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Objectives

In this chapter, you will learn to:• Describe disorders of the pituitary gland leading to hyperpituitarism

and hypopituitarism.• 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.

Pathology of the endocrinesystem

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DISORDERS OF THE PITUITARY

The pituitary (hypophysis) is a small (500–1000 mg),bean-shaped gland lying in the sella turcica in thebase of the skull. It is composed of two parts:

1. Anterior lobe (adenohypophysis)—synthesises and secretes a number ofhormones (Fig. 10.1), most of which act onother endocrine glands.

2. Posterior lobe (neurohypophysis)—stores andsecretes two hormones synthesised in thehypothalamus: antidiuretic hormone (ADH;vasopressin) and oxytocin. This lobe is in directcontinuity with the hypothalamus, to which it isconnected via the pituitary stalk.

Secretion of the pituitary hormones is regulated byneural and chemical stimuli from the hypothalamus,diseases of which cause secondary abnormalities inpituitary function.

This cooperation between the nervous system andendocrine apparatus is referred to as neuroendocrinesignalling. Figure 10.2 shows the integration of signalsbetween the hypothalamus, pituitary and thyroidgland in the release of thyroid hormones, with feed-back loops acting at each level.

Neuroendocrine cells are defined as those thatrelease a hormone in response to a neural stimulus.Important examples include:

• Neurons of the supra-optic nucleus (projectinginto the posterior pituitary), which releaseADH.

• Chromaffin cells of the adrenal medulla, whichrelease epinephrine (adrenaline).

The anterior pituitary:hyperpituitarismHyperpituitarism is defined as excessive secretion ofone or more of the pituitary hormones. Its mostcommon causes are functioning (hormone-secreting)adenomas of the anterior lobe.

Anterior lobe adenomasAnterior lobe adenomas comprise about 10% of allintracranial tumours (posterior lobe adenomas donot occur). These tumours do not usually metastasise,but they are often life threatening because of theirposition and ability to secrete excess hormone.

Effects of pituitary adenomasPituitary adenomas cause problems because of a com-bination of endocrine effects (excessive secretion of aparticular hormone) and compressive effects, causedby an increase in local pressure of the following:

• Remainder of the pituitary → hypopituitarism.• Optic chiasm → visual field defects, notably

bitemporal haemianopia.

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Pathology of the endocrine system

• Brain (large tumours) → distortion of themidbrain with raised intracranial pressure andhydrocephalus.

• Dura → headaches.• Cavernous sinus → CN III, IV or VI nerve

palsies.

The endocrine effects depend on which hormone isbeing excessively secreted (see below).

Investigations:

• Imaging—plain X-ray (can detect enlargementof sella turcica and erosion of the clinoidprocesses) and MRI (for visualisation andsizing of the tumour; this is superior to CTscanning).

• Hormone assays (e.g. growth hormone,prolactin).

• Functional testing of the pituitary–adrenal axis,e.g. ACTH stimulation test in which a doseof adrenocorticotrophic hormone (ACTH) isgiven and the plasma cortisol responsemeasured.

• Visual field assessment.

Types of functioning adenomasFunctioning adenomas may produce any of the ante-rior lobe (adenophyseal) hormones but the majorityproduce prolactin (prolactinomas–lactotroph ade-nomas), growth hormone (somatotroph adenomas)or ACTH (corticotroph adenomas).

ProlactinomasAbnormally raised serum prolactin levels are associ-ated with menstrual irregularity and infertility inwomen, and with ejaculatory failure or impotence inmen. Mild prolactin increases are seen with compres-sion of the hypothalamus by any pituitary adenoma(the ‘stalk effect’).

Galactorrhoea is present in about 30% of affect-ed women, but it is rare in men because oestrogenpriming is required for lactation.

Somatotroph adenomaThis results in hypersecretion of growth hormone, theeffects of which depend on the developmental stageof the affected individual:

• Pre-epiphyseal union (prepubertal) leads togigantism (giantism), i.e. excessive growth in aregular and initially well-proportioned manner.Most giants also show some features ofacromegaly with disproportionate enlargement,e.g. of the hands and jaw.

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cavity ofthird

ventricle

opticchiasma

anteriorpituitary

posteriorpituitary

duramater

sphenoidbone

sellaturcica

mammillarybody

hypothalamus

growth hormone (GH)prolactin

follicle stimulating hormone (FSH)luteinizing hormone (LH)

β endorphinadrenocorticotrophic hormone (ACTH)

thyroid stimulating hormone (TSH)melanocyte stimulating hormone (MSH)

antidiuretic hormone (ADH)

oxytocin

Fig. 10.1 Pituitary and hypothalamus, with the hormones released.

input fromhigher centres

hypothalamus

pituitary

releasing hormonee.g. TRH

trophic hormonee.g. TSH

target glande.g. thyroid

target gland hormonee.g. thyroxine

shortfeedback

loop

directfeedback

loop

+ or −

+ or −

+ or −

+ or −

+ or −

indirectfeedback

loop

+

Fig. 10.2 Schematic representation of the integration between thehigher centre, hypothalamus, pituitary and target organ signalling. Theexample is for thyroid function, highlighting the feedback loops thatcontrol hormone release at each level. (TRH, thyrotrophin releasinghormone, TSH, thyroid stimulating hormone). (Adapted withpermission from Essential Endocrinology, 4th edn, by Brook andMarshall, Blackwell Publishing, 2001).

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Disorders of the pituitary

• Postepiphyseal union (adults) leads toacromegaly, which is characterised byenlargement of the hands, feet, and head. Theymay also present with secondary diabetes(growth hormone is an insulin antagonist) orcardiovascular effects (Fig. 10.3).

There are three types of treatment:

• Surgery—hypophysectomy (transfrontal ortransphenoidal), especially where there are signsof compression of adjacent structures. Thisusually only debulks the tumour, with further(usually drug) therapy required.

• Radiotherapy—fewer complications than surgerybut less successful.

• Drug therapy—bromocriptine (dopamineagonist) and octreotide (somatostatin analogue)can lower growth hormone levels inuncomplicated acromegaly.

Corticotrophin adenomaOverproduction of ACTH by the pituitary gland(Cushing’s disease) causes adrenal hyperplasia,

resulting in the excessive secretion of glucocorticoidscausing Cushing’s syndrome, the effects of which aredescribed later (see page 219).

Other functioning adenomasOther endocrine secreting adenomas, e.g. of thyroid-stimulating hormone (TSH), luteinizing hormone(LH) and follicle-stimulating hormone (FSH), areextremely rare.

The anterior pituitary:hypopituitarismHypopituitarism is defined as insufficient secretion ofthe pituitary hormones. The clinical features dependon the patient’s age and on the type and severity of thehormone deficiencies (Fig. 10.4).

Hypopituitarism can be caused by either hypo-thalamic lesions or pituitary lesions.

Hypothalamic lesions are:

• Idiopathic deficiency of one or more of thereleasing factors, e.g. gonadotrophin-releasinghormone (GnRH; Kallmann’s syndrome),growth-hormone releasing factor (GHRH) or,more rarely, thyrotrophin-releasing hormone(TRH) or corticotrophin-releasing factor (CRF).

• Infarction.• Inflammation, e.g. sarcoidosis, tuberculous

meningitis.• Suprasellar tumours, e.g. craniopharyngioma or,

more rarely, pinealoma, teratoma or a secondarytumour from another site.

Pituitary lesions are:

• Idiopathic deficiency of one or more of thepituitary hormones.

• Non-functioning chromophobe pituitaryadenomas—adenomas of the anterior pituitary(usually derived from non-hormone-secretingchromophobe cells), which may causehypopituitarism by compression or obliterationof normal pituitary tissue.

• Sheehan’s syndrome—ischaemic necrosis ofthe anterior pituitary due to hypotensiveshock occurring as a result of obstetrichaemorrhage.

• Empty sella syndrome—an enlarged, empty sellaturcica that is not filled with pituitary tissue. Thismay be a primary anatomical variant or it mayfollow spontaneous infarction, surgery, orradiotherapy of a tumour.

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skull - enlarged head circumference

brain - mental disturbances- insomnia

face - large lower jaw- spaces between lower teeth due to jaw growth- large nose- large tongue

hands - large, square and spade like

liver and kidneys - enlarged organs

skin - increased greasy sweating- temperature intolerance

blood - hypercalcaemia

feet - large and wide

heart - enlarged

blood pressure - hypertension bones - predisposes to osteoarthritis

Fig. 10.3 Features of acromegaly.

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• Trauma, including surgery and radiotherapy.• Granulomatous lesions—sarcoidosis,

tuberculosis, histiocytosis.

ManagementManagement is by substitution therapy according tothe deficiencies demonstrated, e.g. cortisol replace-ment for ACTH deficiency, thyroid hormonereplacement for TSH deficiency.

