Hormonal control factors

The adenohypophysis lacks any direct arterial supply. Blood from the hypothalamus passes down venous portal channels in the pituitary stalk (Fig. 17.3) into sinusoids which ramify within the gland. In this way hormonal control factors produced by neurosecretory cells in the hypothalamus are carried directly to the hormone-producing cells of the adenohypophysis. The known hormonal control factors and their effects are listed in Table 17.2. In general, these factors stimulate the particular secretory cells under their control into activity; the exception is prolactin-inhibiting factor, whose effect on the lactotrophs is inhibitory.

Table 17.2 Hormonal control factors and their effects on the adenohypophysis

Secretion of these hormonal control factors by the hypothalamus is under two types of control: neural and hormonal. Neural control is via nerves from other parts of the central nervous system, and is important in reactions to stress and in changes during sleep. Hormonal control is a negative feedback mechanism in which the hypothalamus monitors the level of adenohypophysial hormones in the blood and adjusts its output of hormonal control factors accordingly, so as to stabilise the level of each adenohypophysial hormone at the optimum level. This is called the hypothalamic–hypophysial feedback control.

Feedback control

In addition to control via the hypothalamus, a more direct method of control of the adenohypophysis also exists, whereby its cells respond directly to the levels of hormones and metabolites in the blood. Most adenohypophysial hormones stimulate another endocrine gland, termed the ‘target’ gland; for example, ACTH stimulates the adrenal cortex to produce steroid hormones, and TSH stimulates the thyroid to produce thyroxine.

In these examples, the level of hormone from the target gland is monitored for feedback control. However, in the case of growth hormone, which has no single target gland, it is the level of metabolites such as glucose that is monitored. A general scheme of the feedback control mechanisms operating in the regulation of a hypophysial hormone is shown in Figure 17.3.

Adrenocorticotrophic hormone

Adrenocorticotrophic hormone (ACTH), a peptide consisting of 39 amino acids, causes increased cell numbers (hyperplasia) and increased secretory activity in the adrenal cortex. Glucocorticoid output is elevated, but there is no effect on the output of mineralocorticoids, such as aldosterone, that are not under anterior pituitary control. ACTH levels show a marked circadian variation, being highest early in the morning.

Thyroid-stimulating hormone

Thyroid-stimulating hormone (TSH) is a glycoprotein that induces proliferation of the follicular cells of the thyroid, synthesis of thyroxine (T₄) and tri-iodothyronine (T₃), and secretion of these into the blood. Measurement of TSH levels provides information on the state of the control system of the thyroid and is valuable in the diagnosis of thyroid malfunction.

Gonadotrophic hormones

In the female, follicle-stimulating hormone (FSH) induces growth of Graafian follicles in the ovaries; these secrete oestrogens, which in turn cause endometrial proliferation. After rupture of the follicle at ovulation, luteinising hormone (LH) causes a change in the follicle cells known as luteinisation, whereby their secretory product changes from oestrogens to progesterone which induces secretory changes in the endometrium. Both gonadotrophic hormones are glycoproteins.

The hypothalamus monitors circulating levels of the sex steroids including oestrogens and progesterone, and releases probably a single hormonal control factor, FSH/LH-releasing factor (FSH/LH-RF), to control the adenohypophysial gonadotrophs. Their response to this factor depends on the prevailing levels of sex steroids. Cyclical changes in this feedback loop form the hormonal basis for the menstrual cycle.

In the male, FSH and LH both exist but, in the absence of ovaries as the target organ, their names are inappropriate to their actions. LH stimulates testosterone production by the interstitial cells of Leydig in the testes, while FSH stimulates spermatogenesis.

The circulating levels of FSH and LH vary markedly with age: they increase at puberty and are very high in females after the menopause.

