Dysfunction of an endocrine gland

Key terms acute thyroiditis, 270 autoimmune thyroiditis, 270 Cushing’s syndrome, 261 diabetes insipidus, 257 diabetes mellitus, 264 gestational diabetes mellitus, 266 glycosuria, 265 goitre, 267 Graves’ disease, 267 hyperaldosteronism, 259 hypercalcaemia, 274 hypercortisolism, 260 hyperparathyroidism, 272 hyperthyroidism, 266 hypocalcaemia, 275 hypoparathyroidism, 274 hypothyroidism, 270 myxoedema, 270 painless thyroiditis, 270 postpartum thyroiditis, 270 primary hyperaldosteronism, 259 primary hyperparathyroidism, 272 secondary hyperaldosteronism, 259 secondary hyperparathyroidism, 272 subacute thyroiditis, 270 syndrome of inappropriate

antidiuretic hormone secretion (SIADH), 257

thyrotoxic crisis, 269 thyrotoxicosis, 266 toxic adenoma, 268 type 1 diabetes mellitus, 264

Introduction, 256 Mechanisms of hormonal alterations, 256 Alterations of pituitary function, 257 Syndrome of inappropriate antidiuretic

hormone secretion, 257 Diabetes insipidus, 257 Alterations of adrenal function, 259 Hyperaldosteronism, 259 Hypercortisolism, 260 Hypoadrenalism, 262

Alterations of pancreatic function, 264 Type 1 diabetes mellitus, 264 Diabetes in pregnancy, 266 Alterations of thyroid function, 266 Hyperthyroidism, 266 Hypothyroidism, 270 Alterations of parathyroid function, 272 Hyperparathyroidism, 272 Hypoparathyroidism, 274

Chapter outl ine

Alterations of endocrine function across the life span Sarah List

C H A P T E R

11

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256 PArt 2 AlTerATionS To regulATion AnD conTrol

fluid and sodium balance, which is of prime focus within healthcare facilities. Then we briefly look at Cushing’s syndrome, which people taking cortisol medications are at risk of developing. Next we introduce diabetes mellitus, and finally we look at dis s relating to the thyroid gland, which are reasonably common.

Mechanisms of hormonal alterations Significantly elevated or significantly depressed hormone levels may result from various causes (see Fig. 11.1). Feedback systems that recognise the need for a particular hormone may fail to function properly or may respond to inappropriate signals. Dysfunction of an endocrine gland may involve its failure to produce adequate amounts of hormone, or a gland may produce and release too much hormone. Once hormones are released into the circulation,

Introduction The function of the endocrine system involves complex interrelationships and interactions that maintain homeostasis and provide growth and reproductive capabilities. Dysfunction is usually described in terms of excessive or insufficient function of the endocrine gland with alterations in hormone levels. These alterations are caused by either hypersecretion or hyposecretion of the various hormones, leading to abnormal hormone concentrations in the blood.

Most hormones have syndromes or dis s resulting from either too much or too little hormone. However, some of these are quite rare — for example, increased secretions of growth hormone affect about 1500 Australians1 and growth hormone deficiency impacts on a similar number across the child and adult population in Australia.2 In this chapter, we focus on those dis s that have greatest relevance to contemporary Australia and New Zealand. We start by exploring hormone abnormalities that influence

C O

N C

EP T

M AP

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

No

No

No

No

No

No

No

No

No

No

Is appropriate amount of biologically active hormone being delivered

to target cell?

Is appropriate need recognised?

Is secretory cell producing biologically active hormone?

Is delivery system functioning?

Is hormone metabolism appropriate?

Is hormone being ectopically produced?

Target cell is receiving appropriate amount

of hormone

Pathogenic mechanism

Pathogenic mechanism

Is another substance mimicking action of hormone?

Is hormone-receptor binding abnormal?

Is initiation of intracellular events (e.g.

generation of second messenger) lacking?

Is cell response to events lacking?

Target cell is responding appropriately to

hormone

FIGURE 11.1

Hormone delivery to the cells. Phases at which pathogenic mechanisms may develop in delivering appropriate amounts of hormone to the cells.

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CHAPtEr 11 AlTerATionS of enDocrine funcTion AcroSS THe life SpAn 257

throughout the body. It is important to remember that blood concentrations of various substances such as sodium can have powerful effects on body systems.

CLINICAL MANIFESTATIONS A diagnosis of SIADH requires the following signs: (1) low total concentration of solute in the serum (low serum osmolality) and hyponatraemia; (2) urine hyperosmolality (that is, urine osmolality is greater than expected for the serum osmolality); (3) urine sodium excretion that matches sodium intake; (4) normal adrenal and thyroid function; and (5) absence of conditions that can alter fluid volume status (e.g. congestive heart failure, hypovolaemia from any cause, or renal insufficiency).

The symptoms of this syndrome result from hyponatraemia and are determined by its severity and rate of onset. Fig. 11.2 contrasts the range of signs and symptoms and treatment strategies of an acute onset hyponatraemia compared to that of chronic hyponatraemia. Since hospitalised elderly patients are at particular risk, the incidence may increase as a result of our ageing population.

EVALUATION AND TREATMENT Serum electrolyte levels, serum osmolality, urine volume, urine electrolyte levels and urine osmolality are adequate measures of the presence of SIADH. A chest x-ray is necessary to assist with diagnosis to rule out respiratory conditions. The treatment principles of this syndrome are shown in Fig. 11.2. Resolution usually occurs within 3 days, with a 2–3 kg weight loss and correction of hyponatraemia and sodium loss. Excessive rate of correction of hyponatraemia risks the development of the catastrophic neurologic condition known as osmotic demyelination which can be fatal. Although there are some pharmacological treatments, these are not first-line therapy. Vasopressin receptor antagonists (e.g. tolvaptan) are newer agents that prevent the reabsorption of free water back into the circulation.3

Diabetes insipidus Diabetes insipidus is related to an insufficiency of antidiuretic hormone, leading to polyuria and polydipsia. It is actually quite rare, affecting approximately 6 in 100 000 people. Note that this is a different condition to the more common diabetes mellitus (usually referred to simply as diabetes), which is increasing in incidence in Australia and New Zealand (refer to the later section on alterations of pancreatic function). The term diabetes means ‘overflow’, or an increased urine volume. The two forms of diabetes insipidus are as follows (see Fig. 11.3): 1 Neurogenic form. Caused by the absence of antidiuretic

hormone. This occurs with damage or inflammation to the hypothalamus, pituitary stalk or posterior pituitary, such as brain tumours, aneurysm or following pituitary surgery. This interferes with antidiuretic hormone production, transport or release.

they may be degraded at an altered rate or inactivated by antibodies before reaching the target cell. Hormones produced by non-endocrine tissues may cause abnormally elevated hormone levels; an example of this is a type of lung tumour that can secrete antidiuretic hormone. This mechanism operates without the benefit of the normal feedback system for hormone control and is an example of ectopic hormone production whereby it is produced from a part of the body in which it is not normally made. An additional mechanism of endocrine alteration may result from abnormal receptor function or from altered intracellular response to the hormone at the target cell.

Alterations of pituitary function Syndrome of inappropriate antidiuretic hormone secretion Diseases of the posterior pituitary are rare and are usually related to abnormal antidiuretic hormone secretion. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is characterised by high levels of antidiuretic hormone without the normal physiological stimuli for its release.3 The most common cause is ectopic production, which is associated with cancer, wherein tumour cells secrete antidiuretic hormone. Tumours associated with SIADH include small cell carcinoma of the lung (the most common cause).4

Postoperative patients can have fluid volume shifts that result in increased antidiuretic hormone secretion for as long as 5–7 days after surgery. SIADH is seen also in individuals with infectious pulmonary diseases, where antidiuretic hormone is produced by infected lung tissue or posterior pituitary secretion is increased in response to a hypoxia-induced decrease in pulmonary perfusion.

PATHOPHYSIOLOGY The cardinal features of SIADH are symptoms of water intoxication resulting from enhanced renal water retention or increases in total body water, which leads to hyponatraemia (low serum sodium), and urine that is inappropriately concentrated with respect to the serum osmolality. Hyponatraemia is induced due to a relative increase in water without similar increases in sodium concentration. In this syndrome, antidiuretic hormone is released continually. Water retention results from the normal action of antidiuretic hormone on the renal tubules and collecting ducts, increasing their permeability to water and increasing water reabsorption by the kidneys (see Chapter 28).

Due to the retention of water, the extracellular fluid volume expands and a dilutional hyponatraemia develops; this means that sodium is diluted in more fluid.

In Chapter 6, we examined the role of normal concentrations of sodium and potassium in the normal signalling of neurons. Hyponatraemia can lead to alterations of neural signals, which can have widespread effects

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258 PArt 2 AlTerATionS To regulATion AnD conTrol

Dehydration develops rapidly without ongoing fluid replacement.

CLINICAL MANIFESTATIONS The clinical manifestations of diabetes insipidus include polyuria, nocturia, continuous thirst, polydipsia, low urine specific gravity, low urine osmolality5 and high–normal plasma osmolality. Plasma osmolality is always higher than urine osmolality after a supervised water deprivation test. However, as there can also be an increasing hypernatraemia, it is critical that a water deprivation test only be performed under direct clinical supervision.

EVALUATION AND TREATMENT The diagnosis of diabetes insipidus is generally established by correlating the clinical presentation with serum and urine osmolality and serum sodium. Plasma antidiuretic hormone levels may be measured following several hours of deprivation; however it is generally only helpful in identifying the nephrogenic form, as it would be present in high levels. The diagnosis of neurogenic diabetes insipidus is

124127130133136139

Normal reference

range

142145 112

Signs and symptoms

115118121

Thirst Impaired taste Anorexia Dyspnoea on exertion Fatigue Dulled sensorium (ability to interpret sensory inputs)

Severe gastrointestinal symptoms • vomiting • abdominal cramps

Confusion Lethargy Muscle twitching Seizures Severe sometimes irreversible neurological damage may occur

Treatment principles • 3% hypertonic NaCl • Increase serum Na+

by no more than – 8–10 mmol/L in

�rst 24 hrs – 18 mmol/L in

48 hrs • Accurate assessment

and monitoring of weight and �uid balance

• Identify cause and manage

Treatment principles • Fluid restriction

0.5–1 L/day • Accurate assessment

and monitoring of weight and �uid balance

• Medications not �rst line therapy

Can be nonspeci�c and very well tolerated

Lethargy Muscle twitching Confusion Seizure can occur

Rapid onset

Rapid correction

Slow onset

Serum Na+ mmol/L

Slow correction

requires

requires

FIGURE 11.2

Clinical features and management of hyponatraemia. The upper panel shows the progression of numerous clinical features at decreasing levels of sodium, and the management of this acute condition. The lower panel shows the clinical features of chronic hyponatraemia, and illustrates that these do not usually become apparent until substantial declines in serum sodium levels.

