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Objectives

In this chapter, you will learn to: • Describe disorders of the leading to hyperpituitarism and . • Describe the causes and patterns of thyroid dysfunction. • Describe the causes and patterns of parathyroid dysfunction. • Understand Cushing’s syndrome and other disorders of adrenal hyperfunction. • Understand the importance of adrenal hypofunction and crisis. • Recall the pathology and complications associated with diabetes mellitus. • Briefly describe endocrine tumours including the important multiple endocrine neoplasia syndromes.

DISORDERS OF THE PITUITARY • Neurons of the supra-optic nucleus (projecting into the posterior pituitary), which release The pituitary (hypophysis) is a small (500–1000 mg), ADH. bean-shaped gland lying in the sella turcica in the • Chromaffin cells of the adrenal medulla, which base of the skull. It is composed of two parts: release epinephrine (adrenaline). 1. Anterior lobe (adenohypophysis)— synthesises and secretes a number of The : hormones (Fig. 10.1), most of which act on hyperpituitarism other endocrine glands. Hyperpituitarism is defined as excessive secretion of 2. Posterior lobe (neurohypophysis)—stores and one or more of the pituitary hormones. Its most secretes two hormones synthesised in the common causes are functioning (hormone-secreting) hypothalamus: antidiuretic hormone (ADH; adenomas of the anterior lobe. vasopressin) and oxytocin. This lobe is in direct continuity with the hypothalamus, to which it is Anterior lobe adenomas connected via the pituitary stalk. Anterior lobe adenomas comprise about 10% of all intracranial tumours (posterior lobe adenomas do Secretion of the pituitary hormones is regulated by not occur). These tumours do not usually metastasise, neural and chemical stimuli from the hypothalamus, but they are often life threatening because of their diseases of which cause secondary abnormalities in position and ability to secrete excess hormone. pituitary function. This cooperation between the nervous system and Effects of pituitary adenomas endocrine apparatus is referred to as neuroendocrine Pituitary adenomas cause problems because of a com- signalling. Figure 10.2 shows the integration of signals bination of endocrine effects (excessive secretion of a between the hypothalamus, pituitary and thyroid particular hormone) and compressive effects, caused gland in the release of thyroid hormones, with feed- by an increase in local pressure of the following: back loops acting at each level. Neuroendocrine cells are defined as those that • Remainder of the pituitary → hypopituitarism. release a hormone in response to a neural stimulus. • Optic chiasm → visual field defects, notably Important examples include: bitemporal haemianopia. 205 M3422-Ch10.qxd 23/4/07 10:57 AM Page 206

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• Brain (large tumours) → distortion of the cavity of third midbrain with raised intracranial pressure and ventricle hydrocephalus. optic mammillary • Dura → . chiasma body • Cavernous sinus → CN III, IV or VI nerve dura hypothalamus antidiuretic palsies. mater hormone (ADH) oxytocin The endocrine effects depend on which hormone is being excessively secreted (see below). Investigations: anterior posterior • Imaging—plain X-ray (can detect enlargement pituitary pituitary of sella turcica and erosion of the clinoid processes) and MRI (for visualisation and sizing of the tumour; this is superior to CT scanning). sphenoid • Hormone assays (e.g. , bone growth hormone (GH) sella prolactin). turcica follicle stimulating hormone (FSH) • Functional testing of the pituitary–adrenal axis, luteinizing hormone (LH) β endorphin e.g. ACTH stimulation test in which a dose adrenocorticotrophic hormone (ACTH) of adrenocorticotrophic hormone (ACTH) is thyroid stimulating hormone (TSH) given and the plasma cortisol response melanocyte stimulating hormone (MSH) measured. • Visual field assessment. Fig. 10.1 Pituitary and hypothalamus, with the hormones released. Types of functioning adenomas

input from Functioning adenomas may produce any of the ante- higher centres rior lobe (adenophyseal) hormones but the majority +or− indirect produce prolactin (–lactotroph ade- feedback +or− +or− loop nomas), growth hormone (somatotroph adenomas) hypothalamus or ACTH (corticotroph adenomas). Prolactinomas Abnormally raised serum prolactin levels are associ- releasing hormone ated with menstrual irregularity and infertility in e.g. TRH women, and with ejaculatory failure or impotence in +or− men. Mild prolactin increases are seen with compres- +or− sion of the hypothalamus by any pituitary (the ‘stalk effect’). Galactorrhoea is present in about 30% of affect- ed women, but it is rare in men because oestrogen trophic hormone direct priming is required for lactation. e.g. TSH feedback short loop Somatotroph adenoma feedback + loop This results in hypersecretion of growth hormone, the target gland target gland hormone effects of which depend on the developmental stage e.g. thyroid e.g. thyroxine of the affected individual: • Pre-epiphyseal union (prepubertal) leads to Fig. 10.2 Schematic representation of the integration between the higher centre, hypothalamus, pituitary and target organ signalling. The (giantism), i.e. excessive growth in a example is for thyroid function, highlighting the feedback loops that regular and initially well-proportioned manner. control hormone release at each level. (TRH, thyrotrophin releasing Most giants also show some features of hormone, TSH, thyroid stimulating hormone). (Adapted with permission from Essential , 4th edn, by Brook and with disproportionate enlargement, Marshall, Blackwell Publishing, 2001). e.g. of the hands and jaw.

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• Postepiphyseal union (adults) leads to resulting in the excessive secretion of glucocorticoids acromegaly, which is characterised by causing Cushing’s syndrome, the effects of which are enlargement of the hands, feet, and head. They described later (see page 219). may also present with secondary diabetes (growth hormone is an insulin antagonist) or Other functioning adenomas cardiovascular effects (Fig. 10.3). Other endocrine secreting adenomas, e.g. of thyroid- stimulating hormone (TSH), luteinizing hormone There are three types of treatment: (LH) and follicle-stimulating hormone (FSH), are • Surgery—hypophysectomy (transfrontal or extremely rare. transphenoidal), especially where there are signs of compression of adjacent structures. This The anterior pituitary: usually only debulks the tumour, with further hypopituitarism (usually drug) therapy required. Hypopituitarism is defined as insufficient secretion of • Radiotherapy—fewer complications than surgery the pituitary hormones. The clinical features depend but less successful. on the patient’s age and on the type and severity of the • Drug therapy—bromocriptine (dopamine hormone deficiencies (Fig. 10.4). agonist) and octreotide (somatostatin analogue) Hypopituitarism can be caused by either hypo- can lower growth hormone levels in thalamic lesions or pituitary lesions. uncomplicated acromegaly. Hypothalamic lesions are: Corticotrophin adenoma • Idiopathic deficiency of one or more of the Overproduction of ACTH by the pituitary gland releasing factors, e.g. gonadotrophin-releasing (Cushing’s disease) causes adrenal hyperplasia, hormone (GnRH; Kallmann’s syndrome), growth-hormone releasing factor (GHRH) or, more rarely, thyrotrophin-releasing hormone skull brain (TRH) or corticotrophin-releasing factor (CRF). - enlarged head - mental circumference disturbances • Infarction. - insomnia • Inflammation, e.g. sarcoidosis, tuberculous face - large lower jaw meningitis. - spaces between lower • Suprasellar tumours, e.g. craniopharyngioma or, heart teeth due to jaw growth more rarely, pinealoma, teratoma or a secondary - large nose - enlarged - large tongue tumour from another site. Pituitary lesions are: liver and kidneys - enlarged organs • Idiopathic deficiency of one or more of the pituitary hormones. • Non-functioning chromophobe pituitary adenomas—adenomas of the anterior pituitary hands (usually derived from non-hormone-secreting - large, square and spade like blood pressure chromophobe cells), which may cause - hypertension hypopituitarism by compression or obliteration

blood bones of normal pituitary tissue. - hypercalcaemia - predisposes to • Sheehan’s syndrome—ischaemic necrosis of osteoarthritis the anterior pituitary due to hypotensive shock occurring as a result of obstetric skin - increased greasy haemorrhage. sweating • —an enlarged, empty sella - temperature feet intolerance turcica that is not filled with pituitary tissue. This - large and wide may be a primary anatomical variant or it may follow spontaneous infarction, surgery, or Fig. 10.3 Features of acromegaly. radiotherapy of a tumour.

