Endocrinology

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Endocrinology

INTRODUCTION AND OVERVIEW

Endocrine problems are important in the general practice setting, for a range of reasons. First, they are common enough to occur regularly, either as new cases or in patients managing a chronic illness. Secondly, they can cause serious and life-threatening complications if not diagnosed and treated. Thirdly, they often present a challenging diagnostic problem because of their often slow onset and their capacity to produce non-specific symptoms such as weakness, tiredness or weight change, particularly in the early stages.

This chapter explores the endocrinological disorders that are important for a GP to know about and to manage. The common model of managing endocrine problems is as a shared-care model with an endocrinologist.

PITUITARY DISORDERS

The pituitary is the ‘master controller’ of hormone function in the body, converting signals from the brain and hypothalamus to actions via hormones.

The pituitary normally sits in the sella turcica at the base of the middle cranial fossa (Fig 29.1). It is covered by a dural layer known as the diaphragma sella. The pituitary is joined to the hypothalamus by the infundibulum or pituitary stalk, in front of which sits the optic chiasm. The sella turcica is bounded laterally by the cavernous sinuses and their contents, and the sphenoid sinus antero-inferiorly. The anterior pituitary is embryologically derived from the posterior pharynx and secretes prolactin follicle-stimulating hormone (FSH), luteinising hormone (LH), growth hormone (GH), thyrotropin-stimulating hormone (TSH) and adrenocorticotrophic hormone (ACTH) in response to trophic-releasing hormones from the hypothalamus via a portal blood flow system. The posterior pituitary secretes oxytocin and vasopressin under neural control from the hypothalamus.

FIGURE 29.1 Anatomy of the pituitary gland and surrounding structures

PITUITARY TUMOUR

Tumours in the pituitary are common and have been found to occur in around 10% of people in autopsy studies.¹ Various series have reported rates of up to 24%. With the high background rate of pituitary masses seen on MRI, clinical questions about how to proceed are likely to occur. Unless the brain is imaged for another reason, it is more prudent to have a clinical diagnosis and confirmatory tests of a pituitary disorder before requesting a CT or MRI of the pituitary.

Tumours of the pituitary may be developmental cysts, blood or infarcted tissue, physiological hyperplasia or adenomas.

Adenomas may be functioning or non-functioning. Physiological effects may be excess autonomous secretion of hormones or trophic hormones, loss of normal pituitary function or mass effects that include compression of nearby structures such as the optic chiasm.

Tumours smaller than 10 mm in size are called microadenomas, and those bigger than 10 mm, macroadenomas. Compressive effects of a pituitary tumour normally occur when the adenoma grows to > 10 mm and enlarges beyond the pituitary fossa. Common symptoms of a mass effect are headaches and loss of peripheral vision that correlates with a bitemporal hemianopia as the optic chiasm is compressed.

As an adenoma grows, there may be loss of function of the normal anterior pituitary in a typical order. The mnemonic: ‘Go Looking For That Adenoma’ is a good aide memoire for the order of loss of pituitary function:

• growth hormone

• luteinising hormone

• follicle-stimulating hormone

• thyroid-stimulating hormone

• adrenocorticotrophic hormone.

Examination

Target the examination to the symptoms and manifestations of hormone excesses or deficiencies as outlined in Table 29.1. Check for galactorrhoea as well as back and skin lesions in patients suspected with hyperprolactinaemia. Galactorrhoea from one breast in the absence of hyperprolactinaemia requires careful examination to ensure that there is no local breast pathology. Always check visual fields to confrontation.

TABLE 29.1 Signs, symptoms and tests for pituitary tumours

Investigations

Pathology

In a pituitary mass, checking paired trophic hormones and their target hormones is essential for proper interpretation. Check ACTH and cortisol at around 8–9 am, together with FSH, LH and testosterone (oestrogen in females), which also has a diurnal variation, with higher levels in the morning, TSH and thyroxine (T₄), prolactin (with dilution in macroadenomas), GH and insulin-like growth factor 1 (IGF-1). Non-functioning adenomas tend to produce higher levels of alpha-1 glycoprotein subunit, which may be requested on a sample of serum. Be aware that ACTH in particular degrades quickly, and so informing the laboratory beforehand of an impending test can help ensure it is put on ice and sent to the central laboratory quickly.

The above are static tests. If both results are normal, beware of the inappropriate levels such as a T₄ at the lower limit of normal, with a lower limit of normal TSH (inappropriately normal).

If there are any concerns, dynamic tests may be ordered, although these are often ordered by a specialist and/or in a hospital environment. Of the dynamic test, the oral glucose tolerance test (OGTT) to suppress GH to < 1.0 ng/mL is the only one that is reliable and may safely be done as an outpatient. Twenty-four hour urinary free cortisol and 1 mg overnight dexamethasone suppression tests may also be performed as an outpatient, to help with the investigation of cortisol excess. If an excess is confirmed, then a high-dose dexamethasone suppression test will help delineate whether the problem is Cushing’s disease or ectopic ACTH production.

Special tests

Insulin tolerance tests to look for adequate ACTH and GH release can be done, but should be done by an experienced endocrine unit as an inpatient.

Rarely, pituitary adenomas produce central diabetes insipidus, and a water deprivation test needs to be done as an inpatient, to ensure a safe and reliable answer to the test.

Perimetry testing or neuro-ophthalmology should be organised for all patients, especially those with a macroadenoma.

Acromegaly, Cushing’s disease and the rare TSH-omas should be considered for surgical treatment in the first instance by an experienced neurosurgeon, although there have been some advances in medical technology with new drugs such as pasireotide, which have a better blockade of the somatostatin 5 and 3 receptors. These receptors are more commonly expressed in acromegaly, and Cushing’s/non-functioning adenomas respectively.

There may be some benefit in blocking both D2 and somatostatin receptors together in acromegaly, even though only 20–25% of tumours tend to co-secrete both growth hormone and prolactin.

Other medical

In surgically and medically refractory conditions, radiotherapy may be used to try to control mass and growth, and function of pituitary tumours. The effect is more gradual and also tends to result in panhypopituitarism at a rate of around 5–8% per year. Often, maximal medical therapy needs to be continued while awaiting the radiotherapy effects.

If control cannot be achieved, blocking the production of the target hormone, or blocking its effects, may be an option. Ketaconazole and metyrapone have been used to block the production of cortisol in surgical and medically refractive Cushing’s disease. This may also be done in acromegaly with pegvisomant, although with the loss of feedback of IGF-1 on the pituitary, there is the potential for growth of the pituitary tumour.

Ongoing review and/or monitoring

Any patient with a pituitary adenoma should be co-managed by a GP and an endocrinologist. Interval hormone anterior pituitary hormone testing and MRI scans should be organised at intervals that are patient specific.

Important pitfalls

Be wary of the ‘normals’ in paired pituitary and target hormone testing. Pituitary drive of a particular hormone may be normal but inappropriately low for the level of the target hormone.

Testosterone and gonadotrophs, and the hypothalamic-pituitary-thyroid axis, are the two axes that may be affected most by patient conditions and stressors. If the tests don’t make sense, seek endocrinological clarification.

Consider also that sometimes testosterone and growth hormones have been used by athletes to enhance sports performance.

ACROMEGALY

Acromegaly is a condition of monoclonal growth of pituitary somatotrophs that produces excess growth hormone in a non-regulated way. It has a prevalence of around three per million.²

GH is normally secreted in a diurnal and metabolic fashion, with pulsatile release that is highest during sleep. Amino acids and ghrelin from the gut are also stimuli to its release via the hypothalamus.

GH stimulates the production of IGF-1 and IGFBP-3 (insulin-like growth factor binding protein-3) on binding to the receptors in the liver. There are some direct effects on the cartilage but, other than that, the majority of the physiological effects of GH are mediated via IGF-1. The liver’s ability to produce IGF-1 in response to GH is blunted in liver disease, hypothyroidism and poorly controlled diabetes mellitus. Interestingly, malnutrition reduces IGF-1 production, and obesity inhibits GH pulses from the pituitary.

Aetiology and pathology

There are several somatic mutations that confer autonomous monoclonal cell signal proliferation, or loss of apoptosis that may result in somatotroph growth in the person with other genetic predispositions. The growth is a benign monoclonal expansion that results in the excess secretion of GH, in a non-physiological, non-pulsatile fashion.

The excess IGF-1 and IGFBP-3 that result stimulate the growth of tissues through stimulation of cell proliferation and inhibition of apoptosis. The clinical features are listed below.