The posterior pituitaryDiseases of the posterior pituitary are much less com-mon than those of the anterior pituitary and are usuallythe result of damage to the hypothalamus by tumourinvasion or infarction. Posterior pituitary diseases typi-cally cause disorders of abnormal ADH secretion. Thereare no known effects of abnormal oxytocin secretion.

Diabetes insipidusDiabetes insipidus (DI) is a rare condition charac-terised by the persistent excretion of excessive

quantities of dilute urine (polyuria) and by constantthirst (polydipsia).

There are two types (Fig. 10.5):

1. Cranial DI—caused by the failure of ADHproduction.

2. Nephrogenic DI—distal tubules are refractory tothe water reabsorptive action of ADH.

Clinical features—irrespective of aetiology, reabsorp-tion of water from the glomerular filtrate in therenal collecting ducts does not occur, resulting inpolyuria (up to 20 L per day is possible) and high riskof body water depletion. DI is potentially lethal with-out appropriate therapy.

Investigations—there is high clinical suspicion if apatient has a high plasma osmolality, with low orimmeasurable plasma ADH, and a non-maximallyconcentrated urine. A water deprivation test is run for8 hours or until 3% of the body weight is lost.Demonstration of continued polyuria and increasedhaemoconcentration indicates DI. This test serves to

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Hormonedeficiency

Fig. 10.4 Clinical features associated with specific forms of hypopituitarism

Clinical features Tests to exclude hypofunction of anterior pituitary

Gonadotrophindeficiency

Prepubertal:• Failure to enter puberty • Undescended testes• Obesity• EunuchoidismPostpubertal:• Infertility• Amenorrhoea • Oligospermia • Progressive loss of secondary sex characteristics (hypogonadism) • Osteoporotic collapse of spine→ loss of stature

LH reserves adequate if:• Males have a normal testosterone • Females are ovulating FSH reserves adequate if: • Males have a normal spermatogenesis • Females are ovulating

GH deficiency Children: failure of longitudinal growthAdults: tendency to hypoglycaemia

GH reserves adequate if: random plasma level >20 mU/Lstress or otherwise elevated GH peak >20 mU/L

TSH deficiency Fetus or newborn: cretinism Adults: hypothyroidism

TSH reserves adequate if serumthyroxine within normal range

ACTHdeficiency

Features of primary hypoadrenalism but withdecreased pigmentation (rather than an increase)

ACTH reserves adequate if: random plasma cortisol> 550 nmol/L 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.

Fig. 10.4 Clinical features associated withspecific forms of hypopituitarism.

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Disorders of the pituitary

differentiate DI from psychogenic polydipsia. The testis then followed by ADH administration to differen-tiate between cranial DI (kidneys are responsive toADH) or nephrogenic DI (kidneys are unresponsiveto ADH).

Treatment of mild DI—the effects of dehydrationcan be counteracted by greatly increasing water intake(polydipsia).

Treatment of moderate to severe DI

• Cranial DI—treatment with desmopressin(ADH analogue but without vasoactive effects).

• Nephrogenic DI—treatment with thiazidediuretics, producing a decrease in urine volumeby approximately 50%.

Syndrome of inappropriate antidiuretichormone secretionIncreased secretion of ADH occurs as a complicationof other diseases (primary hypersecretion of ADH isnot recognised). The condition is characterised bywater retention with haemodilution and by inappro-priately concentrated urine. In severe cases, cerebraloedema supervenes with impaired consciousness, butbody oedema is not usually seen as free water is even-ly distributed to all body compartments.

The causes are:

• Idiopathic.• Tumours—ectopic secretion of ADH, especially

by small cell carcinomas of the lung and someother neuroendocrine tumours.

• Trauma—skull fracture, head injury or surgerymay produce transiently increased secretion ofADH.

• Intracranial inflammation—meningitis,tuberculosis, syphilis.

• Non-neoplastic lung disease (e.g. pneumonia,pulmonary embolus) probably due toinvolvement of intrathoracic baroreceptors.

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

Cause Features

Cranial DI Hypothalamic or pituitarystalk damage

Surgical damage, usually in thecourse of tumour removalHead injury, usually transientHypothalamic tumour (eitherprimary or secondary)Hypothalamic inflammatorylesions, e.g. sarcoidosis, encephalitis, meningitis

Genetic defect DominantRecessive: 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

Note: ADH, antidiuretic hormone.

Metabolic abnormalities HypokalaemiaHypercalcaemia

Drug therapy LithiumDemethylchlortetracycline

Poisoning Heavy metals

Fig. 10.5 Causes of cranial andnephrogenic diabetes insipidus (DI).

Diabetes insipidus and diabetes mellitusare two distinct conditions that bothfeature polyuria.

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Figure 10.6 shows a comparison table of features of DIwith those of inappropriate ADH secretion.

Disorders of the pineal glandThe pineal gland is located above the third ventricleand it secretes the hormone melatonin. Melatonin isthought to function in circadian rhythm control andgonadal maturation.

Pinealomas (germinomas)These tumours of young adults and children are oftencalled germinomas. They are thought to originatefrom primitive germ cells and, histologically, theyresemble testicular seminomas and/or teratomas:

• Pressure on the midbrain may produceParinaud’s syndrome (paralysis of the conjugateupward gaze without paralysis of convergence).

• Pressure on the hypothalamus can producesymptoms of DI, emaciation or precociouspuberty.

THYROID DISORDERS

Congenital disorders of the thyroidDevelopment of the thyroidThe thyroid gland develops from an endodermalthickening in the floor of the primitive pharynx at apoint later indicated by the foramen caecum of thetongue (Fig. 10.7). As the embryo grows, the thyroiddescends into the neck, passing anterior to the hyoidand laryngeal cartilages. During migration, the gland

remains connected to the tongue by a narrow canal,the thyroglossal duct, which later becomes solid andfinally disappears.

Thyroglossal cystsCystic remnants of parts of the thyroglossal duct areknown as thyroglossal cysts (Fig. 10.7). These cystsmay form anywhere along the course of descent butare always located near or in the midline of the neck,most commonly just inferior to the hyoid bone.Cysts usually develop as painless, progressivelyenlarging and movable masses. Infection of cystsmay result in the formation of sinuses that openthrough the skin.

Thyrotoxicosis (hyperthyroidism)This syndrome is caused by the excessive secretion ofthyroid hormones—typically both thyroxine (T4) andtri-iodothyronine (T3)—in the bloodstream. Symptomsinclude tachycardia, sweating, tremor, anxiety, increasedappetite, loss of weight and intolerance of heat.

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

Condition Imbalance Urinary and plasma osmolality

Diabetes insipidus ↓ ADH Low urinary osmolalityHigh plasma osmolality

Symptoms

Polyuria (5−20 L/day)ThirstPolydipsia (may lead to severe dehydration, exhaustion, coma)

Syndrome of inappropriate ADH secretion

↑ ADH High urinary osmolalityLow plasma osmolality (dilutional hyponatraemia)

OliguriaWater intoxication (may lead to confusion, neurological disturbances, coma)

Note: ADH, antidiuretic hormone.

Fig. 10.6 Comparison of features of diabetes insipidus with those of inappropriate antidiuretic hormone (ADH) secretion.

body of tongue foramen caecum

epiglottis

hyoid bone

thyroid cartilage

cricoid cartilagethyroid gland

thyroglossal cysts

Fig. 10.7 Path of descent of thyroid gland (broken line) and localisationof thyroglossal cysts.

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Thyroid disorders

Hyperthyroidism can be classified on the basis ofaetiology into:

• Primary hyperthyroidism (↑ thyroid hormones,↓ TSH)—hypersecretion of thyroid hormones,which is not secondary to increased levels of TSH(the rise in thyroid hormones actually suppressesTSH).

• Secondary hyperthyroidism (↑ thyroidhormones, ↑ TSH)—overstimulation of thethyroid gland caused by excess TSH producedby a tumour in the pituitary or elsewhere (rare).

Primary hyperthyroidism is caused by:

• Graves’ disease (exophthalmic goitre)—the mostcommon cause of thyrotoxicosis, characterised bya diffusely enlarged thyroid gland that isstimulated to produce excess hormone by an IgGautoantibody.

• Toxic multinodular goitre (Plummer’sdisease)—second most common cause ofhyperthyroidism.

• Toxic adenoma—solitary thyroid noduleproducing excess hormone with remainder of thethyroid gland being suppressed.

• Thyroiditis—inflammation of the thyroidcausing hyperthyroidism (e.g. De Quervain’sthyroiditis). Note that thyroiditis is morecommonly associated with hypothyroidism (seebelow).

• Drugs—either direct ingestion of large doses ofthyroid hormone (thyrotoxicosis factitia) orthrough iodide-inducing drugs (e.g.amiodarone).

Effects of thyrotoxicosisSigns and symptoms of thyrotoxicosis are a conse-quence of an increase in the body’s metabolism, whichoccurs as a direct result of increased concentrations ofthe thyroid hormones.