2 Nephrogenic form. Caused by inadequate response of the renal tubules to antidiuretic hormone. This occurs with diseases that irreversibly damage the renal tubules, such as pyelonephritis; can occur due to drugs, particularly lithium (up to 40%) and also methoxyflurane anaesthesia. These generally are reversible, but can occasionally be permanent.5

There is also a psychogenic form, caused by chronic ingestion of extremely large quantities of fluid. It resolves with effective management of fluid intake.

PATHOPHYSIOLOGY Diabetes insipidus usually has an acute onset. Individuals with diabetes insipidus have a partial or total inability to concentrate urine. Insufficient antidiuretic hormone secretion causes polyuria (excretion of large volumes of dilute urine), leading to increased plasma osmolality. In conscious individuals, the thirst mechanism is stimulated and induces polydipsia (increased thirst, and usually with a craving for cold drinks). The urine output varies and may be more than 12 L/day, with a low specific gravity.

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CHAPtEr 11 AlTerATionS of enDocrine funcTion AcroSS THe life SpAn 259

Alterations of adrenal function Dis s of the adrenal cortex are most commonly related to hyperfunction. Hyperfunction that causes increased levels of aldosterone leads to hyperaldosteronism, and that which causes hypercortisolism leads to Cushing’s syndrome.

Hyperaldosteronism Hyperaldosteronism is characterised by excessive aldosterone secretion by the adrenal glands. In primary hyperaldosteronism there is an excessive secretion of aldosterone from the adrenal cortex. In secondary hyperaldosteronism, excessive aldosterone secretion results from an extra-adrenal stimulus, most often a renin-angiotensin mechanism.

Primary hyperaldosteronism (also known as Conn’s syndrome) presents with hypertension that is difficult to control, even with multiple antihypertensive medications. There can be renal potassium wasting, hypokalaemia and neuromuscular manifestations; however, it is most commonly found in the presence of normokalaemia.6 The most common cause of primary hyperaldosteronism is a benign adrenal adenoma. The incidence of primary hyperaldosteronism is estimated to be 2–10% of all hypertensive individuals.6 This condition therefore is of particular interest in those with hypertension, for which there is a high incidence in Australia and New Zealand6 (hypertension is discussed in detail in Chapter 23).

Aldosterone secretion is normally stimulated by the renin-angiotensin-aldosterone system (see Chapter 28); secondary hyperaldosteronism results from sustained elevated renin release and activation of angiotensin II. This occurs in various situations, including decreased circulating blood volume (e.g. in dehydration, shock or hypoalbuminaemia) and decreased delivery of blood to the kidneys (e.g. heart failure or hepatic cirrhosis). Here, the activation of the renin-angiotensin system and subsequent aldosterone secretion may be seen as compensatory, although in some instances (e.g. congestive heart failure) the increased circulating volume further worsens the condition.

PATHOPHYSIOLOGY In primary hyperaldosteronism, pathophysiological alterations are caused by excessive aldosterone secretion and the fluid and electrolyte imbalances that ensue. Hyperaldosteronism promotes: (1) increased renal sodium and water reabsorption with corresponding hypervolaemia (high blood volume, see Chapter 29) and hypertension; and (2) renal excretion of potassium. The extracellular fluid volume overload, hypertension and suppression of normal feedback mechanisms of renin secretion are characteristic of primary dis s. Oedema usually does not occur with primary hyperaldosteronism.

In secondary hyperaldosteronism, the effect of increased extracellular volume on renin secretion may vary. If renin secretion is abnormal, increased circulating blood volume

NEPHROGENIC DIABETES INSIPIDUS • Renal diseases • ADH-unresponsive kidney • Drugs (lithium)

NEURO- GENIC DIABETES INSIPIDUS • Tumours • Trauma • SurgeryPosterior

pituitary gland

Stalk

Anterior pituitary gland

Loss of water

Polydipsia

Dehydration Polyuria

KIDNEY

ADH deficiency

Hypothalamus

Neuronal axons

1

2

FIGURE 11.3

Diabetes insipidus. The origin of diabetes insipidus, consisting of excess water intake and output, can be neurogenic 1 or nephrogenic 2.

FOCUS ON LEARNING

1 Describe the effects of SIADH on the kidneys.

2 Discuss how fluid balance is altered with diabetes insipidus.

made when, following water deprivation, administration of a drug that mimics the antidiuretic hormone, desmopressin, causes an increase in urinary osmolality. In psychogenic polydipsia the serum osmolality and sodium remain normal but urine osmolality will rise during water deprivation.

Treatment of neurogenic diabetes insipidus is based on the aetiology and degree of symptoms experienced by the patient; intravenous fluid resuscitation may be required initially to match urine output. Ongoing therapy will depend on the patient’s age, endocrine and cardiovascular status, and lifestyle. An intact thirst mechanism will generally ensure adequate oral hydration; however, a disturbed sleep is very difficult for most to tolerate, particularly for those with an output > 5 litres/daily. Long-term treatment requires the administration of desmopressin, which acts on the collecting tubules of the kidney to increase water retention. It is important to remember that an adult with an intact thirst mechanism will usually be able to drink sufficiently to maintain an adequate fluid intake. The treatment of nephrogenic diabetes insipidus is more difficult, with maintaining adequate fluid intake being the main form of therapy.5

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260 PArt 2 AlTerATionS To regulATion AnD conTrol

and hypokalaemia were essential; however, recent evidence suggests that > 60% of cases have normokalaemia.6 Where hypokalaemia has occurred particularly at levels < 2.5 mmol/L muscle weakness, cramping and headache may develop. Hypokalaemic metabolic alkalosis may also occur (see Chapter 29).With sustained hypertension, the chronic effects of elevated arterial pressure become evident; for example, left ventricular dilation and hypertrophy and progressive atherosclerosis, contributing to higher rates of morbidity and mortality in this group.6

EVALUATION AND TREATMENT Like many endocrine dis s Conn’s syndrome requires a stepwise approach to the diagnostic process. Clinical and laboratory measurements should be performed to assist with management: 1 Elevated blood pressure. 2 Serum potassium may be normal or low, but urinary

potassium is elevated. 3 Plasma aldosterone-to-renin ratio (ARR) is regarded as

the most reliable screening tool. However it should be collected as per the local laboratory protocol and repeated at least once before proceeding to more complex testing. An inappropriately raised ARR indicates a need for further assessment. Several classes of antihypertensives can affect ARR. A temporary change of medication may be required over the several weeks of diagnostic work-up.

4 Elevated plasma aldosterone can be determined using aldosterone suppression testing. For example, in the saline load test, 2 litres of saline is given intravenously over 4 hours; plasma aldosterone and renin activity are measured before and after the saline administration. If plasma aldosterone production does not decrease < 138 pmol/L and renin secretion remains undetectable, this supports a diagnosis of primary hyperaldosteronism.6

5 A CT scan is the most appropriate imaging technique to visualise the adrenal glands.6

6 Adrenal vein sampling may then be used to identify whether there is excessive aldosterone production unilaterally or bilaterally.6

Treatment includes management of hypertension and hypokalaemia, as well as correction of any underlying causes. A unilateral oversecretion that matches the site of the adenoma is likely to be treated with surgery. If both adrenal glands are found to be secreting high levels of aldosterone, that is, bilateral oversecretion, medical therapy with a mineralocorticoid receptor agonist such as spironolactone would be the first-line treatment.6 Bilateral adrenalectomy would only be done as a last resort given the significant increased morbidity and mortality associated with primary adrenal insufficiency (see ‘Hypoadrenalism’ below).

Hypercortisolism Hypercortisolism means excessive levels of serum cortisol. When chronic, it leads to the constellation of

may not decrease renin secretion through feedback mechanisms.

Potassium secretion is promoted by aldosterone, so that with excessive aldosterone, hypokalaemia can occur (see Chapter 29). Hypokalaemic alkalosis, changes in myocardial conduction and skeletal muscle alterations may be seen, particularly with severe potassium depletion (refer to Chapter 6 for the role of potassium in neuron signalling and muscle contraction). The renal tubules may become insensitive to antidiuretic hormone, thus promoting excessive loss of water. In this situation, hypernatraemia may also occur because water is not able to follow the sodium that is reabsorbed.

CLINICAL MANIFESTATIONS Primary aldosteronism (also known as Conn’s syndrome) causes sodium retention, hypertension, and increased potassium excretion (see Fig. 11.4). Historically for a diagnosis of Conn’s syndrome, the two signs hypertension

C O

N C

EP T

M AP

Tumour

cause secretion of

Na+ retention

K+ excretion

Water retention

increased increased increased

lead to

K+ (in plasma) Angiotensin II

leads to production of

Aldosterone

Kidney

sets on

Hypertension

Increased blood volume

Renin

FIGURE 11.4

Pathogenesis of aldosterone-induced hypertension. Aldosterone causes the kidneys to retain sodium, and as a result, water is also retained. Overall, this increases the blood volume, which in term increases blood pressure. Aldosterone also causes the kidneys to excrete potassium, and low potassium can cause vasoconstriction, further increasing blood pressure. ECF = extracellular fluid; K+ = potassium; Na+ = sodium.

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CHAPtEr 11 AlTerATionS of enDocrine funcTion AcroSS THe life SpAn 261

increase secretion of these hormones in response to a stressor.9 When the secretion of cortisol exceeds normal cortisol levels, symptoms of hypercortisolism develop.

CLINICAL MANIFESTATIONS Weight gain is the most common feature and results from the accumulation of adipose tissue in the trunk, facial and cervical areas. These characteristic patterns of fat deposition have been described as ‘truncal obesity’, ‘moon face’ and ‘buffalo hump’ (see Figs 11.6 and 11.7). Transient weight gain from sodium and water retention also may be present.

Glucose intolerance occurs because of cortisol-induced insulin resistance and overt diabetes mellitus develops in approximately 20% of individuals with hypercortisolism (see Chapter 36). Polyuria is a manifestation of hyperglycaemia and resultant glycosuria.

Protein wasting is caused by the catabolic (breaking-down) effects of cortisol on peripheral tissues. Muscle wasting leads to muscle weakness. In bone, loss of the protein matrix leads to osteoporosis, with pathological fractures, vertebral compression fractures, bone and back pain, kyphosis and reduced height. Cortisol interferes with the action of growth hormone in long bones — children who present with short stature may be experiencing growth retardation related to Cushing’s syndrome rather than growth hormone deficiency. Bone disease may contribute to hypercalciuria and resulting renal stones, which are experienced by approximately 20% of individuals with disease. Loss of collagen also leads to

signs and symptoms known as Cushing’s syndrome. The most common cause is iatrogenic, that is, it is due to the pharmacological administration of glucocorticoids.7 This may also be referred to as an exogenous cause — arising from outside of the body (see Fig. 11.5). Cushing’s syndrome not due to pharmacological use of glucocorticoids may be referred to as an endogenous form, and is an uncommon dis affecting only 1 in 50 000 people.7,8 It is more common in adults and is two to three times more common in women than in men. Hypercortisolism can occur at any age, but usually occurs between the ages of 30 and 50 years. If the condition is left untreated, 50% of patients will die within 5 years of onset due to overwhelming infection, suicide and cardiovascular complications. In older adults, it usually results from ectopic adrenocorticotrophic hormone secretion, whereas in children it is usually the result of adrenal tumours. Cushing’s disease occurs when the specific cause of hypercortisolism is the result of excess production of adrenocorticotrophic hormone (ACTH) from the pituitary. This leads to excess stimulation of the adrenal cortex to produce cortisol, and it accounts for approximately 70–85% of cases of Cushing’s syndrome.8

PATHOPHYSIOLOGY Individuals with endogenous Cushing’s syndrome do not have diurnal or circadian secretion patterns of adrenocorticotrophic hormone and cortisol, and do not

Causes of Cushing’s syndrome

Glucocorticoid therapy

e.g. prednisone, dexamethasone

inhaled and topical steroids

Exogenous (external to the body)

Stimulates excess adrenal cortisol

This is known as

Cushing’s disease

Stimulates excess adrenal cortisol

Adrenal adenoma produces excess cortisol

Excess pituitary ACTH

Excess non-pituitary ACTH e.g. lung tumour

Endogenous (within the body)

FIGURE 11.5

Causes of Cushing’s syndrome. Cushing’s syndrome may arise from causes originating external to the body (medications), or from dysfunction within the body.

