Endocrinology and Diabetes

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14 Endocrinology and Diabetes

Diabetes mellitus

Diabetes mellitus is a syndrome of chronic hyperglycaemia due to relative insulin deficiency or resistance or both.

Case history (1)

You are telephoned by a GP who has seen a 50-year-old man in his surgery complaining of thirst and polyuria. His venous blood glucose is 24 mmol/L. He is tired but otherwise well.

What are the key decisions in this case?

• Does this patient need admission?

• Does he need insulin?

• What is the immediate management?

The likelihood is that this patient has type 2 diabetes (Table 14.1). The risk of ketoacidosis is small and he will not need admission unless he is either ketotic (ketonuria 3+) or is very dehydrated.

Table 14.1 The spectrum of diabetes: a comparison of type 1 and type 2 diabetes mellitus

	Type 1	Type 2
Epidemiology	Younger (usually < 30 years of age)	Older (usually > 30 years of age)
	Usually lean	Often overweight
	Increased in those of Northern European ancestry	All racial groups. Increased in peoples of Asian, African, Polynesian and American-Indian ancestry
	Seasonal incidence
Heredity	HLA-DR3 or DR4 in > 90%	No HLA links
	30–50% concordance in identical twins	~ 50% concordance in identical twins
Pathogenesis	Autoimmune disease	No immune disturbance
	Islet cell autoantibodies	Insulin resistance
	Insulitis
	Association with other autoimmune diseases
	Immunosuppression after diagnosis delays beta-cell destruction
Clinical	Insulin deficiency	Partial insulin deficiency initially
	May develop ketoacidosis	May develop hyperosmolar state
	Always need insulin	Many come to need insulin when beta-cells fail over time
Biochemical	Eventual disappearance of C-peptide	C-peptide persists

Note: there is a significant rise in the incidence of young patients with type 2 diabetes mellitus, especially in the obese and in Asian populations.

This patient should be advised to avoid sweet drinks (especially sweetened canned drinks) and an appointment arranged for him to attend a diabetic outpatient clinic. Contact the diabetic liaison nurse in your hospital and arrange for the patient to be seen urgently.

Indications for admission

• Severe dehydration (may have hyperosmolality).

• Intercurrent illness such as pneumonia or UTI.

• 3+ ketonuria.

• Tachycardia or tachypnoea.

Information

Diagnostic criteria for diabetes mellitus:

• Fasting venous plasma glucose > 7.0 mmol/L (126 mg/dL) after 8-h fast *

• Random venous plasma glucose > 11.1 mmol/L (200 mg/dL)*

• An HbA1c of > 6.5% (48 mmol/mol) has recently been approved for diagnosis (Table 14.2)

• Impaired fasting glucose: 5.6–6.9 mmol/L

• Impaired glucose tolerance: > 7.8 and < 11.1 mmol/L; 2 h after 75 g oral GTT.

Table 14.2 HBA1c – conversion of percentage values to mmol/mol

DCCT HbA1c %	IFCC HbA1c mmol/mol
4.0	20
5.0	31
6.0	42
6.5	48
7.0	53
7.5	59
8.0	64
9.0	75
10.0	96

DCCT, Diabetes control and complication trial.

IFCC, International Federation of Clinical Chemistry.

An oral glucose tolerance test is only required for borderline cases.

^*Two readings are required for asymptomatic individuals. Note also:

Progress.

At the Diabetic Clinic the diabetic nurse explained lifestyle changes that are an essential part of treatment, i.e. stopping smoking, losing weight with a diet and exercise. The nurse arranges for an appointment for this patient to be checked by the doctor and for eye testing. He was also started on Metformin 500 mg daily, increasing to 1.5 g daily.

Case history (2)

You are telephoned by a GP who has seen a 17-year-old man in his surgery complaining of thirst and polyuria. He has recently lost 8 kg in weight. His blood glucose is 31 mmol/L.

The key decisions are again:

• Does this patient need admission?

• Does he need insulin?

• What is the immediate management?

This patient is much more likely to be presenting with early type 1 diabetes and might not be ketotic yet because he could still have a degree of residual beta cell function (the ‘honeymoon’ phase). Again, assessment of ketosis, acidosis and dehydration must be made to determine whether he needs admission. He should be seen within 24 h either by the diabetic liaison nurse or in hospital to commence insulin. If there is any doubt, the patient should be seen in A&E immediately.

Progress.

At the Diabetic Clinic the patient was dehydrated with mild ketosis. He was admitted to MAU to commence insulin therapy.

Diabetic ketoacidosis (DKA)

Case history (3)

A 21-year-old woman presents to A&E having been generally unwell for 2 weeks and having been treated for a urinary tract infection by her doctor.

Examination reveals severe dehydration, a tachycardia of 120 bpm and a blood pressure of 90/50 mmHg. The nurses have checked her finger-prick blood glucose (BM Stix) and found it to be 30 mmol/L.

Diagnosis.

Diabetic ketoacidosis.

How do patients present with ketoacidosis?

• Unwell ± intercurrent illness (e.g. bacterial or viral infection)

• Polyuria and polydipsia

• Hyperventilation or dyspnoea

• Vomiting ± abdominal pain

• Impaired conscious level.

Patients known to have type 1 diabetes mellitus most commonly develop ketoacidosis when insulin is omitted because of missed meals during an intercurrent illness (e.g. gastroenteritis). Patients become rapidly dehydrated (Fig. 14.1) and acidotic (over hours). Tachypnoea or Kussmaul respiration (a deep sighing respiration) is prominent, with the smell of ketones on the breath. It is the fall in pH that causes coma.

Figure 14.1 Dehydration occurs during ketoacidosis as a consequence of two parallel processes. Hyperglycaemia results in osmotic diuresis, and hyperketonaemia results in acidosis and vomiting. Renal hypoperfusion then occurs and a vicious circle is established as the kidney becomes less able to compensate for the acidosis.

The blood glucose might not be particularly high and severe acidosis be present, with glucose values as low as 10 mmol/L. This might be due to recent self-administration of insulin, which is insufficient alone to correct the acidosis in the presence of dehydration.

