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Pathology of the endocrine 10
In this chapter, you will learn to:
• Describe disorders of the pituitary gland leading to hyperpituitarism
• 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
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 anterior pituitary:
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.
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.
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Pathology of the endocrine system
• Brain (large tumours) → distortion of the
third midbrain with raised intracranial pressure and
optic mammillary • Dura → headaches.
• 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).
anterior posterior • Imaging—plain X-ray (can detect enlargement
of sella turcica and erosion of the clinoid
processes) and MRI (for visualisation and
sizing of the tumour; this is superior to CT
• Hormone assays (e.g. growth hormone,
bone growth hormone (GH)
sella prolactin 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)
melanocyte stimulating hormone (MSH)
given and the plasma cortisol response
Fig. 10.1 Pituitary and hypothalamus, with the hormones released.
• Visual field assessment.
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 (prolactinomas–lactotroph ade-
+ or − + or − loop nomas), growth hormone (somatotroph adenomas)
hypothalamus or ACTH (corticotroph adenomas).
Abnormally raised serum prolactin levels are associ-
releasing hormone ated with menstrual irregularity and infertility in
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 adenoma
(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
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 gigantism (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 Endocrinology, 4th edn, by Brook and acromegaly with disproportionate enlargement,
Marshall, Blackwell Publishing, 2001). e.g. of the hands and jaw.
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Disorders of the pituitary 10
• 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.
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
- large lower jaw
- spaces between lower • Suprasellar tumours, e.g. craniopharyngioma or,
teeth due to jaw growth heart
- enlarged more rarely, pinealoma, teratoma or a secondary
- large nose
- large tongue tumour from another site.
Pituitary lesions are:
liver and kidneys
- enlarged organs • Idiopathic deficiency of one or more of the
• 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
the anterior pituitary due to hypotensive
shock occurring as a result of obstetric
- increased greasy haemorrhage.
sweating • Empty sella syndrome—an enlarged, empty sella
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
• Progressive loss of
secondary sex characteristics
• 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
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
Diabetes insipidus 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
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Disorders of the pituitary 10
Fig. 10.5 Causes of cranial and
Fig. 10.5 Causes of cranial and nephrogenic diabetes insipidus (DI) nephrogenic diabetes insipidus (DI).
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)
lesions, e.g. sarcoidosis,
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
Drug therapy Lithium
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
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
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:
• 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
• 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.
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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
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.
body of tongue foramen caecum
Congenital disorders epiglottis
of the thyroid
thyroglossal cysts hyoid bone
Development of the thyroid
The thyroid gland develops from an endodermal thyroid cartilage
thickening in the floor of the primitive pharynx at a
thyroid gland cricoid cartilage
point later indicated by the foramen caecum of the
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
Note: ADH, antidiuretic hormone.
Fig. 10.6 Comparison of features of diabetes insipidus with those of inappropriate antidiuretic hormone (ADH) secretion.
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Thyroid disorders 10
Hyperthyroidism can be classified on the basis of
hair loss brain
aetiology into: - anxiety
• Primary hyperthyroidism (↑ thyroid hormones, - restlessness
↓ TSH)—hypersecretion of thyroid hormones, - exophthalmos
which is not secondary to increased levels of TSH (protruding eyes) neck
- lid retraction
(the rise in thyroid hormones actually suppresses - lid lag
• Secondary hyperthyroidism (↑ thyroid heart
- proximal myopathy
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
Primary hyperthyroidism is caused by: hands - menorrhagia
• Graves’ disease (exophthalmic goitre)—the most - warm, moist palms
common cause of thyrotoxicosis, characterised by - onycholysis (nail
loose in nail bed)
a diffusely enlarged thyroid gland that is - acropachy
stimulated to produce excess hormone by an IgG
autoantibody. bones skin and adipose
- osteoporosis tissue
• Toxic multinodular goitre (Plummer’s
- increased sweating
disease)—second most common cause of - temperature
- weight loss
• Toxic adenoma—solitary thyroid nodule - 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.
(* = additional features seen only in Graves’ disease.)
causing hyperthyroidism (e.g. De Quervain’s
thyroiditis). Note that thyroiditis is more
commonly associated with hypothyroidism (see Management—options in thyrotoxicosis are:
• 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.
Signs and symptoms 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.
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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
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
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 pituitary disease.
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.
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Thyroid disorders 10
• 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
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
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
- coarse and thin hair - mental slowing
- loss of outer third of - apathy
eyebrows - tiredness Microscopically, the thyroid gland shows:
• 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.
• Acini lined with abnormal, highly eosinophilic
- slowing of activity epithelial cells (proliferation of mitochondria)
- muscle weakness 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
- constipation because of the symptoms of hypothyroidism. The
hands hypothyroid state tends to develop slowly. However,
- cold hands
- carpal tunnel
uterus damage to thyroid follicles may lead to the release of
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
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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.
• Preceding general malaise, pyrexia or upper
A comparison of the main types of thyroiditis is
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
release of thyroglobulin and excessive amounts of
This is the most common cause of toxic goitre
Severe thyroiditis may be fatal in the elderly and
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
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
Hypothyroidism Common Rare Rare
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Thyroid disorders 10
• 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
primary and secondary hyperthyroidism
(substances that induce goitre formation) or
familial in origin. Examples of goitrogenic agents
include certain cabbage species, because of their • Primary hyperthyroidism—↑ thyroid hormones,
thiourea content, and specific drugs or chemicals,
such as iodide, paraminosalicylic acid and drugs • Secondary hyperthyroidism—↑ thyroid hormones,
↑ TSH (excess TSH production due to pituitary
used in the treatment of thyrotoxicosis. Familial
cases show inherited autosomal recessive traits,
which interfere with hormone synthesis via • Primary hypothyroidism—↓ thyroid hormones,
various enzyme pathways (these are
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;
the reason is unclear.