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262 PArt 2 AlTerATionS To regulATion AnD conTrol

EVALUATION AND TREATMENT The diagnosis of Cushing’s syndrome is challenging and various laboratory tests must be used, including 24-hour urinary cortisol excretion, salivary cortisol levels and dexamethasone (a cortisol drug) suppression tests. Visualising procedures may include pituitary MRI and abdominal scanning.9

Treatment is specific for the cause of hypercortisolism and includes surgery, medication, and radiotherapy. Therefore, differentiation among pituitary, adrenal and ectopic causes of hypercortisolism is essential for effective treatment.9

Hypoadrenalism Adrenal crisis, although rare, is a life-threatening condition which, if unrecognised, has high rates of morbidity and mortality.10,11 It is more likely to occur during an acute

thin, weakened integumentary tissues, through which capillaries are more visible and which are easily stretched by adipose deposits. Together, these changes account for the characteristic purple striae in the trunk area. Loss of collagenous support around small vessels makes them susceptible to rupture, leading to easy bruising, even with minor trauma. Thin, atrophied skin is also easily damaged, leading to skin breaks and ulcerations. When the Cushing’s syndrome is the result of excess adrenocorticotrophic hormone production, hyperpigmentation can occur, involving the mucous membranes, hair and skin, all of which acquire a characteristic brownish or bronze colour.

With elevated cortisol levels, vascular sensitivity to catecholamines (adrenaline and noradrenaline) increases significantly, leading to vasoconstriction and hypertension. High circulating cortisol can increase the activation of the mineralocorticoid (aldosterone) receptors. This is because of structural similarities between the glucocorticoid and mineralocorticoid receptors. This promotes sodium retention and hypokalaemia. Elevated blood pressure occurs in most individuals, and suppression of the immune system and increased susceptibility to infections also occurs.

Thinning of scalp hair

Facial flush

Moon face

Purple striae

Pendulous abdomen

Easy bruising

Acne Increased body and facial hair

Supraclavicular fat pad

Hyperpigmentation

Trunk obesity

Thin extremities

FIGURE 11.6

Symptoms of Cushing’s syndrome. Main symptoms include moon face, truncal obesity, and thin extremities.

AAA

B

FIGURE 11.7

Cushing’s syndrome. A Patient before onset of Cushing’s syndrome. B Patient 4 months later: ‘moon face’ is clearly demonstrated.

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CHAPtEr 11 AlTerATionS of enDocrine funcTion AcroSS THe life SpAn 263

hyperpigmentation of the skin and mucous membranes at diagnosis. This is particularly accentuated in sun-exposed areas and over knuckles, elbows and knees. Pigmentation fades once treatment is initiated.

Secondary adrenal insufficiency is due to the hyposecretion of pituitary ACTH, resulting in hyposecretion of cortisol. Aldosterone production is maintained, and therefore hyponatraemia and hypotension are not commonly seen unless presentation is acute.

The most common reason for this condition is exogenous treatment with glucocorticoid therapy which suppresses ACTH production and consequently resulting in understimulation of the adrenal cortex. If regular glucocorticoid therapy is withheld or the dosage is not increased during acute illness secondary adrenal insufficiency can develop. Rarer causes would be from pituitary ACTH deficiency.12

CLINICAL MANIFESTATIONS Mild to moderate deficiency presents with weakness, fatigue, anorexia and weight loss. Nausea, vomiting and diarrhoea may develop as the condition progresses. Of greatest concern is the development of hypotension that can progress to complete vascular collapse and shock. Postural hypotension can occur in up to 90% of cases.10

EVALUATION AND TREATMENT Hypoanatraemia and hyperkalaemia occur in primary adrenal insufficiency. Low cortisol levels reduce the normal movement of leucocytes out of the circulation, resulting in eosinophilia and mild lymphocytosis. Hypoglycaemia is common because of reduced gluconeogenesis from liver stores. Raised ACTH with an inappropriately low serum cortisol levels can be diagnostic for the condition. An ACTH stimulation test may be performed to evaluate cortisol levels if diagnosis is unclear. This involves taking a serum cortisol level, administering an injection of ACTH and then testing cortisol levels 30 and 60 minutes later. The cortisol should increase to > 550 nmol/L. The treatment of primary adrenal insufficiency is lifelong glucocorticosteroid and mineralocorticoids, while secondary adrenal insufficiency is treated with glucocorticoid therapy only.

Adrenal crisis (also known as Addisonian crisis) is a life-threatening situation which may occur when any patient with hypoadrenalism has inadequate circulating cortisol. This may occur if their normal glucocorticoid medication is withheld, or during illness such as vomiting or diarrhoea, infection, trauma, surgery, or even significant life stress. Early intervention is critical using parenteral hydrocortisone. Evaluation and treatment of the precipitating cause can proceed once the emergency treatment has been commenced.13

Education of patients and their families in sick day management is an essential aspect of the current care of all patients with adrenal insufficiency. Many patients now carry and administer hydrocortisone themselves prior to arrival in the emergency department. Emergency medical kits and medical alert bracelets are important clinical aids

illness or stress in someone already known to have primary or secondary adrenal insufficiency. It may also be the way in which someone presents for the first time with these conditions. It is easily treated once recognised, with intravenous hydrocortisone and intravenous fluid rehydration. Emergency medical kits, medical alert bracelets and education on sick day management are important clinical strategies in prevention and early treatment of adrenal crisis.

Note: Although androgens are also produced in the adrenal cortex, lack of this hormone is not life threatening therefore is not discussed in this section.

PATHOPHYSIOLOGY Primary adrenal insufficiency (Addison’s disease) is the hyposecretion of cortisol, aldosterone and androgens. Eighty per cent of cases are caused by autoimmune adrenalitis, with the remainder caused by adrenal infection such as tuberculosis, metastatic disease, adrenal haemorrhage, congenital adrenal hyperplasia or following bilateral adrenalectomy. Low glucocorticoids and mineralocorticoids result in high ACTH production from the pituitary. Because ACTH also stimulates melanocytes, this sustained raised ACTH causes the classic signs of Addison’s disease, that is,

RESEARCH IN F CUS The incidentaloma in endocrinology Incidentalomas are lesions identified during imaging for an unrelated condition. They can be found in several sites; however, in endocrinology incidentalomas of the pituitary and the adrenal glands do present a challenge.

Appropriate laboratory investigations are required initially to determine whether the lesion is functioning, and ongoing monitoring over months to years may be required.

Pituitary incidentalomas can be seen in up to 20% of CTs and 38% of MRIs. They require a complete assessment of pituitary function, may require assessment of visual fields and surgical review and follow-up over a number years to monitor changes in the lesion. A large proportion of these will in fact be non- functioning and never need any intervention.

Adrenal incidentalomas are seen on 4.4% of CTs (up to 10% in the older population) and autopsy studies have identified adrenal lesions in up to 9% of cases. About 10–15% may be secreting hormones, thus requiring surgical intervention. About 3% may be malignant in nature. A considered approach to assessment, treatment and monitoring is required.

The costs associated with these incidental findings are significant. The importance of early detection of hyperfunctioning or malignant lesions needs to be balanced against the increased anxiety, costs of repeat radiological exposure and the high cost of laboratory testing over several months to years. This highlights the importance of appropriate and judicious imaging at all times.

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264 PArt 2 AlTerATionS To regulATion AnD conTrol

is thought to be the result of a gene–environment interaction, with the strongest genetic risk markers in the human leucocyte antigen (HLA) region of chromosome 6. Genetic factors may increase susceptibility to environmental causes of diabetes.16 There is a 50% concordance rate in twins. Between 10% and 13% of individuals with newly diagnosed type 1 diabetes have a first-degree relative (parent or sibling) with type 1 diabetes. Diagnosis peaks at 12 years of age but can present in infancy.

Historically, type 1 diabetes mellitus has been thought to have an abrupt onset. More recently, however, prospective studies show: a distinctive natural history involving genetic susceptibility; a long preclinical period; immunologically mediated destruction of beta cells, eventually leading to insulin deficiency; and hyperglycaemia.

PATHOPHYSIOLOGY Type 1 diabetes results from a severe or absolute lack of insulin caused by loss of beta cells. At presentation some insulin may still be produced, but this will only decrease with time as beta cells are lost. Destruction of islet cells is related to genetic susceptibility, autoimmunity and environmental factors.16,17 It is a slowly progressive autoimmune T-cell mediated disease that destroys beta cells of the pancreas. Autoantibodies (antibodies produced against the body’s own tissues; see Chapter 15) against these pancreatic cells are often detected long before symptoms appear. Environmental factors that may trigger autoimmune injury are summarised in Box 11.1. Non-autoimmune type 1 diabetes can occur secondarily to other diseases such as pancreatitis.

in prevention of complications of this condition. These help patients highlight to clinicians their need for more urgent review on admission to emergency departments, than has previously been the practice.10,11 For example, to improve emergency treatment the New South Wales Ambulance Service has established authorised care protocols. This protocol is a collaborative instruction from the treating clinician and the ambulance service which directs immediate treatment for patient with adrenal insufficiency to receive an emergency injection of hydrocortisone as soon as possible to help prevent and treat adrenal crisis.13

FOCUS ON LEARNING

1 Discuss the effects of hyperaldosteronism on fluid balance.

2 Describe the clinical features of hypercortisolism.

3 Describe the emergency treatment required for the treatment of adrenal crisis.

Drugs and chemicals Alloxan Streptozotocin Pentamidine Vacor (a rodenticide) Nutritional intake Bovine milk (controversial; this may relate to giving cow’s

milk to infants) High levels of nitrosamines Viruses Mumps and coxsackie — type 1 diabetes does occur

rarely as a complication of viral infections, but no evidence of substantial relationship exists.

Rubella — 40% of individuals with congenital rubella infection later develop type 1 diabetes.