The most important symptoms diagnostically are:

• Heat intolerance and excessive sweating(hyperhidrosis).

• Nervousness and irritability.• Weight loss with normal or increased appetite.• Goitre (an enlargement of the thyroid gland).

Other symptoms are summarised in Fig. 10.8.Investigations—hyperthyroidism is confirmed

by raised serum thyroxine and/or lowered serumTSH.

Management—options in thyrotoxicosis are:

• Surgery—reduces the amount of functioningthyroid tissue.

• Radioactive iodine—to destroy part of the gland.• Drugs (such as carbimazole or propylthiouracil)—

interfere with the production of thyroidhormones.

Graves’ diseaseGraves’ disease is an organ-specific autoimmunedisorder that results in thyrotoxicosis due to over-stimulation of the thyroid gland by autoantibodies. Itis the most common form of thyrotoxicosis, femalesbeing affected more than males by 8 :1. It is usuallyassociated with a diffuse enlargement of the thyroid.

Pathogenesis—IgG-type immunoglobulins bind toTSH membrane receptors and cause prolonged stim-ulation of the thyroid, lasting for as long as 12 hours(cf. 1 hour for TSH). The autoantibody binds at a sitedifferent to the hormone-binding locus and is termedthe TSH-receptor autoantibody (TRAb); 95% ofGraves’ disease patients are positive for TRAbs.

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hair loss

hands- tremor- warm, moist palms- onycholysis (nail loose in nail bed)- acropachy

brain- anxiety- insomnia- restlessness- irritability

heart- tachycardia (rapid pulse)- palpitations- atrial fibrillation

muscles- proximal myopathy (in upper arms and legs)

bowel- diarrhoea

uterus- menorrhagia

bones- osteoporosis

skin and adipose tissue- increased sweating- temperature intolerance- weight loss- pretibial myxoedema

neck- goitre

eyes- exophthalmos (protruding eyes)- lid retraction- lid lag

Fig. 10.8 Summary diagram illustrating features of thyrotoxicosis. (* = additional features seen only in Graves’ disease.)

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Histologically, the gland shows diffuse hyper-trophy and hyperplasia of acinar epithelium, reduc-tion of stored colloid and local accumulations oflymphocytes with lymphoid follicle formation.

The clinical features of Graves’ disease are similarto those of general thyrotoxicosis but with someadditional features (see Fig. 10.8), namely:

• Exophthalmos (protrusion of the eyeballs in theirsockets)—due to the infiltration of orbital tissuesby fat, mucopolysaccharides and lymphocytes.May cause compression of the optic nerve, henceblindness. However, only about 5% of Graves’patients show signs of exophthalmos.

• Thyroid acropachy—enlargement of fingernails.• Pretibial myxoedema—accumulation of

mucoproteins in the deep dermis of the skin.

Treatment is as for thyrotoxicosis.

HypothyroidismDecreased activity of the thyroid gland results indecreased production of thyroid hormones. There aretwo forms:

1. Hypothyroidism present at birth → cretinism orcongenital hypothyroidism.

2. Hypothyroidism in adults → myxoedema.

Cretinism (congenital hypothyroidism)This condition occurs as a result of extreme hypothy-roidism during fetal life, infancy or childhood. It hasthe following types and aetiology:

• Endemic cretinism—occurs in iodine-deficientcountries where goitre is common. The motheralmost always has a goitre and the thyroid of theaffected infant is usually enlarged and nodular.

• Sporadic cretinism—caused by congenitalhypoplasia or absence of the thyroid gland andoften associated with deaf mutism.

• Dyshormonogenesis—a congenital familialrecessive enzyme defect causing an inability tocomplete the formation of thyroid hormones.TSH is increased, and the thyroid gland isenlarged and shows epithelial hyperplasia.

The clinical features of cretinism are:

• Mental retardation.• Retarded growth—skeletal growth is inhibited

more than soft tissue growth, resulting in anobese, stocky, short child.

• Coarse, dry skin.

• Lack of hair and teeth.• Pot belly (often with umbilical hernia).• Protruding tongue.

Management is by early detection and treatment withthyroxine, which can prevent an irreversible mentaldefect and cerebellar damage. Many countries nowhave screening programs to measure serum TSHand/or thyroxine levels on heel-prick blood samplestaken on the fourth or fifth day of life.

Hypothyroidism in adults (myxoedema)This common clinical condition is associated withdecreased function of the thyroid gland and adecrease in the circulating level of thyroid hormones.It affects 1% of people in the UK, with females morethan males by 6:1. It can present at any age but mostcommonly between 30 and 50 years of age.

Note that, strictly speaking, myxoedemadescribes a non-pitting, oedematous reaction char-acteristic of hypothyroidism caused by the deposi-tion of a mucoid substance (myxa-is a Greek prefixdenoting mucus) in the skin and elsewhere in thebody. However, the terms ‘myxoedema’ and‘hypothyroidism of adults’ are now frequently usedinterchangeably.

Hypothyroidism can be classified according toaetiology:

• Primary (↓ thyroid hormones, ↑ TSH)—failure ofthe thyroid gland itself. This is much morecommon than secondary hypothyroidism. Notethat subclinical hypothyroidism describes anincrease in TSH but with normal thyroidhormone levels, and is increasingly being treatedwith the aim of reducing progression to fulldisease.

• Secondary (↓ thyroid hormones, ↓TSH)—failureof TSH production due to pituitary disease.

The causes of primary hypothyroidism are:

• Autoimmune thyroiditis—atrophic form, e.g. primary atrophic thyroiditis and goitrousform (such as Hashimoto’s thyroiditis).

• Graves’ disease—approximately 5% of patientswith thyrotoxicosis develop hypothyroidism inlater years, unrelated to treatment. Probablycaused by a spectrum of antithyroid antibodies,some of which stimulate TSH receptor and someof which are destructive.

• Treatment of hyperthyroidism—surgicalablation, radioiodine or drug treatment.

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Thyroid disorders

• Severe iodine deficiency (rare in the UK)—iodinemust be virtually absent from the diet beforemyxoedema develops.

The effects of hypothyroidism are shown in Fig.10.9.

ThyroiditisThis inflammation of the thyroid gland can have aviral or autoimmune aetiology.

Hashimoto’s thyroiditis (most commoncause of hypothyroidism)This organ-specific autoimmune disease results indestructive thyroiditis. It can occur at any age, but typ-ically affects the middle-aged, and females more thanmales by 12 : 1.

Thyroid peroxidase antibodies are most com-monly found in the serum of affected individuals(90% of cases). The disease is associated with theHLA-DR5 and HLA-B8 haplotypes, and patients withHashimoto’s disease (and Graves’ disease) show ahigh incidence of other autoimmune diseases.

Macroscopically, the thyroid gland is usually:

• Diffusely enlarged (typically 2–5 times normalsize).

• 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 bylymphocytes.

Microscopically, the thyroid gland shows:

• Small thyroid follicles infiltrated by lymphocytesand plasma cells.

• Lymphoid follicle formation and increasedfibrous tissue stroma.

• Acini lined with abnormal, highly eosinophilicepithelial cells (proliferation of mitochondria)known as Askanazy or Hürthle cells.

• Reduced colloid content of disrupted acini.

The condition may present due to goitre formation orbecause of the symptoms of hypothyroidism. Thehypothyroid state tends to develop slowly. However,damage to thyroid follicles may lead to the release ofthyroglobulin into the circulation causing transient thy-rotoxicosis. Some cases proceed to primary atrophicthyroiditis. Furthermore, there is an increased incidenceof non-Hodgkin’s lymphoma originating in the thyroidof patients with Hashimoto’s thyroiditis.

Treatment is by oral thyroxine, which overcomeshypothyroidism and reduces the size of the goitre.

De Quervain’s thyroiditisA rare, viral thyroiditis seen in young and middle-agedwomen as a slightly diffuse tender swelling of thethyroid; this is also known as subacute, giant cell or

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Signs and symptoms of hypothyroidism are bothwidespread (due to reduced body metabolism) andlocalised (myxoedema due to the accumulation ofmucoproteins). The most important symptomsdiagnostically are:• Mental and physical slowness.• Tiredness.• Cold intolerance.• Dryness of skin and hair.Investigations are:• Serum thyroxine concentration (decreased).• Serum TSH concentration (reduced in secondary

hypothyroidism but increased in primaryhypothyroidism).

The treatment is oral thyroxine daily for life.

hair- coarse and thin hair- loss of outer third of eyebrows

face- myxoedemic features, i.e.pale puffy face, coarse features- deafness

hands- cold hands- carpal tunnel syndrome

skin and adipose tissue- weight gain/obesity- intolerance to cold- decreased sweating- chronic oedema (caused by increased capillary escape of albumin)- cold, dry skin

brain- mental slowing- apathy- tiredness- psychosis

neck- goitre

muscles- slowing of activity- muscle weakness in upper arms and legs (proximal myopathy)

bowel- constipation

uterus- amenorrhoea

heart- bradycardia

hoarse voice

Fig. 10.9 Summary diagram illustrating features of hypothyroidism inthe adult (myxoedema).