Growth hormone

Growth hormone (GH) is a protein containing 191 amino acids; it binds to receptors on the surface of various cells and thus causes increased protein synthesis, accelerates breakdown of fatty tissue to produce energy, and tends to raise the blood glucose. It is vital for normal growth; deficiency causes dwarfism. Part of its action at tissue level is mediated by a group of peptide growth factors known as somatomedins. The hypothalamic control of GH release from the hypothalamus is complex, there being both a growth hormone-releasing factor (GH-RF) and an inhibitory factor, somatostatin.

Prolactin

Prolactin (PL) is a protein hormone with a structure very similar to that of GH. Although it is present in individuals of both sexes, its function in males remains uncertain. In females, it can produce lactation, provided that the breast has already been prepared during pregnancy by appropriate levels of sex steroids. Prolactin release is a good example of the neural form of hypothalamic control: the sensation of suckling causes reduction in hypothalamic prolactin-inhibiting factor (PIF) release and a consequent rise in PL levels.

Pituitary dwarfism

Pituitary dwarfism is due to deficiency of GH, sometimes associated with deficiency of other adenohypophysial hormones. The child fails to grow, although remaining well proportioned. There is a variety of known causes including adenomas, craniopharyngiomas (rare tumours derived from remnants of Rathke’s pouch) and familial forms.

Post-partum ischaemic necrosis

During pregnancy, the pituitary enlarges and becomes highly vascular. Hypotensive shock due to haemorrhage at the time of birth, compounded by the lack of direct arterial supply to the adenohypophysis, may cause ischaemic necrosis. This specific cause of necrosis is known as Sheehan’s syndromeand the effects of the resulting adenohypophysial hypofunction are termed Simmond’s disease. The neurohypophysis is usually spared. The first symptom following delivery is failure of lactation due to PL deficiency; the effects of lack of FSH/LH, TSH and ACTH then follow—loss of sexual function, hypothyroidism, and the diverse effects of glucocorticoid deficiency. Improvements in obstetric management mean that Sheehan’s syndrome is now rare, although hypotensive shock due to trauma may produce similar effects.

Types of adenoma

All the following adenomas comprise, histologically, nests and cords of a monotonous single cell type, the islands of cells being supported on a richly vascular sinusoidal framework. Amyloid deposition is not infrequent and calcification may occur.

Antidiuretic hormone

Antidiuretic hormone (ADH) controls plasma osmolarity and body water content by increasing the permeability of the renal collecting ducts; this means that more water is reabsorbed and the urine becomes more concentrated. ADH release is stimulated by increased plasma osmolarity and by hypovolaemia.

Damage to the hypothalamus, for example through trauma or tumours, causes deficiency of ADH, leading to production of large volumes of dilute urine accompanied by compensatory polydipsia (excess drinking). This is called diabetes insipidus, from the days when tasting of the patient’s urine was part of the diagnostic process: the urine is tasteless in this condition, whereas in diabetes mellitus it is sweet due to its high glucose content.

Excess ADH is occasionally produced by the neurohypophysis in response to head injury or meningitis, but most clinical cases of ADH excess are due to its ectopic production by tumours, including bronchial carcinomas. The tumours are almost certainly of neuroendocrine origin and thus equipped for the synthesis of peptide hormones.

The rarity of any neurohypophysial tumour secreting ADH (or oxytocin) is perhaps due to the incapacity of the neurones producing these hormones to undergo mitotic division.

Oxytocin

Oxytocin is an aptly named hormone (it is the Greek word for quick birth) as it stimulates the uterine smooth muscle to contract. Interestingly, it is oxytocin from the fetal pituitary that plays the greater role in initiating parturition, suggesting that the fetus orders its own birth. Oxytocin also causes ejection of milk during lactation. The hormone is present in males, although its function, if any, is unknown.

Phaeochromocytoma

Derived from adrenal medullary chromaffin cells

Symptoms due to excess catecholamine secretion (e.g. hypertension, sweating)

May be familial and associated with other endocrine tumours

Occasionally malignant

A curable cause of secondary hypertension

A phaeochromocytoma is derived from the adrenal medullary chromaffin cells (or from those lying in other sites); it is classified as a paraganglioma. The tumour presents through the effects of its catecholamine secretions: hypertension (which is sometimes intermittent), pallor, headaches, sweating and nervousness. Its presence should be suspected especially in younger hypertensive patients. Although it is a rare cause of hypertension, phaeochromocytoma must not be overlooked as it is one of the few curable causes of elevated blood pressure; other causes include adrenal cortical adenoma, renal artery stenosis and aortic coarctation.