Cytomegalovirus (CMV) — persistent CMV infections appear to be relevant to pathogenesis of some cases of type 1 diabetes.

BOX 11.1 Environmental factors contributing to type 1 diabetes

Alterations of pancreatic function Diabetes mellitus is not a single disease, but a group of dis s with abnormal glucose metabolism in common. The term diabetes mellitus describes a syndrome characterised by chronic hyperglycaemia and other disturbances of carbohydrate, protein and fat metabolism. While diabetes indicates an increased urine output, mellitus is Latin for honey — hence the urine is sweet (contains glucose) and copious. There are three main categories of diabetes mellitus: 1 type 1 (absolute insulin deficiency) 2 type 2 (insulin resistance with an insulin secretory deficit) 3 gestational diabetes.

In this chapter, we consider type 1 and gestational diabetes. Type 2 diabetes is one of the main chronic health complications in Australia and New Zealand, with strong links to obesity, and has had a relatively recent surge in incidence — thus, it is discussed fully in Chapter 36. Importantly, general features that are common to type 2 and other forms of diabetes are reserved for Chapter 36. Other specific types of diabetes are rare and are not covered in this text.

Type 1 diabetes mellitus Type 1 diabetes mellitus accounts for approximately 10% of diabetes mellitus in Australia, with an incidence of 22 per 100 000 person years among 0–14-year olds. This rates in the top 10 globally for type 1 diabetes diagnosis, affecting some 87 100 Australians,14 25 000 being under 30 years.15 Type 1 diabetes mellitus results from autoimmune destruction of beta (β) cells in the islets of Langerhans and

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CHAPtEr 11 AlTerATionS of enDocrine funcTion AcroSS THe life SpAn 265

The pH drops, triggering the buffering systems associated with metabolic acidosis (see Chapter 29). If acidosis progresses the respiratory system compensates with deeper rapid breaths in an attempt to eliminate carbonic acid. This is known as Kussmaul respirations. Acetone (a volatile form of ketones) is then blown off, giving the breath a sweet or ‘fruity’ odour. These ketones are also excreted by the kidneys and so a urinalysis that detects hyperglycaemia and large ketones may be the first test that detects type 1 diabetes in a patient. Occasionally, diabetic coma is the initial symptom of the disease. Further details that are common with type 2 diabetes mellitus are discussed in Chapter 36.

EVALUATION AND TREATMENT The diagnosis of diabetes is not difficult when the symptoms of polydipsia, polyuria, polyphagia, weight loss and hyperglycaemia are present in fasting and postprandial states.

Currently, treatment regimens are designed to avoid high and low levels of glucose and insulin.17 Management requires individual planning according to type of disease, age and activity level, but all individuals require some combination of insulin, meal planning and exercise. Glycated haemoglobin A1c (abbreviated to HbA1c) testing is useful in confirming the diagnosis and in monitoring the effectiveness of treatment and preventing complications (refer to Chapter 36). When assessing blood glucose control, the blood glucose levels that are determined by a glucometer (by the patient) or a blood test indicate the glucose at a particular point in time, while the HbA1c testing gives a longer term view of glucose control over recent weeks. Both types of information are used to determine the effectiveness of the blood glucose control.

Before hyperglycaemia occurs, 80–90% of the insulin-secreting beta cells of the islets of Langerhans must be destroyed. This is because the remaining cells can increase their production of insulin to compensate, but with so few beta cells remaining, insulin production is no longer adequate. Beta cell abnormalities are present long before the acute clinical onset of type 1 diabetes. In addition to the decline in insulin secretion, the production of amylin, another beta cell hormone that is co-secreted with insulin, also falls. One of the critical actions of amylin is to suppress glucagon release from the alpha cells.

Regardless of cause, a disequilibrium of hormones produced by the islets of Langerhans occurs in diabetes mellitus. Both beta cell function and alpha cell function are abnormal, with a lack of insulin and a relative excess of glucagon (produced by alpha cells). Hyperglycaemia and ketonaemia can result from insulin deficiency alone, but a relative excess of glucagon clearly facilitates the metabolic alterations seen in diabetes — elevated blood glucose levels fail to suppress the production of glucagon.

CLINICAL MANIFESTATIONS Type 1 diabetes mellitus affects the metabolism of fat, protein and carbohydrates. Hyperglycaemia and glycosuria occur (see below). In addition, proteins and fats break down because of the lack of insulin, resulting in weight loss. Initial clinical manifestations of type 1 diabetes are generally acute, with the classical presentation for those with type 1 diabetes mellitus being: • polyphagia (increased hunger) • polyuria (increased urine production) • polydipsia (increased thirst).

Polyphagia occurs because glucose (and lipids) do not enter cells in sufficient amounts and therefore cells are deprived of nutrients, which in turn stimulates increased food intake. Polyuria occurs due to the kidneys’ inability to manage the high amount of glucose in the bloodstream. Glucose filters freely at the nephron, but in the non-diabetic person, all glucose is returned to the blood by reabsorption in the kidneys. However, in the diabetic, the hyperglycaemia means that there is a much higher amount of glucose in the blood that is filtered that cannot be fully reabsorbed, as the transport maximum (or maximum capacity to reabsorb glucose back into the blood) is exceeded. Therefore, some of the glucose appears in the urine, which is known as glycosuria (refer to Chapter 28 for the normal renal handling of glucose). The osmotic effect of glucose in the urine draws water into the urine from the bloodstream, increasing the production of urine (polyuria). The water being lost from the body in the urine leads to dehydration, which triggers increased thirst (polydipsia) in an attempt to rehydrate the cells. Dehydration can lead to low blood volume and hypotension. These features are summarised in Table 11.1. Weight loss and wide fluctuations in blood glucose levels occur.

Ketoacidosis is caused by increased metabolism of fats and proteins resulting in high levels of circulating ketones.

TABLE 11.1 Clinical manifestations and mechanisms for type 1 diabetes mellitus

MANIFEStAtION rAtIONALE

Polydipsia Because of elevated blood sugar levels, water is osmotically attracted from body cells, resulting in intracellular dehydration and stimulation of thirst in the hypothalamus

Polyuria Hyperglycaemia acts as an osmotic diuretic; the amount of glucose filtered by the glomeruli of the kidneys exceeds that which can be reabsorbed by the renal tubules; glycosuria results, accompanied by large amounts of water lost in the urine

Polyphagia Depletion of cellular stores of carbohydrates, fats and proteins results in cellular starvation and a corresponding increase in hunger

Weight loss Weight loss occurs because of fluid loss in osmotic diuresis and the loss of body tissue as fats and proteins are used for energy

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Alterations of thyroid function Hyperthyroidism Hyperthyroidism is one of the more common endocrine dis s. It is a condition where thyroid hormone levels are higher than normal. When these high levels result in a hypermetabolic state, this is known as thyrotoxicosis. Approximately 2 out of every 100 women will experience hyperthyroidism.23 Factors that contribute to higher rates in females include the pregnancy-related thyroid condition postpartum thyroiditis and a higher female:male incidence of Graves’ disease of 8 : 1 (see below).

All forms of thyrotoxicosis share common physiological effects on the individual that are caused by the high thyroid hormone level.24 These effects are the result of an increase in adrenergic stimulation and increased metabolic effects. They

Islet cell transplantation is being explored for treatment of type 1 diabetes and early results are promising.18 Pancreatic transplant is generally reserved for those individuals with type 1 diabetes and associated end-stage renal failure.18 The transition from childhood through to adulthood with this chronic condition is now recognised as a time when accessing healthcare is often limited and focus of support at this time is essential in healthcare services.15 The acute and chronic complications, evaluation and treatment of type 1 diabetes mellitus are similar to those seen in type 2 (refer to Chapter 36 for full discussion).

Diabetes in pregnancy Diabetes in pregnancy is common, affecting 1 in 20 pregnancies. Some women will have preexisting type 1 or type 2 diabetes. Other women will develop diabetes only during the pregnancy. This is called gestational diabetes mellitus and it resolves once the baby and, more importantly, the placenta has delivered. Those with type 1 and type 2 diabetes should have glycaemic control optimised prior to conception to reduce the risk of fetal abnormality and miscarriage. All diabetes in pregnancy requires focused management to reduce the rates of adverse events including gestational hypertension premature births, caesarian section, and stillbirth.19

Gestational diabetes mellitus develops when glucose intolerance appears during pregnancy. Recent Australian and New Zealand guidelines advise for early screening of gestational diabetes early in pregnancy, through a blood test for HbA1c (refer to Chapter 36) by 20 weeks gestation; where appropriate, an oral glucose tolerance test using 75 g of glucose should be undertaken at 24–48 weeks gestation.19,20 Further to this, women at risk should be screened earlier at the first opportunity after conception with a 75 g oral glucose tolerance test. Risk factors include a family history of diabetes (i.e. first degree relative or sister with gestational diabetes mellitus), membership in a high-risk ethnic group, advanced maternal age (> 40 years of age), a history of delivering large babies, a prior history of gestational diabetes or polycystic ovary syndrome, being overweight before pregnancy (a body mass index, or BMI, > 35 kg/m2), women on corticosteroids or antipsychotics. In Australia, 4–5% of pregnant women are affected with gestational diabetes.19 Approximately one-third of these women are over the age of 35, although only 20% of total births are in this age group; this indicates a higher proportion of women with gestational diabetes in this age group compared with younger mothers.

Aggressive treatment is required to prevent morbidity and fetal mortality. When dietary changes do not maintain glucose targets, insulin is recommended as first-line treatment and will be used until delivery.19,21 Metformin has been shown to be effective; however, long-term safety is still of concern.21 Gestational diabetes can progress to type 2 diabetes, particularly within the first 5 years, with the fasting glucose levels during pregnancy being the main risk factor associated with this future risk.22

RESEARCH IN F CUS As type 1 diabetes is a result of pancreatic beta cell destruction, strategies to repopulate the pancreas with insulin-producing beta cells is a long-held vision for researchers. There are many challenges that need to be overcome for optimal therapeutic outcomes.

The first challenge is to develop cells that are not limited by the availability to produce the donor cells. Currently, each islet transplantation requires three cadaveric donors, which is unsustainable. To address this, reprogramming stem cells is an option.

The second challenge to overcome is to develop beta cells that do not elicit an immune response. This can be avoided either by encapsulating the donor beta cells so that they are hidden from the immune system but at the same time are still responsive to changes in blood glucose levels, or by reprogramming patient-derived stem cells to grow into beta cells. This still requires the additional reprogramming of the cells so they are protected from the autoimmune response that destroyed the beta cells in the first place.

The third challenge is for the beta cells to be self-renewing, a characteristic of all cells of the body, so that repeated beta cell replacement is avoided. However, uncontrolled cell division can lead to cancer so the difficulty is to strike a balance between cell renewal and death.

Finally, with all of this in place the replaced beta cells have to act like normal beta cells and respond in a physiological manner to various stimuli such as blood glucose.