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Fig. 10.4 Clinical features associated with specific forms of hypopituitarism. Fig. 10.4 Clinical features associated with specific forms of hypopituitarism

Hormone Tests to exclude hypofunction deficiency Clinical features of anterior pituitary Gonadotrophin Prepubertal: LH reserves adequate if: deficiency • Failure to enter puberty • Males have a normal • Undescended testes testosterone • Obesity • Females are ovulating • Eunuchoidism FSH reserves adequate if: Postpubertal: • Males have a normal • Infertility spermatogenesis • Amenorrhoea • Females are ovulating • Oligospermia • Progressive loss of secondary sex characteristics (hypogonadism) • Osteoporotic collapse of spine→ loss of stature GH deficiency Children: failure of GH reserves adequate if: longitudinal growth random plasma level >20 mU/L Adults: tendency to stress or otherwise elevated GH hypoglycaemia peak >20 mU/L TSH deficiency Fetus or newborn: cretinism TSH reserves adequate if serum Adults: hypothyroidism thyroxine within normal range ACTH Features of primary ACTH reserves adequate if: deficiency hypoadrenalism but with random plasma cortisol

decreased pigmentation > 550 nmol/L (rather than an increase) stress-induced cortisol

rise > 550 nmol/L

Note: ACTH, adrenocorticotrophic hormone; FSH, follicle-stimulating hormone; GH, growth hormone; LH, luteinizing hormone; TSH, thyroid-stimulating hormone.

• Trauma, including surgery and radiotherapy. quantities of dilute urine (polyuria) and by constant • Granulomatous lesions—sarcoidosis, thirst (polydipsia). tuberculosis, histiocytosis. There are two types (Fig. 10.5):

Management 1. Cranial DI—caused by the failure of ADH production. Management is by substitution therapy according to 2. Nephrogenic DI—distal tubules are refractory to the deficiencies demonstrated, e.g. cortisol replace- the water reabsorptive action of ADH. ment for ACTH deficiency, thyroid hormone replacement for TSH deficiency. Clinical features—irrespective of aetiology, reabsorp- tion of water from the glomerular filtrate in the The posterior pituitary renal collecting ducts does not occur, resulting in Diseases of the posterior pituitary are much less com- polyuria (up to 20 L per day is possible) and high risk mon than those of the anterior pituitary and are usually of body water depletion. DI is potentially lethal with- the result of damage to the hypothalamus by tumour out appropriate therapy. invasion or infarction. Posterior pituitary diseases typi- Investigations—there is high clinical suspicion if a cally cause disorders of abnormal ADH secretion. There patient has a high plasma osmolality, with low or are no known effects of abnormal oxytocin secretion. immeasurable plasma ADH, and a non-maximally concentrated urine. A water deprivation test is run for 8 hours or until 3% of the body weight is lost. Diabetes insipidus (DI) is a rare condition charac- Demonstration of continued polyuria and increased terised by the persistent excretion of excessive haemoconcentration indicates DI. This test serves to 208 M3422-Ch10.qxd 23/4/07 10:57 AM Page 209

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Fig. 10.5 Causes of cranial and Fig. 10.5 Causes of cranial and nephrogenic diabetes insipidus (DI) nephrogenic diabetes insipidus (DI).

Cause Features

Cranial DI Hypothalamic or pituitary Surgical damage, usually in the stalk damage course of tumour removal Head injury, usually transient Hypothalamic tumour (either primary or secondary) Hypothalamic inflammatory lesions, e.g. sarcoidosis, encephalitis, meningitis Genetic defect Dominant Recessive: DIDMOAD syndrome- association of DI with diabetes mellitus (DM), optic atrophy (OA) and deafness (D) Idiopathic About 30% of cases have no known cause Nephrogenic DI Hereditary Abnormal ADH receptors Metabolic abnormalities Hypokalaemia Hypercalcaemia Drug therapy Lithium Demethylchlortetracycline Poisoning Heavy metals

Note: ADH, antidiuretic hormone.

differentiate DI from psychogenic polydipsia. The test Syndrome of inappropriate antidiuretic is then followed by ADH administration to differen- hormone secretion tiate between cranial DI (kidneys are responsive to Increased secretion of ADH occurs as a complication ADH) or nephrogenic DI (kidneys are unresponsive of other diseases (primary hypersecretion of ADH is to ADH). not recognised). The condition is characterised by Treatment of mild DI—the effects of dehydration water retention with haemodilution and by inappro- can be counteracted by greatly increasing water intake priately concentrated urine. In severe cases, cerebral (polydipsia). oedema supervenes with impaired consciousness, but Treatment of moderate to severe DI body oedema is not usually seen as free water is even- • Cranial DI—treatment with desmopressin ly distributed to all body compartments. (ADH analogue but without vasoactive The causes are: effects). • Idiopathic. • Nephrogenic DI—treatment with thiazide • Tumours—ectopic secretion of ADH, especially diuretics, producing a decrease in urine volume by small cell carcinomas of the lung and some by approximately 50%. other neuroendocrine tumours. • Trauma—skull fracture, head injury or surgery may produce transiently increased secretion of ADH. • Intracranial inflammation—meningitis, Diabetes insipidus and diabetes mellitus tuberculosis, syphilis. are two distinct conditions that both • Non-neoplastic lung disease (e.g. pneumonia, feature polyuria. pulmonary embolus) probably due to involvement of intrathoracic baroreceptors. 209 M3422-Ch10.qxd 23/4/07 10:57 AM Page 210

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Figure 10.6 shows a comparison table of features of DI remains connected to the tongue by a narrow canal, with those of inappropriate ADH secretion. the thyroglossal duct, which later becomes solid and finally disappears. Disorders of the pineal gland The pineal gland is located above the third ventricle Thyroglossal cysts and it secretes the hormone melatonin. Melatonin is Cystic remnants of parts of the thyroglossal duct are thought to function in circadian rhythm control and known as thyroglossal cysts (Fig. 10.7). These cysts gonadal maturation. may form anywhere along the course of descent but are always located near or in the midline of the neck, Pinealomas (germinomas) most commonly just inferior to the hyoid bone. These tumours of young adults and children are often Cysts usually develop as painless, progressively called germinomas. They are thought to originate enlarging and movable masses. Infection of cysts from primitive germ cells and, histologically, they may result in the formation of sinuses that open resemble testicular seminomas and/or teratomas: through the skin. • Pressure on the midbrain may produce Parinaud’s syndrome (paralysis of the conjugate Thyrotoxicosis (hyperthyroidism) upward gaze without paralysis of convergence). This syndrome is caused by the excessive secretion of

• Pressure on the hypothalamus can produce thyroid hormones—typically both thyroxine (T4) and symptoms of DI, emaciation or precocious tri-iodothyronine (T3)—in the bloodstream. Symptoms puberty. include tachycardia, sweating, tremor, anxiety, increased appetite, loss of weight and intolerance of heat.

THYROID DISORDERS body of tongue foramen caecum Congenital disorders epiglottis of the thyroid thyroglossal cysts Development of the thyroid hyoid bone The thyroid gland develops from an endodermal thyroid cartilage thickening in the floor of the primitive pharynx at a point later indicated by the foramen caecum of the thyroid gland cricoid cartilage tongue (Fig. 10.7). As the embryo grows, the thyroid

descends into the neck, passing anterior to the hyoid Fig. 10.7 Path of descent of thyroid gland (broken line) and localisation and laryngeal cartilages. During migration, the gland of thyroglossal cysts.

Fig. 10.6 Comparison of features of diabetes insipidus with those of inappropriate ADH secretion

Condition Imbalance Urinary and plasma osmolality Symptoms

Diabetes insipidus ↓ ADH Low urinary osmolality Polyuria (5−20 L/day) High plasma osmolality Thirst Polydipsia (may lead to severe dehydration, exhaustion, coma) Syndrome of ↑ ADH High urinary osmolality Oliguria inappropriate Low plasma osmolality Water intoxication (may lead to ADH secretion (dilutional hyponatraemia) confusion, neurological disturbances, coma)

Note: ADH, antidiuretic hormone.