Management: fluid replacement

Severely shocked patients may require colloid to restore circulating plasma volume. Table 14.3 shows examples of blood values in severe ketoacidosis and compares these with those seen in the hyperosmolar, hyperglycaemic state described on page 418.

Table 14.3 Examples of blood values

The guidelines for fluid replacement are shown in Table 14.4. These are applicable for young patients.

• When blood glucose falls to less than 12 mmol/L convert to a 5% glucose infusion. This will enable the insulin infusion to be continued. Continued insulin is required to inhibit ketone production.

• Continue with IV fluids 1 L every 4–6 h until rehydrated and ketosis resolves (~24 h).

Table 14.4 Guidelines for average fluid replacement in young patients

Volume	Duration/timing
1 L 0.9% saline + 20 mmol/KCl	Over the first 30 min
1 L 0.9% saline + 20 mmol/KCl	Over next 1 h
1 L 0.9% saline + 20 mmol/KCl	Over next 2 h
1 L 0.9% saline + 20 mmol/KCl	Over next 4–6 h

Management: insulin regimen

• Add 50 units of soluble insulin to 50 mL 0.9% saline and administer by intravenous infusion; this equates to 1 U/mL.

• Commence at 6 U/h and continue at 3 U/h after venous glucose falls to < 11.5 mmol/L.

• Glucose must then be administered to prevent hypoglycaemia (see above).

• Continue IV insulin infusion until ketosis resolves, the patient is eating and for 2–4 h after the first SC dose of soluble insulin.

Management: potassium replacement (Table 14.5)

Total body potassium can be depleted by approximately 1000 mmol and the plasma potassium falls rapidly as potassium shifts into the cells under the action of insulin. Use less potassium in patients with renal impairment or oliguria.

• Monitor serum [K⁺] every 2 h initially then every 4 h until stable.

• Use premixed potassium-containing infusions wherever possible.

Table 14.5 Potassium replacement in patients with diabetic ketoacidosis

Serum potassium (mmol/L)	Amount of KCl (mmol/hour)
<3	40
3–1	30
4–5	20
5–6	10
> 6	Stop KCl

Management: acidosis

• If the pH < 7.0: isotonic (1.26%) sodium bicarbonate given at a rate of 500 mL over 4 h is safe. If the pH > 7.0, bicarbonate need not be given.

Assessment during treatment

• Remember the role of insulin is primarily to suppress ketogenesis rather than to lower blood glucose.

• Blood glucose (BM Stix every hour, laboratory blood glucose 4-hourly).

• Plasma potassium every 4 h: the main risk is hypokalaemia.

• Repeat ABGs after 2 h. A calculated anion gap (needs chloride estimation) may be adequate for monitoring.

Remember

Causes of death in DKA:

• Hyperkalaemia

• Aspiration due to gastric stasis

• Cerebral oedema due to acidosis ± overhydration

• Hypokalaemic respiratory arrest

Progress.

This patient started eating and treatment with SC insulin after 48 hours. She was shown a video on diabetes and its self management. She was helped with her insulin injections and discharged on the 6th day with support from the Community Diabetic Nurse.

Hyperosmolar hyperglycaemic state

Case history (4)

A 60-year-old woman is referred to A&E following a collapse. She has been generally unwell for the last year. Her husband confirms that she has had polyuria and polydipsia with nocturia of three to four times every night. Over the last month, she has started using sugar drinks to build herself up because she has been losing weight.

Examination reveals an extremely dehydrated woman with increased tissue turgor. Pulse 100 regular, BP 100/60. JVP not visible. Glasgow coma scale 12.

Investigations revealed:

Na⁺ 165; K⁺ 5.9; U 24.7; Cr 170; Bicarb 20; Glucose 64 mmol/L; pH 7.31; pCO₂ 4.7 kPa; pO₂ 11.2 kPa; plasma osmolality 2 × (165 + 5.9) + 64 + 24.7 = 429.7 mOsmol/kg.

These findings are typical of hyperosmolar hyperglycaemic state (see Table 14.3).

Information

Calculation of osmolality:

2 × (Na⁺ + K⁺) + glucose (normal range 285–300 mOsmol/kg)

How should this patient be managed?

Hyperosmolar hyperglycaemic state occurs in older patients with type 2 diabetes. It is characterised by a very high glucose, a relatively normal acid–base balance and high plasma osmolality. These patients are also at increased risk of venous and arterial thromboses. The mortality is higher than for DKA. This patient’s biochemistry has been slowly getting worse over many weeks, so normalisation must be equally slow.

Remember

Ketones can be found in the urine in any starved person.

How do patients present?

• The patient is middle aged or elderly

• Insidious onset of polyuria and polydipsia

• Severe dehydration

• Altered conscious level

• Most middle-aged or elderly patients have not previously been diagnosed with diabetes

• Respiration is usually normal

• Presentation is usually precipitated by infection, stroke or myocardial infarction.

Diagnosis and investigations

Information

Calculation of corrected sodium concentration: Add 2.0 mmol/L to the measured serum sodium for every 5 mmol/L increase in glucose concentration. Thus a fall in glucose from 50 to 25 mmol/L will be accompanied by a rise in [Na⁺] of 10 mmol/L.

Remember

The principal cause of death and morbidity in hyperosmolar hyperglycaemic state is arterial and venous thrombosis due to the hyperosmolar state.

Assessment of severity

• The degree of consciousness correlates most closely with plasma osmolality. Coma is usually associated with an osmolality of greater than 400 mOsmol/kg.

• A coexistent lactic acidosis considerably worsens the prognosis.

How would you manage this patient?

General treatment measures

Progress.

This patient was discharged on metformin 1 g daily and instructed on lifestyle changes, e.g. controlling weight and an urgent appointment with the Community Diabetic Nurse.

Hypoglycaemic coma

Case history (1)

A 25-year-old man is brought to A&E by the police, having been found behaving abnormally. He is aggressive and irrational and attempts to punch the staff. He is restrained and a MedicAlert bracelet is found under his shirt indicating that he has diabetes. A finger-prick glucose reads ‘low’.