FOCUS ON LEARNING

1 Describe the pathophysiology of type 1 diabetes.

2 Discuss the importance of diagnosing gestational diabetes.

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CHAPtEr 11 AlTerATionS of enDocrine funcTion AcroSS THe life SpAn 267

may include varying degrees of tachycardia, palpitations, nervousness, insomnia, heat intolerance, moist skin, tremor, lid retraction in the eye, increased systolic blood pressure, increased cardiac contractility and weight loss. Goitre is the term used to describe an enlarged thyroid gland, and in the case of hyperthyroidism, goitre occurs by the gland increasing in size as it increases its production of thyroid hormone. Determining the cause of the hyperthyroidism is critical, as it will determine the management of the condition. Fig. 11.8 outlines several causes of hyperthyroidism.23

The most common causes are discussed in the sections that follow. They are all forms of primary hyperthyroidism. This means there is a primary thyroid abnormality. In secondary hyperthyroidism the pituitary gland has the abnormality. This is extremely rare and is not discussed further in this text.25

Graves’ disease Graves’ disease is the most common cause of hyperthyroidism. It is an autoimmune condition. In normal thyroid physiology thyroid-stimulating hormone (TSH) binds to receptors on the thyroid gland cells to stimulate production and release of thyroid hormone. In Graves’ disease an abnormal immune response triggers the production of antibodies against the TSH receptor. The result is that the thyroid cells are inappropriately stimulated to produce and release high concentrations of the two thyroid hormones thyroxine (T4) and triiodothyronine (T3)24,25 (see Fig. 11.9).

The combined action of increased serum levels of thyroid hormone and the immune response produces the signs and symptoms of Graves’ disease: • Thyrotoxicosis: the signs and symptoms listed above will

commonly be more significant in Graves’ disease. The active hormone, triidothryonine, is commonly at much higher levels relative to thyroxine as a result of increased

Causes of Hyperthyroidism

Graves’ disease autoimmune

Toxic nodule

Single nodule

Multi nodular

Thyroiditis

• Subacute • Postpartum • Lymphocytic

Rare causes

• TSH secreting pituitary tumour

• Thyroid hormone ingestion

FIGURE 11.8

Causes of hyperthyroidism. The most common causes of hyperthyroidism include autoimmune disease, toxic nodules and thyroiditis.

C O

N C

EPT M AP

Antibodies bind to the thyroid-stimulating receptors

on the thyroid gland

Thyroid gland to release thyroid hormone

causing

which means that

however negative feedback

means that

resulting in resulting in

Blood level of thyroid hormone rises

Thyroid-stimulating hormone production in the anterior pituitary

is decreased

Low levels of circulating thyroid-stimulating

hormone

Antibodies to thyroid- stimulating

receptors at thyroid gland continue

Thyroid hormone levels continue to rise

FIGURE 11.9

Thyroid hormone levels with Graves’ disease. In Graves’ disease, the receptors for thyroid-stimulating hormone are activated by the binding of antibodies. This stimulates the thyroid gland to produce and release thyroid hormone, in a continual process, leading to constantly high levels of thyroid hormone.

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268 PArt 2 AlTerATionS To regulATion AnD conTrol

viral or genetic dis s. When the condition requiring increased thyroid hormone resolves, TSH secretion normally subsides and the thyroid gland returns to its original size.

Irreversible changes may occur in some follicular cells, however, so that they then function autonomously. Hyperthyroidism may or may not result from these irreversible changes. Autonomously functioning cells may produce less thyroid hormone than the body requires. The remainder of the gland then functions to supply the remainder of the body’s need and a euthyroid state (normal thyroid hormone level) is achieved and maintained. If the autonomously functioning cells produce sufficient or excessive thyroid hormone for the usual body requirements, the remainder of the gland undergoes involution, becoming normal but inactive tissue. This condition may result in euthyroidism or hyperthyroidism, depending on the amount of thyroid hormone produced.

When hyperthyroidism occurs this is called a toxic multinodular goitre. If only one nodule is hyperfunctioning, it is termed toxic adenoma. Symptoms usually develop slowly and consist of rapid heart action; tremors; elevated basal metabolic rate; enlarged, multinodular goitre or a single, large nodule; and weight loss. Lid lag and lid retraction may be seen, but exophthalmos and pretibial myxoedema do not occur.25

Hyperthyroidism resulting from thyroiditis Normal thyroid tissue consists of thyroid cells grouped into spherical units called thyroid follicles. They produce, store and secrete thyroid hormone. Thyroiditis is the inflammation of this thyroid tissue. It can occur due to viruses, from trauma, it can be drug induced or it can occur during the postpartum period as the immune system becomes more active.25 During viral (subacute) thyroiditis the gland may be tender. Damaged follicles leak preformed hormone into the circulation causing thyrotoxicosis. Depending on the degree of thyroiditis this may be mild to severe. Thyroxine (T4) has a long half-life of about 7–10 days.25 This means that thyrotoxic symptoms may be present for several weeks until the thyroiditis subsides and the thyroid hormone has been metabolised. The pituitary detects high thyroid hormone levels so TSH will be suppressed and the gland itself does not make extra hormone during this time. A thyroid scan performed would show a negative uptake in this case. Once the thyroiditis phase has passed and thyroid hormone levels have returned to normal, monitoring is still required because a phase of hypothyroidism may occur due to damage to the follicular cells. Occasionally this damage may be permanent and the individual may require thyroxine therapy (see ‘Hypothyroidism’ below).25

CLINICAL MANIFESTATIONS The clinical effects have already been detailed above and are summarised in Fig. 11.11. The degree an individual will present with these manifestations depends on several factors including the thyroid hormone levels, length of time exposed to them, the underlying cause, comorbidities and the

production and release and peripheral conversion of T4 to T3. This amplifies the proximal muscle weakness and fine tremor. Eye changes may also include upper lid lag on downward gaze and lag of the eyeball on upward gaze due to adrenergic stimulation.

• Immunological stimulation causes several physiological changes unique to Graves’ disease: TSH receptor antibodies stimulate thyroid cells, increasing the gland size and vascularity. This is described as a diffuse enlarged gland (goitre). It is smooth, painless and commonly the increased blood flow can be detected as a bruit on auscultation with a stethoscope placed over the gland. TSH receptors are found on tissue within the orbit which results in antibody infiltration and results in progressive effects on eye position, movement and function. This includes enlargement of the ocular muscles, and results in eyeball protrusion, paralysis of extraocular muscles and damage to the retina and optic nerve which can lead to blindness. These changes result in exophthalmos (protrusion of the eyeball), periorbital oedema and extraocular muscle weakness leading to diplopia (double vision). The individual may experience irritation, pain, lacrimation, photophobia, blurred vision, decreased visual acuity, papilloedema, visual field impairment, exposure keratosis and corneal ulceration (see Fig. 11.10). Smoking is known to exacerbate thyroid eye disease.25 TSH receptor antibody infiltration of the skin can be seen but is rare. Dermopathy (pretibial myxoedema), a thickening of the skin over the tibial region, and acropachy, a thickening of the subperiosteal layer of the metacarpals, can result.

Hyperthyroidism resulting from nodular thyroid disease The thyroid gland normally enlarges in response to the increased demand for thyroid hormone that occurs in puberty, pregnancy, iodine deficiency and immunological,

FIGURE 11.10

Graves’ disease. Note the large and protruding eyeballs.

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CHAPtEr 11 AlTerATionS of enDocrine funcTion AcroSS THe life SpAn 269

and treatment for thyrotoxicosis will be targeting changes in these levels. In primary hyperthyroidism (which is the most common form of hyperthyroidism) thyroid hormone levels are raised and as a result TSH will decrease (see Table 11.2). The presence of TSH receptor antibodies is diagnostic for Grave’s disease.26

A thyroid scan may be required to confirm the diagnosis where the clinical picture is not clear. The scan would show diffuse increased uptake of radiolabelled technetium 99 (a tracer isotope) which is used to image the thyroid gland.24,27

Treatment needs to consider two issues: achieve symptom control and reduce thyroid hormone levels where possible. Symptom relief commonly requires the prescribing of a beta-blocking agent such as propranolol. To reduce thyroid hormone, antithyroid medication is commonly the first-line therapy used in Australia.24,25 Carbimazole and propylthiouracil (PTU) interfere with thyroid hormone production and secretion from the thyroid cells. Both medications can cause liver disturbances and monitoring of liver function is essential. Rarely, they can cause agranulocytosis, and so patients should be advised to immediately report sore throats, mouth ulcers or other signs of infection. Antithyroid medications are used particularly for Graves’ disease. Where this therapy fails or is not appropriate radioactive iodine therapy or surgery may be required. Thyroidectomy when performed by experienced thyroid surgeons carries a small risk of permanent hypoparathyroidism of < 2% and recurrent laryngeal nerve damage of < 1%.24,25 Current treatment for Graves’ disease does not reverse the ocular changes. Glucocorticosteroids and surgical intervention may be required in severe cases.24,25

Thyrotoxic crisis Thyrotoxic crisis (thyroid storm) is a rare but dangerous worsening of the thyrotoxic state, in which death occurs within 48 hours without treatment. The condition may develop spontaneously, but it usually occurs in individuals who have undiagnosed or partially treated Graves’ disease. While thyrotoxic they have been subjected to excessive stress, such as infection, or proceeded to thyroid surgery. Handling the thyroid gland during the surgery compounds the problem and the release of excess thyroid hormones creates the ‘storm’.25,28

The systemic symptoms of thyrotoxic crisis include hyperthermia, tachycardia, high-output heart failure, agitation or delirium, and nausea, vomiting or diarrhoea contributing to fluid volume depletion. The symptoms may

individual’s age. Minimal or atypical symptoms are common in the elderly population. Up to 20% may have atrial fibrillation, and shortness of breath is seen in this group, which may reflect the cardiovascular and respiratory comorbidities of the older patient.26

EVALUATION AND TREATMENT Thyroid hormone is measured as the hormones that are not protein bound, namely free thyroxine (T4) and free triiodothyronine (T3). These are the bioavailable hormones

FIGURE 11.11

Hyperthyroidism due to Graves’ disease. Main clinical symptoms of Graves’ disease include goitre, tachycardia and heat intolerance.

TABLE 11.2 Changes to thyroid and pituitary hormones in primary hyperthyroidism

tSH FrEE t4 FrEE t3

(0.500–4.2 IU/L) (10–20 pmol/L) (3.5–6.0 pmol/L)

NORMAL 2.6 16 4.2

PRIMARY HYPERTHYROIDISM < 0.01 49 18

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Secondary hypothyroidism is very rare and is usually caused by the pituitary’s failure to produce adequate amounts of TSH. Pituitary tumours, or the results of their treatment, are the most common causes of secondary hypothyroidism.

CLINICAL MANIFESTATIONS Hypothyroidism generally affects all body systems and occurs insidiously over months or years. The decrease in thyroid hormone lowers energy metabolism, heat production and delays neuromuscular processes within the body. The individual develops a low basal metabolic rate, cold intolerance, lethargy, tiredness, constipation, thinning brittle hair and slightly lowered basal body temperature. The decrease in thyroid hormone leads to excessive TSH production and goitre (see Fig. 11.13).