The diagnosis of phaeochromocytoma is usually based on estimating the urinary excretion of vanillylmandelic acid (VMA), a catecholamine metabolite, which is generally at least doubled in the presence of the tumour. Localisation of the tumour is assisted by computed tomography of the abdomen and by radio-isotope scanning with ¹³¹I-mIBG, a catecholamine precursor that accumulates in the tumour.

Phaeochromocytoma may be familial, associated with medullary carcinoma of the thyroid or with hyperparathyroidism as part of a multiple endocrine neoplasia (MEN) syndrome. The familial cases are frequently bilateral. Other associations are with neurofibromatosis and the rare von Hippel–Lindau syndrome.

Phaeochromocytomas are brown, solid nodules, usually under 50 mm in diameter, often with areas of haemorrhagic necrosis (Fig. 17.9). Histologically, they consist of groups of polyhedral cells which give the chromaffin reaction, and are highly vascular (Fig. 17.10).

Fig. 17.9 Phaeochromocytoma. The adrenal medulla is expanded by a dark-coloured tumour with areas of degeneration and haemorrhage.

Fig. 17.10 Chromaffin cells in a phaeochromocytoma. There are groups of cells with granular cytoplasm, amidst which there are numerous branching capillaries.

Although most are benign, a few phaeochromocytomas pursue a malignant course. It is not generally possible to predict this behaviour from the histological appearance.

Neuroblastoma

Neuroblastoma is a rare and highly malignant tumour found in infants and children. Derived from sympathetic nerve cells it may, like phaeochromocytoma, secrete catecholamines, and there may be elevated levels of their metabolites in the urine. Neuroblastomas may also originate from parts of the sympathetic chain outside the adrenal medulla. Secondary spread to liver, skin and bones (especially those of the skull) is common. Surprisingly, neuroblastoma may occasionally mature spontaneously to ganglioneuroma, a benign tumour.

Glucocorticoids

The glucocorticoids have important effects on a wide range of tissues and organs. At physiological levels they:

In excess, as a result of therapeutic administration or high levels of endogenous secretion, they cause:

The most important of the hormones is cortisol (hydrocortisone), but other steroid metabolites have similar effects. The synthesis and secretion of glucocorticoids are controlled by ACTH from the pituitary.

Mineralocorticoids

The most important of the mineralocorticoids, aldosterone, acts on the renal tubules to increase reabsorption of sodium and chloride, reducing their loss in urine at the expense of potassium exchange. Unlike the production of glucocorticoids, the synthesis and release of aldosterone is not under pituitary control, but is regulated instead by the renin–angiotensin system (Fig. 17.12). Low perfusion pressure in the kidney stimulates release of renin, an enzyme, from the juxtaglomerular apparatus of the kidney. This converts angiotensinogen into angiotensin I. Angiotensin I is then converted to angiotensin II (an octapeptide) by angiotensin converting enzyme, mainly in the lung. Angiotensin II stimulates secretion of aldosterone from the adrenal cortex. Thus, aldosterone is released to combat fluid depletion.

Fig. 17.12 The renin–angiotensin–aldosterone system. See text for details.

Sex steroids

The production of sex steroids in the adrenal cortex is low compared with that in the gonads and may not be physiologically important. However, virilising androgens may be produced in conditions such as certain congenital enzyme defects and adrenal cortical tumours, especially if these are malignant.