Diagnosis.

Hypoglycaemia.

Always consider hypoglycaemia in confused patients and check a blood glucose using a glucostix (or BM Stix), confirming with a laboratory determination wherever possible. The most common cause of coma in a patient with diabetes is hypoglycaemia due to drugs. The long-acting sulphonylureas, such as glibenclamide, or long-acting insulins, such as Isophane, are prone to do this. Patients who are not known to have diabetes but who are hypoglycaemic should have a laboratory-determined blood glucose and blood saved (serum) for insulin and C-peptide determination (to diagnose insulinoma or factitious drug administration).

How do patients present? (Table 14.6)

Patients with tightly controlled diabetes can have frequent episodes of hypoglycaemia and can become desensitised to sympathetic activation. These patients can develop neuroglycopenia before sympathetic activation and complain of ‘loss of warning’. Use of beta blockers can also minimise the warning signs of hypoglycaemia by blocking the features of an activated sympathetic nervous system.

Table 14.6 Presentation of patients with hypoglycaemic coma

Sympathetic overactivity (glucose < 3.5 mmol/L)	Neuroglycopenia (glucose < 2.6 mmol/L)
Tachycardia	Confusion
Palpitations	Slurred speech
Sweating	Localised neurological impairment
Anxiety	Coma
Pallor
Tremor
Cold extremities

Conversely, patients with poorly controlled diabetes develop sympathetic signs early and avoid these by running a high blood glucose. They complain of ‘being hypo’ when their blood sugar is normal or high. They do not require glucose.

Information

Patients with type 2 diabetes who are on diet alone or metformin (but no insulin or sulphonylureas) cannot become hypoglycaemic.

How would you manage hypoglycaemia?

Conscious patient

Treat with 15–20 g carbohydrate, i.e. four glucose tablets, or glucose drink.

Hypoglycaemia in the non-diabetic patient

Hypoglycaemia in patients without diabetes is rare and always needs investigation – usually as an inpatient. Always:

• Confirm the hypoglycaemia with a laboratory sample before treatment.

• Take a simultaneous serum sample for insulin and C-peptide (the fragment of proinsulin that is found in endogenous insulin), sent urgently to the laboratory for centrifugation and separation.

Sick diabetic patient

Case history

A 40-year-old man with a 15-year history of type 1 diabetes mellitus and previously documented proteinuria is referred from A&E with vomiting and feeling generally unwell. Glucose was 20 mmol/L, electrolytes were normal and blood gases did not support diabetic ketoacidosis (pH 7.4; bicarbonate 20 mmol/L). An ECG shows evidence of evolving anterior myocardial infarction. This is the typical presentation of a ‘silent MI’. Chest pain is frequently atypical or absent in diabetes due to small fibre neuropathy. The other major cause of this type of non-specific presentation is occult infection and often further investigations are required:

Treatment/progress

This patient has a diagnosis of STEMI and requires immediate therapy with aspirin 300 mg chewed and clopidogrel 300 mg oral gel. He was immediately transferred to the Coronary Care Unit for further assessment and possible percutaneous coronary intervention, which is instantly available (p. 285). His diabetes was initially controlled on insulin infusion because he was nil by mouth for the cardiac procedures (Table 14.7). The infusion was continued until the patient was eating and drinking. Insulin treatment has been proven to improve outcome in patients with diabetes in the immediate period after myocardial infarction.

Table 14.7 Intravenous infusion insulin management of type 1 diabetes mellitus in hospital

Level of blood glucose (measured hourly)	Insulin infusion (units per hour)
< 4.0 mmol/L	0.5
4.0–7.0 mmol/L	1
7.1–9.0 mmol/L	2
9.1–11.0 mmol/L	3
11.1–14.0 mmol/L	4
14.1–17.0 mmol/L	5
17.1–28 mmol/L	6
> 28 mmol/L	8

Note: the above is only a guide and insulin doses should be adjusted upwards if the patient is known to have a high insulin requirement, and always reviewed regularly to see if the doses are appropriate. The aim is to keep blood glucose in the 7–9 region.

Once eating and drinking, the patient can be converted back to his or her usual insulin regimen or, if tight glycaemic control is essential, on to × 4 daily insulin (see below), which gives greater ease of adjustment.

Remember

Always carefully inspect the feet in unwell diabetic patients – infected ulcers are common and may be painless.

Protocol for converting diabetics from intravenous to subcutaneous insulin

• Calculate total dose over last 24 h.

• Give 25% of total as soluble insulin 30 min before each meal (i.e. × 3 daily).

• Give 25% of total dose as intermediate-acting isophane insulin at 22:00.

• Monitor blood glucose fasting and 2 h after meals (post-prandial) – each finger-prick glucose measures the adequacy of the previous dose.

• Aim for glucose < 10 mmol/L post-prandial and < 8 mmol/L fasting.

• Do not discontinue IV insulin until 1–2 h after the first subcutaneous insulin dose is administered, because IV insulin has a half-life of only 3 min.

Management of new type 2 diabetic presenting for surgery

Case History

You are asked to see a 50-year-old man with no previous history of diabetes who is admitted for coronary artery bypass surgery and found to have a blood glucose of 13 mmol/L. This patient has suffered from angina for 5 years but he still has symptoms on maximal medical therapy. He has had coronary angiography which shows triple vessel disease and his cardiologist has recommended surgery rather than percutaneous coronary intervention.

How would you manage this patient?

• Ask about symptoms of diabetes, e.g. thirst, polyuria, lack of energy.

• Check that a laboratory glucose has been sent to confirm the diagnosis of diabetes (random glucose 13.4 mmol/L).

• Discuss patient’s angina symptoms and discuss with cardiologist the urgency of CABG surgery.

• It is agreed by all, including the patient, that his diabetes should be treated and blood sugar controlled before surgery is performed.

• The patient is referred to the Diabetic Liaison Nurse for assessment and discussion of treatment as an outpatient.