The characteristic sign of severe or long-standing hypothyroidism is myxoedema, which results from the altered composition of the dermis and other tissues. The connective fibres are separated by large amounts of protein and other substances that bind water, producing non-pitting, boggy oedema, especially around the eyes (see Fig. 11.14), hands and feet and in the supraclavicular fossae. The tongue

be attributed to increased sympathetic nervous system stimulation. The treatment is designed to: (1) reduce circulating thyroid hormone levels by inducing a block of thyroid hormone production (using the antithyroid medication propylthiouracil) thereby reducing their effects to eliminate the precipitating dis ; and (2) provide symptomatic and supportive care.28

Hypothyroidism Deficient production of thyroid hormone by the thyroid gland results in hypothyroidism. Primary causes include: (1) congenital defects; (2) defective hormone production resulting from autoimmune thyroiditis, iodine deficiency or antithyroid drugs; or (3) iatrogenic (inadvertent) loss of thyroid tissue after surgical or radioactive treatment for hyperthyroidism. Causes of secondary hypothyroidism are less common and are related to either pituitary or hypothalamic failure. Hypothyroidism is the most common dis of thyroid function. It occurs more commonly in women than men and affects 6–10% of women. A number of factors contribute to this incidence and 10% of women in the fifth and sixth decade will have thyroid autoantibodies which predispose to chronic lymphocytic thyroiditis. In the case of hypothyroidism, goitre occurs as the gland attempts to produce thyroid hormone, but lacks the capacity to complete hormone production and secretion. As a result, the gland becomes enlarged as it works harder, yet remains unable to secrete thyroid hormone.

Primary hypothyroidism Primary hypothyroidism results from several dis s: acute thyroiditis, subacute thyroiditis, autoimmune thyroiditis, painless thyroiditis and postpartum thyroiditis. Acute thyroiditis is caused by a bacterial infection of the thyroid gland and is rare. Subacute thyroiditis is a nonbacterial inflammation of the thyroid often preceded by a viral infection. Both conditions are accompanied by fever, tenderness and enlargement of the thyroid gland. Symptoms may last for 2–4 months and corticosteroids usually resolve symptoms. Autoimmune thyroiditis (Hashimoto’s disease) is the most common cause of hypothyroid disease in Australia.29,30 It results in destruction of thyroid tissue by circulating thyroid antibodies and infiltration of lymphocytes. Autoimmune thyroiditis also may be caused by an inherited immune defect. Goitre formation is common. Painless thyroiditis has a course similar to subacute thyroiditis but is pathologically identical to Hashimoto’s disease. Postpartum thyroiditis generally occurs up to 6 months after delivery with a course similar to Hashimoto’s disease. Spontaneous recovery occurs in 95% of these hypothyroid conditions.29,30

PATHOPHYSIOLOGY In primary hypothyroidism, loss of thyroid tissue leads to decreased production of thyroid hormone and increased secretion of TSH which results in remaining thyroid tissue increasing in size and a goitre developing (see Fig. 11.12).

C O

N C

EPT M AP

Loss of thyroid tissue

Low levels of circulating thyroid hormone

Thyroid gland unable to produce more thyroid hormone

Anterior pituitary to release more thyroid-stimulating

hormone

High levels of thyroid- stimulating hormone to target

the thyroid gland

means there are

which stimulate

and

but

FIGURE 11.12

Secretion of thyroid hormone in hypothyroidism. In hypothyroidism, lack of thyroid hormone usually occurs due to inability to produce sufficient thyroid hormone. The level of thyroid-stimulating hormone is usually high, but due to an inability to produce thyroid hormone for reasons such as thyroid gland dysfunction, the level of thyroid hormone does not increase sufficiently. As a result, the thyroid gland may enlarge, which is known as goitre.

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CHAPtEr 11 AlTerATionS of enDocrine funcTion AcroSS THe life SpAn 271

be timed appropriately; a regimen of hormonal therapy depends on the individual’s age, the duration and severity of the hypothyroidism, and the presence of other dis s, particularly cardiovascular dis s. Therapy may be increased gradually over months to avoid precipitating acute cardiac events in the elderly. Thyroxine needs to be taken separately from food, vitamins and mineral supplements to ensure adequate absorption.24,25

Thyroid disease and pregnancy The thyroid undergoes significant physiological changes to meet the demand of metabolism in pregnancy. This includes increased thyroid hormone production and changes in thyroid hormone transport systems which changes the normal reference ranges for thyroid function tests. Iodine is essential for normal thyroid hormone production; however, because of increased renal clearance of iodine in pregnancy, iodine requirements increase. Maintaining adequate iodine intake during the preconception period, pregnancy and breastfeeding is essential to prevent potential detrimental effects on the fetus and infant.31,32 An intake of at least 250 micrograms daily in pregnancy and 270 micrograms per day while breastfeeding is recommended.

FIGURE 11.13

Hypothyroidism. Main clinical symptoms of hypothyroidism include fatigue, low cognitive function, bradycardia, and cold intolerance.

FIGURE 11.14

Myxoedema. Note oedema around the eyes and facial puffiness.

TABLE 11.3 Changes to thyroid and pituitary hormones in primary hypothyroidism

tSH FrEE t4 FrEE t3

(0.500–4.2 IU/L) (10–20 pmol/L) (3.5–6.0 pmol/L)

NORMAL 2.6 16 4.2

PRIMARY HYPOTHYROIDISM 25 8.2 3.3

and laryngeal and pharyngeal mucous membranes thicken, producing thick, slurred speech and hoarseness.

EVALUATION AND TREATMENT In addition to the clinical symptoms of hypothyroidism, a decrease in serum-free T4 is nearly always present. TSH concentration increases because of loss of negative feedback from thyroid hormone.24 (See Table 11.3.) Hormone replacement therapy is the treatment of choice. The restoration of normal thyroid hormone levels should

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Alterations of parathyroid function Hyperparathyroidism Hyperparathyroidism is characterised by greater than normal secretions of parathyroid hormone. Hyperparathyroidism is classified as primary, secondary and tertiary.

PATHOPHYSIOLOGY Estimates suggest that primary hyperparathyroidism occurs in 0.2–0.3% of the adult population, with twice as many cases in women. It is generally found in older adults.38 Because postmenopausal women are at risk for developing osteoporosis, the effects of increased levels of parathyroid hormone (which breaks down bone to release calcium to the blood) on bone disease can be significant. In primary hyperparathyroidism, parathyroid hormone secretion is increased and is not under the usual feedback control mechanisms. Most cases of primary hyperparathyroidism (approximately 80%) result from a single parathyroid adenoma with an increased secretion of parathyroid hormone. Other cases are caused by genetic mutations which are not discussed here.38, 39

Secondary hyperparathyroidism is a compensatory response of the parathyroid glands to chronic hypocalcaemia. Activated vitamin D (which is 1,25 dihydroxy vitamin D, also known as calcitriol), is required to absorb dietary calcium. Fig. 11.15 shows the pathway of vitamin D activation and highlights the stages where deficiencies may occur. In Australia many elderly people will have low ultraviolet light exposure causing vitamin D deficiency, which may lead to a secondary hyperparathyroidism.40,41 If not treated, this may contribute to the development of osteoporosis. Chronic renal disease causes a significant proportion of cases of secondary hyperparathyroidism.42–44

The normal process of activation of vitamin D is shown on the left of Fig. 11.15. Alterations to this pathway may arise from dietary and UV deficiencies, liver dysfunction, or renal causes. Treatments are shown on the right.

Tertiary hyperparathyroidism occurs when hyperplasia (increase in the number of cells) of the parathyroid glands and loss of sensitivity to circulating calcium levels cause autonomous secretion of parathyroid hormone, even with normal calcium levels. It occurs in individuals with chronic renal failure even after renal transplant. Signs and symptoms are similar to those of primary hyperparathyroidism.38,45

Since 2009 in both Australia and New Zealand, it has been a requirement that all bread (except organic) is fortified with iodised salt.33,34 This has helped to address an overall iodine deficiency identified in communities of Australia and New Zealand. Since 2010 pregnancy supplements have included iodine.32,35

HYPERTHYROIDISM The levels of the beta human chorionic gonadotrophin hormone (βHCG) peaks towards the end of the first trimester. It has a similar chemical structure to the TSH and can stimulate thyroid hormone production. This may cause a mild hyperthyroidism, resulting in a low normal or mildly suppressed TSH in the first trimester. This effect generally resolves in the second trimester when βHCG levels reduce as the placenta takes over pregnancy hormone production. The relative higher levels of βHCG seen in this group of women is felt to be associated with a transient hyperthyroidism and suppressed TSH which may not resolve until the middle trimester.36 The other most common form of hyperthyroidism in pregnancy is Graves’ disease. Undiagnosed Graves’ disease in pregnancy may carry significant maternal and fetal complications.36 All patients should receive pre-pregnancy planning and expert antenatal care to monitor thyroid function and titrate medication. Common to other autoimmune conditions, Graves’ disease improves during pregnancy as the immune system is suppressed. TSH receptor antibodies status needs to be assessed as the antibody can cross the placenta and potentially cause hyperthyroidism in the neonate.36 It is important to monitor patients postpartum to detect recurrence when the immune system returns to normal level of function.

HYPOTHYROIDISM In iodine replete communities the most common cause of hypothyroidism is autoimmune thyroiditis. Overt hypothyroidism in pregnancy is associated with serious adverse outcomes to the fetus including miscarriage, early delivery and poor neurocognitive development of the infant. Early detection and treatment with thyroxine should be commenced, aiming to normalise thyroid function as rapidly as possible. Over the last decade it has been established that the reference range for TSH is lower than in the non-pregnant population. Treatment of subclinical hypothyroidism in pregnancy is controversial.37 All women already on thyroxine prior to pregnancy will commonly require an increase in dose of between 30% and 50% once they are pregnant. Monitoring of TSH levels should be carried out 4–6 weekly until it is in the target range. In Australia it is recommended that all women with thyroid autoantibodies with a TSH > 2.5 mIU/L should be commenced on thyroxine. Fifty per cent of all women with thyroid autoantibodies are at risk of developing postpartum thyroiditis which may impact on their general wellbeing during the time when caring for a new infant.

FOCUS ON LEARNING

1 Explain how increased thyroid hormone relates to the clinical manifestations of hyperthyroidism.

2 Discuss the visual changes associated with Graves’ disease.

3 List common symptoms associated with hypothyroidism.

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CHAPtEr 11 AlTerATionS of enDocrine funcTion AcroSS THe life SpAn 273

or renal collecting ducts. These may be associated with infections. Both kidney stones and renal infection can lead to impaired renal function. Hypercalcaemia also impairs the concentrating ability of the renal tubule by decreasing its response to antidiuretic hormone. This causes polyuria leading to increased thirst.