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granulomatous thyroiditis. The condition usuallyoccurs in association with a transient febrile illness,often during various viral epidemics.

The most commonly associated viruses areCoxsackie, mumps and adenovirus.

Characteristic features are:

• Painful enlargement of the thyroid (about twicenormal size; normal weight is 20–30 g).

• History of usually short duration.• Preceding general malaise, pyrexia or upper

respiratory infection.

Histological examination shows:

• Inflammation with a giant cell granulomatousreaction engulfing leaked colloid (hence thesynonyms giant cell or granulomatousthyroiditis).

• Degeneration of follicles with inflammatory cellinfiltration (neutrophils, plasma cells,lymphocytes and histiocytes).

• Fibrous scarring (late).

The illness is usually self-limiting and settles in a fewweeks. Transient hyperthyroidism can result from therelease of thyroglobulin and excessive amounts ofthyroid hormone.

Severe thyroiditis may be fatal in the elderly anddebilitated.

Subacute lymphocytic thyroiditisThis form of autoimmune thyroiditis is characterisedby focal lymphocytic infiltration of the thyroid (alsoknown as focal lymphocytic thyroiditis).

Histological changes are similar to those inHashimoto’s thyroiditis but they are focalrather than diffuse. The disease is less severe than

Hashimoto’s thyroiditis, and it is often asympto-matic. It may also present with the symptoms ofhyperthyroidism.

Note that some degree of progressive lymphocyticinfiltration of the thyroid is seen in 5–10% ofthyroid autopsies, and these are thought to be a nor-mal ageing change. However, in subacute lympho-cytic thyroiditis, lymphocytic infiltration is in excessof what would normally be expected for age-relatedchange.

A comparison of the main types of thyroiditis isprovided in Fig. 10.10.

Thyroid goitresDefinitionsA goitre is any enlargement of part or whole of thethyroid gland. There are two types:

1. Toxic goitre, i.e. goitre associated withthyrotoxicosis.

2. Non-toxic goitre, i.e. goitre associated withnormal or reduced levels of thyroid hormones.

Toxic goitreGraves’ diseaseThis is the most common cause of toxic goitre(described above).

Toxic multinodular goitreThis results from the development of hyperthy-roidism in a multinodular goitre (see below).

Non-toxic goitresDiffuse non-toxic goitre (simple goitre)This diffuse enlargement of the thyroid gland isclassified into:

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Fig. 10.10 Summary of features of thyroiditis

Hashimoto's thyroiditis

De Quervain's thyroiditis

Aetiology Autoimmune Viral

Common Rare Rare

Subacute lymphocytic thyroiditis

Autoimmune

Histological features

Diffuse lymphocyticinfiltration of thyroid

Giant cell granulomatous inflammatory reaction

Focal lymphocytic infiltration of thyroid

Hypothyroidism

Fig. 10.10 Summary of features ofthyroiditis.

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Thyroid disorders

• Endemic goitre—due to iodine deficiency. Rare inthe UK but may occur in certain geographicalareas remote from the sea.

• Sporadic goitre—caused by goitrogenic agents(substances that induce goitre formation) orfamilial in origin. Examples of goitrogenic agentsinclude certain cabbage species, because of theirthiourea content, and specific drugs or chemicals,such as iodide, paraminosalicylic acid and drugsused in the treatment of thyrotoxicosis. Familialcases show inherited autosomal recessive traits,which interfere with hormone synthesis viavarious enzyme pathways (these aredyshormonogenic goitres).

• Physiological goitre—enlargement of the thyroidgland in females during puberty or pregnancy;the reason is unclear.

Multinodular goitreThis is the most common cause of thyroid enlarge-ment and is seen particularly in the elderly (nearly allsimple goitres eventually become multinodular). Theexact aetiology is uncertain but it may represent anuneven responsiveness of various parts of the thyroidto fluctuating TSH levels over a period of many years.

Morphological features are:

• Irregular hyperplastic enlargement of the entirethyroid gland due to the development of well-circumscribed nodules of varying size.

• Larger nodules filled with brown, gelatinouscolloid; consequently, it is often termedmultinodular colloid goitres.

Most patients have normal thyroid function and gen-erally seek treatment for cosmetic reasons (anunsightly swelling in the neck) or compression symp-toms, e.g. pressure on the trachea producing stridor orpressure on the recurrent laryngeal nerve producinghoarseness.

However, toxic changes occasionally occur in amultinodular goitre resulting in hyperthyroidism,when it is termed a toxic multinodular goitre.

Neoplasms of the thyroidTumours of the thyroid are generally benign.Carcinomas are rare and lymphomas are rarer still.

Benign tumoursThyroid adenomasThese are solitary, or multiple, encapsulated solidnodules. Compression of the adjacent gland is a common

feature, and the centre may show areas of haemor-rhage and cystic changes. The most common type isfollicular adenoma, which consists of colloid-con-taining microfollicles and columns of larger cells ofalveolar arrangement.

Rarely, follicular adenomas may synthesise excessthyroid hormones (‘toxic adenomas’), causing thyro-toxicosis.

Malignant tumoursThese rare tumours account for less than 1% of totalcancer deaths in the UK, with females affected morethan males by 3 : 1. Although the aetiology of thyroidcancer is unknown in the majority, it is likely thatchildhood radiation exposure is involved in somecases (there is an increased incidence in those exposedto the Chernobyl fallout). Types of malignant thyroidtumours and their basic features are outlined inFig. 10.11.

Papillary adenocarcinomaThis well-differentiated tumour is most commonlyfound in younger patients. It presents as a non-encapsulated infiltrative mass. It is a slow growingtumour with an excellent prognosis.

Histologically, it consists of epithelial papillaryprojections between which calcified spherules may bepresent. Epithelial cell nuclei are characteristicallylarge with optically clear areas centrally (described as‘Orphan Annie nuclei’).

Follicular adenocarcinomaThis well-differentiated, single, encapsulated lesion ishistologically similar to follicular adenoma but can

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A reminder of the differences betweenprimary and secondary hyperthyroidismand hypothyroidism:• Primary hyperthyroidism—↑ thyroid hormones,

↓ TSH.• Secondary hyperthyroidism—↑ thyroid hormones,

↑ TSH (excess TSH production due to pituitarytumour).

• Primary hypothyroidism—↓ thyroid hormones, ↑ TSH.

• Secondary hypothyroidism—↓ thyroid hormones,↓ TSH (failure of TSH production due to pituitarydisease).

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be differentiated by its invasion of the capsule and/orblood vessels. Spread is usually to bones, lungs andbrain via the bloodstream.

Many of these tumours retain the ability to take upradioactive iodine (131I), which may be used as a highlyeffective targeted form of radiotherapy, usually aftersurgical thyroidectomy. The prognosis, therefore, isgood.

Anaplastic carcinomaThis highly malignant, poorly differentiated adeno-carcinoma usually presents in the elderly as a diffuselyinfiltrative mass. In about half of cases there is ahistory of multinodular goitre.

Histologically, the dominant features are those ofa spindle cell tumour with or without giant cell areas,or a small cell pattern.

The prognosis is very poor due to the rapid localinvasion of structures such as the trachea, producingrespiratory obstruction.

Medullary carcinomaThis rare neuroendocrine tumour arises from para-follicular C cells, which commonly synthesiseand secrete calcitonin but which may also secrete5-hydroxytryptamine (serotonin), various peptides ofthe tachykinin family, ACTH and prostaglandins.

High levels of serum calcitonin are useful diagnos-tically but produce no clinical effects.

Although medullary carcinoma is most commonin the elderly, it also occurs in younger individuals,where it is commonly associated with other endocrinetumours, such as phaeochromocytoma as part of the

multiple endocrine neoplasia (MEN) syndromes IIaand IIb (see pages 227–228).

LymphomasMost thyroid lymphomas are regarded as tumours ofmucosa-associated lymphoma tissue. Interestingly,non-Hodgkin’s B cell lymphomas occasionally arisein long-standing, autoimmune thyroiditis, especiallyHashimoto’s disease.

PARATHYROID DISORDERS

Parathyroid hormoneParathyroid hormone (PTH) is a polypeptide (84amino acid residues) secreted by the chief cells ofthe parathyroid glands (four glands: two in each of thesuperior and inferior lobes of the thyroid; total weight120 mg).

The main action of PTH is to increase serum calci-um and decrease serum phosphate. Its actions aremediated by the bones and kidneys as described below.

In bone, PTH stimulates osteoclastic bone resorp-tion and inhibits osteoblastic bone deposition. Thenet effect is the release of calcium from bone.

