increases with age. The condition is associated with other autoimmune disease such as pernicious anaemia. In some instances the condition shows intermittent hypothyroidism with recovery.
HASHIMOTO’S THYROIDITIS. This form of autoimmune thyroiditis, again commoner in women and commonest in late middle age, produces atrophic changes with regeneration, leading to goitre formation. This is usually firm and rubbery but may range from soft to hard. Thyroid microsomal antibodies are again present, often in very high titres. Patients may be hypothyroid or euthyroid, though may go through an initial toxic phase, ‘Hashitoxicity’. Thyroxine therapy may shrink the goitre even when the patient is not hypothyroid, though this may take a long time.
IODINE DEFICIENCY. In mountainous areas (the Alps, Himalayas, South America, Central Africa) dietary iodine deficiency still exists, in some areas as ‘endemic goitre’ where goitre, occasionally massive, is common. The patients may be euthyroid or hypothyroid depending on the severity of iodine deficiency. The mechanism is thought to be borderline hypothyroidism leading to TSH stimulation and thyroid enlargement in the face of continuing iodine deficiency.
DYSHORMONOGENESIS. This rare condition is due to genetic defects in the synthesis of thyroid hormones; patients develop hypothyroidism with a goitre. One particular familial form is associated with sensorineural deafness (Pendred’s syndrome).

Primary
Congenital
Agenesis
Ectopic thyroid remnants
Defects of hormone synthesis
Iodine deficiency
Dyshormonogenesis
Antithyroid drugs
Other drugs, e.g. lithium, amiodarone
Autoimmune
Atrophic thyroiditis
Hashimoto’s thyroiditis
Infective
Post subacute thyroiditis
Post surgery
Post irradiation
13’1 therapy
External neck irradiation
Infiltration
Tumour
Peripheral resistance to thyroid hormone
Secondary
Hypopituitarism
Isolated TSH deficiency