Chronic hypercalcaemia of hyperparathyroidism is associated with mild insulin resistance, necessitating increased insulin secretion to maintain normal glucose levels. Hypercalcaemia also affects the muscular, nervous and gastrointestinal systems, causing fatigue, headache, depression, anorexia, nausea and vomiting. It can also cause changes in cardiac muscle function leading to bradycardia and a shortened QT interval (see Fig. 11.16).38,45

EVALUATION AND TREATMENT Primary hyperparathyroidism is generally diagnosed by excluding all other possible causes of hypercalcaemia.

CLINICAL MANIFESTATIONS Parathyroid hormone hypersecretion causes hypercalcaemia and may be asymptomatic or present with excessive osteoclastic and osteocytic activity, resulting in bone resorption.43,44 (Bone resorption is discussed in Chapter 20.) This leads to the development of osteoporosis and increased risk of fracture. Kyphosis of the dorsal spine and compression fractures of the vertebral bodies may be present. The increased renal filtration load of calcium leads to hypercalciuria.

Hypercalcaemia also affects proximal renal tubular function, causing metabolic acidosis and production of an abnormally alkaline urine. Parathyroid hormone hypersecretion enhances renal phosphate excretion and results in hypophosphataemia and hyperphosphaturia. The combination of hypercalciuria, alkaline urine and hyperphosphaturia predisposes the individual to the formation of calcium stones, particularly in the renal pelvis

C O

N C

EPT M AP

Pre vitamin D2 and D

Inactive 25 hydroxyvitamin D

25(OH) D

Active 1,25 dihydroxy vitamin D

1,25(OH)2 D

Ca+ absorption from the gut

↓ Pre vitamin D2 and D3

↓ Formation of inactive 25 hydroxy vitamin D

25(OH) D

• ↓ 25(OH) vitamin D • ↓ or normal Ca+

• ↑ PTH • Normal renal function

• ↓ or normal 25(OH) vitamin D

• ↑ PTH • ↑ Phosphate

↓ Formation of active 1,25 hydroxy vitamin D

1,25(OH)2 D

↓ Ca+ absorption from the gut

which ↑ parathyroid hormone secretion

which ↑ Ca+ resorption from bone

is hydroxylated in liver to form

or

or

or

↓ hydroxylation in liver which

decreased hydroxylation

in kidney which

resulting in

resulting in hypocalcaemia

which is hydroxylated in the kidney into

which promotes

Normal vitamin D activation pathway

Problems in the vitamin D activation

pathway

Laboratory test results

Low dietary Vitamin D2 and D3

Low ultraviolet exposure

Liver failure

Renal impairment In renal disease

• Cholecalciferol (vitamin D3)

• Calcium supplements

• Calcitriol 1,25(OH)2 vitamin D

• Phosphate binding diet

Treatment

In renal disease

FIGURE 11.15

Vitamin D activation and its role in secondary hyperparathyroidism. The multiple steps in the activation of vitamin D include sun exposure, and roles by the liver and kidney. Activated vitamin D promotes calcium absorption from the gut. Dis s relating to insufficient sun exposure, and liver or kidney dysfunction, may prevent activation of vitamin D, and hence lead to calcium deficiency. As a result of the calcium deficiency, there is increased secretion of parathyroid hormone.

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274 PArt 2 AlTerATionS To regulATion AnD conTrol

6–12 monthly when the estimated glomerular filtration rate is < 45 mL/min/1.73 m2. Treatment includes calcitriol and restricted dietary phosphate intake.38,45

Hypercalcaemia is acutely treated with hydration and may require bisphosphonate therapy to suppress osteoclast activity.42 In some cases of hyperparathyroidism where surgical treatment is contraindicated and hypercalcaemia is chronic there is a newer agent available called cinacalcet. This is a calcimimetic which increases the sensitivity of the parathyroid gland’s calcium-sensing receptors to extracellular calcium. This decreases secretion of parathyroid hormone leading to a decrease in serum calcium. It is currently available in Australia only for chronic renal failure patients on dialysis who have secondary hyperparathyroidism; however, it has been shown to effectively treat hypercalcaemia of primary hyperparathyroidism where surgery is contraindicated.38,44

Hypoparathyroidism Hypoparathyroidism is most commonly caused by damage to the parathyroid glands during thyroid surgery. This occurs because of the anatomical proximity of the parathyroid glands to the thyroid. Transient hypoparathyroidism may also occur when a single hyperfunctioning parathyroid adenoma is removed and the remaining parathyroid glands take time to reestablish secretion.46 Rarer autoimmune and genetic causes of hypoparathyroidism are not discussed.

PATHOPHYSIOLOGY A lack of circulating parathyroid hormone causes depressed serum calcium levels and increased serum phosphate levels. In the absence of parathyroid hormone, resorption of calcium from bone and regulation of calcium reabsorption from the renal tubules are impaired. Phosphate reabsorption by the renal tubules is therefore increased, causing hyperphosphataemia.

Magnesium is essential for parathyroid hormone production and secretion, consequently low magnesium levels can lead to hypoparathyroidism. Once serum magnesium levels return to normal, parathyroid hormone secretion does likewise. Hypomagnesaemia may be related to chronic alcoholism, malnutrition, malabsorption, increased renal clearance of magnesium caused by use of aminoglycoside antibiotics or certain chemotherapeutic agents, or prolonged magnesium-deficient parenteral nutritional therapy.

CLINICAL MANIFESTATIONS Symptoms associated with hypoparathyroidism are primarily those of hypocalcaemia. Hypocalcaemia causes a lowered threshold for nerve and muscle excitation so that a nerve impulse may be initiated by a slight stimulus anywhere along the length of a nerve or muscle fibre (see Chapter 6). This creates spontaneous tonic muscular contractions known as tetany. Early signs of acute tetany will be tingling around the mouth and lips and paraesthesia of the fingers, which may progress to painful carpopedal spasms. Left

A definitive diagnosis must be supported by at least a 6-month history of symptoms associated with hypercalcaemia, including kidney stones, hypophosphataemia, hyperchloraemia and increased urinary calcium levels. With continued improvements in the ability to measure parathyroid hormone, the evaluation of hyperparathyroidism has become simplified. Simultaneous measurements of serum parathyroid hormone and calcium will document elevations of both, and diagnosis is confirmed by measuring 24-hour urinary calcium excretion. A bone mineral density scan should be performed to assess and monitor for osteoporosis.38,43,44

Definitive treatment involves surgical removal of the solitary adenoma or, in the case of hyperplasia, complete removal of three and partial removal of the fourth hyperplastic parathyroid glands. Observation of asymptomatic individuals with mild hyperparathyroidism is also an option. These individuals are advised to avoid dehydration and limit dietary calcium intake.38

Secondary hyperparathyroidism from vitamin D deficiency will benefit from some ultraviolet exposure and oral vitamin D3 supplementation. This is recommended in the elderly to reduce risk of osteoporotic fracture.38 In the last decade a great deal of research has focused on the role of low vitamin D and its association with muscle strength and conditions like diabetes, cardiovascular disease and some cancers.39,42

For those with chronic renal failure Kidney Health Australia recommends monitoring of parathyroid hormone

NEUROLOGICAL SYMPTOMS

• Memory loss • Confusion

MUSCULOSKELETAL CHANGES

• Osteoporosis • Muscle weakness

RENAL CHANGES

• Calciuria • Polyuria • Renal stones

GASTROINTESTINAL CHANGES

• Peptic ulcer • Constipation • Pancreatitis

Parathyroid adenoma or hyperplasiaElectro-

cardiogram (ECG) changes

LABORATORY RESULTS

Ca2+ PTH

FIGURE 11.16

Clinical changes associated with hyperparathyroidism. Main symptoms of hyperparathyroidism include confusion, ECG changes, and osteoporosis.

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CHAPtEr 11 AlTerATionS of enDocrine funcTion AcroSS THe life SpAn 275

back into muscle; for example, sternocleidomastoid muscle. Short-term hypocalcaemia may still result for several weeks until the parathyroid tissue regains normal function.46 Postsurgical monitoring of serum calcium and parathyroid hormone levels is essential in all patients following thyroid, parathyroid or neck dissection.46

Hypocalcaemia must be treated to prevent acute symptoms. This involves parenteral administration of calcium, which corrects serum calcium within minutes. Treatment of chronic hypocalcaemia is more difficult, requiring regular pharmacological doses of the active form of vitamin D (calcitriol) and oral calcium. Hypoplastic dentition, cataracts, bone deformities and basal nuclei calcifications do not respond to the correction of hypocalcaemia, but the other symptoms of hypocalcaemia are reversible.46,47

untreated it may progress to convulsions, laryngeal spasms and, in severe cases, death by asphyxiation Other symptoms of chronic hypocalcaemia include dry skin, loss of body and scalp hair, hypoplasia of developing teeth, horizontal ridges on the nails, cataracts, basal nuclei calcifications (may be associated with a parkinsonian syndrome) and bone deformities.

Phosphate retention caused by increased renal reabsorption of phosphate is also associated with hypoparathyroidism. Hyperphosphataemia results from parathyroid hormone deficiency and, in turn, hyperphosphataemia further lowers calcium by inhibiting the activation of vitamin D, thereby lowering gastrointestinal absorption of calcium.46

EVALUATION AND TREATMENT A low serum calcium and high phosphorus level in the absence of renal failure, intestinal dis s or nutritional deficiencies is diagnostic of hypoparathyroidism.

Ideally the four parathyroid glands are identified during thyroid surgery and left in their natural positions. If removal cannot be avoided, they can be transplanted back into the body through a procedure called auto-transplantation. Parathyroid tissue is identified, finely cut up and inserted

FOCUS ON LEARNING

1 How does excessive parathyroid hormone affect bones?

2 What are the results of a lack of circulating parathyroid hormone?

chapter SUMMARY

Mechanisms of hormonal alterations • Abnormalities in endocrine function may be caused by

elevated or depressed hormone levels. This may result from: (a) faulty feedback systems, whereby all of the components of a negative feedback loop are not working appropriately; (b) dysfunction of the gland, in that it produces too much or too little of the hormone, despite normal levels of stimulus; (c) altered metabolism of hormones, such that they are metabolised faster or slower than normal; and (d) production of hormones from non-endocrine tissues such as cancerous growths.

Alterations of pituitary function • Dis s of the posterior pituitary include syndrome of

inappropriate antidiuretic hormone secretion (SIADH) and diabetes insipidus. SIADH is characterised by abnormally high antidiuretic hormone secretion; while in diabetes insipidus, antidiuretic hormone secretion is abnormally low.

• In SIADH, high antidiuretic hormone levels interfere with renal water excretion. As a result, large quantities of retained water dilute plasma sodium, leading to

hyponatraemia and hypo-osmolality. This condition usually arises due to brain injury or with certain forms of cancer, apparently because of secretion of antidiuretic hormone by tumour cells.

• Diabetes insipidus is mainly neurogenic (caused by insufficient amounts of antidiuretic hormone) or nephrogenic (caused by an inadequate response by the kidneys to hormone). Its principal clinical features are polyuria and polydipsia.

Alterations of adrenal function • Dis s of the adrenal cortex are most commonly

related to excessive secretion of hormones. • Excessive aldosterone secretion causes

hyperaldosteronism, which may be primary or secondary. Primary hyperaldosteronism is caused by an abnormality of the adrenal cortex. Secondary hyperaldosteronism involves an extra-adrenal stimulus, often angiotensin.