In the kidney, PTH has the following effects:

• Increases calcium reabsorption.• Decreases phosphate reabsorption.• Increases 1-hydroxylation of 25-hydroxyvitamin

D (i.e. activates vitamin D).

PTH also increases gastrointestinal calcium absorption.

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Follicular cells

Fig. 10.11 Types and features of malignant thyroid tumours

Origin oftumour

Follicular cells

Papillary

Tumourtype

Anaplastic

70

Frequency(%)

Typicalage range (years) Spread

5

ParafollicularC cells

−− 5−10

Prognosis(% for 10-year survival)

20−40 Lymph nodes 95

Follicular Follicular cells 10 40−60 Bloodstream 60

> 60 Aggressivelocal invasion;bloodstream

1

> 40 Local,lymphaticand blood

50 (but veryvariable)

Differentiatedcarcinoma

Undifferentiatedcarcinoma

Medullarycarcinoma

Lymphoma −− Lymphocytes 5−10 > 60 Lymphatic 10

Fig. 10.11 Types and features of malignant thyroid tumours.

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Parathyroid disorders

HyperparathyroidismHyperparathyroidism is defined as an elevated secre-tion of PTH, of which there are three main types:

1. Primary—hypersecretion of PTH by adenoma orhyperplasia of the gland.

2. Secondary—physiological increase in PTHsecretions in response to hypocalcaemia of anycause.

3. Tertiary—supervention of an autonomoushypersecreting adenoma in long-standingsecondary hyperparathyroidism.

Primary hyperparathyroidismThis is the most common of the parathyroid disor-ders, with a prevalence of about 1 per 800 in the UK.It is an important cause of hypercalcaemia. More than90% of patients are over 50 years of age and the con-dition affects females more than males by nearly 3 : 1.The aetiology of primary hyperparathyroidism is out-lined in Fig. 10.12.

Effects of hyperparathyroidismThe clinical effects are the result of hypercalcaemiaand bone resorption.

Effects of hypercalcaemia:

• Renal stones due to hypercalcuria.• Excessive calcification of blood vessels.• Corneal calcification.• General muscle weakness and tiredness.• Exacerbation of hypertension and potential

shortening of the QT interval.• Thirst and polyuria (may be dehydrated due to

impaired concentrating ability of kidney).• Anorexia and constipation.

Effects of bone resorption:

• Osteitis fibrosa—increased bone resorption withfibrous replacement in the lacunae.

• ‘Brown tumours’—haemorrhagic and cystictumour-like areas in the bone, containing largemasses of giant osteoclastic cells.

• Osteitis fibrosa cystica (von Recklinghausendisease of bone)—multiple brown tumourscombined with osteitis fibrosa.

• Changes may present clinically as bone pain,fracture or deformity.

However, about 50% of patients with biochemicalevidence of primary hyperparathyroidism areasymptomatic.

Investigations are:

• Biochemical—increased PTH and Ca2+, anddecreased PO4

3−.• Radiological—90% normal; 10% show evidence

of bone resorption, particularly phalangealerosions.

Management is by rehydration, medical reduction inplasma calcium using bisphosphonates and eventualsurgical removal of abnormal parathyroid glands.

Secondary hyperparathyroidismThis is compensatory hyperplasia of the parathyroidglands, occurring in response to diseases of chroniclow serum calcium or increased serum phosphate.

Its causes are:

• Chronic renal failure and some renal tubulardisorders (most common cause).

• Steatorrhoea and other malabsorptionsyndromes.

• Osteomalacia and rickets.• Pregnancy and lactation.

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Understanding the physiologicalfunctions of PTH is essential to anunderstanding of the clinical effectsproduced by its hypo- or hypersecretion.

Fig. 10.12 Aetiology of primary hyperparathyroidism

FrequencyType Features

Adenoma 75% Orange−brown, well-encapsulated tumour of various size but seldom > 1 cm diameterTumours are usually solitary, affecting only one of the parathyroids, the others often showing atrophy; they are deep seated and rarely palpable

20% Diffuse enlargement of all the parathyroid glands

Primary hyperplasia

Parathyroid carcinoma

5% Usually resembles adenoma but is poorly encapsulated and invasive locally

Fig. 10.12 Aetiology of primary hyperparathyroidism.

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Morphological changes of the parathyroid glands are:

• Hyperplastic enlargement of all parathyroidglands, but to a lesser degree than in primaryhyperplasia.

• Increase in ‘water clear’ cells and chief cells of theparathyroid glands, with loss of stromal fat cells.

Clinical manifestations—symptoms of bone resorptionare dominant.

Renal osteodystrophySkeletal abnormalities, arising as a result of raisedPTH secondary to chronic renal disease, are known asrenal osteodystrophy.

The pathogenesis of renal osteodystrophy is shownin Fig. 10.13.

Abnormalities vary widely according to the natureof the renal lesion, its duration and the age of thepatient, but include:

• Osteitis fibrosa (see above).• Rickets or osteomalacia due to reduced activation

of vitamin D.• Osteosclerosis—increased radiodensity of certain

bones, particularly the parts of vertebrae adjacentto the intervertebral discs.

Note that the symptoms of hypercalcaemia are not afeature of secondary hyperparathyroidism; calcium

levels are likely to be decreased as this is driving thecompensatory PTH secretion.

The investigations are both biochemical (raisedPTH and normal or lowered Ca2+) and radiological(bone changes).

Management is by treatment of the underlyingdisease and oral calcium supplements to correcthypocalcaemia.

Tertiary hyperparathyroidismThis condition, resulting from chronic overstimu-lation of the parathyroid glands in renal failure,causes one or more of the glands to become anautonomous hypersecreting adenoma with resultanthypercalcaemia.

Figure 10.14 gives a comparison of primary,secondary and tertiary hyperparathyroidism.

HypoparathyroidismHypoparathyroidism is a condition of reduced orabsent PTH secretion, resulting in hypocalcaemia andhyperphosphataemia. It is far less common thanhyperparathyroidism.

The causes of hypoparathyroidism are:

• Removal or damage of the parathyroid glandsduring thyroidectomy—most common cause of

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Fig. 10.13 Pathogenesis of renalosteodystrophy.

Fig. 10.14 Comparison of primary, secondary and tertiary hyperparathyroidism

Primary Secondary

↑PTH; ↑Ca2+ ↑PTH; normal or ↑Ca2+

Hyper- calcaemia

Increased bone absorption

Hypercalcaemia and increased bone resorption

Tertiary

↑PTH; ↑Ca2+

AdenomaHyperplasiaCarcinoma

Chronic renal failureMalabsorptionOsteomalacia and ricketsPregnancy and lactation

Adenoma resulting from overstimulation of glands in secondary hyperparathyroidism

Serum PTH and Ca2+

Aetiology

Predominant effects

Note: PTH, parathyroid hormone.

Fig. 10.14 Comparison of primary,secondary and tertiaryhyperparathyroidism.

Renal disease →

↓ vit. D activation

→ ↓ serum Ca2+ →↑ PTH → ↓ bone absorption+

↓Ca2+ reabsorption

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Disorders of the adrenal gland

hypoparathyroidism resulting from inadvertentdamage or removal.

• Autoimmune parathyroid disease—usually occursin patients who have another autoimmuneendocrine disease, e.g. Addison’s disease(autoimmune endocrine syndrome type 1).

• Congenital deficiency (DiGeorge syndrome)—rare, congenital disorder caused by arresteddevelopment of the third and fourth branchialarches, resulting in an almost complete absenceof the thymus (see Chapter 13) and parathyroidgland.

The effects of hypoparathyroidism are:

• ↓ release of Ca2+ from bones.• ↓ Ca2+ reabsorption but ↑ PO4

3− re absorption bykidney.

• ↓ 1-hydroxylation of 25-hydroxyvitamin D bykidney.

Most symptoms of hypoparathyroidism are those ofhypocalcaemia:

• Tetany—muscular spasm provoked by loweredplasma Ca2+.

• Convulsions.• Paraesthesiae.• Psychiatric disturbances, e.g. depression,

confusional state and even psychosis.• Rarely—cataracts, parkinsonian-like movement

disorders, alopecia, brittle nails.

Management is by treatment with large doses of oralvitamin D; the acute phase requires intravenous cal-cium and calcitriol (1,25-dihydroxycholecalciferol,i.e. activated vitamin D).

DISORDERS OF THE ADRENALGLAND

Hormones of the adrenal glandThe adrenal gland has two structurally and func-tionally distinct endocrine components derivedfrom different embryonic tissue: the cortex and themedulla.

CortexThis is the outer part of the gland, which is derivedfrom the mesoderm. It synthesises, stores, and secretesvarious cholesterol-derived hormones, namely:

• Glucocorticoid hormones, e.g. cortisol—primarily from the zona fasciculata.