Remember

Always get diabetes under control before patients undergo surgery unless this is an emergency.

Progress.

This patient was managed with lifestyle changes and Metformin, initially 500 mg daily. He will undertake surgery when his HbA1c is <7% (53 mmol/mol).

Management for surgery

Non-insulin-treated patients should stop medication 2 days before the procedure. Patients with mild hyperglycaemia (fasting blood glucose < 8 mmol/L) can be treated as non-diabetic. Those with higher levels are treated with soluble insulin prior to the procedure/surgery, and with glucose, insulin and potassium infusion during and after the procedure (p. 426). Be careful of hypoglycaemia due to the additive effect of medications taken previously. Postoperatively, patients should return to their normal management regimen when they begin eating and drinking.

Who needs insulin perioperatively?

• All patients who usually use insulin

• All acute surgical emergencies (type 1 and type 2 diabetes)

• All patients undergoing major surgery (type 1 and type 2 diabetes).

In other words, all diabetic patients should receive insulin except type 2 diabetic subjects undergoing minor surgery. For patients on insulin, give the usual evening and/or night-time insulin and commence glucose and insulin as above at 06:00.

Urgent surgery in patients with diabetes

Surgery requires patients to fast for several hours. In addition, a general anaesthetic and surgery themselves produce significant stresses on an individual. The hormonal response to stress involves a significant rise in counter-regulatory hormones to insulin, in particular cortisol and adrenaline. For this reason, patients with diabetes undergoing surgery will require an increased dose of insulin despite their fasting state. Long-acting hypoglycaemic agents must be stopped the night before surgery because hypoglycaemia might otherwise occur. In case of an emergency operation where the patient has taken a long-acting insulin, an infusion of 10% glucose can be used (usually with potassium), together with a controlled infusion of insulin.

The procedure for insulin-treated patients is simple:

Patients whose diabetic control is poor and when surgery is not an emergency should have their diabetic control reassessed and therapy adjusted with HbA1c < 8.5% (70 mmol/mol), if possible preoperatively.

Preoperative glucose levels should be in the range of 7–11 mmol/L.

The patient’s usual insulin is given the night before the operation and, whenever possible, diabetic patients should be first on the morning procedure/operating list.

An infusion of glucose, insulin and potassium is given during the procedure/surgery. The insulin can be mixed into the glucose solution or administered separately by syringe pump. A standard combination is 16 U of soluble insulin with 10 mmol of KCl in 1 L of 5–10% glucose, infused at 125 mL/hour. The insulin dose is adjusted:

• Blood glucose < 4 mmol/L – 8 U/L

• Blood glucose 4–15 mmol/L – 16 U/L

• Blood glucose 15–20 mmol/L – 32 U/L.

Postoperatively, the infusion is maintained until the patient is able to eat. Other fluids needed in the perioperative period must be given through a separate IV line and must not interrupt the glucose/insulin/potassium infusion. Glucose levels are checked every 2–4 hours and potassium levels are monitored. The amount of insulin and potassium in each infusion bag is adjusted either upwards or downwards according to the results of regular monitoring of the blood glucose and serum potassium concentrations.

The same approach is used in the emergency situation, with the exception that a separate variable-rate insulin infusion may be needed to bring blood glucose under control before surgery.

Diabetic foot

Case history

The chiropodist in the diabetic clinic asks you to review an 84-year-old woman who is complaining of severe pain in her big toe. She had attempted to cut a toe-nail a week ago and the toe had become painful and infected. She is known to have type 2 diabetes for which she takes glibenclamide 10 mg daily. She does not have regular supervision of her diabetes.

On examination she has a 2-cm ulcer on the medial side of her big toe with swelling and erythema.

Remember

• Many foot problems are avoidable. Older diabetic patients must be taught good foot care and should not cut their own toe-nails

• Diabetic foot problems can occur in patients with type 1 and type 2 diabetes.

Management

Information

How should this patient be managed?

Meticulous glycaemic control is of paramount importance in pregnancy. The patient should initially be taught to monitor her blood glucose levels and be advised on lifestyle changes, including diet. Blood glucose levels should be measured 1 h after each meal. If blood glucoses are below 7 mmol/L, then insulin is not required. Oral hypoglycaemic agents are avoided in pregnancy because they cross the placental barrier (although there is evidence that glibenclamide is safe), so that if glucose levels are above 7 mmol/L, insulin therapy is required. High levels of glucose are associated with risk of neonatal macrosomia, fetal death and postnatal hypoglycaemia. Thus the patient should be commenced on soluble insulin with each meal and a long-acting insulin at night if glucose is not controlled to < 7 mmol/L.

Information

• Normal subjects have lower blood glucose during pregnancy

• Thresholds vary between diabetic units but a fasting glucose > 6 mmol/L or a random/post-prandial glucose > 7.8 mmol/L is an indication for home blood glucose monitoring

• Diet should be healthy but not restricted

• Have a low threshold to start insulin

Progress.

This patient required insulin therapy, which was continued until she delivered at normal term.

Case history (2)

You are called to the labour ward to see a patient who is on insulin and in labour. She has been on soluble insulin 12 units three times daily and Isophane insulin 18 units last thing at night, with very good control of her blood sugar. She is now in labour and is nil by mouth.

Immediate management of this patient?

An infusion of 5% glucose containing 10 mmol of KCl and 16 units of insulin in 1 litre is commenced at an initial rate of 125 mL/hour.

The dose of insulin is adjusted with hourly glucose assessment (see p. 426), with a target blood glucose of 4–9 mmol/L. The infusion is maintained until the patient is able to eat and drink.

It is essential to determine whether the patient had type 1 diabetes before pregnancy (in which case insulin should never be stopped) or whether she has gestational diabetes, when insulin therapy can be stopped after delivery. The placental hormones cause insulin resistance and, after the third stage of labour, gestational diabetes can disappear.

Progress.

This mother has type 1 diabetes, so she was commenced on her pre-pregnancy dose of insulin when she started eating. Intravenous insulin must be continued until 4 h after the first dose of subcutaneous insulin. She is followed up at her doctor’s diabetic clinic.