If excess GH is produced before the closing of the epiphyses, gigantism occurs and the diagnosis is made relatively quickly with overt clinical signs. In adults the diagnosis may be delayed, due to slow insidious changes in appearance and the overlap with the common primary conditions of diabetes, weight gain, obstructive sleep apnoea and osteoarthritis.

Diagnostic approach

If the clinical diagnosis is suspected on clinical grounds, then testing the visual fields to confrontation and measurement of a static GH and IGF-1 should be done. If the levels are normal but the clinical suspicion is high, then an OGTT suppression test should be performed, to confirm that the GH can suppress to < 1 ng/mL. This is a very sensitive test, with about 85% specificity if > 2 ng/mL after 2 hours.

Investigations

Consulting room:

• An ECG should be performed and a spot capillary glucose with a glucometer may be performed.

Pathology:

• GH, IGF-1

• Remaining anterior pituitary tests with target hormones including prolactin, given acromegaly commonly is a macroadenoma and may therefore exhibit mass effects on the remainder of the anterior pituitary cells.

• Corrected calcium, which may be increased.

Special tests:

• Once the diagnosis has been made, an MRI of the pituitary, a colonoscopy, echocardiogram and staging of the diabetes mellitus should be done.

Integrated management

See Fig 29.2 for an overview of management.

FIGURE 29.2 Integrated management of acromegaly

Active surveillance

The patient’s preference may be to not have surgery at the time. Acromegaly has been shown to confer an increased mortality, which may limit lifespan by approximately 10 years. This is mainly due to increased cardiovascular morbidity and mortality, and cancer-related mortality.

With either surgical or medical treatment, there is a reduction in mortality back to the baseline with cure.

The metabolic manifestations such as diabetes, hypertension, diastolic heart failure, arrhythmias and hyperhidrosis are all improved with treatment, but patients should be warned that much of the soft tissue growth will not regress, but neither will it progress further. Obstructive sleep apnoea may improve but is often not cured. The longer the patient waits, the more soft tissue will grow.

Surgical

Surgical management is the currently accepted primary treatment for the majority of acromegalic adenomas. Macroadenomas have a lower cure rate and higher complication rate than microadenomas, on the whole. Complications include diabetes insipidus or syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH), and hypopituitarism, including panhypopituitarism. Immediate surgical risks include bleeding and CSF leaks.

Pharmacological

While surgical management is still thought to be the primary option for acromegaly, there are some data indicating that long-acting octreotide, in the form of octreotide LAR, shrinks acromegalic adenomas without complete regression. This takes several months of treatment and the effects are modest. At this stage there are no outcome data indicating that this improves surgical outcomes when used in this neo-adjuvant way. Microadenomas do have a higher surgical cure rate and lower complication rate than do macroadenomas.

Somatostatin analogues or SRIFs (somatomedin-releasing inhibitory factors) currently on the market are octreotide, octreotide LAR and lanreotide. These three tend to be more active against the SST-2 receptors expressed in lower levels on acromegalic tumours, and less active at blocking the SST-5 receptors, which are more prevalent. Pasireotide has a stronger effect at blocking SST-5 receptors and less effect at SST-2, so as it becomes available, medical therapy may become more successful at controlling acromegaly. Octreotide or lanreotide ± D2 agonist is the current medical treatment. The somatostatin analogues may be given as injections once a month and should be started at the lowest dose, warning the patient of diarrhoea, nausea and cholecystitis as possible complications of therapy. Dopamine agonists (DA) may produce nausea and peripheral vasodilatation, resulting in postural hypotension on the days it is given.

Ongoing review and/or monitoring

Given that the majority of acromegalic tumours are macroadenomas at the time of diagnosis, complete surgical cure is not a certainty. Confirmation of cure should be carried out with a measurement of GH in the perioperative period together with confirmation of pituitary reserve.

Cure and return to background-for-age mortality risk occurs when an OGTT is able to suppress GH to a level of < 1 ng/mL. Yearly MRI is prudent for a few years, to ensure no recurrence of the tumour, together with biochemical testing as required.

For those with improved but not cured acromegaly, medical management should be aimed at the same GH target. The interval for re-imaging the pituitary with contrast will be patient specific, depending on the size and location of residual tumour and symptomatology, but should be at least yearly as a default. The neurosurgeons or endocrinologists will provide guidance if different from this.

Important pitfalls

Acromegaly may be missed by even the most astute clinicians, and unless the diagnosis is entertained, a history checked and the tests done, it will not be discovered.

Prognosis

The prognosis depends on whether the GH levels return to normal. If so, the mortality, which is mainly due to cardiovascular disease, returns to the background for non-acromegalic patients. There may be some residual medical morbidity associated with the irreversible issues of joint pains and osteoarthritis, OSA and cosmetic changes.

HYPOPITUITARISM

Hypopituitarism may be complete (pan-) or partial. It may be congenital, acquired or iatrogenic.

Congenital problems are many and rare, and such things as PIT-1 gene mutations cause a loss of lactotrophs (prolactin), thyrotrophs (TSH) and somatotrophs (GH). Others, such as Kallmann’s syndrome, result in loss of the gonadotrophs and a normal male phenotype but hypogonadotrophic hypogonadism and a degree of olfactory deficit.

Acquired hypopituitarism may occur due to problems such as trauma affecting the pituitary stalk (infundibulum), apoplexy or infarction in Sheehan’s syndrome. Other issues such as lymphocytic hypophysitis are being increasingly recognised with higher-teslar MRI machines. Infections and inflammatory lesions such as sarcoid and histiocytosis may affect the pituitary, as well as intra- and extrasellar masses.

Iatrogenic causes include radiation-associated pituitary damage or surgical complication after attempted removal of a macroadenoma.

Lastly, hypopituitarism can be secondary to hypothalamic disease.

Diagnostic approach

Screening for hypopituitarism should be thought of in those with developmental problems such as:

• failure to start puberty

• lack of linear growth

or those with:

• significant head trauma

• postpartum haemorrhage or sudden drop in blood pressure post-partum

• brain tumours that proximate the hypothalamus or pituitary

or those who have had pituitary surgery or cranial radiation.

Once suspected, paired trophic hormones and their target hormones should be checked, being careful not to miss the inappropriately normal trophic hormone level, but with low normal target hormone.

History

Depending on the suspected aetiology, a developmental, pubertal and menstrual history should be taken. Some of the symptoms of each of the trophic deficiencies are listed in Table 29.2.

TABLE 29.2 Symptoms of trophic deficiencies

Trophic hormone	History/symptoms	Tests
LH/FSH	• Pubertal and developmental history • Inability to adequately lactate post partum • Erections/shaving • Menstrual history • Height

• FSH, LH and oestradiol or testosterone

• Bone age

• Failure of linear growth

• Neonatal hypoglycaemia (with ACTH and TSH deficiency)

• GH, IGF-1 IGFBP-3

• Provocative test (insulin tolerance test) not used in children

• Bone age

ACTH

• Hypotension

• Lethargy ± hyponatraemia

• Hypoglycaemia

• Abdominal pains, nausea and diarrhoea

• Weight loss

• 0800 ACTH/cortisol

• Insulin tolerance test (often manifestations of complete loss are clear and life threatening, but insufficiency may require an ITT

• Treat with steroids after blood has been taken, if clinical concern is high

TSH

• Hypotension and coma

ADH/vasopressin

• Polyuria and polydipsia

• Lethargy

• Coma

• Water-deprivation test

Special tests

• Imaging of the brain and pituitary with MRI may be indicated, depending on the suspected cause.

• Measurement of testes size and checking of genitalia is important in children thought to be hypopituitary.

• Plotting growth, weight and developmental milestones should be done in children.

Integrated management

Pharmacological

Many of the deficiencies of the hypothalamic-pituitary axis are life threatening. Replacement of glucocorticoids, if these are thought to be deficient, should be done prior to thyroxine replacement and would generally be instigated by an endocrinologist and in hospital. If a patient is in a critical condition, then 200 mg of IV hydrocortisone should be given. Otherwise 100 mg of IV hydrocortisone with 50 mg q6h can be started and blood tests awaited. Maintenance doses of glucocorticoids are not fully elucidated but hydrocortisone equivalent 20–30 mg given in 2–3 divided doses, or cortisone acetate at 25–37.5 mg per day in two divided doses for adults, is a good place to start. The goal is to very slowly and carefully titrate down to the lowest dose that keeps the patient well. Thyroxine may then be replaced if necessary at a dose of 1.6 μg/kg.

Taking a child through puberty requires slow introduction of oestrogen and progesterone in girls and testosterone in boys. This should be done by a paediatrician.

Central diabetes insipidus may be treated by dDAVP® (desmopressin) administration via oral tablet or nasal spray. Starting dose should be 50 μg per day for the tablet and 10 μg a day for the nasal spray.