• Mineralocorticoid hormones, e.g. aldosterone—from the zona glomerulosa.

• Sex steroids, i.e. oestrogens and androgens—fromthe zona reticularis.

MedullaThis is the inner part of the gland, which is derivedfrom the neuroectoderm, forming part of the sym-pathetic nervous system. Chromaffin cells synthesiseand secrete the vasoactive amines epinephrine(adrenaline) and norepinephrine (noradrenaline).

Hyperfunction of the adrenalcortexCushing’s syndromeThe symptoms and signs of Cushing’s syndrome areassociated with prolonged inappropriate elevation offree corticosteroid levels (Fig. 10.15).

Clinical features—the main effects of sustainedelevation of glucocorticoid secretion are:

• Central obesity and moon face.• Plethora and acne.• Menstrual irregularity.• Hirsutism and hair thinning.• Hypertension.• Diabetes.• Osteoporosis—may cause collapse of vertebrae,

rib fractures.• Muscle wasting and weakness.• Atrophy of skin and dermis—paper thin skin

with bruising tendency, purple striae.

Aetiopathogenesis—patients with Cushing’s syndromecan be classified into two groups on the basis ofwhether the aetiology of the condition is ACTH-dependent or independent (Fig. 10.16).

ACTH-dependent aetiology:

• Pituitary hypersecretion of ACTH (Cushing’sdisease)—bilateral adrenal hyperplasia secondaryto excessive secretion of ACTH by a corticotrophadenoma of the pituitary gland (see page 207).

• Production of ectopic ACTH or corticotrophin-releasing hormone (CRH) by non-endocrineneoplasm, e.g. small cell lung cancer and somecarcinoid tumours. In cases of malignant bronchialtumour, the patient rarely survives long enough todevelop any physical features of Cushing’ssyndrome.

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Non-ACTH-dependent aetiology:

• Iatrogenic steroid therapy—most common causeof Cushing’s syndrome.

• Adrenal cortical adenoma—well-circumscribedyellow tumour usually 2–5 cm in diameter.Extremely common as an incidental finding in upto 30% of all post-mortem examinations. Theyellow colour is due to stored lipid (mainlycholesterol) from which the hormones aresynthesised. The vast majority have no clinicaleffects (i.e. they are non-functioning adenomas),with only a small percentage producingCushing’s syndrome.

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hair- thin- male pattern baldness

eyes- cataract

face- moon face (due to increased fat deposition)- acne

brain- depression- confusion- insomnia- psychosis

heart- predisposes to congestive cardiac failure

muscles- 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

blood- glucose intolerance, some have diabetes

adipose tissue- truncal obesity- striae (stretchmarks)- buffalo hump

bones- osteoporosis- tendency to fracture- vertebral collapse (kyphosis)

ankles- oedema

skin- thin skin- hirsutism- easy bruising- tendency to skin infections(- increased skin pigmentation in Cushing s disease only)

Fig. 10.16 Classification of Cushing's syndrome

ACTH dependent

CauseType

Iatrogenic (ACTH therapy)Pituitary hypersecretion of ACTHEctopic ACTH syndrome (benign or malignant non-endocrine tumour)

Iatrogenic, e.g. prednisoloneAdrenal cortical adenomaAdrenal cortical carcinoma

Non-ACTH dependent

Fig. 10.15 Systemic effects of Cushing’ssyndrome.

Fig. 10.16 Classification of Cushing’s syndrome.

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Disorders of the adrenal gland

• Adrenal cortical carcinoma—rare and almostalways associated with the overproduction ofhormones, usually glucocorticoids and sexsteroids. Patients usually have features ofCushing’s syndrome mixed with androgeniceffects which are particularly noticeable inwomen. Tumours are usually large and yellowish-white in colour. Local invasion and metastaticspread are common.

Irrespective of the aetiology, the diagnosis is based onclinical features and the demonstration of a raisedplasma cortisol level.

The aetiology of the disorder is elucidated through:

• Raised urinary cortisol in the first instance, butfurther testing is required.

• Low-dose dexamethasone suppression test(suppression of cortisol levels in Cushing’sdisease due to suppression of pituitary ACTHsecretion, but a lack of suppression suggestsACTH-independent Cushing’s syndrome).

• MRI and CT scan visualisation of pituitary andadrenal glands.

• Analysis of blood ACTH (high = pituitaryadenoma or ectopic ACTH source; low = primaryadrenal tumour due to feedback suppression).

Treatment of the underlying cause is essential asuntreated Cushing’s syndrome has a 50% 5-year mor-tality rate.

HyperaldosteronismExcessive production of aldosterone by the zonaglomerulosa of the adrenal cortex results in increasedNa+ retention and increased K+ loss.

The aetiology is as follows:

• Primary hyperaldosteronism—autonomoushypersecretion of aldosterone, which is almost

invariably caused by adrenal cortical adenoma(Conn’s syndrome).

• Secondary hyperaldosteronism—hypersecretion of aldosterone secondary to anincreased production of angiotensin IIfollowing activation of the renin–angiotensinsystem. May be precipitated by congestivecardiac failure, cirrhosis, pregnancy, nephroticsyndrome or decreased renal perfusion. Thisis more common than the primary form of thedisorder.

The effects of hyperaldosteronism are shown inFig. 10.17.

Clinical features are:

• Hypertension—often the only presentingfeature. Commonly occurs in the younger agegroup.

• Hypokalaemia—usually accompanieshypertension and may give rise to polyuria,nocturia, polydipsia, paraesthesia, cardiacarrhythmias, muscle weakness or paralysis.

Secondary hyperaldosteronism also has additionalfeatures of underlying disease.

Biochemical diagnosis:

• ↑ Na+, ↓ K+.• ↑ Aldosterone.• Plasma renin—↓ in Conn’s syndrome but ↑ in

secondary hyperaldosteronism.

Radiological diagnosis is by visualisation of adrenalcortical adenoma by CT scan or MRI.

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The therapeutic administration ofglucocorticosteroids (e.g. prednisolone) isa common cause of the features ofCushing’s syndrome. Avoid confusing the disease andthe syndrome. Remember: Cushing’s disease is usedspecifically to describe Cushing’s syndrome secondaryto excessive pituitary ACTH secretion.

hypersecretion ofaldosterone

hypokalaemia

cardiacarrhythmias

alkalosishypertension

Na+ reabsorptionfrom renal tubules

excretion of K+

Na+ + H2Oretention

Fig. 10.17 Effects of hyperaldosteronism.

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Management:

• Primary hyperaldosteronism—medicalaldosterone antagonism (e.g. spironolactone) orsurgical removal of the affected adrenal.

• Secondary hyperaldosteronism—treatment of theunderlying cause.

Congenital adrenal hyperplasiaThis rare, autosomal recessive disorder is usually causedby a deficiency of the enzyme 21-hydroxylase, requiredfor the synthesis of both cortisol and aldosterone.21-hydroxylase acts on 17OH-progesterone, and con-sequently raised levels of 17OH-progesterone are mea-sured in the blood of affected individuals; this isroutinely tested in the first week of life. Failure of corti-sol production produces an increase in ACTH secretionby the pituitary and hyperplasia of the adrenal cortex.

Production of androgens by the adrenal cortex doesnot require 21-hydroxylase. Consequently, adrenalhyperplasia causes excessive secretion of androgensresulting in masculinisation of females and precociouspuberty in males. Also, aldosterone deficiency is seri-ous, causing a life-threatening salt loss (‘salt wastingsyndrome’) unless replacement therapy is given.

Hypofunction of the adrenalcortexAddison’s diseaseThis rare condition of chronic adrenal insufficiency isdue to a lack of glucocorticoids and mineralocorti-coids. Its estimated prevalence in the developed worldis 0.8 cases per 100 000 population.

The clinical features outlined in Fig. 10.18 are aresult of glucocorticoid and mineralocorticoid

insufficiency, loss of adrenal androgen productionand increased ACTH secretion.

Aetiology—autoimmune destruction of the cortex ofboth adrenals is the most common cause of Addison’sdisease. It is often associated with autoimmune thy-roid disease, autoimmune gastritis and otherendocrine organ autoimmune diseases. Addison’s dis-ease is also a well-recognised complication of patientswith acquired immune deficiency syndrome (AIDS),bilateral adrenal tuberculosis (caseous necrosis) and,more rarely, metastatic cancers, haemochromatosisand amyloidosis.

Biochemical features:

• Measurement of plasma ACTH and cortisol—↑ ACTH, ↓ cortisol.

• ACTH stimulation test—ACTH is administeredand plasma cortisol levels are monitored. Failureof cortisol levels to rise indicates Addison’sdisease.

• Plasma electrolytes—↓ Na+, normal or ↑ K+, ↑ urea.• Blood glucose—usually low.• ↑ Plasma renin activity and normal or

↓ aldosterone.

Management is by glucocorticoid replacement ther-apy, and usually mineralocorticoid therapy.