Cushing’s syndrome

Due to excess glucocorticoids

Main features include central obesity, hirsutism, hypertension, diabetes and osteoporosis

Main causes are excess ACTH secretion from the pituitary, adrenal cortical neoplasms, or the iatrogenic effects of ACTH or steroid administration

Cushing’s syndrome refers to the constellation of bodily responses to excess glucocorticoids, whatever the underlying cause. Exogenous administration of glucocorticoids or ACTH is a common iatrogenic cause of Cushing’s syndrome. The syndrome occurs most commonly in adult women, and sometimes there is also excess androgen production causing virilisation. The main physical features of the syndrome in an adult are shown in Figures 17.13 and 17.14. In children, there is also growth retardation.

Fig. 17.13 Cushing’s syndrome. There is rounding of the face, acne and central obesity causing double chin.

Fig. 17.14 The systemic features of Cushing’s syndrome.

Hyperaldosteronism

Hypersecretion of sex steroids

Some adrenal cortical adenomas secrete sex steroids, most commonly androgens. In Cushing’s syndrome, quantities of androgens are occasionally secreted along with the glucocorticoids, causing virilisation of females, especially those with adrenocortical carcinomas.

Rarely, congenital enzyme defects of the pathways of steroid synthesis may result in excess production of sex steroids. The least rare example is ‘congenital adrenal hyperplasia’ due to deficiency of the enzyme 21-hydroxylase, needed for the synthesis of both cortisol and aldosterone (Fig. 17.15). Failure of cortisol production leads to increased ACTH secretion, resulting in hyperplasia of the adrenal cortex. The production of androgens occurs before the metabolic block caused by the enzyme deficiency, and their excessive secretion results in masculinisation of females and precocious puberty in males. 21-Hydroxylase deficiency is serious because deficiency of mineralocorticoids causes life-threatening salt loss unless replacement therapy is given.

Fig. 17.15 21-Hydroxylase deficiency: the commonest cause of congenital adrenal hyperplasia. Normal metabolism. 21-Hydroxylase deficiency. Failure of aldosterone production leads to salt-wasting, while cortisol lack causes the anterior pituitary to release ACTH, resulting in adrenal cortical hyperplasia. The resulting excess intermediate steroids are converted to androgens, leading to virilisation.

Acute insufficiency

Acute insufficiency (‘adrenal apoplexy’) was first noted in children by Waterhouse and Friderichsen who, in 1911 and 1918 respectively, independently described acute haemorrhagic necrosis of the adrenals in the course of meningococcal septicaemia. Other acute septicaemias, especially those due to Gram-negative bacteria, may cause a similar effect. The adrenal cortices are necrotic and the medullae contain acute haemorrhage (Fig. 17.18). The adrenal necrosis is probably due to disseminated intravascular coagulation (DIC). The symptoms are attributable to lack of mineralocorticoids (salt and water loss with hypovolaemic shock) and of glucocorticoids (failure of gluconeogenesis resulting in hypoglycaemia).

Fig. 17.18 Adrenals in Waterhouse–Friderichsen syndrome. The adrenals from a child dying from meningococcal septicaemia are destroyed by haemorrhage.

Chronic insufficiency

Thomas Addison first described an association between destruction of the adrenal cortex and the constellation of symptoms caused by the resulting chronic insufficiency of adrenal cortical hormones (Addison’s disease). The effects are due to a combined lack of mineralocorticoids and glucocorticoids:

Patients with chronic adrenocortical insufficiency may develop an acute Addisonian crisis, in which even minor illnesses such as infections may cause vomiting, fluid loss, electrolyte disturbances and circulatory collapse.

The commonest cause of Addison’s disease was once caseous necrosis of the adrenal cortices due to tuberculosis. Autoimmune destruction of the cortex is now a commoner cause; this is associated with other ‘organ-specific’ autoimmune diseases, such as pernicious anaemia (also described by Addison), thyroiditis, insulin-dependent diabetes mellitus and parathyroid failure.

In all cases of Addison’s disease, plasma cortisol levels are low. Estimation of ACTH levels enables a distinction to be made between primary adrenocortical insufficiency (ACTH raised) and secondary insufficiency (ACTH low).