Surgical

If a mass is blocking normal pituitary function, neurosurgical opinion may be sought as to whether pituitary surgery may help. Normally, 90% of the pituitary mass has to be lost, to render the patient panhyopituitary.

Ongoing review and/or monitoring

Hypogonadotrophic hypogonadal patients may be able to successfully become parents with assisted reproductive technologies.

Discussion about a Medicalert bracelet, and teaching the patient and carer how to administer intramuscular glucocorticoids, are critical. Teaching the patient about sick-day management is also very important. A minor illness such as a respiratory virus would require a doubling of the dose for at least 3 days and then decreasing to normal dose. In an illness significant enough to make the patient bed-bound, a tripling of the dose for at least 3 days, or for as long as the condition remains, is advisable. A vomiting illness preventing the patient from taking their glucocorticoids requires administration of IM glucocorticoids and attendance at a hospital.

Long-term slow-down titration of the glucocorticoids to the lowest dose that keeps the patient well is the goal. Seek expert endocrine advice if necessary.

Important pitfalls

Measurement of trophic hormones without their paired target hormones makes the interpretation very difficult and will miss many cases of relative deficiency.

Prognosis

While the reason is not known, there is an increase in the mortality in panhypopituitary patients after pituitary surgery of about double that of the normal population. This is even after replacement therapy was instituted. Further information and evidence is still being gathered on adult replacement of growth hormone, and the physiological replacement doses of glucocorticoids.

PARATHYROID DISORDERS

Located generally behind the thyroid gland are the four parathyroid glands, which have the role of producing parathyroid hormone (PTH). PTH is the main controller of calcium levels within the blood and bones, and this of course has important implications for neuromuscular function.

HYPERCALCAEMIA

Extracellular calcium is a tightly controlled electrolyte. Significant symptoms, including life-threatening conditions, occur when control is lost and the levels of calcium in the body go outside the tightly controlled range. The largest store of calcium within the body is in the bones, but calcium is stored within skeletal and cardiac muscle, and within the neuronal signalling and neuromuscular junctions.

The most common symptoms of hypercalcaemia are the classic ‘stones, bones, moans and groans’ of kidney stones, bone pains, mood changes including depressive symptoms and abdominal pains including constipation. Polyuria and dehydration can occur secondary to high serum calcium. The most common cause for congenital hypercalcaemia is familial hypocalciuric hypercalcaemia. The most common acquired causes of hypercalcaemia are hyperparathyroidism and malignancy. A useful thought map to think about acquired hypercalcaemia is to think about PTH-dependent and PTH-independent causes of hypercalcaemia (see Fig 29.3).

FIGURE 29.3 Integrative management of hypercalcaemia

Aetiology

Extracellular calcium is normally controlled very tightly by two interrelated hormones, namely parathyroid hormone (PTH) and vitamin D. There is a sigmoidal inverse relationship between serum calcium levels and PTH levels, such that a decrease in serum calcium results in increased PTH and vice versa.

Familial hypocalciuric hypercalcaemia is a congenital variation in the sensitivity of the calcium-sensing receptor, with a reduced sensitivity to serum calcium and so a higher set point of serum calcium at which the PTH is turned down. Serum calcium is high, as is PTH, but urine 24-hour calcium excretion is low.

Milk–alkali syndrome is less common now that histamine receptor antagonists and proton pump inhibitors are the mainstay treatment of hyperacidity syndromes of the stomach. The use of antacids together with the ingestion of milk products results in increased absorption and mild hypercalcaemia. While there has been a reduction in the presentation of milk–alkali syndrome from these less-used drugs, there have been a number of case reports of similar presentations in those using large doses of calcium carbonate, which provides both calcium and alkali. High calcium level together with high bicarbonate and perhaps some renal impairment should prompt the GP to ask about calcium carbonate intake.

PTH-independent causes of hypercalcaemia are usually due to excesses in active vitamin D, or lytic lesions of the bone. The far less common production of PTHrp (PTH-related protein) is usually associated with squamous cell carcinomas, or renal, bladder, breast or ovarian cancers. The conditions that result in excess active vitamin D (1,25-dihydroxy vitamin D) are excess intake of calcitriol, or granulomatous diseases such as sarcoid, tuberculosis and lymphoma, both non-Hodgkins and Hodgkins. In these conditions the macrophages in the granulomata convert the inactive vitamin D to active vitamin D without the need for PTH, which normally carries this out by stimulating the 1-alpha-hydroxylase enzyme in the kidneys.

Other causes such as multiple myeloma and breast cancer are the two more common malignancies that can lead to lytic bone lesions and uncontrolled release of calcium into the extracellular fluid, independently of a suppressed PTH level.

Diagnostic approach

The first thing to do is to try to ameliorate the symptoms and effects of the hypercalcaemia. In many cases there is a degree of dehydration from polyuria. Correction of the volume status will often correct some of the hypercalcaemia.

Thinking of the causes, checking the PTH together with 25 OH vitamin D, calcium and phosphate, electrolytes and liver function tests, and a full blood count, is a good place to start. If the PTH is normal or high with a high calcium, think of familial hypocalciuric hypercalcaemia (FHH) or hyperparathyroidism, whether it be primary or tertiary. Hyperparathyroidism will have a high 24-hour urinary calcium, whereas FHH will not, and so this is the next test.

If PTH is low, the cause is high calcium with an appropriately suppressed PTH. Check active vitamin D (1,25 dihydroxycholecalciferol), PTHrp, selenoprotein P (sEPP), ask for a chest X-ray and, if the sEPP shows a monoclonal protein band, a skeletal survey for lytic lesions. These tests are best done stepwise, to avoid unnecessary tests and costs, although the patient’s condition and preference may dictate otherwise.

History

• First ask about symptoms and history suggestive of hypercalcaemia and duration of these. Ask about symptoms of nocturia or polyuria and dehydration.

• Ask about any specific areas of bone pains, with nocturnal inflammatory rest bone pains being the most discriminatory.

• Ask about risk factors for breast, ovarian, head and neck or lung cancer.

• Check for other medical conditions, notably renal failure or osteoporosis.

• Check medications, most notably calcitriol, caltrate and antacids.

• Ask about a family history of hypercalcaemia and its manifestations, and MEN1 or MEN2 conditions.

Examination

• Examine the patient’s volume status and fluid balance.

• Examine the abdomen for signs of constipation or faecal loading.

• Examine any bones described as painful by the patient.

• Examine for peripheral lymphadenopathy.

• Examine the neck for any masses, particularly anterior neck masses. With hypercalcaemia, a palpable neck mass may be lymphadenopathy of lymphoma, granulomatous disease or a parathyroid carcinoma. Parathyroid adenomas are not often palpable.

• Examine the patient for a peripheral mononeuropathy of sarcoid, or a painful peripheral neuropathy of a hypergammaglobulinaemia of multiple myeloma.

• Breast exam if appropriate for a breast cause of PTHrp.

Integrative management

Surgery is indicated for primary hyperparathyroidism in symptomatic disease. In the case of asymptomatic primary hyperparathyroidism, surgery can be considered if:

• serum calcium is >0.25 mmol/L higher than the upper limit of normal of your assay

• age < 50 years

• osteoporosis established by minimal trauma fracture or BMD

• renal failure with eGFR < 60 mL/min.

If the patient is not a surgical candidate, due to frailty, then Cinacalcet, a calcium sensing receptor agonist, may be an option, but at the time of publication is only indicated for secondary hyperparathyroidism in renal failure and parathyroid cancer.

Pharmacological

While determining the cause of hypercalcaemia, it is important to treat the symptoms. Ensure good hydration, which will help with kaliuresis. IV fluids can be given in hospital and, if need be, the addition of a loop diuretic can help lower serum calcium and make the patient feel much better. In the case of severe hypercalcaemia not adequately treated with IV fluids and frusemide, bisphosphonates can be used, particularly in hypercalcaemia of malignancy, with the normal precautions in their use. There have been concerns over osteonecrosis of the jaw with bisphosphonate treatment in those who then undergo dental treatment, mostly teeth extractions. This is estimated to be 1:250 to 1:1000 with IV bisphosphonates treatment and much lower with oral treatment, in the order of 1:100,000 to 1:250,000. It is wise to ensure, where possible, that the patient has had a dental review prior to starting IV bisphosphonates treatment particularly. Sometimes this is not practicable. Treating the root cause of the hypercalcaemia is the basis for definitive treatment.

Self-help

If no treatment for the primary hyperparathyroidism is given, make sure the person stays well hydrated, to prevent renal stones and help with natural diuresis, which will minimise excess serum calcium.