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-
• 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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Pathology of the endocrine system
Fig. 10.11 Types and features of malignant thyroid tumours
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
Follicular Follicular cells 10 40−60 Bloodstream 60
Undifferentiated Anaplastic Follicular cells 5 > 60 Aggressive 1
carcinoma local invasion;
Medullary −− Parafollicular 5−10 > 40 Local, 50 (but very
carcinoma C cells lymphatic variable)
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
radioactive iodine (131I), 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.
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
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.
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Parathyroid disorders 10
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.
• Exacerbation of hypertension and potential
3. Tertiary—supervention of an autonomous
shortening of the QT interval.
hypersecreting adenoma in long-standing
secondary hyperparathyroidism. • Thirst and polyuria (may be dehydrated due to
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
• Radiological—90% normal; 10% show evidence
Fig. 10.12 Aetiology of primary hyperparathyroidism
of bone resorption, particularly phalangeal
Type Frequency 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
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.
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.
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Pathology of the endocrine system
Fig. 10.13 Pathogenesis of renal
osteodystrophy. ↓ vit. D activation
Renal disease → + → ↓ serum Ca2+ →↑ PTH → ↓ bone absorption
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
• 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.
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
autonomous hypersecreting adenoma with resultant
The pathogenesis of renal osteodystrophy is shown
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:
• 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
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
Note: PTH, parathyroid hormone.
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Disorders of the adrenal gland 10
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
• ↓ Ca2+ reabsorption but ↑ PO43− re absorption by cortex
• ↓ 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:
plasma Ca2+. • 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:
• Pituitary hypersecretion of ACTH (Cushing’s
Hormones of the adrenal gland 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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Pathology of the endocrine system
Fig. 10.15 Systemic effects of Cushing’s
hair - cataract brain
- thin - depression
- male pattern baldness - confusion
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)
- peptic ulcer
- renal calculi
- menstrual disturbances
- thin skin
bones - easy bruising
- osteoporosis - tendency to skin infections
- tendency to fracture (- increased skin
- vertebral collapse pigmentation in Cushing s
(kyphosis) disease only)
- glucose intolerance,
some have diabetes
• Iatrogenic steroid therapy—most common cause
Fig. 10.16 Classification of Cushing's syndrome of Cushing’s syndrome.
Type Cause • Adrenal cortical adenoma—well-circumscribed
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.
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Disorders of the adrenal gland 10
• 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
The effects of hyperaldosteronism are shown in
The therapeutic administration of
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
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.
• 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
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-
Na+ + H2O
Excessive production of aldosterone by the zona
glomerulosa of the adrenal cortex results in increased
Na+ retention and increased K+ loss.
The aetiology is as follows: arrhythmias
• Primary hyperaldosteronism—autonomous
hypersecretion of aldosterone, which is almost Fig. 10.17 Effects of hyperaldosteronism.
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Pathology of the endocrine system
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
endocrine organ autoimmune diseases. Addison’s dis-
ease is also a well-recognised complication of patients
Congenital adrenal hyperplasia
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.
21-hydroxylase acts on 17OH-progesterone, and con-
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
This may occur as a result of:
This rare condition of chronic adrenal insufficiency 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
Lethargy and weakness
Mineralocorticoid insufficiency ↓serum Na+, ↑serum K+
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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Disorders of the endocrine pancreas 10
• 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
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
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.
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
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Pathology of the endocrine system
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
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
previously shielded β-cell antigens and leading to the
Diagnosis of diabetes mellitus
recruitment and activation of lymphocytes in the
Irrespective of aetiology, the diagnosis of DM
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
Diagnostic criteria (Fig. 10.20) are, therefore, arbi-
Type II diabetes mellitus trary and, in general, diabetes mellitus is indicated by
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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Disorders of the endocrine pancreas 10
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)
2 hours after 75g
and microvascular (small vessel microangiopathy).
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
basement membrane (termed hyaline arterioloscle-
Diabetes ≥ 7.0 mmol/L ≥ 11.1 mmol/L Therefore, the most important chronic complica-
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
• 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):
• 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:
• 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
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.
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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Pathology of the endocrine system
Fig. 10.21 Chronic complications of
diabetes mellitus. brain
- retinopathy, cataracts and
glaucoma (diabetes is the
commonest cause of blindness
under the age of 60)
- ischaemic heart
- nephropathy leads to
- prone to infections
- ischaemia, neuropathy
leads to dry anaesthetic
- prone to skin infections blood vessels
- peripheral vascular disease
causes claudication in legs,
gangrene in feet
- prone to ulcers and gangrene
• 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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Multiple endocrine neoplasia syndromes 10
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
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
• Diet alone—in type II patients. pancreatic δ-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
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
VIPoma Rare Water diarrhoea, hypokalaemia
Glucagonoma Rare Secondary diabetes mellitus, necrolytic
migratory erythema and uraemia
Somatostatinoma Rare Diabetes mellitus, cholelithiasis
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.