Graves’ thyroiditis

Graves’ thyroiditis is the commonest cause of thyrotoxicosis, usually associated with a diffuse goitre. The thyroid is moderately enlarged, firm and beefy-red due to increased vascularity (Fig. 17.21). Histologically, the gland shows hyperplasia of the acinar epithelium, reduction of stored colloid, and local accumulations of lymphocytes with lymphoid follicle formation (Fig. 17.22). This full spectrum of features is now rarely seen in subtotal thyroidectomy specimens of the condition, because antithyroid drugs are given before surgery.

Fig. 17.21 Graves’ thyroiditis. The gland is diffusely enlarged, fleshy and dark-coloured due to increased vascularity.

Fig. 17.22 Histological features of Graves’ thyroiditis. There is hyperplasia of the follicular epithelium with nuclear irregularity, depletion of colloid and focal lymphoid aggregates (arrowed).

Graves’ thyroiditis is one of the so-called ‘organ-specific’ autoimmune diseases. The pathogenesis is the production of an auto-antibody of the IgG class which binds to the thyroid epithelial cells and mimics the stimulatory action of TSH. The auto-antibody is known as long-acting thyroid stimulator (LATS) and its effect on the thyroid can be classed as a form of hypersensitivity reaction, ‘stimulatory hypersensitivity’. LATS stimulates the function and growth of thyroid follicular epithelium. In addition to showing the usual features of thyrotoxicosis, patients with Graves’ thyroiditis may also show exophthalmos, pretibial myxoedema (accumulation of mucopolysaccharides in the deep dermis of the skin) and finger-clubbing. The latter two signs are rare effects, but exophthalmos is common. It results from infiltration of the orbital tissues by fat (interestingly, adipocytes have been shown to have cell surface TSH receptors), mucopolysaccharides and lymphocytes, and may be due to an additional auto-antibody reacting with these tissues.

Functioning adenoma

Functioning adenomas of the thyroid may cause thyrotoxicosis, but less than 1% of adenomas show enough secretory activity to do so. Histologically, the tumour is composed of thyroid follicles and is sometimes so small that it is visualised only on an ¹³¹I radio-isotope scan. Occasionally it may present as a solitary thyroid mass.

Toxic nodular goitre

Rarely one or two nodules in a nodular goitre may develop hypersecretory activity, a condition termed toxic nodular goitre.

Hashimoto’s thyroiditis

Hashimoto’s thyroiditis may initially cause thyroid enlargement, but later there may be atrophy and fibrosis. The gland appears firm, fleshy and pale (Fig. 17.25). Histologically, the gland is densely infiltrated by lymphocytes and plasma cells, with lymphoid follicle formation. Colloid content is reduced, and the thyroid epithelial cells show a characteristic change in which they enlarge and develop eosinophilic granular cytoplasm due to proliferation of mitochondria; they are then termed Askanazy cells, Hürthle cells or oncocytes (Fig. 17.26). In advanced cases there may be fibrosis. Paradoxically, in the early stages of Hashimoto’s thyroiditis, the damage to the thyroid follicles may lead to release of thyroglobulin into the circulation, causing a transient phase of thyrotoxicosis.

Fig. 17.25 Hashimoto’s thyroiditis. The gland is slightly enlarged and the lobes have been sliced to show the uniformly pale and fleshy cut surface.

Fig. 17.26 Histological features of Hashimoto’s thyroiditis. There is destruction of follicles by a dense lymphocytic infiltrate with germinal centre formation. Some of the surviving epithelial cells show Hürthle cell change (arrowed).

Like Graves’ thyroiditis, Hashimoto’s thyroiditis is one of the ‘organ-specific’ autoimmune diseases (Ch. 9). Two auto-antibodies can be detected in the serum of most patients with Hashimoto’s thyroiditis, one reacting with thyroid peroxidase and the other reacting with thyroglobulin. These auto-antibodies are probably formed locally by the plasma cells infiltrating the thyroid, and are possibly the result of a loss of specific suppressor T-lymphocytes. In common with other organ-specific autoimmune diseases, there is a female preponderance, and certain HLA antigens (Ch. 3) are commonly found in affected individuals—especially HLA-B8 and -DR5.