Ongoing review and/or monitoring

By far the most common problem associated with hyperparathyroidism is vitamin D deficiency. Checking for vitamin D deficiency particularly in those at high risk is important to prevent secondary hyperparathyroidism. Elderly people in nursing homes, and those whose cultural dress requires total cover, are worth assessing for vitamin D deficiency. With the high use of sunscreens and avoidance of direct exposure to sunlight in countries such as Australia and New Zealand, it can occur even in children.

Pitfalls

Don’t forget that mild hypercalcaemia may occur in cases of prolonged bed rest or immobility, and marked hypercalcaemia may occur in Graves’ disease, due to increased turnover of bone, and in Addison’s disease.

HYPERPARATHYROIDISM

Most of the investigation and treatment of hyperparathyroidism is covered above, in the hypercalcaemia section. Brief further information is given below.

Hyperparathyroidism can be primary, secondary or tertiary.

Primary hyperparathyroidism (PHPTH) is due to between one and four functioning adenomas of the parathyroid glands. In 85% of cases there is a single parathyroid gland adenoma, which secretes PTH independent of the serum calcium. It is most common in women over the age of 55 years. The remainder of PHPTH is due to multiple adenomas, hyperplasia and, very rarely, parathyroid carcinoma. The incidence of PHPTH is around 4 per 100,000.

Secondary hyperparathyroidism is usually found in the setting of vitamin D deficiency. With the strength of the sun and concerns about skin cancer, in some countries such as Australia and New Zealand, and the increasingly indoor lifestyle of the population in developed countries, vitamin D deficiency can be very common. Those at highest risk are the elderly, such as those in institutional care, dark-skinned races and societies where it is culturally appropriate to wear head-to-toe clothing.

In vitamin D deficiency, the control of serum calcium falls back onto PTH, which stimulates renal absorption of calcium, liberation of calcium from the mineralised bone at the expense of bone mineral density, and increased hydroxylation of the low levels of 25-OH Vit D to 1,25-OH Vit D. These patients are normally eucalcaemic. Secondary hyperparathyroidism can also occur in the setting of renal failure, with loss of kidney parenchyma to convert 25-OH Vit D to 1,25-OH Vit D under the control of PTH. As such, the patient has reduced active vitamin D, and PTH predominates. 1,25-OH Vit D actively inhibits the growth of the PTH glands. The renal physician may elect to give the patient active vitamin D in the form of calcitriol, but it depends on the levels of calcium and phosphate. Elective parathyroidectomy may be indicated at very high levels of secondary hyperparathyroidism, depending on the stage of their chronic kidney disease.

Tertiary hyperparathyroidism usually occurs in renal patients who have had long-standing secondary hyperparathyroidism. With low levels of active vitamin D, there is loss of inhibition of parathyroid gland hyperplasia, and autonomous PH secretion results from the hyperplastic glands, even when the cause of the secondary hyperparathyroidism is corrected.

Diagnostic approach

Endocrinologists are friendly people who like to do things in pairs, including measuring hormone-releasing hormones, hormones and their targets. In the setting of calcium, and parathyroid hormone, corrected calcium, phosphate, 25-OH Vit D and PTH should be measured together. The results may then be interpreted properly.

History

Tertiary hyperparathyroidism should be evident with a patient who has chronic kidney disease being managed by a renal physician. Treatment and management of this condition should be discussed with that specialist physician.

Secondary hyperparathyroidism may be a surprising finding in a patient for whom the only real risk factors are avoidance of sunlight, increasing age, and culture in which patients tend to cover up. Asking about fragility fractures is wise, as these patients may have a low BMD from long-standing high levels of PTH.

Primary hyperparathyroidism can occur as part of a genetic syndrome, the most common of which is MEN1, where it clusters with pituitary tumours, and pancreatic/neuroendocrine tumours. PHPTH is the predominant finding in this condition, being present in 90% of cases of MEN1. It can also occur in MEN2A, with medullary thyroid cancer and phaeochromocytoma being the other components. Medullary thyroid cancer occurs in > 90% of MEN2A, and PHPTH occurs only in 10–20%. Asking about a family history of PHPTH and these associated endocrine problems is appropriate in the family history.

Asking about urolithiasis and fragility fractures is important in the diagnosis of PHPTH and in consideration of surgical treatment.

Examination

One finding not to miss is a noticeable or palpable tumour in the anterior triangle of the neck, as a palpable tumour and primary hyperparathyroidism should raise concern about a parathyroid carcinoma, and a biopsy should be obtained. Other examination should be targeted based on the history obtained.

Investigations

The triad of PTH, 25-OH Vit D and corrected calcium are the three investigations that should be ordered together, to interpret the result properly. Although not as common as it used to be, osteitis fibrosis cystica is the classic manifestation of hyperparathyroidism of the bones. While the radiological findings of subperiosteal erosions on the radial side of the middle phalanges, erosion of the tips of the distal phalanges and lateral clavicles, brown tumours of the long bones and ‘salt and pepper skull’ are not used in diagnosis, their appearance on imaging of the bones should prompt a check of the intact PTH, corrected calcium and vitamin D.

In order to differentiate between familial hypocalciuric hypercalcaemia and primary hyperparathyroidism, 24-hour urinary calcium and creatinine should be collected.

Checking the renal function and phosphorus, as well as magnesium, can be done but is not necessary for diagnosis. It is useful for screening for complications.

Special tests

With hyperparathyroidism, either primary or secondary, a bone mineral densitometry should be estimated with a DEXA scan. If primary hyperparathyroidism is confirmed, an ultrasound and sestamibi technetium scan to localise the parathyroid adenoma can be requested, if the patient would be considered for surgical removal of the adenoma.

Pitfalls

A normal level of PTH with a high corrected serum calcium is in fact hyperparathyroidism, as it is inappropriately normal.

PTH is very unstable, and when blood is taken it must be processed and frozen immediately, otherwise it breaks down and gives a low level. It is not uncommon for a result to come back with normal calcium and phosphate with a very low or un-recordable level of PTH. Before being alarmed, request the vitamin D, corrected calcium and PTH again.

Integrative management

Active surveillance

There is a case for conservative management of primary hyperparathyroidism if there are no symptoms of hypercalcaemia, the hypercalcaemia is mild, there is no loss of BMD, the renal function is normal or the patient is older. They should be advised to keep well hydrated, to minimise the extent of hypercalcaemia, and to avoid thiazide diuretics. This decision can be made in conjunction with a specialist, in order to ensure ongoing follow-up.

Lifestyle

Lifestyle factors are as listed above, in the section on ‘history’.

To prevent the complications of secondary hyperparathyroidism and the resulting loss of bone density to maintain serum calcium, a check and replacement of low 25-OH Vit D is suggested. This is normally achieved with 5–7 minutes in the sun each day, with increasing requirements in older and darker-pigmented patients. If regular moderate sun exposure is not desired, a loading dose then 1000 IU of cholecalciferol is appropriate treatment for lower serum levels.

Surgical

In primary hyperparathyroidism, the newer imaging techniques and newer surgical approaches have meant that, for experienced surgeons, the parathyroid adenoma that has been identified pre-surgery may be excised through a limited neck dissection. If surgery is not indicated or not chosen, then good hydration and maintaining 25-OH Vit D > 50 nmol/L should be pursued. Cinacalcet is currently indicated for parathyroid carcinoma, and secondary hyperparathyroidism of renal disease with hypercalcaemia. It may be possible to consider the use of Cinacalcet in non-surgical PHPTH patients.

Other medical

Frusemide may be added to a forced increased water intake to minimise the degree of hypercalcaemia. Care must be taken to ensure that pre-renal renal failure does not ensue.

Ongoing review and/or monitoring

Serum calcium and renal function should be checked each year, with a 2-yearly BMD, and surgery considered each time.

There have been some benefits in reduction of serum calcium with drugs used to treat osteoporosis with primary hyperparathyroidism. These include oestrogen/medroxyprogesterone therapies, bisphosphonates and the selective oestrogen receptor modulator, raloxifene.

HYPOPARATHYROIDISM

Hypoparathyroidism is most commonly acquired, with transient or permanent hypoparathyroidism post surgery for thyroid disorders. Aside from surgery, there are several causes of hypoparathyroidism that arise due to aplasia of the glands, autoimmune destruction or inhibition of the release of PTH by activating antibodies to the calcium-sensing receptor. Many of the causes of hypoparathyroidism that appear in childhood are parts of rare but important syndromes, which should be managed by a paediatric endocrinologist. The more common cause for childhood hypoparathyroidism, as part of the autoimmune polyglandular syndrome type 1, is discussed in this section.