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Hyperthyroidism can be classified on the basis of hair loss brain aetiology into: - anxiety - insomnia • Primary hyperthyroidism (↑ thyroid hormones, - restlessness eyes ↓ - irritability TSH)—hypersecretion of thyroid hormones, - exophthalmos which is not secondary to increased levels of TSH (protruding eyes) neck (the rise in thyroid hormones actually suppresses - lid retraction - goitre - lid lag TSH). Secondary hyperthyroidism (↑ thyroid heart muscles • - proximal myopathy ↑ - tachycardia hormones, TSH)—overstimulation of the (rapid pulse) (in upper arms thyroid gland caused by excess TSH produced - palpitations and legs) by a tumour in the pituitary or elsewhere - atrial fibrillation bowel (rare). - diarrhoea uterus Primary hyperthyroidism is caused by: hands - menorrhagia - tremor • Graves’ disease (exophthalmic goitre)—the most - warm, moist palms common cause of thyrotoxicosis, characterised by - onycholysis (nail a diffusely enlarged thyroid gland that is loose in nail bed) - acropachy stimulated to produce excess hormone by an IgG autoantibody. bones skin and adipose - osteoporosis • Toxic multinodular goitre (Plummer’s tissue - increased sweating disease)—second most common cause of - temperature hyperthyroidism. intolerance Toxic adenoma—solitary thyroid nodule - weight loss • - pretibial producing excess hormone with remainder of the myxoedema thyroid gland being suppressed. • Thyroiditis—inflammation of the thyroid Fig. 10.8 Summary diagram illustrating features of thyrotoxicosis. causing hyperthyroidism (e.g. De Quervain’s (* = additional features seen only in Graves’ disease.) thyroiditis). Note that thyroiditis is more commonly associated with hypothyroidism (see Management—options in thyrotoxicosis are: below). • Drugs—either direct ingestion of large doses of • Surgery—reduces the amount of functioning thyroid hormone (thyrotoxicosis factitia) or thyroid tissue. through iodide-inducing drugs (e.g. • Radioactive iodine—to destroy part of the gland. amiodarone). • Drugs (such as carbimazole or propylthiouracil)— interfere with the production of thyroid Effects of thyrotoxicosis hormones. of thyrotoxicosis are a conse- quence of an increase in the body’s metabolism, which Graves’ disease occurs as a direct result of increased concentrations of Graves’ disease is an organ-specific autoimmune the thyroid hormones. disorder that results in thyrotoxicosis due to over- The most important symptoms diagnostically are: stimulation of the thyroid gland by autoantibodies. It is the most common form of thyrotoxicosis, females Heat intolerance and excessive sweating • being affected more than males by 8:1. It is usually (). associated with a diffuse enlargement of the thyroid. Nervousness and irritability. • Pathogenesis—IgG-type immunoglobulins bind to Weight loss with normal or increased appetite. • TSH membrane receptors and cause prolonged stim- Goitre (an enlargement of the thyroid gland). • ulation of the thyroid, lasting for as long as 12 hours Other symptoms are summarised in Fig. 10.8. (cf. 1 hour for TSH). The autoantibody binds at a site Investigations—hyperthyroidism is confirmed different to the hormone-binding locus and is termed by raised serum thyroxine and/or lowered serum the TSH-receptor autoantibody (TRAb); 95% of TSH. Graves’ disease patients are positive for TRAbs. 211 M3422-Ch10.qxd 23/4/07 10:57 AM Page 212

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Histologically, the gland shows diffuse hyper- • Lack of hair and teeth. trophy and hyperplasia of acinar epithelium, reduc- • Pot belly (often with umbilical hernia). tion of stored colloid and local accumulations of • Protruding tongue. lymphocytes with lymphoid follicle formation. Management is by early detection and treatment with The clinical features of Graves’ disease are similar thyroxine, which can prevent an irreversible mental to those of general thyrotoxicosis but with some defect and cerebellar damage. Many countries now additional features (see Fig. 10.8), namely: have screening programs to measure serum TSH • Exophthalmos (protrusion of the eyeballs in their and/or thyroxine levels on heel-prick blood samples sockets)—due to the infiltration of orbital tissues taken on the fourth or fifth day of life. by fat, mucopolysaccharides and lymphocytes. May cause compression of the optic nerve, hence Hypothyroidism in adults (myxoedema) blindness. However, only about 5% of Graves’ This common clinical condition is associated with patients show signs of exophthalmos. decreased function of the thyroid gland and a • Thyroid acropachy—enlargement of fingernails. decrease in the circulating level of thyroid hormones. • Pretibial myxoedema—accumulation of It affects 1% of people in the UK, with females more mucoproteins in the deep dermis of the skin. than males by 6:1. It can present at any age but most Treatment is as for thyrotoxicosis. commonly between 30 and 50 years of age. Note that, strictly speaking, myxoedema Hypothyroidism describes a non-pitting, oedematous reaction char- acteristic of hypothyroidism caused by the deposi- Decreased activity of the thyroid gland results in tion of a mucoid substance (myxa-is a Greek prefix decreased production of thyroid hormones. There are denoting mucus) in the skin and elsewhere in the two forms: body. However, the terms ‘myxoedema’ and 1. Hypothyroidism present at birth → cretinism or ‘hypothyroidism of adults’ are now frequently used congenital hypothyroidism. interchangeably. 2. Hypothyroidism in adults → myxoedema. Hypothyroidism can be classified according to aetiology: Cretinism (congenital hypothyroidism) • Primary (↓ thyroid hormones, ↑ TSH)—failure of This condition occurs as a result of extreme hypothy- the thyroid gland itself. This is much more roidism during fetal life, infancy or childhood. It has common than secondary hypothyroidism. Note the following types and aetiology: that subclinical hypothyroidism describes an • Endemic cretinism—occurs in iodine-deficient increase in TSH but with normal thyroid countries where goitre is common. The mother hormone levels, and is increasingly being treated almost always has a goitre and the thyroid of the with the aim of reducing progression to full affected infant is usually enlarged and nodular. disease. • Sporadic cretinism—caused by congenital • Secondary (↓ thyroid hormones, ↓TSH)—failure hypoplasia or absence of the thyroid gland and of TSH production due to . often associated with deaf mutism. The causes of primary hypothyroidism are: • Dyshormonogenesis—a congenital familial recessive enzyme defect causing an inability to • Autoimmune thyroiditis—atrophic form, complete the formation of thyroid hormones. e.g. primary atrophic thyroiditis and goitrous TSH is increased, and the thyroid gland is form (such as Hashimoto’s thyroiditis). enlarged and shows epithelial hyperplasia. • Graves’ disease—approximately 5% of patients with thyrotoxicosis develop hypothyroidism in The clinical features of cretinism are: later years, unrelated to treatment. Probably • Mental retardation. caused by a spectrum of antithyroid antibodies, • Retarded growth—skeletal growth is inhibited some of which stimulate TSH receptor and some more than soft tissue growth, resulting in an of which are destructive. obese, stocky, short child. • Treatment of hyperthyroidism—surgical • Coarse, dry skin. ablation, radioiodine or drug treatment. 212 M3422-Ch10.qxd 23/4/07 10:57 AM Page 213

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• Severe iodine deficiency (rare in the UK)—iodine Thyroiditis must be virtually absent from the diet before This inflammation of the thyroid gland can have a myxoedema develops. viral or autoimmune aetiology. The effects of hypothyroidism are shown in Fig.10.9. Hashimoto’s thyroiditis (most common cause of hypothyroidism) Signs and symptoms of hypothyroidism are both This organ-specific autoimmune disease results in widespread (due to reduced body metabolism) and destructive thyroiditis. It can occur at any age, but typ- localised (myxoedema due to the accumulation of ically affects the middle-aged, and females more than mucoproteins). The most important symptoms males by 12 : 1. diagnostically are: Thyroid peroxidase antibodies are most com- • Mental and physical slowness. monly found in the serum of affected individuals • Tiredness. (90% of cases). The disease is associated with the • Cold intolerance. HLA-DR5 and HLA-B8 haplotypes, and patients with • Dryness of skin and hair. Hashimoto’s disease (and Graves’ disease) show a Investigations are: high incidence of other autoimmune diseases. • Serum thyroxine concentration (decreased). Macroscopically, the thyroid gland is usually: • Serum TSH concentration (reduced in secondary hypothyroidism but increased in primary • Diffusely enlarged (typically 2–5 times normal hypothyroidism). size). The treatment is oral thyroxine daily for life. • Firm in consistency. • White or grey on a cut surface as a result of the disappearance of brown (iodine-rich) colloid (thyroglobulin), and its replacement by hair brain - coarse and thin hair - mental slowing lymphocytes. - loss of outer third of - apathy eyebrows - tiredness Microscopically, the thyroid gland shows: - psychosis face • Small thyroid follicles infiltrated by lymphocytes - myxoedemic features, i.e.pale puffy face, hoarse voice and plasma cells. coarse features neck • Lymphoid follicle formation and increased - deafness - goitre fibrous tissue stroma. heart • Acini lined with abnormal, highly eosinophilic - bradycardia muscles - slowing of activity epithelial cells (proliferation of mitochondria) - in known as Askanazy or Hürthle cells. upper arms and legs (proximal myopathy) • Reduced colloid content of disrupted acini. The condition may present due to goitre formation or bowel - constipation because of the symptoms of hypothyroidism. The hands hypothyroid state tends to develop slowly. However, - cold hands uterus - carpal tunnel damage to thyroid follicles may lead to the release of - amenorrhoea syndrome thyroglobulin into the circulation causing transient thy- rotoxicosis. Some cases proceed to primary atrophic thyroiditis. Furthermore, there is an increased incidence of non-Hodgkin’s lymphoma originating in the thyroid skin and adipose tissue - weight gain/obesity of patients with Hashimoto’s thyroiditis. - intolerance to cold Treatment is by oral thyroxine, which overcomes - decreased sweating - chronic oedema hypothyroidism and reduces the size of the goitre. (caused by increased capillary escape of albumin) De Quervain’s thyroiditis - cold, dry skin A rare, viral thyroiditis seen in young and middle-aged Fig. 10.9 Summary diagram illustrating features of hypothyroidism in women as a slightly diffuse tender swelling of the the adult (myxoedema). thyroid; this is also known as subacute, giant cell or 213 M3422-Ch10.qxd 23/4/07 10:57 AM Page 214