Cushing’s syndrome

Cortisol is the principal endogenous glucocorticoid secreted from the adrenal glands; the amount controlled by the level of plasma ACTH.

Cushing’s syndrome is due to excess glucocorticoids due to the causes shown in the Information box, of which exogenous corticosteroid administration is the commonest.

Patients have undiagnosed Cushing’s syndrome for some time, and present due to metabolic decompensation either due to hypokalaemia (which can be severe) or hyperglycaemia and resultant dehydration.

Other complications follow, including secondary infection, bruising and bleeding, uncontrollable hypertension and osteoporotic fractures (Fig. 14.2).

Figure 14.2 Symptoms and signs of Cushing’s syndrome. The bold type indicates the signs of most value in discriminating Cushing’s syndrome from simple obesity and hirsutism.

Information

Causes (percentages in brackets refer to incidence of primary cause)

• Excess corticosteroid administration

• Pituitary-dependent Cushing’s disease (85%)

• Adrenal adenoma (10%)

• Ectopic ACTH protection (5%)

Case history

A 55-year-old woman presents with a 2-year history of atypical depression and 3 weeks of confusion, altered behaviour and an inability to climb stairs due to muscular weakness. Her weight has increased marginally but she has lost muscle bulk from the arms and legs.

On examination she was obese, plethoric with a moon face and buffalo hump. Her skin was thin with multiple striae over breasts, abdomen and thighs.

Diagnosis.

Cushing’s syndrome.

She was dehydrated and was found to have glycosuria with a blood glucose of 30 mmol/L.

Arterial blood gases reveal:

• pH 7.60

• pO₂ 12.0 kPa

• pCO₂ 5.4 kPa.

This patient has a metabolic alkalosis due to chronic hypokalaemia found in Cushing’s. Electrolytes came back from the laboratory, confirming your suspicions:

• Na⁺ 145 mmol/L

• K⁺ 2.5 mmol/L

• Urea 15.0 mmol/L

• Creatinine 120 µmol/L

• Bicarb 37 mmol/L

• Glucose 27 mmol/L.

How would you manage this patient?

The hypokalaemia and hyperglycaemia need prompt treatment. Total body potassium is likely to be extremely low, and as potassium is replaced, the initial effect will be to reduce the bicarbonate rather than to increase the extracellular (serum) potassium.

• Start potassium replacement both orally and intravenously (not more than 20 mmol in any 3 h) to provide at least 200 mmol per day.

• Rehydrate the patient with 0.9% saline + potassium chloride (40 mmol/L) added to each bag (see p. 426) with 2-hourly K⁺ monitoring.

• Start an intravenous infusion of insulin at 4 units per hour. This might exacerbate the fall in serum potassium.

• After 48 hours the lady was rehydrated with a serum K⁺ of 4.5 mmol/L.

• Confirm the diagnosis of Cushing’s syndrome.

• Collect 24-h urine for urinary free cortisol (normal < 700 nmoles in 24 hours)

• Measure midnight cortisol (normal < 50 nmol/L).

• 8-h low-dose dexamethasone suppression (0.5 mg 6-hourly for 48 h at 09:00, 15:00, 21:00, 03:00 followed by 09:00 cortisol).

Progress.

Cushing’s is confirmed and the patient is referred for specialist investigation. These investigations will include determination of ACTH dependence, pituitary and adrenal CT scanning and localisation procedures.

Hyperthyroidism

Case history (1)

A 65-year-old woman is brought to A&E with acute breathlessness and cough with frothy blood tinged sputum.

On examination she had profuse sweating with rapid severe breathlessness. She has atrial fibrillation and auscultation reveals wheezes and crackles throughout the chest. Your diagnosis of pulmonary oedema is confirmed by the chest X-ray showing bilateral perihilar shadowing and Kerley B lines of interstitial oedema.

ECG shows fast AF 160/min but no evidence of cardiac ischaemia or other abnormality.

What should you do?

• Admit the patient to HDU and start treatment of acute heart failure, oxygen, IV furosemide 50 mg and vasodilation therapy glyceryl trinitrate infusion 100–200 µg min.

• She responds well but still has fast AF.

• Urgent. Thyroid function tests reveal a free T4 of 45 pmol/L (NR 9.0–23) with a suppressed TSH.

Diagnosis.

Hyperthyroidism

Treatment

• Control the heart rate using beta blockers (propranolol 40 mg every 8 h) and digoxin if required.

• Avoid amiodarone as this will potentially interfere with investigation and management.

• Anti-coagulate the patient (heparin and warfarin).

• Start anti-thyroid medication, e.g. carbimazole 40 mg daily.

• Determine the cause of the hyperthyroidism (see below).

Beta adrenoreceptors are sensitised to normal circulating catecholamines by high levels of thyroxine and beta blockade is useful in achieving symptom control in hyperthyroidism, and is also helpful in treating high-output heart failure and achieving rate control. Propranolol is used in high doses (40 mg every 8 h) because, being lipid soluble, it crosses the blood–brain barrier.

Remember

• TSH is invariably suppressed in hyperthyroidism (except for the exceptionally rare TSH-secreting pituitary adenoma)

• Hyperthyroidism often presents in the elderly with atrial fibrillation and few other features.

Investigations

• Thyroid anti-microsomal autoantibodies and anti-thyroglobulin antibodies (in the serum): positive in up to 90% of patients with Graves’ disease

• Thyroid technetium scan to distinguish a ‘hot nodule’ (focal uptake) from Graves’ disease (uniform uptake) and from viral thyroiditis (zero uptake)

Progress.

This lady was confirmed as having Graves’ disease. She was followed up for her hyperthyroidism with reduction of her carbimazole dosage. A cardiologist advised her to stay on digoxin and warfarin and she remained in AF at 6 months.

Hyperthyroidism in the elderly

• Weight loss

• Atrial fibrillation

• Lethargy

• Proximal myopathy

Tests in patients with goitres

• Thyroid function tests – TSH plus free T₄ or T₃.