Aetiology

Normally, as extracellular calcium drops, there is less activation of the calcium-sensing receptor on the surface of the parathyroid cells, and thus less inhibition of PTH synthesis and release. PTH action requires adequate magnesium, and results in the stimulation of the 1-alpha hydroxylase of the kidney to activate 25-OH Vit D to its active form, 1,25-OH Vit D. The active vitamin D then stimulates renal resorption of calcium cations, and gut absorption of calcium, to raise serum calcium. The PTH directly stimulates the kidney to resorb calcium ions, secrete phosphate ions and stimulate osteoclasts to resorb calcium from mineralised bone. PTH secretion is thus stimulated by low extracellular levels of calcium and high levels of phosphate. Hypoparathyroidism therefore results in hypocalcaemia, due to lack of direct effects of PTH and the effects on activating vitamin D.

Pathology

Congenital and genetic:

• X-linked and autosomal-recessive conditions occur where there is aplasia of the parathyroid glands.

• Aplasia of the parathyroid glands occurs in rare syndromes such as DiGeorge’s syndrome, where there is failure of development of the third and fourth pharyngeal pouches.

• Congenital and genetic problems with the parathyroid gland are detected early in life, and are so rare and complex that they will be managed by specialist paediatricians.

PTH release problems:

• There have been point mutations of the PTH gene that result in aberrant production of PTH and therefore hypoparathyroidism.

• Severe hypermagnesaemia and hypomagnesaemia are associated with reduced release of PTH and also end-organ resistance to PTH, in the case of hypomagnesaemia.

Surgery:

• Surgical manipulation of the thyroid gland, especially in total or subtotal thyroidectomy, can result in transient hypoparathyroidism in around 20% of cases, and permanent hypoparathyroidism in less than 1% of cases.

Autoimmune:

• Autoimmune hypoparathyroidism is mostly associated with activating antibody production to the calcium sensing receptor, mimicking calcium and providing a signal to suppress PTH release. This is most commonly found as part of polyglandular autoimmune syndrome type 1, which consists classically of the triad of hypoparathyroidism, mucocutaneous candidiasis and autoimmune hypoadrenalism. Other immune endocrinopathies and autoimmune conditions have also been associated with APS-1 (autoimmune polyglandular syndrome type 1).

• It is much rarer for destructive antibodies to the parathyroid gland to be the cause of autoimmune hypoparathyroidism.

Pseudohypoparathyroidism:

• American endocrinologist Fuller Albright described a condition of short-statured patients with distinctive morphological features such as shortened third metacarpals and hypocalcaemia together with hyperphosphataemia, which was then found to be due to parathyroid hormone resistance. These will usually come to attention of specialist paediatricians.

History

Asking about symptoms of hypocalcaemia such as paraesthesias, inability to open the mouth normally (trismus), breathing problems and twitching is an important first step. Some patients will have no symptoms with hypocalcaemia. The duration is important, to try to establish whether it may be a long-standing congenital condition, or acquired. Given that the most common cause is surgical, the onset should be clear with the surgery.

Ask about any candidiasis or symptoms of adrenal insufficiency, such as syncope, prolonged recovery from illnesses, or postural hypotension particularly, thinking of autoimmune polyglandular syndrome type 1 (APS1). A family history of the same is important. APS1 usually presents in the first years of life and, if it has not occurred by the age of 20 years, is not likely to be a possibility.

Examination

Chvostek’s sign is elicited by tapping the facial nerve just in front of the tragus of the ear—if positive, this results in a twitch of the corner of the mouth on the same side.

Trousseau’s sign occurs when a blood pressure cuff is inflated above the systolic blood pressure for 3 minutes, and is positive when there is carpal spasm shown in ‘Le Main d’Accoucheur’ or the hands of the obstetrician. There is forced adduction of the thumb, flexion of the metacarpophalangeal (MCP) joints and extension of the proximal interphalangeal (PIP)/distal interphalangeal (DIP) joints.

Look for involuntary muscle twitches and listen for stridor.

Investigations

Consulting room:

• ECG—looking for prolonged QTc interval

• Flow-volume loop—looking for extrathoracic obstruction.

Pathology:

• PTH, vitamin D, corrected calcium and phosphate. If the symptoms are transient, an arterial blood gas can be useful to look for respiratory alkalosis, which can lead to a lower ionised calcium level and symptoms that are the same as those of prolonged hypocalcaemia.

• Symptomatic patients with tetany, laryngeal spasm, prolonged QTc or reduced level of consciousness with a low corrected calcium should be given calcium gluconate as an infusion. Use 10 mL of 10% calcium gluconate in 100 mL of 5% dextrose running over an hour, or 100 mL of 10% calcium gluconate in 1000 mL running over 24 hours.

• Patients with surgically induced hypoparathyroidism will need calcitriol and calcium carbonate. Typical doses are 0.5 μg calcitriol b.i.d and 1200 mg b.i.d. of calcium carbonate. These may be started 1–2 days before high-risk thyroid surgery, as the half-life of calcitriol is about 1 day and it will therefore take around 5 days to reach a steady level. If there is sufficient PTH demonstrated by blood test on day 1 post surgery, the calcitriol and calcium carbonate may be stopped.

• Teriparatide, a recombinant portion of human PTH, is not yet indicated for treatment of transient or permanent hypoparathyroidism (only for osteoporosis).

• Cholecalciferol or 25-OH Vit D₃ is of no benefit to correct hypocalcaemia secondary to hypoparathyroidism, as the enzyme required to activate vitamin D is PTH dependent.

Important pitfalls

Transient low ionised calcium may occur with symptoms of hypocalcaemia in respiratory alkalosis of hyperventilation.

Always measure PTH, vitamin D, corrected calcium and phosphate together for correct interpretation. PTH is very unstable and may degrade before being assayed, leading to a falsely low PTH. If the patient has a normal calcium level, consider repeating the test before investigating further.

Prognosis

If the patient has hypoparathyroid hypocalcaemia, they will need ongoing calcitriol treatment to maintain corrected calcium levels in the lower normal range, to prevent nephrolithiasis.

PARATHYROID TUMOUR

Parathyroid adenoma and carcinoma are difficult to differentiate clinically. Parathyroid carcinoma is an uncommon but important condition occurring in around 2% of investigated hyperparathyroidism. With a different prognosis and natural history, it is important to identify. Typically, parathyroid carcinomas tend to cause higher levels of hyperparathyroidism and hypercalcaemia than primary hyperparathyroidism.

Aetiology

Parathyroid carcinomas are often associated with a germline mutation of a gene on chromosome 1, known as HRPT2, which is a tumour suppressor gene. The gene encodes a protein called parafibromin, which is expressed in parathyroid carcinomas but not in adenomas, and this makes it a useful diagnostic tool in histopathological analysis of a parathyroid tumour.

Diagnostic approach

Patients who present with a neck mass and primary hyperparathyroidism should be suspected for parathyroid carcinoma, especially if they have PTH levels greater than five times the upper limit of normal, or a corrected calcium greater than 3.5 mmol/L. Referral to a surgeon and endocrinologist with concerns about parathyroid carcinoma should prompt appropriate surgical therapy and pathological testing.

Patients will often be symptomatic of severe hypercalcaemia, including the bone complications of hyperparathyroidism, and will often need hospitalisation for treatment of the hypercalcaemia. The parathyroid carcinomas are rarely non-functioning with normal levels of parathyroid hormone and calcium.

History

Assessing for symptoms of hypercalcaemia is important, as correction of this will improve the patient’s wellbeing.

Anyone who presents with a neck mass and hyperparathyroidism should be considered to possibly have a parathyroid carcinoma. Parathyroid carcinoma is more common in patients aged 45–55 years, in equal male:female ratio. Parathyroid carcinoma is more likely to have a PTH level greater than five times the upper limit of normal, with a corrected calcium level > 3.5 mmol/L.

A patient with a neck mass, hyperparathyroidism and symptoms of local invasion such as a change in voice and signs of a laryngeal nerve palsy should be suspected of a parathyroid carcinoma.

Examination

Hypercalcaemia and a neck mass may represent a lymphoma or a chronic granulomatous disease such as sarcoid or tuberculosis. Examination for other signs of these conditions, such as generalised lymphadenopathy, hepatosplenomegaly, nerve palsies and CNS findings and rashes may be helpful. Biochemical testing will help differentiate between PTH-dependent hyperparathyroidism that occurs in parathyroid carcinoma and the PTH-independent hypercalcaemia that occurs in the granulomatous diseases, lymphomas and other cancers.