Aetiology

The aetiology of simple goitre is thought to involve a phase of relative lack of T₃ and T₄ so that TSH rises and causes hyperplasia of the thyroid epithelium. This lack of T₃ and T₄ can be brought about in three main ways:

Endemic goitre was formerly common in areas remote from the sea, where the soil contains little iodine, for example in the Derbyshire hills (UK), parts of Switzerland and mountainous regions. The addition of iodine to the diet by iodination of table salt has reduced the incidence of goitre in some areas.

Giant cell thyroiditis

Giant cell thyroiditis (de Quervain’s thyroiditis) is a distinctive form of slight thyroid swelling with tenderness on palpation, and fever, usually with fairly abrupt onset. Histologically, the gland is infiltrated by a mixture of neutrophil polymorphs and lymphocytes, with a focal giant cell reaction possibly due to epithelial cell fusion. The disease is thought to be induced by viral infections such as mumps, but the reason why only a few individuals develop this rare disease is not known.

Riedel’s thyroiditis

Riedel’s thyroiditis is an exceptionally rare cause of thyroid enlargement with dense fibrosis which may involve adjacent muscles; this renders the thyroid firm and immobile on palpation, thus mimicking carcinoma. Histologically, there is dense fibrous replacement of the gland and, characteristically, occlusion of thyroid veins by fibrosis. The condition is of unknown aetiology, but may be associated with retroperitoneal fibrosis.

Benign tumours

Follicular adenoma is a common cause of a solitary thyroid nodule. It usually consists of a solid mass within a fibrous capsule, compressing the adjacent gland (Fig. 17.31), but the centre may show areas of haemorrhage and cystic changes. Microscopically, a range of appearances may be seen, but the commonest type consists of very compact follicles, lined by epithelial cells with slight nuclear hyperchromatism, containing little colloid. There is a surrounding fibrous capsule which is not breached by the tumour.

Fig. 17.31 Follicular adenoma. The tumour is encapsulated.

Rarely, follicular adenomas may synthesise excess T3 and T4, appearing ‘hot’ on a radio-isotope scan, and sometimes causing thyrotoxicosis.

Malignant tumours

Carcinoma of the thyroid is not a common tumour and, because the majority of these tumours are well-differentiated types with a good prognosis, it accounts for less than 1% of cancer deaths. It is one of the malignancies known to be associated with radiation exposure, whether as X-rays to the neck or as nuclear fall-out, that contains radio-isotopes of iodine which are selectively trapped by the gland. The main features of the four types of thyroid carcinoma are summarised in Table 17.5. In addition, some of the thyroid tumours once classified as anaplastic carcinoma are now known to be lymphomas.

Papillary adenocarcinoma

Papillary adenocarcinoma is a well-differentiated form of adenocarcinoma most commonly found in younger (less than 45 years old) patients. It presents as a non-encapsulated infiltrative mass (Fig. 17.32) which may be firm and white due to fibrosis. Histologically, it consists of epithelial papillary projections (Fig. 17.33) between which calcified spherules (psammoma bodies) may be present. The epithelial cell nuclei are characteristically large with central clear areas; for this reason, they are sometimes termed ‘Orphan Annie’ nuclei (Fig. 17.34).

Fig. 17.32 Papillary adenocarcinoma and multinodular goitre. At the lower pole of the right lobe there is an infiltrating white mass (arrowed) which histologically was found to be a papillary adenocarcinoma. The gland also shows multinodular goitre.

Fig. 17.33 Papillary adenocarcinoma of the thyroid. High-power photomicrograph showing atypical epithelial cells with large vesicular (‘Orphan Annie’) nuclei forming papillae.

Fig. 17.34 Orphan Annie.This cartoon-strip character first appeared in the New York News in 1926. Her forlorn-looking eyes inspired the name ‘Orphan Annie’ for the clear nuclei seen in papillary adenocarcinoma.