• Hyperaldosteronism promotes increased sodium reabsorption by the kidneys, so that sodium remains in the blood. This corresponds with hypervolaemia (as

Continued

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276 PArt 2 AlTerATionS To regulATion AnD conTrol

water is retained with the sodium), increased extracellular volume (which is variable) and may cause hypokalaemia (as potassium is excreted by the kidneys when sodium is reabsorbed).

• Hypercortisolism leads to the development of the constellation signs and symptoms known as Cushing’s syndrome.

• Hypercortisolism is usually caused by Cushing’s disease but can also be caused by adrenocortical tumours.

• Complications include obesity, diabetes mellitus, protein wasting, immune suppression and mental status changes.

• Hypoadrenalism though rare is a potentially life- threatening condition. Glucocorticoid replacement for life is required and in some mineralocorticoids are needed.

• When unwell increased doses are required. • Patients and their closest family members need to be

well educated in understanding how to manage sick days, how to recognise adrenal crisis and how to initiate early treatment with intramuscular hydrocortisone.

Alterations of pancreatic function • Diabetes mellitus is a group of dis s characterised by

glucose intolerance, chronic hyperglycaemia (raised blood glucose levels) and disturbances of carbohydrate, protein and fat metabolism.

• Type 1 diabetes mellitus is characterised by a gradual process of autoimmune destruction of pancreatic beta cells in genetically susceptible individuals. This leads to a lack of insulin.

• In type 1 diabetes mellitus, hyperglycaemia results in glucose being excreted in the urine. The glucose passing through the kidney tubules attracts water and therefore larger amounts of water are lost in the urine. As a result, polyuria and polydipsia are common symptoms.

• Women with type 1 and type 2 diabetes have a significant risk of fetal abnormality and miscarriage when there is poor glycaemic control at conception and during the first trimester.

• Gestational diabetes is glucose intolerance during pregnancy. It can result in serious life-threatening consequences for the fetus and therefore screening during pregnancy is recommended to allow early treatment.

Alterations of thyroid function • In general, hyperthyroidism has a range of

manifestations related to the endocrine, cardiovascular and gastrointestinal systems. It also affects the eyes. These manifestations are caused by increased circulating levels of thyroid hormone and by stimulation of the sympathetic division of the autonomic nervous system.

• Goitre, which is an enlarged thyroid gland, can occur with either hyperthyroidism or hypothyroidism, although the cause of the enlargement is different in both cases.

• Thyrotoxicosis describes the greater than normal physiological responses to the excess thyroid hormone

levels. The condition can be caused by a variety of specific diseases, each of which has its own pathophysiology and course of treatment.

• Graves’ disease, the most common form of hyperthyroidism, is caused by an autoimmune mechanism that overrides normal mechanisms for control of thyroid hormone secretion and is characterised by thyrotoxicosis, ophthalmopathy and circulating thyroid-stimulating immunoglobulins.

• Toxic multinodular goitre is caused by independently functioning follicular cell adenomas.

• Thyrotoxic crisis (thyroid storm) is a rare but severe form of hyperthyroidism that is associated with physiological or psychological stress. Without treatment, death occurs quickly.

• Primary hypothyroidism is caused by deficient production of thyroid hormone by the thyroid gland. Secondary hypothyroidism is caused by hypothalamic or pituitary dysfunction. Symptoms depend on the degree of thyroid hormone deficiency. Common manifestations include decreased energy metabolism, decreased heat production and myxoedema.

• Acute thyroiditis is inflammation of the thyroid gland, often caused by bacteria, which can result in hypothyroidism.

• Subacute thyroiditis is a self-limiting nonbacterial inflammation of the thyroid gland. The inflammatory process damages follicular cells, causing leakage of T3 and T4. Hyperthyroidism is then followed by transient hypothyroidism, which is corrected by cellular repair and a return to normal levels in the thyroid.

• Autoimmune thyroiditis is associated with infiltration or fibrosis of the thyroid, circulating thyroid antibodies and gradual loss of thyroid function. Autoimmune thyroiditis occurs in those individuals with genetic susceptibility to an autoimmune mechanism that causes thyroid damage and eventual hypothyroidism.

• Myxoedema is a sign of hypothyroidism caused by alterations in connective tissue with water-binding proteins that lead to oedema and thickened mucous membranes.

• Pregnancy places an increased demand on thyroid function with a corresponding increase in demand on iodine.

• Iodine supplementation is of benefit in preconception, pregnancy and during breastfeeding.

• Laboratory reference ranges change for thyroid- stimulating hormone and free T4 during pregnancy.

• Women with current hyperthyroidism in pregnancy should be screened for Graves’ disease and managed appropriately to reduce risk to the fetus and neonate.

• The presence of thyroid autoantibodies can increase the risk of miscarriage and early delivery. Women have benefited from thyroid hormone treatment.

Alterations of parathyroid function • Hyperparathyroidism, which may be primary, secondary

or tertiary, is characterised by greater than normal secretion of parathyroid hormone.

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CHAPtEr 11 AlTerATionS of enDocrine funcTion AcroSS THe life SpAn 277

• Primary hyperparathyroidism is caused by an interruption of the normal mechanisms that regulate calcium and parathyroid hormone levels. Manifestations include chronic hypercalcaemia, increased bone resorption and hypercalciuria.

• Secondary hyperparathyroidism is a compensatory response to hypocalcaemia and often occurs with chronic renal failure or vitamin D deficiency.

• Hypoparathyroidism, defined by abnormally low parathyroid hormone levels, is caused by thyroid surgery, autoimmunity or genetic mechanisms.

• The lack of circulating parathyroid hormone in hypoparathyroidism causes depressed serum calcium levels, increased serum phosphate levels, decreased bone resorption and eventual hypocalciuria.

ADULT Susan is a 51-year-old information technology professional. She recently started losing weight without trying, which she found to be quite satisfying! At the same time, she also noticed that she felt quite hot when others around her do not complain of the heat. Susan thought she was probably getting into menopause, as she knows that this is characterised by hot flushes. She tires easily, but put this down to working long hours and getting older. None of these symptoms gave Susan any real cause for alarm. However, what made her think that there might be something wrong is the increasing number of heart palpitations she has — she can feel her heart racing quite quickly. She has been feeling more anxious and suspects that this is because her fast heart rate makes her quite worried. So she decides to seek medical attention.

Physical examination reveals tachycardia (a high heart rate of 105 beats per minute), moist hands, fine tremor of her outstretched hands and brisk reflexes. She had systolic hypertension (high blood pressure of 145/80). Her eyes appear somewhat wide open and there is an enlargement in the anterior (front) of her neck. 1 Which endocrine dis is consistent with Susan’s signs

and symptoms? 2 Discuss the enlargement found in Susan’s neck. 3 Explain why it might be possible to have low levels of

thyroid-stimulating hormone and high levels of thyroid hormone.

4 Relate Susan’s symptoms to your diagnosis of the dis .

5 Briefly discuss some treatment options for Susan.

CASE STUDY

AGEING Helena is an 82-year-old woman who has been self-caring and living in a granny flat in her daughter Gina’s home. She has no significant medical history and is on a cholesterol- lowering medication only. Over several weeks her daughter notices Helena has lost her appetite, complains of nausea and constipation but is thirsty and regularly visits the bathroom to ‘pass water’. This normally happy and sociable woman appears to be mildly confused, is unusually sad and is unsteady on her feet. Late one night Helena is found on the bathroom floor, confused and holding her right hand which is swollen at the wrist. An ambulance is called because Helena is too confused and weak to get up. In the emergency department Helena’s observations include blood pressure of 168/96 pulse 64. Her electrocardiogram shows sinus rhythm but the QT interval is shortened.

Clinically she is mildly dehydrated but regularly wants to pass urine. Her urine is noted to be clear and dilute. She has proximal weakness and complains of bone pain. Her right wrist is swollen and she is unable to lift her hand. She is mildly confused despite answering some questions well. 1 What condition do you think Helena is acutely suffering

from? 2 Her calcium is 2.95 (2.15–2.55 mmol/L). Which endocrine

abnormality is the most common cause of this condition? 3 Explain how this endocrine dis increases the risk of

osteoporosis. 4 Explain how Helena’s signs and symptoms relate to the

endocrine dis . 5 What are the possible treatments for this endocrine

dis ?

CASE STUDY

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278 PArt 2 AlTerATionS To regulATion AnD conTrol

1 Describe how the syndrome of inappropriate antidiuretic hormone secretion (SIADH) relates to hyponatraemia.

2 Why do people with diabetes insipidus have large volumes of urine?

3 What are the effects of hyperaldosteronism on the body? 4 What do dis s of antidiuretic hormone and aldosterone

share in common? 5 Describe how hyperaldosteronism and hypertension are

linked.

6 Explain the clinical manifestations of hypercortisolism, including the effects on immunity.

7 Discuss the cause of type 1 diabetes and relate this to dependency on insulin treatments.

8 List the manifestations of Graves’ disease. 9 Discuss the effects of hypothyroidism.

10 Explain the consequences of hyperparathyroidism.

REVIEW QUESTIONS

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  • 11 Alterations of endocrine function across the life span
    • Chapter outline
    • Key terms
    • Introduction
    • Mechanisms of hormonal alterations
    • Alterations of pituitary function
      • Syndrome of inappropriate antidiuretic hormone secretion
        • Pathophysiology
        • Clinical manifestations
        • Evaluation and treatment
      • Diabetes insipidus
        • Pathophysiology
        • Clinical manifestations
        • Evaluation and treatment
    • Alterations of adrenal function
      • Hyperaldosteronism
        • Pathophysiology
        • Clinical manifestations
        • Evaluation and treatment
      • Hypercortisolism
        • Pathophysiology
        • Clinical manifestations
        • Evaluation and treatment
      • Hypoadrenalism
        • Pathophysiology
        • Clinical manifestations
        • Evaluation and treatment
    • Alterations of pancreatic function
      • Type 1 diabetes mellitus
        • Pathophysiology
        • Clinical manifestations
        • Evaluation and treatment
      • Diabetes in pregnancy
    • Alterations of thyroid function
      • Hyperthyroidism
        • Graves’ disease
        • Hyperthyroidism resulting from nodular thyroid disease
        • Hyperthyroidism resulting from thyroiditis
          • Clinical manifestations
          • Evaluation and treatment
        • Thyrotoxic crisis
      • Hypothyroidism
        • Primary hypothyroidism
          • Pathophysiology
          • Clinical manifestations
          • Evaluation and treatment
        • Thyroid disease and pregnancy
          • Hyperthyroidism
          • Hypothyroidism
    • Alterations of parathyroid function
      • Hyperparathyroidism
        • Pathophysiology
        • Clinical manifestations
        • Evaluation and treatment
      • Hypoparathyroidism
        • Pathophysiology
        • Clinical manifestations
        • Evaluation and treatment
    • Review questions
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