Examine the jaw for bone tumour, which may occur with parathyroid carcinoma in the parathyroid carcinoma–jaw tumour syndrome.

Once a parathyroid carcinoma has been histologically diagnosed, genetic testing for HRPT gene mutation is useful for monitoring the patient and for investigation and surveying the patient’s family members.

Integrative management

Pharmacological

The patient’s first concern will be that of the symptoms of their hypercalcaemia. Rehydration, forced diuresis and loop diuretics are necessary, and hospitalisation may be required. Bisphosphonates may be useful, such as pamidronate given as an IV infusion.

Cinacalcet, a calcimimetic, has been approved for use in parathyroid carcinoma for symptomatic control of hypercalcaemia.

There is little data on adjuvant chemotherapy or radiotherapy for parathyroid carcinoma.

Surgical

Surgical management is the mainstay of a parathyroid adenoma with symptomatic hypercalcaemia or parathyroid carcinoma. Once the diagnosis of parathyroid carcinoma is confirmed, a significant proportion of patients will need further neck surgery.

Ongoing review and/or monitoring

About one-third of patients will be cured with surgical treatment, one-third will have recurrence requiring further surgery and one-third will have a poor prognosis.

Patients should have their calcium, PTH and vitamin D levels checked every 6 months, unless earlier is clinically indicated. With a high rate of recurrence, and increased possibility of transformation of normal parathyroid tissue to parathyroid carcinoma in those who carry the HRPT gene mutation, recurrence may be detected early.

Family members of those with HRPT mutations should be screened for the mutation. If negative, screening for hyperparathyroidism may not be necessary. Referral to a clinical geneticist may be helpful to guide screening and follow-up.

THYROID DISORDERS

The thyroid gland is a butterfly-shaped gland that sits in the neck around the thyroid and cricoid cartilages of the larynx and trachea. It is primarily responsible for producing the hormone thyroxine, which accelerates or brakes the body’s metabolic processes. The symptoms of an over- or underactive thyroid vary, and can be quite different between patients.

HYPERTHYROID DISORDERS

Symptoms of hyperthyroidism are those of a metabolism that is sped up, and include symptoms resembling anxiety and agitation, tremors, weight loss despite an increased appetite, palpitations, a syncopated heartbeat, spread out or absent periods, frequent opening of bowels, heat intolerance and lethargy. There is often a family history of thyroid problems, either hyperthyroidism or hypothyroidism. There are a few common causes for an overactive thyroid, described below.

Diagnosis

The first challenge in diagnosing a thyroid disorder is to consider it. It may not always be obvious, as the symptoms can creep up over a prolonged period, or they may imitate other health problems such as anxiety or stress, or they may aggravate other health problems such as ischaemic heart disease. It should also be mentioned that significant and prolonged emotional stress can produce a mildly elevated level of thyroid hormones. When suspected, or when needing to exclude it as a possible diagnosis, the following tests are recommended:

• T₄ (thyroxine) and T₃ (triiodothyronine)—raised

• TSH—low due to suppression in the presence of raised T₄ and T₃

• radioisotope scan—evidence of diffuse and uniform overactivity in Graves’ disease, and irregularly increased uptake seen in multinodular goitre.

Graves’ disease

Normally the thyroid gland’s production is controlled by the pituitary gland. The control is finely tuned. Graves’ disease is an autoimmune condition and is the most common cause of hyperthyroidism, affecting up to 2% of women—it is approximately four times more common in women than in men. In Graves’ disease, the immune response, rather than destroying the thyroid gland, stimulates it, making it grow in both size and production of thyroxine. This creates a goitre, which is typically painless, and the symptoms of thyrotoxicosis mentioned above.

The antibodies or proteins that stimulate the thyroid gland may also stimulate the tissues behind the eyes, and the anterior tibial region. If these antibodies stimulate the tissues behind the eyes it leads to exophthalmos, creating an impression of staring, and may affect vision if extreme. Referral to an ophthalmologist is appropriate. Eye problems in Graves’ disease seem to be more common in smokers.

Treatment

Carbimazole (Neomercazole®) 10–45 mg orally daily blocks the thyroid’s ability to make thyroxine. Surgery to remove the thyroid, or radioactive iodine, which selectively destroys the thyroid gland, may also be used, more commonly if carbimazole is contraindicated or ineffective. An endocrinologist’s guidance will be helpful in determining which management approach will suit the patient, and to monitor the effectiveness of treatment.

Medication may need to be continued for at least 12–18 months. There is some chance that, with a 12–18 month treatment with tablets, the thyroid will settle down and not need further treatment.

Toxic multinodular goitre

Toxic multinodular goitre is a condition in which overactive nodules in the thyroid overproduce thyroxine, producing the symptoms of hyperthyroidism.

The nodules are common, and tend to grow slowly over time and become a little more active. As they get bigger they may produce a noticeable goitre. Carbimazole can be effective in treating these nodules, but sometimes surgery or radioactive iodine may be needed if the goitre grows large enough to cause dyspnoea, dysphagia or breathing problems. Surgery can be used if the goitre is cosmetically disfiguring to the patient, or if there are concerns about whether the nodule is neoplastic. Fine-needle biopsy is indicated if a nodule grows or has atypical features on ultrasound.

Subacute (de Quervain’s) thyroiditis

In subacute thyroiditis there is inflammation of the thyroid, often post viral infection, which typically results in symptoms of hyperthyroidism and a painful neck. The thyroid will be tender to palpation. This condition may be transient and follow a viral illness such as a common cold, and tends to settle down over several weeks. Analgesia is commonly required. Steroids may be used if aspirin or anti-inflammatory medications are not effective. Beta-blockers may be used to treat the symptoms of hyperthyroidism if they are significant. The condition tends to resolve spontaneously over a few weeks to months, and may be followed by a short period of hypothyroidism, as it recovers and reverts to normal.

Commonly used medications for thyrotoxicosis

Carbimazole or methimazole, and propylthiouracil, block the production of thyroid hormone by the thyroid gland, and are typically used in Graves’ disease or toxic multinodular goitre. They can take a few weeks to get the thyroxine levels under control. Thyroid function tests will need to be checked every few weeks to make sure the doses are correct.

Precautions:

• If a rash develops, medication will need to be ceased.

• Immune function may be affected.

• Liver function should be monitored.

• Women of childbearing age should be advised not to become pregnant during treatment.

Symptoms associated with anxiety and stress can mimic symptoms associated with hyperthyroid disorders, and vice versa. Furthermore, significant and chronic stress can lead to an elevation in thyroid activity and even trigger the activation of autoimmune thyroiditis. Therefore it is advisable to always consider the potential diagnosis of thyroid problems in patients who present complaining of stress-related symptoms, and to consider the role of psychological factors in the management of hyperthyroid disorders.

HYPOTHYROID DISORDERS

The symptoms associated with an underactive thyroid gland and low levels of thyroxine include tiredness, weight gain and reduced appetite, dyspnoea on exertion, peripheral oedema, dry skin and hair, cold intolerance, menorrhagia and easy bruising. The most common cause is autoimmune destruction of the thyroid gland, Hashimoto’s thyroiditis.

Hashimoto’s thyroiditis

This is an autoimmune condition resulting in destruction of the thyroid gland and consequently a low level of thyroid hormone. It is not uncommon, tending to be more prevalent in women, and tending to run in families. There may or may not be a noticeable goitre.

The rate of loss of function of the thyroid may be rapid, but function can also decline slowly over months. The treatment is to replace the missing hormone with thyroxine, starting at 50–100 μg and increasing to 100–150 μg once daily. For the elderly and those with a history of arrhythmias or ischaemic heart disease, it would be useful to commence with a lower dose of 25–50 μg, to avoid the precipitation of palpitations. TSH levels and resolution of symptoms are monitored, to ensure the right maintenance dose of thyroxine. Any symptoms from the low levels of thyroid hormone will respond very effectively to replacement with normal levels of thyroxine. The dose may need some adjustment as the function of the thyroid gland declines, but once the correct dose is found, the dose generally does not need to be altered through life, except in the case of pregnancy.

Thyroid nodules

Thyroid nodules are common and it is estimated that they occur in around two-thirds of people normally. Most nodules are benign and do not produce excess thyroid hormone, and need no active management. In fact, 95–99% of found nodules in the thyroid are benign nodules, cysts or adenomas. The most appropriate test for thyroid nodules is fine-needle biopsy. If a nodule is found to contain thyroid cancer cells on biopsy (papillary carcinoma is the most common thyroid malignancy), the management generally includes total thyroidectomy and radioactive iodine, and replacement of thyroxine. The prognosis is very good. Post-surgical follow-up and monitoring, including nuclear scans, is recommended.