Primary acute adrenocortical insufficiency(adrenal crisis)This may occur as a result of:

• Iatrogenic—abrupt cessation of prolonged high-dose therapeutic corticosteroids (prolongedcorticosteroid therapy produces loweredendogenous steroid production, leading toatrophy of the adrenal cortex).

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Fig. 10.18 Clinical features of Addison's disease

Clinical featuresHormonal abnormality

Glucocorticoid insufficiency Vomiting and loss of appetiteWeight lossLethargy and weaknessPostural hypotensionHypoglycaemia

Brownish pigmentation of skin and buccal mucosa

Mineralocorticoid insufficiency ↓serum Na+, ↑serum K+

Chronic dehydrationHypotension

Increased ACTH secretion

Decreased body hair, especially in femalesLoss of adrenal androgen

Note: ACTH, adrenocorticotrophic hormone

Fig. 10.18 Clinical features of Addison’sdisease.

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Disorders of the endocrine pancreas

• Bilateral massive adrenal haemorrhage—causedby Gram-negative (usually meningococcal)septicaemia (Waterhouse–Friderichsensyndrome) producing haemorrhage anddisseminated intravascular coagulation. Adrenalhaemorrhage is also seen in neonates followingtraumatic birth.

• Complication of chronic adrenal failure—Addisonian crisis is precipitated by sudden stressrequiring increased output from chronicallyfailing adrenal glands.

Secondary adrenocortical insufficiencyThis adrenocortical insufficiency is caused by adrenalatrophy secondary to:

• Hypothalamic or pituitary disease (tumours,infection, infarction, surgical destruction), whichproduces lowered ACTH, hence loweredendogenous glucocorticoids and aldosterone.

• Glucocorticoid therapy, which produces loweredACTH (suppression), hence lowered endogenousglucocorticoids and aldosterone.

The adrenal medullaPhaeochromocytomaThis is a rare tumour of the chromaffin cells—the cellsthat secrete epinephrine (adrenaline) and norepi-nephrine (noradrenaline) in the adrenal medulla (seepage 62).

Tumours of extra-adrenal paragangliaNeuroblastomasThese rare tumours are derived from neuroblasts.Affected sites are the adrenal medulla, the medi-astinum (usually in association with the sympatheticchain) and the coeliac plexus.

Neuroblastomas are almost exclusively tumours ofchildren, occurring very rarely over the age of 5 years.They are highly malignant and usually inoperable.

GanglioneuromaA benign tumour derived from sympathetic nerves.Most commonly found in the posterior mediastinum,although 10% of cases arise in the adrenal medulla.

DISORDERS OF THE ENDOCRINEPANCREAS

Diabetes mellitusDiabetes mellitus (DM) is a multisystem disease of anabnormal metabolic state characterised by hypergly-caemia due to inadequate insulin action/production.It can be classified into primary and secondary.

Primary DM is a disorder of insulin production/action. It accounts for 95% of diabetic cases.

In 5% of cases, diabetes may be secondary to:

• Pancreatic diseases, e.g. chronic pancreatitis.• Hypersecretion of hormones that antagonise the

effects of insulin, e.g. glucocorticoids inCushing’s syndrome, growth hormone inacromegaly, epinephrine (adrenaline) inpheochromocytomas.

Primary DM is by far the most important cause of dia-betes and it is further classified into:

• Type I, also known as insulin-dependent DM(IDDM) or juvenile-onset diabetes.

• Type II, also known as non-insulin-dependentDM (NIDDM) or mature-onset diabetes.

The basic features of these two types of diabetes aredescribed in Fig. 10.19.

Type I diabetes mellitusAetiology and pathogenesis—type I diabetes mellitus isan organ-specific, autoimmune-induced disordercharacterised by antibody-mediated destruction of theβ-cell population of the islet of Langerhans.

Two main factors are thought to predispose toautoimmunity:

1. Genetic predisposition—90–95% of patientswith type I diabetes are HLA-DR3 or HLA-DR4positive, a feature that is also seen in other organ-specific autoimmune diseases. However, identicaltwins show a 40% concordance in the

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Clinical features of an adrenal crisis are:• Profound hypotension and cardiovascular collapse

(shock).• Vomiting.• Diarrhoea.• Abdominal pain.• Pyrexia.An adrenal crisis is a medical emergency and requiresintravenous hydrocortisone and fluid replacement.The precipitating cause should be sought and ifpossible treated.

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development of the disease, indicating theadditional importance of environmental factors.

2. Viral infection—viral infection may trigger theautoimmune reaction; viruses implicated includemumps, measles and Coxsackie B.

One postulated mechanism is that viruses induce mildstructural damage to the islet cells, thereby releasingpreviously shielded β-cell antigens and leading to therecruitment and activation of lymphocytes in thepancreatic tissue.

Histologically, the pancreas shows lymphocyticinfiltration and destruction of insulin-secreting cellsof islets of Langerhans (β-cells). This results in insulindeficiency with hyperglycaemia and other secondarymetabolic complications.

Type II diabetes mellitusAetiology and pathogenesis—the precise aetiopatho-genesis of type II diabetes is unclear but the follow-ing factors are thought to be involved:

• Genetic factors—familial tendency with up to90% concordance rate amongst identical twins.However, there are no HLA associations andinheritance is considered to be polygenic.

• Insulin resistance—tissues are unable to respondto insulin because of an impairment in thefunction of insulin receptors on the surface of

target cells. This is associated with obesity,sedentary lifestyle and poor diet; it is increasinglybeing seen in younger (even adolescent)individuals.

• Relative insulin deficiency—reduced secretioncompared with the amounts required, possiblyrelated to islet cell ageing.

Diagnosis of diabetes mellitusIrrespective of aetiology, the diagnosis of DMdepends on the finding of hyperglycaemia.However, the distribution curve of blood glucoseconcentration for whole populations is unimodal,with no clear division between normal andabnormal values.

Diagnostic criteria (Fig. 10.20) are, therefore, arbi-trary and, in general, diabetes mellitus is indicated byeither:

• Fasting venous plasma glucose level of > 7.0 mmol/L.

• Random venous plasma glucose level of > 11.1 mmol/L.

A distinction is made between diabetes mellitus andimpaired glucose tolerance in cases where fasting orrandom blood sugar level is borderline; in this case,the response to an oral load of glucose can be assessedvia a glucose tolerance test.

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

Type IIType I

Childhood/adolescent onset Middle-aged/elderly onset

Females = males

1/3 of primary diabetes 2/3 of primary diabetes

Females = males

Gradual onsetAcute/subacute onset

ObeseThin

Ketoacidosis rareKetoacidosis common

Plasma insulin normal or raisedPlasma insulin absent or low

Insulin insensitive (end-organ resistance)Insulin sensitive

Non-autoimmune mechanism (no islet cell antibodies)

Autoimmune mechanism (islet cell antibodies present)

Polygenic inheritanceGenetic predisposition associated with HLA-DR genotype

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

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Disorders of the endocrine pancreas

Complications of diabetes mellitusAcute complicationsIndividuals with diabetes are particularly prone toseveral types of coma. These result from (in decreas-ing order of frequency):

• Hypoglycaemia—complication of overtreatmentwith insulin.

• Diabetic ketoacidosis (DKA)—common in type Idiabetes due to ↑ breakdown of triglycerides →↑ production of ketone bodies → ketoacidosis →impaired consciousness.

• Hyperosmolar non-ketotic (HONK) state—↑ plasma glucose concentration → ↑ plasmaosmolarity → cerebral dehydration → coma.More common in type II diabetes.

• Lactic acidosis—increased concentrations oflactic acid (produced as an end product ofglycolysis instead of pyruvate) may cause coma.

Chronic complicationsIn recent years, with the advent of insulin therapy andvarious oral hypoglycaemic agents, morbidity andmortality associated with DM are more commonly

the result of the chronic rather than the acute compli-cations of the disorder (Fig. 10.21).

The complications of diabetes are macrovascular(affecting large and medium-sized muscular arteries)and microvascular (small vessel microangiopathy).

Macrovascular changes involve accelerated athero-sclerosis. In diabetic microangiopathy, small arteriolesand capillaries show a characteristic pattern of wallthickening, which is due to a marked expansion of thebasement membrane (termed hyaline arterioloscle-rosis).

Therefore, the most important chronic complica-tions of diabetes are:

• Macrovascular accelerated atherosclerosisincreasing stroke and myocardial infarction risk.

• Renal disease—diabetic nephropathy (mainlymicrovascular).

• Eye disease—diabetic retinopathy(microvascular).

• Peripheral nerve damage—diabetic neuropathy(microvascular).

• Predisposition to infections.

Macrovascular diseaseCompared with non-affected people of the same ageand sex, individuals with diabetes suffer from anincreased severity of atherosclerosis, probably due to theincreased plasma levels of cholesterol and triglycerides.