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granulomatous thyroiditis. The condition usually Hashimoto’s thyroiditis, and it is often asympto- occurs in association with a transient febrile illness, matic. It may also present with the symptoms of often during various viral epidemics. hyperthyroidism. The most commonly associated viruses are Note that some degree of progressive lymphocytic Coxsackie, mumps and adenovirus. infiltration of the thyroid is seen in 5–10% of Characteristic features are: thyroid autopsies, and these are thought to be a nor- mal ageing change. However, in subacute lympho- • Painful enlargement of the thyroid (about twice cytic thyroiditis, lymphocytic infiltration is in excess normal size; normal weight is 20–30 g). of what would normally be expected for age-related • History of usually short duration. change. • Preceding general malaise, pyrexia or upper A comparison of the main types of thyroiditis is respiratory infection. provided in Fig. 10.10. Histological examination shows: • Inflammation with a giant cell granulomatous Thyroid goitres reaction engulfing leaked colloid (hence the Definitions synonyms giant cell or granulomatous A goitre is any enlargement of part or whole of the thyroiditis). thyroid gland. There are two types: • Degeneration of follicles with inflammatory cell infiltration (neutrophils, plasma cells, 1. Toxic goitre, i.e. goitre associated with lymphocytes and histiocytes). thyrotoxicosis. • Fibrous scarring (late). 2. Non-toxic goitre, i.e. goitre associated with normal or reduced levels of thyroid hormones. The illness is usually self-limiting and settles in a few weeks. Transient hyperthyroidism can result from the Toxic goitre release of thyroglobulin and excessive amounts of Graves’ disease thyroid hormone. This is the most common cause of toxic goitre Severe thyroiditis may be fatal in the elderly and (described above). debilitated. Toxic multinodular goitre Subacute lymphocytic thyroiditis This results from the development of hyperthy- This form of autoimmune thyroiditis is characterised roidism in a multinodular goitre (see below). by focal lymphocytic infiltration of the thyroid (also known as focal lymphocytic thyroiditis). Non-toxic goitres Histological changes are similar to those in Diffuse non-toxic goitre (simple goitre) Hashimoto’s thyroiditis but they are focal This diffuse enlargement of the thyroid gland is rather than diffuse. The disease is less severe than classified into:

Fig. 10.10 Summary of features of thyroiditis. Fig. 10.10 Summary of features of thyroiditis

Subacute Hashimoto's De Quervain's lymphocytic thyroiditis thyroiditis thyroiditis Aetiology Autoimmune Viral Autoimmune Histological Diffuse lymphocytic Giant cell Focal lymphocytic features infiltration of granulomatous infiltration of thyroid thyroid inflammatory reaction Hypothyroidism Common Rare Rare

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• Endemic goitre—due to iodine deficiency. Rare in the UK but may occur in certain geographical areas remote from the sea. A reminder of the differences between • Sporadic goitre—caused by goitrogenic agents (substances that induce goitre formation) or primary and secondary hyperthyroidism familial in origin. Examples of goitrogenic agents and hypothyroidism: ↑ include certain cabbage species, because of their • Primary hyperthyroidism— thyroid hormones, ↓ thiourea content, and specific drugs or chemicals, TSH. ↑ such as iodide, paraminosalicylic acid and drugs • Secondary hyperthyroidism— thyroid hormones, ↑ used in the treatment of thyrotoxicosis. Familial TSH (excess TSH production due to pituitary cases show inherited autosomal recessive traits, tumour). ↓ which interfere with hormone synthesis via • Primary hypothyroidism— thyroid hormones, ↑ various enzyme pathways (these are TSH. ↓ dyshormonogenic goitres). • Secondary hypothyroidism— thyroid hormones, ↓ TSH (failure of TSH production due to pituitary • Physiological goitre—enlargement of the thyroid gland in females during puberty or pregnancy; disease). the reason is unclear.

Multinodular goitre This is the most common cause of thyroid enlarge- feature, and the centre may show areas of haemor- ment and is seen particularly in the elderly (nearly all rhage and cystic changes. The most common type is simple goitres eventually become multinodular). The follicular adenoma, which consists of colloid-con- exact aetiology is uncertain but it may represent an taining microfollicles and columns of larger cells of uneven responsiveness of various parts of the thyroid alveolar arrangement. to fluctuating TSH levels over a period of many years. Rarely, follicular adenomas may synthesise excess Morphological features are: thyroid hormones (‘toxic adenomas’), causing thyro- toxicosis. • Irregular hyperplastic enlargement of the entire thyroid gland due to the development of well- Malignant tumours circumscribed nodules of varying size. These rare tumours account for less than 1% of total • Larger nodules filled with brown, gelatinous cancer deaths in the UK, with females affected more colloid; consequently, it is often termed than males by 3 : 1. Although the aetiology of thyroid multinodular colloid goitres. cancer is unknown in the majority, it is likely that Most patients have normal thyroid function and gen- childhood radiation exposure is involved in some erally seek treatment for cosmetic reasons (an cases (there is an increased incidence in those exposed unsightly swelling in the neck) or compression symp- to the Chernobyl fallout). Types of malignant thyroid toms, e.g. pressure on the trachea producing stridor or tumours and their basic features are outlined in pressure on the recurrent laryngeal nerve producing Fig. 10.11. hoarseness. Papillary adenocarcinoma However, toxic changes occasionally occur in a This well-differentiated tumour is most commonly multinodular goitre resulting in hyperthyroidism, found in younger patients. It presents as a non- when it is termed a toxic multinodular goitre. encapsulated infiltrative mass. It is a slow growing tumour with an excellent prognosis. Neoplasms of the thyroid Histologically, it consists of epithelial papillary Tumours of the thyroid are generally benign. projections between which calcified spherules may be Carcinomas are rare and lymphomas are rarer still. present. Epithelial cell nuclei are characteristically large with optically clear areas centrally (described as Benign tumours ‘Orphan Annie nuclei’). Thyroid adenomas Follicular adenocarcinoma These are solitary, or multiple, encapsulated solid This well-differentiated, single, encapsulated lesion is nodules. Compression of the adjacent gland is a common histologically similar to follicular adenoma but can

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Fig. 10.11 Types and features of malignant thyroid tumours

Prognosis Tumour Origin of Frequency Typical (% for 10- type tumour (%) age range (years) Spread year survival)

Differentiated Papillary Follicular cells 70 20−40 Lymph nodes 95 carcinoma Follicular Follicular cells 10 40−60 Bloodstream 60 Undifferentiated Anaplastic Follicular cells 5 > 60 Aggressive 1 carcinoma local invasion; bloodstream Medullary −− Parafollicular 5−10 > 40 Local, 50 (but very carcinoma C cells lymphatic variable) and blood Lymphoma −− Lymphocytes 5−10 > 60 Lymphatic 10

Fig. 10.11 Types and features of malignant thyroid tumours.