Thyroid nodules may be detected in several ways: the patient may present with a lump or pain in the neck; it may be noticed on an ultrasound or CT scan that includes the thyroid; or it may be felt by palpation of a patient’s neck.

A thyroid nodule may be investigated in several ways:

• blood tests

• thyroid function tests (TSH, free T_3, free T₄)

• ultrasound—can be very sensitive; can find nodules 2 mm in size

• fine needle aspiration and biopsy—usually done when ultrasound suggests atypical features

• nuclear scan—to assess whether the nodule in question is functioning normally.

THYROID DISEASE: SUMMARY OF THERAPEUTICS

Hypothyroidism:

• Medication—thyroxine, commence on 100 μg, lower dose in the elderly.

• Test urinary iodine levels—if deficient, correct iodine deficiency. Food sources include seaweed, crustaceans, sardines and other saltwater fish and iodised salt. Iodine supplements are available in tablets and drops.

• Screen for coeliac disease.

• Ensure sufficient dietary zinc, vitamins E, C, A and B, to metabolically support the thyroid gland. Supplement if necessary.

• Fresh wholefoods.

• Strict low-cholesterol diet is important, because of the association between hypothyroidism and hypercholesterolaemia.

• Foods that depress thyroid activity by blocking iodine utilisation include turnips, soybeans, peanuts, pine nuts, mustard, broccoli, cabbage, brussel sprouts, cauliflower, kale and spinach. These foods should be avoided in a hypothyroid condition.

• Supplements:

• Vitamins C (1 g per day), A (10,000–25,000 IU per day), B complex (50–100 mg per day), augmented with B₂ (riboflavin, 10–15 mg), B₃ (niacin, 10–25 mg), and B₆ (pyridoxine, 25–50 mg), selenium (200 μg per day), vitamin E (400 IU per day) and zinc (30 mg per day) are necessary for normal thyroid hormone production.

• Calcium (1000 mg per day) and magnesium (200–600 mg per day) may help metabolic processes function correctly.

• Selenium status influences thyroid hormone production, particularly in the elderly. Recommended dose is 200–300 μg daily. Selenium and iodine also have an antagonistic relationship. It is theoretically dangerous to give selenium supplements by themselves in iodine-deficient areas. Correct iodine levels first.

• Essential fatty acids (1000–1500 mg three times per day), found in flaxseed oil and fish oil, in the management of hypercholesterolaemia.

• Iron may interfere with absorption of thyroid hormone medication, so if supplementation is needed, take at different times of the day.

• Zinc and copper—either copper deficiency or copper excess can affect thyroid chemistry. As a broad generalisation: in hypothyroidism, zinc deficiency is a common problem; in hyperthyroidism, it is often copper deficiency. Copper and zinc have an antagonistic effect on each other. At the very least, it is easy to check serum copper levels, but for accuracy you should also do ceruloplasmin levels. Red cell zinc levels can also be tested.

• Exercise—stimulates thyroid hormone secretion and raises metabolic rate. Recommendation: 30–60 minutes per day of aerobic exercise and resistance (weight) training.

• Herbs:

• Coleus forskohlii (50–100 mg 2–3 times per day) may stimulate thyroid function, to increase thyroid hormone.

• Guggul (Commiphora mikul) and hawthorn (Crataegus monogyna) (500 mg twice a day) help to lower high cholesterol.

Thyroiditis:

• Avoid refined foods, sugar, dairy products, wheat, caffeine, alcohol.

• Essential fatty acids (1000–1500 mg three times per day), found in flaxseed oil and fish oil, are anti-inflammatory and necessary for hormone production.

• Bromelain (250–500 mg three times per day between meals) may reduce inflammation in thyroiditis.

• Turmeric (Curcuma longa) enhances the effect of bromelain and should be taken between meals, 500 mg t.d.s.

• Carefully monitor any intervention, because thyroiditis may convert from hyperthyroidism to hypothyroidism very quickly.

Hyperthyroidism:

• Foods that depress thyroid activity by preventing iodine utilisation include turnips, soybeans, peanuts, pine nuts, mustard, broccoli, cabbage, brussel sprouts, cauliflower, kale and spinach. These foods should be included in the diet of patients with overactive thyroid.

• Check whether the patient is taking any herbs or supplements that may affect thyroid function. For example, ashwagandha (Withania somnifera) and bladderwrack (Fucus vesiculosus) should be avoided in thyroid disease, as they can stimulate hyperthyroidism.

ADRENAL GLAND DISORDERS

The adrenal glands sit atop the kidneys and are primarily responsible for releasing a range of chemical mediators of the stress response, such as glucocorticoids (e.g. cortisol) from the outer cortex. The cortex is also responsible for releasing mineralocorticoids such as aldosterone, which has an important role in regulating blood pressure, and androgens such as dehydroepiandrosterone (DHEA). Catecholamines such as adrenaline and noradrenaline are released from the central area of the gland, called the medulla.

ADDISON’S SYNDROME

Adrenal insufficiency is an important treatable condition, and can be life-threatening if not identified and treated properly. The incidence varies between developed and developing countries, due to the higher incidence of infective diseases affecting the adrenal gland, in the latter—it is estimated at 1 in 100,000 in developed countries and up to 11 per 100,000 in developing countries, and is likely to increase in the latter in line with the incidence of Mycobacterium tuberculosis disease and HIV/AIDS.

Aetiology

Adrenal insufficiency may be secondary, due to pituitary disease. It usually occurs in panhypopituitary patients after surgery, trauma affecting the stalk, hypothalamic disease or radiotherapy. ACTH chromophobe cells of the pituitary are usually the last cells to lose their function in the setting of a compressing macroadenoma. ACTH may be selectively lost in isolation, as in lymphocytic hypophysitis. These patients differ clinically in that they do not have typical hyperkalaemia, due to the fact that they have an intact renin-angiotensin-aldosterone system.

More commonly, adrenal insufficiency is primary, due to diseases that directly affect the adrenal gland itself. These patients are more likely to be hyperkalaemic, with loss of the mineralocorticoid as well as the glucocorticoid production. Primary adrenal diseases may be congenital anatomical problems such as adrenal hypoplasia, or congenital enzyme problems, as in congenital adrenal hyperplasia where the genes encoding enzymes involved in the production of cortisol are defective.

Infections such as Mycobacterium tuberculosis may produce a granulomatous destruction of the adrenal cortex and medulla, usually in the setting of disseminated tuberculosis. Syphilis and HIV have been documented to result in adrenal insufficiency. Neisseria meningitidis septicaemia may result in adrenal infarction and the Waterhouse-Friderichsen syndrome of associated adrenal insufficiency. Infarction may occur in any form of septicaemia, as can haemorrhage due to disseminated intravascular coagulation (DIC) and coagulopathy. Supratherapeutic anticoagulation may also result in adrenal haemorrhage and insufficiency.

Fungal infections with Histoplasmosis and Cryptococcus may result in adrenal insufficiency, which may or may not recover with appropriate treatment.

Ketaconazole, which may be used for its antifungal effects or for metastatic prostate cancer, may also block enzymes in the steroidogenesis pathway of cortisol and result in reversible loss of adrenal cortisol production. It and other drugs such as metyrapone etomidate and mitotane may be used with the indication of medically and surgically resistant Cushing’s syndrome, due to their effects on decreasing cortisol production from the adrenal cortex.

The very common but often forgotten cause of adrenal insufficiency is withdrawal of corticosteroids too quickly after a course long enough and at high enough dose to suppress ACTH stimulation of the adrenal cortices, and thus atrophy, and poor ACTH response when exogenous steroids are withdrawn. The static laboratory test of adrenal function with an early-morning cortisol and ACTH or the dynamic short synacthen test are identical, and history should point to the cause. Steroids must then be reintroduced and tapered at a slower rate. It is variable but a prednisone equivalent dose to around 10 mg per day for approximately 3 weeks should be assumed to suppress the adrenal cortex, and will require a slower taper. Adrenocortical suppression is more likely in elderly patients and those with dexamethasone or nocturnal doses of steroids. The nocturnal doses more effectively suppress the early morning peak of ACTH and thus lead more quickly to adrenal cortex atrophy and blunted ACTH response.

Adrenal cortical dysfunction is most commonly autoimmune in the developed world. It may occur in isolation or in the setting of APS types 1 and 2. Type 1 APS is characterised by mucocutaneous candidiasis, hypoparathyroidism and autoimmune adrenalitis that usually occurs in the first years of life and almost invariably occurs before the age of 20 years. APS Type 2 is more common than type 1 and occurs later in life than type 1, with autoimmune adrenalitis, autoimmune thyroid disease (hypo- more than hyperthyroidism) and type 1 diabetes mellitus. Adrenalitis usually occurs first but may follow the other manifestation in a good proportion of patients.