The main clinical sequelae of this are seen in:

• Heart → ischaemic heart disease.• Brain → cerebral ischaemia.• Legs and feet → gangrene—ischaemia of toes and

areas on the heel is a characteristic feature ofdiabetic gangrene.

• Kidney → chronic nephron ischaemia, animportant component of the multiple renallesions in diabetes.

Diabetic nephropathyDiabetes is now one of the most common causes ofend-stage renal failure. Associated renal disease canbe divided into three forms:

• Complications of diabetic vascular disease—macrovascular atherosclerosis affecting aorta andrenal arteries → ischaemia; microvascularglomerular capillary basement membranethickening (hyaline arteriolosclerosis) →ischaemic glomerular damage. Microalbuminuriais a reliable marker of the progression of diabeticnephropathy.

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The complications of DM are important;80% of adults with diabetes die fromcardiovascular disease and patientsfrequently develop serious renal and retinal disease.

Fig. 10.20 Diagnostic criteria for diabetes mellitus using an oral glucose tolerance test

Venous plasma blood glucose

Fasting sample2 hours after 75 g glucose load

5.6–6.9 mmol/L 7.8–11.0 mmol/L

<5.6 mmol/L <7.8 mmol/LNormal

Impaired glucose tolerance

Diabetes mellitus

Diagnosis

≥7.0 mmol/L ≥11.1 mmol/L

Fig. 10.20 Diagnostic criteria for diabetes mellitus using an oral glucosetolerance test.

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• Diabetic glomerulosclerosis (diffuse and nodulartypes)—↑ leakage of plasma proteins throughcapillary wall into glomerular filtrate →proteinuria and progressive glomerularhyalinisation with eventual chronic renal failure.

• Increased susceptibility to infections → papillarynecrosis. Acute pyelonephritis is a commoncomplication of diabetes mellitus and occurs as aresult of the relative immunosuppression ofdiabetes together with reduced neutrophilfunction.

Eye diseaseDiabetes is the most common cause of acquiredblindness in the Western world. It can affect the eyesin five main ways:

1. Background retinopathy—small vesselabnormalities in the retina leading to hardexudates, haemorrhages and microaneurysms.Does not usually affect acuity.

2. Proliferative retinopathy—extensive proliferationof new capillaries in the retina. Suddendeterioration in vision may result from vitreoushaemorrhage as a consequence of proliferating newvessels or from the development of retinaldetachment.

3. Maculopathy—caused by oedema, hard exudatesor retinal ischaemia and results in a markedreduction of acuity.

4. Cataract formation—greatly increased incidencein individuals with diabetes.

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brain- cerebrovascular disease/strokeseyes

- retinopathy, cataracts and glaucoma (diabetes is the commonest cause of blindness under the age of 60)

heart- ischaemic heart disease

blood vessels- peripheral vascular disease causes claudication in legs, gangrene in feet

kidneys- nephropathy leads to renal failure- prone to infections

penis- impotence

limbs- ischaemia, neuropathy leads to dry anaesthetic skin

skin- prone to skin infections

feet- prone to ulcers and gangrene- neuropathy

blood vessels- atherosclerosis

Fig. 10.21 Chronic complications ofdiabetes mellitus.

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Multiple endocrine neoplasia syndromes

5. Glaucoma—increased incidence in those withdiabetes due to neovascularisation of the iris(rubeosis iridis).

Predisposition to infectionsPatients with diabetes have an increased tendency todevelop infections, usually of a bacterial or fungalnature. The main target organs are:

• Skin—folliculitis, erysipelas, cellulitis andsuperficial fungal infections.

• Oral and genital mucosae—especially withCandida.

• Urinary tract—increased predisposition to acutepyelonephritis, often associated with recurrentlower urinary tract infections.

Persistent glycosuria in individuals with poorly con-trolled diabetes predisposes to urinary and genitalinfection.

Diabetic neuropathyClinically, most cases of diabetic neuropathy affect theperipheral nervous system, although central nervoussystem pathology does occur. The main effects are:

• Microvascular thickening of basement membraneand microthrombi formation in small vesselssupplying peripheral nerves.

• Axonal degeneration with patchy, segmentaldemyelination.

• Thickening of Schwann cell basal lamina.

The presentation may be of polyneuropathy (classically‘glove and stocking’ sensory impairment), mononeu-ropathy (e.g. carpal tunnel syndrome) or autonomicneuropathy (symptoms include postural hypotension,nausea, vomiting, impotence and gustatory sweating).

Islet cell tumoursThese tumours are rare compared with those of theexocrine pancreas. They occur most commonly inindividuals aged 30–50 years.

InsulinomasThe most common tumour of the islet cells.Insulinomas are derived from pancreatic β-cells:

• Produce hypoglycaemia through hypersecretionof insulin.

• May produce attacks of confusion, stupor andloss of consciousness.

• Majority are solitary, non-metastasising lesions(10% are multiple and 10% are malignant).

Zollinger–Ellison syndromeThis syndrome of gastric hypersecretion, multiple pepticulcers and diarrhoea is caused by the gastrin-secretingtumour (gastrinoma) of the pancreatic G cells. Tumoursare multiple in 50% of cases and are often malignant,with 10–20% occurring in other sites, e.g. the duodenum.

It may also be part of the MEN I syndrome, withadenomas also present in other endocrine glands (seebelow).

Other islet cell tumoursFor a summary of islet cell tumours see Fig. 10.22.

VIPomasThese produce vasoactive intestinal polypeptide(VIP), resulting in a syndrome of watery diarrhoea,hypokalaemia and achlorhydria (WDHA).

GlucagonomasThese glucagon-secreting tumours are derived frompancreatic α-cells and cause secondary diabetes mel-litus (usually mild), necrolytic migratory erythema(skin rash) and uraemia.

SomatostatinomasThese somatostatin-producing tumours derived frompancreatic δ-cells are associated with diabetes mellitus,cholelithiasis and steatorrhoea.

MULTIPLE ENDOCRINE NEOPLASIASYNDROMES

These are syndromes in which patients developtumours in a number of different endocrine organs.

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Blood glucose control in diabetes lowers theincidence and progression of vascular complications.This can be achieved by:• Diet alone—in type II patients.• Diet and oral hypoglycaemic drugs (e.g.

sulphonylureas, biguanides, thiazolidinediones)—in type II patients who fail on diet alone.

• Diet and insulin—all type I patients and sometype II.

Pancreatic transplantation is curative in type Idiabetes but is limited by organ availability. Islet celltransplants are a potential future therapy.

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Patients are younger than those who develop singlesporadic tumours and usually have a strong familyhistory of multiple endocrine tumours with autoso-mal dominant inheritance.

There are three main types of MEN syndrome:

1. MEN I (Werner’s) syndrome.2. MEN IIa (Sipple’s) syndrome.3. MEN IIb (sometimes called MEN III) syndrome.

MEN I (Werner’s) syndromePatients usually show a combination of hyper-parathyroidism (chief cell hyperplasia and adeno-mas), pituitary adenomas (usually prolactinomas)and pancreatic tumours (gastrin and insulin produc-ing). Rarely, there may also be thyroid tumours andadrenal cortical adenomas. MEN I syndrome is causedby a germ-line mutation in the MEN-1 tumoursuppressor gene.

MEN IIa (Sipple’s) syndromePatients have a combination of phaeochromocytoma(50% bilateral) and medullary carcinoma of the

thyroid (often bilateral and multinodular). Rarely,there may also be hyperparathyroidism due toparathyroid hyperplasia. MEN IIa and IIb syndromeshave been linked to mutations in the RET oncogene,with near 100% disease penetrance

MEN IIb (MEN III) syndromePatients have all of the features of MEN IIa withadditional features of:

• Neuromas and ganglioneuromas in the dermisand submucosal regions throughout the body.

• Marfanoid body habitus with poor muscledevelopment.

• Skeletal abnormalities, e.g. kyphosis, pes cavusand high arch palate.

The facial appearance is characteristic with thick,bumpy lips, broad-based nose, everted eyelids andgrossly abnormal dental enamel.

Genetic screening of at-risk family members inMEN II families now allows prophylactic thyroidec-tomy in those with RET mutations to avoid the nearcertainty of medullary carcinoma.

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Fig. 10.22 Summary of islet cell tumours

OccurrenceIslet cell tumour

Insulinoma 70–75%

Rare

Gastrinoma 20–25%

VIPoma

Rare

Clinical features

Hypoglycaemia

Water diarrhoea, hypokalaemia and achlorhydria

Zollinger–Ellison syndrome: gastric hypersecretion, multiple peptic ulcers and diarrhoea

Secondary diabetes mellitus, necrolytic migratory erythema and uraemia

Glucagonoma

Rare Diabetes mellitus, cholelithiasis and steatorrhoea

Somatostatinoma

Fig. 10.22 Summary of islet cell tumours.

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