be differentiated by its invasion of the capsule and/or multiple endocrine neoplasia (MEN) syndromes IIa blood vessels. Spread is usually to bones, lungs and and IIb (see pages 227–228). brain via the bloodstream. Lymphomas Many of these tumours retain the ability to take up Most thyroid lymphomas are regarded as tumours of 131 radioactive iodine ( I), which may be used as a highly mucosa-associated lymphoma tissue. Interestingly, effective targeted form of radiotherapy, usually after non-Hodgkin’s B cell lymphomas occasionally arise surgical thyroidectomy. The prognosis, therefore, is in long-standing, autoimmune thyroiditis, especially good. Hashimoto’s disease. Anaplastic carcinoma This highly malignant, poorly differentiated adeno- carcinoma usually presents in the elderly as a diffusely PARATHYROID DISORDERS infiltrative mass. In about half of cases there is a history of multinodular goitre. Parathyroid hormone Histologically, the dominant features are those of Parathyroid hormone (PTH) is a polypeptide (84 a spindle cell tumour with or without giant cell areas, amino acid residues) secreted by the chief cells of or a small cell pattern. the parathyroid glands (four glands: two in each of the The prognosis is very poor due to the rapid local superior and inferior lobes of the thyroid; total weight invasion of structures such as the trachea, producing 120 mg). respiratory obstruction. The main action of PTH is to increase serum calci- Medullary carcinoma um and decrease serum phosphate. Its actions are This rare neuroendocrine tumour arises from para- mediated by the bones and kidneys as described below. follicular C cells, which commonly synthesise In bone, PTH stimulates osteoclastic bone resorp- and secrete calcitonin but which may also secrete tion and inhibits osteoblastic bone deposition. The 5-hydroxytryptamine (serotonin), various peptides of net effect is the release of calcium from bone. the tachykinin family, ACTH and prostaglandins. In the kidney, PTH has the following effects: High levels of serum calcitonin are useful diagnos- • Increases calcium reabsorption. tically but produce no clinical effects. • Decreases phosphate reabsorption. Although medullary carcinoma is most common • Increases 1-hydroxylation of 25-hydroxyvitamin in the elderly, it also occurs in younger individuals, D (i.e. activates vitamin D). where it is commonly associated with other endocrine tumours, such as phaeochromocytoma as part of the PTH also increases gastrointestinal calcium absorption. 216 M3422-Ch10.qxd 23/4/07 10:57 AM Page 217

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Hyperparathyroidism Effects of hyperparathyroidism The clinical effects are the result of hypercalcaemia Hyperparathyroidism is defined as an elevated secre- and bone resorption. tion of PTH, of which there are three main types: Effects of hypercalcaemia: 1. Primary—hypersecretion of PTH by adenoma or Renal stones due to hypercalcuria. hyperplasia of the gland. • Excessive calcification of blood vessels. 2. Secondary—physiological increase in PTH • Corneal calcification. secretions in response to hypocalcaemia of any • General muscle weakness and tiredness. cause. • Exacerbation of hypertension and potential 3. Tertiary—supervention of an autonomous • shortening of the QT interval. hypersecreting adenoma in long-standing Thirst and polyuria (may be dehydrated due to secondary hyperparathyroidism. • impaired concentrating ability of kidney). • Anorexia and constipation. Effects of bone resorption: Understanding the physiological • Osteitis fibrosa—increased bone resorption with functions of PTH is essential to an fibrous replacement in the lacunae. understanding of the clinical effects • ‘Brown tumours’—haemorrhagic and cystic produced by its hypo- or hypersecretion. tumour-like areas in the bone, containing large masses of giant osteoclastic cells. • Osteitis fibrosa cystica (von Recklinghausen Primary hyperparathyroidism disease of bone)—multiple brown tumours combined with osteitis fibrosa. This is the most common of the parathyroid disor- • Changes may present clinically as bone pain, ders, with a prevalence of about 1 per 800 in the UK. fracture or deformity. It is an important cause of hypercalcaemia. More than 90% of patients are over 50 years of age and the con- However, about 50% of patients with biochemical dition affects females more than males by nearly 3 : 1. evidence of primary hyperparathyroidism are The aetiology of primary hyperparathyroidism is out- asymptomatic. lined in Fig. 10.12. Investigations are: + • Biochemical—increased PTH and Ca2 , and 3− decreased PO4 . • Radiological—90% normal; 10% show evidence Fig. 10.12 Aetiology of primary hyperparathyroidism of bone resorption, particularly phalangeal TypeFrequency Features erosions.

Adenoma 75% Orange−brown, Management is by rehydration, medical reduction in well-encapsulated plasma calcium using bisphosphonates and eventual tumour of various size but surgical removal of abnormal parathyroid glands. seldom > 1 cm diameter Tumours are usually solitary, affecting only one of the Secondary hyperparathyroidism parathyroids, the others often This is compensatory hyperplasia of the parathyroid showing atrophy; they are glands, occurring in response to diseases of chronic deep seated and rarely low serum calcium or increased serum phosphate. palpable Its causes are: Primary 20% Diffuse enlargement of all the hyperplasia parathyroid glands • Chronic renal failure and some renal tubular Parathyroid 5% Usually resembles adenoma disorders (most common cause). carcinoma but is poorly encapsulated • Steatorrhoea and other malabsorption and invasive locally syndromes. • Osteomalacia and rickets. Fig. 10.12 Aetiology of primary hyperparathyroidism. • Pregnancy and lactation. 217 M3422-Ch10.qxd 23/4/07 10:57 AM Page 218

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Fig. 10.13 Pathogenesis of renal osteodystrophy. ↓ vit. D activation

Renal disease → + → ↓ serum Ca2+ →↑ PTH → ↓ bone absorption ↓Ca2+ reabsorption

Morphological changes of the parathyroid glands are: levels are likely to be decreased as this is driving the compensatory PTH secretion. • Hyperplastic enlargement of all parathyroid The investigations are both biochemical (raised glands, but to a lesser degree than in primary PTH and normal or lowered Ca2+) and radiological hyperplasia. (bone changes). • Increase in ‘water clear’ cells and chief cells of the Management is by treatment of the underlying parathyroid glands, with loss of stromal fat cells. disease and oral calcium supplements to correct Clinical manifestations—symptoms of bone resorption hypocalcaemia. are dominant. Tertiary hyperparathyroidism Renal osteodystrophy This condition, resulting from chronic overstimu- Skeletal abnormalities, arising as a result of raised lation of the parathyroid glands in renal failure, PTH secondary to chronic renal disease, are known as causes one or more of the glands to become an renal osteodystrophy. autonomous hypersecreting adenoma with resultant The pathogenesis of renal osteodystrophy is shown hypercalcaemia. in Fig. 10.13. Figure 10.14 gives a comparison of primary, Abnormalities vary widely according to the nature secondary and tertiary hyperparathyroidism. of the renal lesion, its duration and the age of the patient, but include: Hypoparathyroidism • Osteitis fibrosa (see above). • Rickets or osteomalacia due to reduced activation Hypoparathyroidism is a condition of reduced or of vitamin D. absent PTH secretion, resulting in hypocalcaemia and • Osteosclerosis—increased radiodensity of certain hyperphosphataemia. It is far less common than bones, particularly the parts of vertebrae adjacent hyperparathyroidism. to the intervertebral discs. The causes of hypoparathyroidism are: Note that the symptoms of hypercalcaemia are not a • Removal or damage of the parathyroid glands feature of secondary hyperparathyroidism; calcium during thyroidectomy—most common cause of

Fig. 10.14 Comparison of primary, secondary and tertiary Fig. 10.14 Comparison of primary, secondary and tertiary hyperparathyroidism hyperparathyroidism. Primary Secondary Tertiary

Serum PTH ↑PTH; ↑Ca2+ ↑PTH; normal or ↑PTH; ↑Ca2+ and Ca2+ ↑Ca2+ Aetiology Adenoma Chronic renal failure Adenoma resulting Hyperplasia Malabsorption from overstimulation Carcinoma Osteomalacia and rickets of glands in secondary Pregnancy and lactation hyperparathyroidism Predominant Hyper- Increased bone Hypercalcaemia and effects calcaemia absorption increased bone resorption

Note: PTH, parathyroid hormone.

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hypoparathyroidism resulting from inadvertent • Glucocorticoid hormones, e.g. cortisol— damage or removal. primarily from the zona fasciculata. • Autoimmune parathyroid disease—usually occurs • Mineralocorticoid hormones, e.g. aldosterone— in patients who have another autoimmune from the zona glomerulosa. endocrine disease, e.g. Addison’s disease • Sex steroids, i.e. oestrogens and androgens—from (autoimmune endocrine syndrome type 1). the zona reticularis. • Congenital deficiency (DiGeorge syndrome)— rare, congenital disorder caused by arrested Medulla development of the third and fourth branchial This is the inner part of the gland, which is derived arches, resulting in an almost complete absence from the neuroectoderm, forming part of the sym- of the thymus (see Chapter 13) and parathyroid pathetic nervous system. Chromaffin cells synthesise gland. and secrete the vasoactive amines epinephrine (adrenaline) and norepinephrine (noradrenaline). The effects of hypoparathyroidism are:

+ • ↓ release of Ca2 from bones. Hyperfunction of the adrenal ↓ 2+ ↑ 3− • Ca reabsorption but PO4 re absorption by cortex kidney. Cushing’s syndrome • ↓ 1-hydroxylation of 25-hydroxyvitamin D by kidney. The symptoms and signs of Cushing’s syndrome are associated with prolonged inappropriate elevation of Most symptoms of hypoparathyroidism are those of free corticosteroid levels (Fig. 10.15). hypocalcaemia: Clinical features—the main effects of sustained • Tetany—muscular spasm provoked by lowered elevation of glucocorticoid secretion are: 2+ plasma Ca . • Central obesity and moon face. • Convulsions. • Plethora and acne. • Paraesthesiae. • Menstrual irregularity. • Psychiatric disturbances, e.g. depression, • Hirsutism and hair thinning. confusional state and even psychosis. • Hypertension. • Rarely—cataracts, parkinsonian-like movement • Diabetes. disorders, alopecia, brittle nails. • Osteoporosis—may cause collapse of vertebrae, Management is by treatment with large doses of oral rib fractures. vitamin D; the acute phase requires intravenous cal- • Muscle wasting and weakness. cium and calcitriol (1,25-dihydroxycholecalciferol, • Atrophy of skin and dermis—paper thin skin i.e. activated vitamin D). with bruising tendency, purple striae. Aetiopathogenesis—patients with Cushing’s syndrome can be classified into two groups on the basis of whether the aetiology of the condition is ACTH- DISORDERS OF THE ADRENAL dependent or independent (Fig. 10.16). GLAND ACTH-dependent aetiology: Hormones of the adrenal gland • Pituitary hypersecretion of ACTH (Cushing’s disease)—bilateral adrenal hyperplasia secondary The adrenal gland has two structurally and func- to excessive secretion of ACTH by a corticotroph tionally distinct endocrine components derived adenoma of the pituitary gland (see page 207). from different embryonic tissue: the cortex and the • Production of ectopic ACTH or corticotrophin- medulla. releasing hormone (CRH) by non-endocrine neoplasm, e.g. small cell lung cancer and some Cortex carcinoid tumours. In cases of malignant bronchial This is the outer part of the gland, which is derived tumour, the patient rarely survives long enough to from the mesoderm. It synthesises, stores, and secretes develop any physical features of Cushing’s various cholesterol-derived hormones, namely: syndrome.

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Fig. 10.15 Systemic effects of Cushing’s syndrome. eyes hair - cataract brain - thin - depression - male pattern baldness - confusion - insomnia adipose tissue - psychosis - truncal obesity - striae (stretchmarks) face - buffalo hump - moon face (due to increased fat deposition) heart - acne - predisposes to congestive cardiac muscles failure - skeletal muscle weakness and wasting (causes thin arms and legs)

stomach - peptic ulcer kidney - renal calculi

uterus - menstrual disturbances e.g. amenorrhoea blood pressure - hypertension

skin - thin skin - hirsutism bones - easy bruising - osteoporosis - tendency to skin infections - tendency to fracture (- increased skin - vertebral collapse pigmentation in Cushing s (kyphosis) disease only)

blood - glucose intolerance, some have diabetes ankles - oedema

Non-ACTH-dependent aetiology: • Iatrogenic steroid therapy—most common cause Fig. 10.16 Classification of Cushing's syndrome of Cushing’s syndrome. Adrenal cortical adenoma—well-circumscribed Type Cause • yellow tumour usually 2–5 cm in diameter. ACTH dependent Iatrogenic (ACTH therapy) Extremely common as an incidental finding in up Pituitary hypersecretion of ACTH Ectopic ACTH syndrome (benign to 30% of all post-mortem examinations. The or malignant non-endocrine tumour) yellow colour is due to stored lipid (mainly Non-ACTH Iatrogenic, e.g. prednisolone cholesterol) from which the hormones are dependent Adrenal cortical adenoma synthesised. The vast majority have no clinical Adrenal cortical carcinoma effects (i.e. they are non-functioning adenomas), with only a small percentage producing Fig. 10.16 Classification of Cushing’s syndrome. Cushing’s syndrome. 220 M3422-Ch10.qxd 23/4/07 10:57 AM Page 221

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• Adrenal cortical carcinoma—rare and almost invariably caused by adrenal cortical adenoma always associated with the overproduction of (Conn’s syndrome). hormones, usually glucocorticoids and sex • Secondary hyperaldosteronism— steroids. Patients usually have features of hypersecretion of aldosterone secondary to an Cushing’s syndrome mixed with androgenic increased production of angiotensin II effects which are particularly noticeable in following activation of the renin–angiotensin women. Tumours are usually large and yellowish- system. May be precipitated by congestive white in colour. Local invasion and metastatic cardiac failure, cirrhosis, pregnancy, nephrotic spread are common. syndrome or decreased renal perfusion. This is more common than the primary form of the disorder. The effects of hyperaldosteronism are shown in The therapeutic administration of Fig. 10.17. glucocorticosteroids (e.g. prednisolone) is Clinical features are: a common cause of the features of Cushing’s syndrome. Avoid confusing the disease and • Hypertension—often the only presenting the syndrome. Remember: Cushing’s disease is used feature. Commonly occurs in the younger age specifically to describe Cushing’s syndrome secondary group. to excessive pituitary ACTH secretion. • Hypokalaemia—usually accompanies hypertension and may give rise to polyuria, nocturia, polydipsia, paraesthesia, cardiac arrhythmias, muscle weakness or paralysis. Secondary hyperaldosteronism also has additional Irrespective of the aetiology, the diagnosis is based on features of underlying disease. clinical features and the demonstration of a raised Biochemical diagnosis: plasma cortisol level. + + The aetiology of the disorder is elucidated through: • ↑ Na , ↓ K . • ↑ Aldosterone. • Raised urinary cortisol in the first instance, but • Plasma renin—↓ in Conn’s syndrome but ↑ in further testing is required. secondary hyperaldosteronism. • Low-dose dexamethasone suppression test (suppression of cortisol levels in Cushing’s Radiological diagnosis is by visualisation of adrenal disease due to suppression of pituitary ACTH cortical adenoma by CT scan or MRI. secretion, but a lack of suppression suggests ACTH-independent Cushing’s syndrome). • MRI and CT scan visualisation of pituitary and adrenal glands. hypersecretion of • Analysis of blood ACTH (high = pituitary aldosterone adenoma or ectopic ACTH source; low = primary adrenal tumour due to feedback suppression). + Na reabsorption excretion of K+ Treatment of the underlying cause is essential as from renal tubules untreated Cushing’s syndrome has a 50% 5-year mor- tality rate.

Na+ + H O Hyperaldosteronism 2 hypokalaemia retention Excessive production of aldosterone by the zona glomerulosa of the adrenal cortex results in increased Na+ retention and increased K+ loss. hypertension cardiac alkalosis The aetiology is as follows: arrhythmias • Primary hyperaldosteronism—autonomous hypersecretion of aldosterone, which is almost Fig. 10.17 Effects of hyperaldosteronism. 221 M3422-Ch10.qxd 23/4/07 10:57 AM Page 222

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Management: insufficiency, loss of adrenal androgen production and increased ACTH secretion. • Primary hyperaldosteronism—medical Aetiology—autoimmune destruction of the cortex of aldosterone antagonism (e.g. spironolactone) or both adrenals is the most common cause of Addison’s surgical removal of the affected adrenal. disease. It is often associated with autoimmune thy- • Secondary hyperaldosteronism—treatment of the roid disease, autoimmune gastritis and other underlying cause. endocrine organ autoimmune diseases. Addison’s dis- Congenital adrenal hyperplasia ease is also a well-recognised complication of patients with acquired immune deficiency syndrome (AIDS), This rare, autosomal recessive disorder is usually caused bilateral adrenal tuberculosis (caseous necrosis) and, by a deficiency of the enzyme 21-hydroxylase, required more rarely, metastatic cancers, haemochromatosis for the synthesis of both cortisol and aldosterone. and amyloidosis. 21-hydroxylase acts on 17OH-progesterone, and con- Biochemical features: sequently raised levels of 17OH-progesterone are mea- sured in the blood of affected individuals; this is • Measurement of plasma ACTH and cortisol— routinely tested in the first week of life. Failure of corti- ↑ ACTH, ↓ cortisol. sol production produces an increase in ACTH secretion • ACTH stimulation test—ACTH is administered by the pituitary and hyperplasia of the adrenal cortex. and plasma cortisol levels are monitored. Failure Production of androgens by the adrenal cortex does of cortisol levels to rise indicates Addison’s not require 21-hydroxylase. Consequently, adrenal disease. + + hyperplasia causes excessive secretion of androgens • Plasma electrolytes—↓ Na , normal or ↑ K , ↑ urea. resulting in masculinisation of females and precocious • Blood glucose—usually low. puberty in males. Also, aldosterone deficiency is seri- • ↑ Plasma renin activity and normal or ous, causing a life-threatening salt loss (‘salt wasting ↓ aldosterone. syndrome’) unless replacement therapy is given. Management is by glucocorticoid replacement ther- apy, and usually mineralocorticoid therapy. Hypofunction of the adrenal cortex Primary acute adrenocortical insufficiency (adrenal crisis) Addison’s disease This may occur as a result of: This rare condition of chronic is due to a lack of glucocorticoids and mineralocorti- • Iatrogenic—abrupt cessation of prolonged high- coids. Its estimated prevalence in the developed world dose therapeutic corticosteroids (prolonged is 0.8 cases per 100 000 population. corticosteroid therapy produces lowered The clinical features outlined in Fig. 10.18 are a endogenous steroid production, leading to result of glucocorticoid and mineralocorticoid atrophy of the adrenal cortex).