Papillary adenocarcinoma metastasises via the lymphatics within the thyroid gland, which may give a multifocal appearance, and to the cervical lymph nodes. However, it is a slow-growing tumour which may even regress; thus the prognosis is excellent.

Follicular adenocarcinoma

Follicular adenocarcinomas usually present in a similar way to follicular adenomas and on naked-eye inspection are often round encapsulated nodules. However, histology reveals invasion of the capsule, blood vessels (Fig. 17.35) or the surrounding gland.

Fig. 17.35 Vascular invasion by follicular carcinoma of the thyroid. Medium-power photomicrograph of a section stained for elastin which appears dark brown in the wall of the large vein (centre). The vein is plugged by infiltrating follicular carcinoma.

Metastasis characteristically occurs via the blood stream, with the bones and lungs the commonest sites of secondary spread. However, many of the tumours retain the ability to take up ¹³¹I, which may be used as a highly effective targeted form of radiotherapy. The prognosis is therefore good.

Anaplastic carcinoma

Anaplastic carcinomas (undifferentiated) usually present in the elderly as diffusely infiltrative masses. There are various histological appearances, but spindle cell and giant cell types are common (Fig. 17.36). There is evidence that anaplastic carcinomas are poorly differentiated adenocarcinomas derived from thyroid epithelium. The prognosis is very poor, due to rapid local invasion of structures such as the trachea, producing respiratory obstruction.

Fig. 17.36 Anaplastic carcinoma of the thyroid. High-power photomicrograph showing pleomorphic hyperchromatic nuclei, some lying in tumour giant cells.

Medullary carcinoma

Medullary carcinoma is derived from the thyroid C-cells and commonly both synthesises and secretes calcitonin. Histologically, the tumour is composed of sheets of neoplastic cells with, between them, a hyaline stroma with the staining reactions of amyloid; this is due to polymerisation of calcitonin into a beta-pleated sheet (Fig. 17.37).

Fig. 17.37 Medullary carcinoma of the thyroid. High-power photomicrograph showing small spherical tumour cells adjacent to masses of amorphous hyaline material; the latter is amyloid.

Although the patient often has very high circulatory levels of calcitonin, this produces no clinical effects. Being a tumour of neuroendocrine (also termed APUD) cells (Ch. 15), medullary carcinoma may produce other secretory products, such as 5-HT, and may lead to symptoms of the carcinoid syndrome (Ch. 15).

Some cases, especially those presenting in young patients, are familial and may be part of one of the so-called multiple endocrine neoplasia (MEN) syndromes. These syndromes are rare, but it is important to recognise them in order to suspect, and diagnose early, associated endocrine neoplasms.

The tumour usually pursues a rather indolent course, but some familial cases are aggressive.

Lymphoma

Some thyroid tumours that previously would have been classified as anaplastic carcinoma are now known, largely on the basis of immunohistochemistry, to be mostly non-Hodgkin’s lymphomas (Fig. 17.38). There is an increased incidence of these types of lymphoma originating in the thyroid in Hashimoto’s thyroiditis. Most thyroid lymphomas are regarded as neoplasms of mucosa-associated lymphoid tissue (see Ch. 22).

Fig. 17.38 Non-Hodgkin’s lymphoma of the thyroid. High-power photomicrograph showing infiltration of the thyroid tissue by lymphocytes which invade through follicular epithelium.

Primary hyperparathyroidism

Primary hyperparathyroidism is a fairly common condition, occurring in almost 0.1% of the population, most frequently in post-menopausal females. It presents through the symptoms of hypercalcaemia:

In rare cases the effects of hyperparathyroidism on bone—osteitis fibrosa and brown tumour (Ch. 25)—are also apparent clinically.