• Thyroid antibodies – to exclude auto-immune aetiology.

• Ultrasound. Ultrasound with high resolution is a sensitive method for delineating nodules and can demonstrate whether they are cystic or solid. In addition, a multinodular goitre may be demonstrated when only a single nodule is palpable. Unfortunately, even cystic lesions can be malignant and thyroid tumours may arise within a multinodular goitre; therefore fine-needle aspiration (see below) is often required and performed under ultrasound control at the same time as the scan.

• Fine-needle aspiration (FNA). In patients with a solitary nodule or a dominant nodule in a multinodular goitre, there is a 5% chance of malignancy; in view of this, FNA should be performed. This can be done in the outpatient clinic. Cytology in expert hands can usually differentiate the suspicious or definitely malignant nodule.

• FNA reduces the necessity for surgery, but there is a 5% false-negative rate which must be borne in mind (and the patient appropriately counselled). Continued observation is required when an isolated thyroid nodule is assumed to be benign without excision.

• Thyroid scan (99^m technetium) can be useful to distinguish between functioning (hot) or non-functioning (cold) nodules. A hot nodule is only rarely malignant; however, a cold nodule is malignant in only 10% of cases and FNA has largely replaced 99^m technetium scans in the diagnosis of thyroid nodules.

Drug treatment in hyperthyroidism

• Rapid symptomatic treatment (if necessary): propranolol 40–80 mg 8-hourly

• Control thyroid overactivity:

• Carbimazole 40 mg once daily or

• Propylthiouracil (PTU) 200 mg × 3 daily.

The latter two drugs inhibit the formation of thyroid hormones (Fig. 14.3). Carbimazole and PTU will induce hypothyroidism after 4–8 weeks at these doses and treatment should either be titrated down to a maintenance level (e.g. carbimazole 10 mg daily) or thyroxine added back at a dose of 100–150 µg in a ‘block and replace’ regimen. Patients are typically treated for 6–18 months with anti-thyroid drugs. All patients commencing anti-thyroid drugs should be warned about possible rashes, which are common and usually self-limiting without discontinuation, and severe sore throats or mouth ulcers, which may indicate a dangerous fall in neutrophils.

Figure 14.3 The hypothalamic-pituitary-thyroid axis. Pituitary TSH is secreted in response to hypothalamic TRH and stimulates secretion of T₄ and T₃ from the thyroid. T₄ and T₃ have actions in peripheral tissues and exert negative feedback on pituitary and hypothalamus.

Treatment with radioiodine is frequently employed if patients relapse after medical treatment but may also be used as primary treatment, particularly in multinodular goitres or toxic adenoma. Surgery is reserved for large goitres or for patient preference after relapse.

Remember

Agranulocytosis occurs in 1 : 1000 patients on anti-thyroid drugs. All patients prescribed anti-thyroid drugs should be warned to report severe mouth ulcers or sore throats immediately, and should have an urgent full blood count if symptoms are experienced.

Information

Investigation of a solitary nodule

• All solitary nodules > 1 cm should be evaluated, as should ‘dominant’ nodules in nodular goitres

• Fine-needle aspiration cytology is the first-line investigation to identify a papillary carcinoma or follicular neoplasm

• Ultrasound is used to diagnose multinodular goitre

• Isotope scanning might identify a toxic ‘hot’ solitary nodule; these are almost always benign

Progress.

This patient was treated with carbimazole and at 3 months was euthyroid.

Case history (3)

You have been telephoned by a doctor who has received the results of some thyroid function tests (TFTs) on one of his patients. The blood test report showed a high free T4: 45 pmol/L (10–25 normal range) with a suppressed TSH (< 0.1 mU/L). On further questioning it transpires that the test was performed in a patient who was unwell with a painful neck. You recommend a thyroid technetium uptake scan which shows minimal uptake, and arrange for the patient to come to outpatients in 2 weeks.

When you see the patient he is better but still clinically hyperthyroid and repeat TFTs are as follows: free T4 7 pmol/L; TSH 25 mU/L.

This patient is now biochemically hypothyroid, although the initial biochemistry demonstrated hyperthyroidism.

This presentation is strongly suggestive of viral thyroiditis (de Quervain’s). Thyroid hormones are released in the early stage (when the patient is thyrotoxic) and patients typically become biochemically, and later clinically, hypothyroid. The tissue effects of high levels of thyroxine last longer than their serum levels and sypmtoms often lag behind the biochemical changes.

Progress.

Viral thyroiditis does not usually require treatment; hypothyroidism is often transient, although a short course of thyroxine (3–6 months) should be used if high TSH persists. Autoantibodies might be positive because of the viral damage and do not necessarily predict long-term thyroid dysfunction. Thyroid function tests at 6–12 months were normal in this patient.

Features of viral (de Quervain’s) thyroiditis

• Neck discomfort or pain on swallowing and a short course of prednisolone is used if pain is severe

• History of viral illness

• Hyperthyroidism (usually 1–3 weeks followed by hypothyroidism), followed by resolution

• Disparity between clinical features and biochemistry

• High ESR

• Reduced uptake on technetium uptake scan

• Weakly positive anti-thyroid antibodies.

Case history (4)

A 42-year-old female was brought to A&E as an emergency with a 24-hour history of vomiting, diarrhoea and two seizures. She had become confused and was now very drowsy.

She was accompanied by her partner who explains that she has been unwell for 6 months with a thyroid problem, for which she takes tablets. Following a severe cold 7 days ago he thinks that she has stopped her therapy.

On examination she has a GCS of 8 with the following findings.

• Tachycardia > 145 beats per minute, ? atrial fibrillation

• Hyperpyrexia > 41°C

• Heart failure

• Jaundice

• Psychosis.

Patients who have two or more of the above have a high mortality. Symptoms can also include vomiting, diarrhoea, seizures and coma.

Thyroid storm

This is defined as being present in a patient with hyperthyroidism biochemically and any two of the above features. It is a rare medical emergency because thyrotoxicosis is now easy to diagnose biochemically and can be treated earlier than formerly.