Fig. 10.18 Clinical features of Addison’s disease. Fig. 10.18 Clinical features of Addison's disease

Hormonal abnormality Clinical features Glucocorticoid insufficiency Vomiting and loss of appetite Weight loss Lethargy and weakness Postural hypotension Hypoglycaemia Mineralocorticoid insufficiency ↓serum Na+, ↑serum K+ Chronic dehydration Hypotension Increased ACTH secretion Brownish pigmentation of skin and buccal mucosa Loss of adrenal androgen Decreased body hair, especially in females Note: ACTH, adrenocorticotrophic hormone

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• Bilateral massive adrenal haemorrhage—caused Neuroblastomas are almost exclusively tumours of by Gram-negative (usually meningococcal) children, occurring very rarely over the age of 5 years. septicaemia (Waterhouse–Friderichsen They are highly malignant and usually inoperable. syndrome) producing haemorrhage and Ganglioneuroma disseminated intravascular coagulation. Adrenal A benign tumour derived from sympathetic nerves. haemorrhage is also seen in neonates following Most commonly found in the posterior mediastinum, traumatic birth. although 10% of cases arise in the adrenal medulla. • Complication of chronic adrenal failure— Addisonian crisis is precipitated by sudden stress requiring increased output from chronically failing adrenal glands. DISORDERS OF THE ENDOCRINE PANCREAS

Clinical features of an adrenal crisis are: Diabetes mellitus • Profound hypotension and cardiovascular collapse Diabetes mellitus (DM) is a multisystem disease of an (shock). abnormal metabolic state characterised by hypergly- • Vomiting. caemia due to inadequate insulin action/production. • Diarrhoea. It can be classified into primary and secondary. • Abdominal pain. Primary DM is a disorder of insulin production/ • Pyrexia. action. It accounts for 95% of diabetic cases. An adrenal crisis is a medical emergency and requires In 5% of cases, diabetes may be secondary to: intravenous hydrocortisone and fluid replacement. The precipitating cause should be sought and if • Pancreatic diseases, e.g. chronic pancreatitis. possible treated. • Hypersecretion of hormones that antagonise the effects of insulin, e.g. glucocorticoids in Cushing’s syndrome, growth hormone in Secondary adrenocortical insufficiency acromegaly, epinephrine (adrenaline) in pheochromocytomas. This adrenocortical insufficiency is caused by adrenal atrophy secondary to: Primary DM is by far the most important cause of dia- betes and it is further classified into: • Hypothalamic or pituitary disease (tumours, infection, infarction, surgical destruction), which • Type I, also known as insulin-dependent DM produces lowered ACTH, hence lowered (IDDM) or juvenile-onset diabetes. endogenous glucocorticoids and aldosterone. • Type II, also known as non-insulin-dependent • Glucocorticoid therapy, which produces lowered DM (NIDDM) or mature-onset diabetes. ACTH (suppression), hence lowered endogenous The basic features of these two types of diabetes are glucocorticoids and aldosterone. described in Fig. 10.19. The adrenal medulla Phaeochromocytoma Type I diabetes mellitus Aetiology and pathogenesis—type I diabetes mellitus is This is a rare tumour of the chromaffin cells—the cells an organ-specific, autoimmune-induced disorder that secrete epinephrine (adrenaline) and norepi- characterised by antibody-mediated destruction of the nephrine (noradrenaline) in the adrenal medulla (see β-cell population of the islet of Langerhans. page 62). Two main factors are thought to predispose to Tumours of extra-adrenal paraganglia autoimmunity: Neuroblastomas 1. Genetic predisposition—90–95% of patients These rare tumours are derived from neuroblasts. with type I diabetes are HLA-DR3 or HLA-DR4 Affected sites are the adrenal medulla, the medi- positive, a feature that is also seen in other organ- astinum (usually in association with the sympathetic specific autoimmune diseases. However, identical chain) and the coeliac plexus. twins show a 40% concordance in the 223 M3422-Ch10.qxd 23/4/07 10:57 AM Page 224

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Fig. 10.19 Table comparing type I and type II diabetes mellitus (DM). Fig. 10.19 Table comparing type I and type II diabetes mellitus (DM)

Type I Type II Childhood/adolescent onset Middle-aged/elderly onset 1/3 of primary diabetes 2/3 of primary diabetes Females = males Females = males Acute/subacute onset Gradual onset Thin Obese Ketoacidosis common Ketoacidosis rare Plasma insulin absent or low Plasma insulin normal or raised Insulin sensitive Insulin insensitive (end-organ resistance) Autoimmune mechanism Non-autoimmune mechanism (islet cell antibodies present) (no islet cell antibodies) Genetic predisposition associated Polygenic inheritance with HLA-DR genotype

development of the disease, indicating the target cells. This is associated with obesity, additional importance of environmental factors. sedentary lifestyle and poor diet; it is increasingly 2. Viral infection—viral infection may trigger the being seen in younger (even adolescent) autoimmune reaction; viruses implicated include individuals. mumps, measles and Coxsackie B. • Relative insulin deficiency—reduced secretion compared with the amounts required, possibly One postulated mechanism is that viruses induce mild related to islet cell ageing. structural damage to the islet cells, thereby releasing β previously shielded -cell antigens and leading to the Diagnosis of diabetes mellitus recruitment and activation of lymphocytes in the Irrespective of aetiology, the diagnosis of DM pancreatic tissue. depends on the finding of hyperglycaemia. Histologically, the pancreas shows lymphocytic However, the distribution curve of blood glucose infiltration and destruction of insulin-secreting cells concentration for whole populations is unimodal, of islets of Langerhans (β-cells). This results in insulin with no clear division between normal and deficiency with hyperglycaemia and other secondary abnormal values. metabolic complications. Diagnostic criteria (Fig. 10.20) are, therefore, arbi- Type II diabetes mellitus trary and, in general, diabetes mellitus is indicated by either: Aetiology and pathogenesis—the precise aetiopatho- genesis of type II diabetes is unclear but the follow- • Fasting venous plasma glucose level of ing factors are thought to be involved: > 7.0 mmol/L. • Random venous plasma glucose level of • Genetic factors—familial tendency with up to > 11.1 mmol/L. 90% concordance rate amongst identical twins. However, there are no HLA associations and A distinction is made between diabetes mellitus and inheritance is considered to be polygenic. impaired glucose tolerance in cases where fasting or • Insulin resistance—tissues are unable to respond random blood sugar level is borderline; in this case, to insulin because of an impairment in the the response to an oral load of glucose can be assessed function of insulin receptors on the surface of via a glucose tolerance test.

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the result of the chronic rather than the acute compli- Fig. 10.20 Diagnostic criteria for diabetes mellitus using an oral glucose tolerance test cations of the disorder (Fig. 10.21). The complications of diabetes are macrovascular Venous plasma blood glucose (affecting large and medium-sized muscular arteries) and microvascular (small vessel microangiopathy). 2 hours after 75 g Diagnosis Fasting sample glucose load Macrovascular changes involve accelerated athero- sclerosis. In diabetic microangiopathy, small arterioles Normal <5.6 mmol/L <7.8 mmol/L and capillaries show a characteristic pattern of wall Impaired 5.6–6.9 mmol/L 7.8–11.0 mmol/L thickening, which is due to a marked expansion of the glucose basement membrane (termed hyaline arterioloscle- tolerance rosis). ≥ ≥ Diabetes 7.0 mmol/L 11.1 mmol/L Therefore, the most important chronic complica- mellitus tions of diabetes are:

Fig. 10.20 Diagnostic criteria for diabetes mellitus using an oral glucose • Macrovascular accelerated atherosclerosis tolerance test. increasing stroke and myocardial infarction risk. • Renal disease—diabetic nephropathy (mainly microvascular). • Eye disease—diabetic retinopathy Complications of diabetes mellitus (microvascular). Acute complications • Peripheral nerve damage—diabetic neuropathy Individuals with diabetes are particularly prone to (microvascular). several types of coma. These result from (in decreas- • Predisposition to infections. ing order of frequency): Macrovascular disease • Hypoglycaemia—complication of overtreatment Compared with non-affected people of the same age with insulin. and sex, individuals with diabetes suffer from an • Diabetic ketoacidosis (DKA)—common in type I increased severity of atherosclerosis, probably due to the diabetes due to ↑ breakdown of triglycerides → increased plasma levels of cholesterol and triglycerides. ↑ production of ketone bodies → ketoacidosis → The main clinical sequelae of this are seen in: impaired consciousness. → Hyperosmolar non-ketotic (HONK) state— • Heart ischaemic heart disease. • → ↑ plasma glucose concentration →↑plasma • Brain cerebral ischaemia. → osmolarity → cerebral dehydration → coma. • Legs and feet gangrene—ischaemia of toes and More common in type II diabetes. areas on the heel is a characteristic feature of Lactic acidosis—increased concentrations of diabetic gangrene. • → lactic acid (produced as an end product of • Kidney chronic nephron ischaemia, an glycolysis instead of pyruvate) may cause coma. important component of the multiple renal lesions in diabetes.