Hyperparathyroidism is only one of several important possible causes of hypercalcaemia. The commonest causes of hypercalcaemia are:

In the investigation of a patient with hypercalcaemia, the results that point to hyperparathyroidism as the cause are:

In about 80% of cases, primary hyperparathyroidism is due to a secretory adenoma of one of the parathyroid glands; this consists of a neoplastic mass of functioning parathyroid cells surrounded by a compressed rim of inactive parathyroid tissue (Fig. 17.40). The remaining of cases are usually due to hyperplasia of all the parathyroid glands, especially when hyperparathyroidism forms part of one of the MEN syndromes (Ch. 11).

Fig. 17.40 Parathyroid adenoma from a patient with primary hyperparathyroidism. The adenomatous nodule (arrowed) is surrounded by a compressed rim of parathyroid tissue (arrowheads).

The management of hyperparathyroidism usually consists of operative inspection of all four parathyroid glands wherever possible, followed by removal of any suspected adenoma which is then submitted for intra-operative diagnosis by rapid frozen section.

Pathogenesis

The actions of insulin (Table 17.9) are all anabolic, that is, they promote the laying down of tissue stores from circulating nutrients. The consequences of insulin deficiency are therefore catabolic, that is, there is breakdown of tissue energy stores.

The major features of diabetes mellitus are:

In hyperglycaemia the renal threshold for glucose conservation is exceeded, so that there is osmotic diuresis resulting in polyuria, dehydration and thirst. Lipolysis may also have serious consequences. Free fatty acids are converted in the liver to ketone bodies, such as acetoacetate, acetone and beta-hydroxybutyrate. These dissociate to release hydrogen ions, and a profound metabolic acidosis may ensue.

The combined result of severe ketosis, acidosis, hyperglycaemia, hyperosmolarity and electrolyte disturbance is to impair cerebral function, producing diabetic ketoacidotic coma. This is quite distinct from the hypoglycaemic coma that may also be found in diabetic patients; this is due to insulin overdosage, and has entirely different clinical features.

Classification

The two major types of diabetes mellitus are defined according to the clinical setting in which they occur. Research into pathogenesis of the disease has reinforced this classification, as the two types appear to have distinct pathogeneses. In addition, diabetes sometimes appears as a secondary consequence of other diseases.

Complications

The major complications of diabetes mellitus are shown in Table 17.11. The commonest complications are seen in blood vessels. Atheroma, often ultimately severe and extensive, develops at an earlier age than in the non-diabetic population. Small blood vessels show basal lamina thickening and endothelial cell proliferation (diabetic microangiopathy), frequently causing retinal and renal damage. About 80% of adult diabetics die from cardiovascular disease, while patients with longstanding diabetes, especially type 1, frequently develop serious renal and retinal disease. Improved metabolic control through modern insulin regimens has only partially reduced the incidence of such serious complications.

Table 17.11 Complications of diabetes

Small blood vessels

Peripheral nerveNeuropathy, possibly due to disease of small vessels supplying the nervesNeutrophilsSusceptibility to infectionPregnancy

Insulinoma

Insulinoma is the commonest islet cell tumour and produces hypoglycaemia through hypersecretion of insulin. During hypoglycaemic attacks, the patient develops confusion, psychiatric disturbances and possibly coma. Diagnosis is urgent because hypoglycaemia may produce permanent cerebral damage.

Glucagonoma

Glucagonoma is much less common; it leads to hypersecretion of glucagon, producing secondary diabetes and a distinctive skin rash known as necrolytic migratory erythema.

Other islet cell tumours

Other islet cell tumours are very rare, but include somatostatinomas and tumours secreting vasoactive intestinal peptide (VIP), which leads to watery diarrhoea.

Gastrinomas

Although gastrin is usually produced in the G-cells of the stomach, tumours of the G-cells, called gastrinomas, most commonly originate in the pancreas. These APUD tumours lead to intractable hypersecretion of gastric acid due to the action of gastrin, resulting in widespread severe peptic ulceration (Zollinger–Ellison syndrome). Most gastrinomas are malignant.

Islet cell tumours and gastrinomas may occur as part of one of the MEN syndromes (Ch. 11), most commonly MEN type 1.

Commonly confused conditions and entities relating to endocrine pathology