Other congenital causes of adrenal insufficiency such as adrenoleukodystrophy are more rare.

Infiltration from amyloid or metastatic breast or lung cancer is also rare.

Diagnostic approach

History and examination will often lead to a feeling for whether there is a problem with adrenocortical function, and may point to a possible cause. (See the section on history, below, for common symptoms and signs.)

Hyponatraemia is common in adrenal insufficiency, but hyperkalaemia is less common and does not occur in secondary adrenal insufficiency due to intact aldosterone production. An early-morning paired cortisol and ACTH will indicate whether there is a problem with primary or secondary hypoadrenalism. A cortisol peak of 400 nmol/L has a high specificity for adequate adrenal function. Regardless of ACTH levels, there is no need to further investigate adrenocortical insufficiency.

ACTH is released in a peak and is relatively unstable if not collected properly, but, those issues aside, a low cortisol with a low or inappropriately normal ACTH would tend to point to secondary adrenal insufficiency. A high ACTH at any time of the day with a less than adequate cortisol is very indicative of primary adrenal problems. In the indeterminate range, a short synacthen test of 250 μg of synacthen given as an intramuscular injection with cortisol measured at 0, 30 and 60 minutes can be performed. If done at 0800 with a morning ACTH and cortisol, a basal result of > 400 nmol/L or a stimulated rise of about 550 nmol/L indicates adequate adrenal function. Check with your local laboratory as to the normal cut-offs for its particular assay. The short synacthen test does not differentiate between primary and secondary adrenal insufficiency in the chronic setting, where there is inadequate ACTH drive with resulting adrenal atrophy and blunting of adrenal response, as one would see in primary disease.

Some have argued that this is a supraphysiological test, which may not properly assess for partial adrenal insufficiency. It has been suggested that a 1 μg synacthen test may be more of a physiological test dose.

History

The diagnosis of adrenal insufficiency may become apparent during an adrenal crisis with an intercurrent illness. As well as looking for the aetiological factors listed above, symptoms of weight loss, anorexia, fatigue, vomiting, abdominal pains, fevers, joint pains, recurrent illnesses that have a prolonged recovery phase, and postural symptoms, should be asked about. If the history points to a secondary cause, ask about menstrual history, hypothyroid symptoms and galactorrhoea.

Examination

Check the patient for signs of shock. Check for signs of hyperpigmentation, which should only occur in chronic primary adrenal insufficiency. Check the palms, new scars and wounds, pressure areas such as the elbows and knees, and the mucosal surfaces of the lips, buccal surfaces, anus and labia for signs of hyperpigmentation. Check postural blood pressure, including the pulse rate in each position. Examination of the abdomen may reveal what appears to be a surgical abdomen. It is important to investigate this, but also consider adrenal problems if any of the other features on history or exam point to adrenal insufficiency. In secondary adrenal insufficiency, visual fields should be checked with confrontation testing using a red hatpin.

The replacement with glucocorticoids is an estimation and therefore may be initially a higher dose than physiologically required. Maintaining a healthy diet and exercise, and being aware that excess steroids will stimulate appetite, will help the patient maintain a healthy weight.

Pharmacological

If the patient has presented unwell, hypotensive and shocked, and you suspect adrenal insufficiency, establish large-bore IV access and take blood for FBC, eLFT, ACTH and cortisol, and then commence treatment for shock, as well as giving 100 mg of IV hydrocortisone. The patient should be transferred to care in hospital. If the cortisol result returns as adequate in 1–2 days, then the steroids treatment may be stopped.

All steroids except dexamethasone have mineralocorticoid effects. Patients with secondary adrenal insufficiency will have an intact mineralocorticoid output, so addition of any extra mineralocorticoid in the form of fludrocortisone is not necessary.

In chronic adrenal insufficiency, replacement regimens are many but the aim is to try to provide enough glucocorticoid replacement in a normal physiological pattern that follows a diurnal variation, with a peak early in the morning that then tapers through the day. This may be achieved with hydrocortisone 20–30 mg per day in 2–3 divided doses in a regimen such as 12 mg on waking, 8 mg at lunch and 4 mg at afternoon tea. A simpler strategy is hydrocortisone 20 mg mane and 10 mg in the early afternoon, or cortisone acetate 25 mg mane and 12.5 mg in the early afternoon. The afternoon dose may be brought closer to midday if the patient reports difficulty sleeping. If the patient reports feeling unwell and quite fatigued in the early evening, then using a three-times-a-day split dose with a smaller proportion in the late afternoon can be trialled.

Be aware that fatigue as a symptom of inadequate replacement may lead to excessive replacement. There are many causes of fatigue. If hydrocortisone is used, checking a 24-hour urine collection for free cortisol may be used to assess whether the replacement is excessive.

In the setting of adrenal suppression from long-term steroids, treatment for other conditions in someone who should otherwise have an intact hypothalamic–pituitary–adrenal (HPA) axis, then a slow taper of the steroids, should allow for recovery of their normal axis function. The longer the patient has been on steroids, and the older the patient, the slower the taper. This may require a taper over several months to a year. Adequacy of their axis may be checked with a morning ACTH and cortisol prior to their normal dose, noting that the dexamethasone with its longer duration of action is likely to interfere with this technique.

If patients with primary adrenal insufficiency have documented postural hypotension or symptoms, and are on adequate glucocorticoid replacement, fludrocortisones 0.05–0.1 mg/day may be added.

Other medical and complementary therapies

There are some data indicating that in secondary hypoadrenalism in panhypopituitary women, replacement of adrenal androgens with DHEA 25–50 mg per day has some beneficial effects on quality of life and libido. This has only been shown in women so far. Men have their own stronger androgens in the form of testosterone, either from their own testes or from replacement in hypopituitary patients.

Some advocate the benefits of DHEA in patients with otherwise normal steroid production. At this stage there is no evidence that there is objective benefit with treatment. Be aware also that many of the forms of DHEA that are available have a very variable content. DHEA can be obtained by prescription from compounding pharmacies. The forms available may vary in the quantities of active substance. Further studies are ongoing to assess any benefits of adrenal androgen replacement.

Paramedical

• Patients should be advised about sick-day management. For a minor illness the replacement dose should be doubled for 3 days.

• For illnesses that require the patient to be bed-bound, a tripling of the dose for 3 days can be advised.

• If the patient has a vomiting or diarrhoeal illness, an IM dose of 100 mg hydrocortisone should be given and the patient should then go to the nearest hospital immediately. The injection is available as Solu-Cortef® as a powder for reconstitution, in many but not all countries.

• The patient should be educated about self-injection techniques, to ensure they can manage in a crisis. The partner or significant other should also be involved in the education.

• A MedicAlert bracelet is recommended, in case the patient is hospitalised or is found unwell or unconscious.

Cushing’s disease is the disorder described by Harvey Cushing, with pituitary disease with ACTH-dependent hypercortisolism. Cushing’s syndrome describes the other forms of cortisol excess. (See Table 28.3 for a list of other causes of hypercortisolaemia.) The incidence of Cushing’s disease or syndrome is difficult to quantify. There is significant overlap between the manifestation of Cushing’s disease, and that of obesity and its complications. European series have estimated the incidence at 1–3 per million patients.

TABLE 28.3 Causes of hypercortisolaemia

Name	Cause
Cushing’s disease	ACTH-dependent pituitary disease
Pseudocushing’s disease	• Obesity • Alcohol use (rarely causes) • Cushing’s syndrome depression—rare cause of Cushing’s syndrome but common elevator of UFC or 1 mg DST

Factitious Cushing’s Iatrogenic or surreptitious glucocorticoid excess Ectopic ACTH Bronchogenic tumours producing ACTH Primary hypercortisolism Cortisol-secreting adrenal tumour

Establishing the diagnosis of hypercortisolaemia involves establishing a clinical likelihood or pre-test probability, establishing the biochemical excess of glucocorticoids, and then establishing the cause, in order to plan effective treatment.

The diagnosis may be perplexing, given that there is much overlap between normal levels in biochemical testing and levels in those with true glucocorticoid excess.

Aside from iatrogenic Cushing’s syndrome, Cushing’s disease accounts for the majority of cases of Cushing’s syndrome, at 60–70%. Adrenal disease is also not uncommon, accounting for approximately 20% of cases. Ectopic ACTH secretion and resultant Cushing’s syndrome accounts for approximately 10–15% of cases, with the other causes responsible for the few remaining per cent.