Diabetic nephropathy Diabetes is now one of the most common causes of The complications of DM are important; end-stage renal failure. Associated renal disease can 80% of adults with diabetes die from be divided into three forms: cardiovascular disease and patients • Complications of diabetic vascular disease— frequently develop serious renal and retinal disease. macrovascular atherosclerosis affecting aorta and renal arteries → ischaemia; microvascular glomerular capillary basement membrane Chronic complications thickening (hyaline arteriolosclerosis) → In recent years, with the advent of insulin therapy and ischaemic glomerular damage. Microalbuminuria various oral hypoglycaemic agents, morbidity and is a reliable marker of the progression of diabetic mortality associated with DM are more commonly nephropathy.

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Fig. 10.21 Chronic complications of diabetes mellitus. brain - cerebrovascular eyes disease/strokes - retinopathy, cataracts and glaucoma (diabetes is the blood vessels commonest cause of blindness - atherosclerosis under the age of 60)

heart - ischaemic heart disease

kidneys - nephropathy leads to renal failure - prone to infections

penis - impotence

limbs - ischaemia, neuropathy leads to dry anaesthetic skin

skin - prone to skin infections blood vessels - peripheral vascular disease causes claudication in legs, gangrene in feet

feet - prone to ulcers and gangrene - neuropathy

• Diabetic glomerulosclerosis (diffuse and nodular 1. Background retinopathy—small vessel types)—↑ leakage of plasma proteins through abnormalities in the retina leading to hard capillary wall into glomerular filtrate → exudates, haemorrhages and microaneurysms. proteinuria and progressive glomerular Does not usually affect acuity. hyalinisation with eventual chronic renal failure. 2. Proliferative retinopathy—extensive proliferation • Increased susceptibility to infections → papillary of new capillaries in the retina. Sudden necrosis. Acute pyelonephritis is a common deterioration in vision may result from vitreous complication of diabetes mellitus and occurs as a haemorrhage as a consequence of proliferating new result of the relative immunosuppression of vessels or from the development of retinal diabetes together with reduced neutrophil detachment. function. 3. Maculopathy—caused by oedema, hard exudates Eye disease or retinal ischaemia and results in a marked Diabetes is the most common cause of acquired reduction of acuity. blindness in the Western world. It can affect the eyes 4. Cataract formation—greatly increased incidence in five main ways: in individuals with diabetes.

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5. Glaucoma—increased incidence in those with Islet cell tumours diabetes due to neovascularisation of the iris These tumours are rare compared with those of the (rubeosis iridis). exocrine pancreas. They occur most commonly in Predisposition to infections individuals aged 30–50 years. Patients with diabetes have an increased tendency to develop infections, usually of a bacterial or fungal Insulinomas nature. The main target organs are: The most common tumour of the islet cells. Insulinomas are derived from pancreatic β-cells: • Skin—folliculitis, erysipelas, cellulitis and superficial fungal infections. • Produce hypoglycaemia through hypersecretion • Oral and genital mucosae—especially with of insulin. Candida. • May produce attacks of confusion, stupor and • Urinary tract—increased predisposition to acute loss of consciousness. pyelonephritis, often associated with recurrent • Majority are solitary, non-metastasising lesions lower urinary tract infections. (10% are multiple and 10% are malignant). Persistent glycosuria in individuals with poorly con- trolled diabetes predisposes to urinary and genital Zollinger–Ellison syndrome infection. This syndrome of gastric hypersecretion, multiple peptic Diabetic neuropathy ulcers and diarrhoea is caused by the gastrin-secreting Clinically, most cases of diabetic neuropathy affect the tumour (gastrinoma) of the pancreatic G cells. Tumours peripheral nervous system, although central nervous are multiple in 50% of cases and are often malignant, system pathology does occur. The main effects are: with 10–20% occurring in other sites, e.g. the duodenum. It may also be part of the MEN I syndrome, with • Microvascular thickening of basement membrane adenomas also present in other endocrine glands (see and microthrombi formation in small vessels below). supplying peripheral nerves. • Axonal degeneration with patchy, segmental Other islet cell tumours demyelination. For a summary of islet cell tumours see Fig. 10.22. Thickening of Schwann cell basal lamina. • VIPomas The presentation may be of polyneuropathy (classically These produce vasoactive intestinal polypeptide ‘glove and stocking’ sensory impairment), mononeu- (VIP), resulting in a syndrome of watery diarrhoea, ropathy (e.g. carpal tunnel syndrome) or autonomic hypokalaemia and achlorhydria (WDHA). neuropathy (symptoms include postural hypotension, Glucagonomas nausea, vomiting, impotence and gustatory sweating). These glucagon-secreting tumours are derived from pancreatic α-cells and cause secondary diabetes mel- litus (usually mild), necrolytic migratory erythema (skin rash) and uraemia. Blood glucose control in diabetes lowers the incidence and progression of vascular complications. Somatostatinomas This can be achieved by: These somatostatin-producing tumours derived from δ • Diet alone—in type II patients. pancreatic -cells are associated with diabetes mellitus, • Diet and oral hypoglycaemic drugs (e.g. cholelithiasis and steatorrhoea. sulphonylureas, biguanides, thiazolidinediones)— in type II patients who fail on diet alone. • Diet and insulin—all type I patients and some MULTIPLE ENDOCRINE NEOPLASIA type II. Pancreatic transplantation is curative in type I SYNDROMES diabetes but is limited by organ availability. Islet cell transplants are a potential future therapy. These are syndromes in which patients develop tumours in a number of different endocrine organs.

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Pathology of the endocrine system

Fig. 10.22 Summary of islet cell tumours. Fig. 10.22 Summary of islet cell tumours

Islet cell tumour Occurrence Clinical features Insulinoma 70–75% Hypoglycaemia Gastrinoma 20–25% Zollinger–Ellison syndrome: gastric hypersecretion, multiple peptic ulcers and diarrhoea VIPoma Rare Water diarrhoea, hypokalaemia and achlorhydria Glucagonoma Rare Secondary diabetes mellitus, necrolytic migratory erythema and uraemia Somatostatinoma Rare Diabetes mellitus, cholelithiasis and steatorrhoea

Patients are younger than those who develop single thyroid (often bilateral and multinodular). Rarely, sporadic tumours and usually have a strong family there may also be hyperparathyroidism due to history of multiple endocrine tumours with autoso- parathyroid hyperplasia. MEN IIa and IIb syndromes mal dominant inheritance. have been linked to mutations in the RET oncogene, There are three main types of MEN syndrome: with near 100% disease penetrance 1. MEN I (Werner’s) syndrome. MEN IIb (MEN III) syndrome 2. MEN IIa (Sipple’s) syndrome. 3. MEN IIb (sometimes called MEN III) syndrome. Patients have all of the features of MEN IIa with additional features of: MEN I (Werner’s) syndrome • Neuromas and ganglioneuromas in the dermis Patients usually show a combination of hyper- and submucosal regions throughout the body. parathyroidism (chief cell hyperplasia and adeno- • Marfanoid body habitus with poor muscle mas), pituitary adenomas (usually prolactinomas) development. and pancreatic tumours (gastrin and insulin produc- • Skeletal abnormalities, e.g. kyphosis, pes cavus ing). Rarely, there may also be thyroid tumours and and high arch palate. adrenal cortical adenomas. MEN I syndrome is caused The facial appearance is characteristic with thick, by a germ-line mutation in the MEN-1 tumour bumpy lips, broad-based nose, everted eyelids and suppressor gene. grossly abnormal dental enamel. Genetic screening of at-risk family members in MEN IIa (Sipple’s) syndrome MEN II families now allows prophylactic thyroidec- Patients have a combination of phaeochromocytoma tomy in those with RET mutations to avoid the near (50% bilateral) and medullary carcinoma of the certainty of medullary carcinoma.

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