It can be precipitated by thyroid surgery, the administration of radioiodine, the withdrawal of or non-compliance with anti-thyroid medication and by acute illness.

Treatment

• Cool the patient with tepid sponging and a fan. Do not use aspirin, which is contraindicated in thyroid storm (it displaces thyroxine from its binding globulin and increases the free T4).

• Beta blockers (propranolol 5 mg IV then 40–80 mg 8-hourly orally) unless contraindicated by asthma (Note: heart failure is not a contraindication to beta blockers).

• Fluid replacement: this needs careful assessment with central venous monitoring. Heart failure will rapidly come under control once the patient’s heart rate is lowered.

• Hydrocortisone 100 mg IV 6-hourly. This blocks T4 to T3 conversion.

• Propylthiouracil 250 mg 4-hourly.

• Potassium iodide 60 mg 8-hourly as iodine blocks thyroxine synthesis and release. This should be given at least 1 h after the propylthiouracil, which blocks iodine incorporation, but not uptake.

Progress.

This woman responded to her emergency treatment and was referred back to the Endocrine team who have now recommended radioactive thyroid treatment.

Amiodarone and thyroid function

Case history

A 45-year-old patient presents in A&E with increased breathlessness over the last few days. On direct questioning she says that she has been losing weight (8 kg) for 4 months. She gave a past history of heart problems, for which she is under the care of a cardiologist. She is unsure of the exact problem but says that she does take tablets for an irregular pulse that she has brought with her. She is on amiodarone and also takes warfarin and a diuretic.

On examination she has an irregular pulse 120/min, a raised JVP with crackles at both bases.

You diagnose mild heart failure with atrial fibrillation which is confirmed by ECG.

Treatment

You increase her diuretic to furosemide 80 mg daily and start her on enalapril at a small initial dose of 2.5 mg daily.

On post-take ward round:

Your consultant is pleased with your summary of the woman’s condition and your initial management. He asks you about the weight loss, which you have noted but so far have no explanation for.

Fortunately you have done many blood tests, including thyroid function tests, the results of which are now available. These show a free T4 30.7 pmol/L and a TSH < 0.1 mU/L. How should you proceed?

• Confirm how long the patient has been on amiodarone and check the clinical record to establish whether there are any previous TFT results, particularly those before amiodarone therapy was commenced.

• Amiodarone can cause hypo- or hyperthyroidism. In patients who have nodular thyroid disease the synthesis of thyroxine may be autonomous and is limited only by iodine availability: thyrotoxicosis may be precipitated. In others, the Wolff–Chaikoff effect may result in hypothyroidism. Amiodarone also blocks T4 to T3 conversion, causing a high T4 and normal T3.

• Examine the patient for clinical evidence of hyperthyroidism.

• The patient is clinically, as well as biochemically thyrotoxic, so start carbimazole 40 mg daily and ask the patient’s cardiologist to discontinue amiodarone and use other therapy for her atrial fibrillation. Amiodarone-induced thyrotoxicosis can require high doses of carbimazole and sometimes prednisolone is helpful in controlling the condition. Because amiodarone contains large amounts of iodine, radioiodine cannot be used.

Information

Amiodarone contains a substantial amount of iodine and has a half-life of about a month. Thus amiodarone behaves like slow-release iodine.

TFTs on amiodarone:

• Normal

• High fT4 normal TSH due to reduced conversion: monitor

• Subclinical thyrotoxicosis, i.e. suppressed TSH: change therapy

• Clinical thyrotoxicosis: change treatment and control overactivity

• Hypothyroidism: titrate thyroxine very gradually starting at 25 µg daily

Information

Wolff and Chaikoff first noted that excessive iodine suppresses thyroid function and causes short-term atrophy of the thyroid gland. Surgeons use this effect by administration of potassium iodide for 10 days before surgery. This is also why potassium iodide is used in thyroid storm.

Progress.

Cardiologists agreed that this patient should stop amiodarone and start verapamil. They said that two attempts at DC conversion had failed in the past and DC was unlikely to be successful now. The patient became euthyroid after 3 months carbimazole therapy.

Hypothyroidism

Case history

A 42-year-old woman is seen in the Well Women’s Clinic because she is having irregular periods which are sometimes very heavy. She thinks she has become menopausal and wonders about HRT. A more detailed history reveals that she has general malaise, weight gain (5 kg in 6 months), constipation and a hoarse voice.

On examination she is overweight at 68 kg (BMI 30). There is no palpable goitre but she does have swollen, non-pitting oedema of her legs and slow relaxation of her ankle jerks.

Diagnosis: Hypothyroidism.

Investigations show a raised TSH (30 µg/L) and free T4 of 4.2 pmol/L, confirming hypothyroidism. Interpretation of thyroid function tests is shown in Figure 14.4.

Figure 14.4 Interpretation of thyroid function tests.

Hypothyroidism is now diagnosed by a multitude of practitioners:

• Lipid clinic: cause of hypercholesterolaemia

• Psychiatrists: organic psychosis or depression

• Neurologists: ataxia

• ENT surgeons: dysphonia or deafness

• Cardiologists: during follow-up on amiodarone treatment

• Dermatologists: dry skin or hair

• Gynaecologists: menorrhagia, oligo- or amenorrhoea, infertility

• Geriatricians: screening test

• Diabetologists: screening test in diabetes.

In primary hypothyroidism, the TSH will always be elevated and often very high.

Adult-onset primary hypothyroidism is usually due to autoimmune disease, unless:

• Amiodarone treatment

• Previous thyroid surgery

• Previous radioiodine treatment

• Viral or post-partum thyroiditis.

Treatment

The patient, who is otherwise fit and not at risk of ischaemic heart disease, is started on 100 µg levothyroxine daily.

And then …?

It takes about 6 weeks for a steady state to be reached. Aim to increase the levothyroxine dose in 25 µg increments every 6 weeks until the TSH is within or just below the normal range (3–3.5 mU/L). Occasionally, patients require only 50–75 µg daily although usually 100–150 µg daily is required. Think about associated autoimmune diseases:

• Vitamin B₁₂ deficiency

• Myasthenia gravis

• Addison’s disease

• Coeliac disease

• Other organ specific autoimmune diseases.

If the patient had angina, be very careful indeed. Many clinicians start at 25 µg per day (or even alternate days) and increase every 4–6 weeks. With hypothyroidism or when attempting thyroxine replacement with unstable angina, treat the heart disease first.

Addison’s disease

Case history

A 35-year-old teacher has been under the care of a gynaecologist whom she consulted for amenorrhoea and menopausal symptoms. She has been increasingly tired and has lost weight over a 6-month period. She presents acutely to A&E with a 2-day history of vomiting and postural hypotension.

On examination she has a dull, slightly grey/brown pigmentation easily seen on her palmar creases. Her blood pressure is 80/60 with a postural drop.

Electrolytes:

• Sodium: 127 mmol/L

• Potassium: 5.2 mmol/L

• Urea: 16 mmol/L

• Creatinine: 140 µmol/L.

The clinical presentation and electrolytes indicate adrenal insufficiency. Treatment with glucocorticoids (e.g. hydrocortisone) and IV 0.9% saline is life-saving in this situation and should be started immediately after a blood sample is taken for plasma cortisol/ACTH measurements.

Adrenal insufficiency presents gradually – over months – but also, as in this case, with acute haemodynamic collapse, often precipitated by infection, trauma or surgery. Crises can also occur in patients with known Addison’s disease during relatively trivial episodes such as a viral infection; for this reason patients are advised to increase (typically double) the dose of hydrocortisone during illness.

Patients who are on long-term steroids for inflammatory conditions such as asthma also have pituitary adrenal suppression but do not develop the same pattern of electrolyte disturbance and rarely become so unwell because they have preserved mineralocorticoid (i.e. aldosterone) secretion.

Clinical findings in Addison’s disease

Acute

• Hypotension (may be severe or postural)

• Nausea and vomiting

• Diarrhoea

• Hyponatraemia and hyperkalaemia

• Metabolic acidosis

• Hypercalcaemia

• Mild elevation of TSH.

Immediate management of this patient

General

• IV 0.9% saline

• Correct hypoglycaemia with 5% glucose

• Identify and treat a precipitating cause.

Specific

• Take samples for cortisol and ACTH.

• Hydrocortisone (100 mg IM); the intramuscular route gives sustained plasma levels.

• Continue hydrocortisone 50–100 mg IV/IM × 4 daily.

Further investigations

• FBC (anaemia, normochromic normocytic)

• Glucose (hypoglycaemia)

• Serum calcium (might be high)

• ABGs (acidosis)

• CXR (TB, carcinoma)

• Short tetracosactide test (see Information box) if necessary to confirm diagnosis

• Pituitary MRI if hypopituitarism suspected

The initial cortisol in this woman was < 100 nmol/L so that Addison’s disease is confirmed. In a less clear cut case, use a tetracosactide test.

Patients on steroids for surgery

Case history

A 50-year-old woman who is known to have chronic asthma and who has been on oral prednisolone between 10 mg and 40 mg for at least the last 10 years is admitted for a right hemicolectomy for a caecal carcinoma. Her asthma has been difficult to control on inhalers alone and she finds that her asthma worsens whenever her dose of oral prednisolone is reduced to 10 mg, which she is on at present.

How should the patient’s steroids be continued following surgery?

Patients who have been on prednisolone for more than 3 months are likely to have a suppressed pituitary–adrenal axis (Fig. 14.5). Adrenal mineralocorticoid production will be normal, so that the risks of a typical Addisonian crisis are small, but nevertheless this patient will not be able to mount the normal cortisol response to surgery. Glucocorticoid replacement should be given as follows:

• At induction: hydrocortisone 100 mg IM; then

• 50–100 mg IM or IV for 3 days.

An intravenous infusion of hydrocortisone (25–100 mg over 24 h, i.e. 1–4 mg per hour) should be given to all patients who will have a prolonged period NBM or who are on ITU. The pharmacokinetics of hydrocortisone are such that such a continuous infusion of 4 mg will achieve a steady-state plasma cortisol level of > 500 nmol/L, similar to patients on ITU with normal adrenals. A serum cortisol sample after 12 h of infusion can be used to titrate the hydrocortisone infusion down to achieve a cortisol level of 500–750 nmol/L. Hydrocortisone 100 mg every 6 h when given IM will also achieve a similar concentration of cortisol.

Figure 14.5 Control of the hypothalamic-pituitary-adrenal axis. Pituitary ACTH is secreted in response to hypothalamic CRH (corticotrophin-releasing hormone) triggered by circadian rhythm, stress and other factors, and stimulates secretion of cortisol from the adrenal. Cortisol has multiple actions in peripheral tissues and exerts negative feedback on pituitary and hypothalamus.

Note: Oral hydrocortisone has a greater bioavailability than intravenous hydrocortisone.

Information

Once-daily steroids are used in pharmacological doses to treat inflammatory conditions. Such treatment is not appropriate for hydrocortisone replacement in patients with Addison’s disease, patients who have congenital adrenal hyperplasia (who might not be able to synthesise any adrenal steroids) or following adrenalectomy, when patients are at risk of true Addisonian crises. These patients need twice-daily treatment.

Progress.

This patient’s postoperative period was prolonged due to her asthma and she spent 48 hours in ITU. She eventually made a good recovery but is continuing to need oral steroids.

Hypercalcaemia

Case history (1)

A 56-year-old female patient who has been found to have fibroids has been admitted for a hysterectomy. She has treated hypertension but no other known illness, and no symptoms other than menorrhagia. A routine biochemical screen has revealed a corrected calcium of 2.75 mmol/l (NR 2.20–2.60 mmol/L).

Information

An incidental finding of a raised serum calcium is a common presentation of hypercalcaemia and should be evaluated.

Biochemical features of primary hyperparathyroidism

• Elevated PTH in the presence of hypercalcaemia. High normal PTH with hypercalcaemia also suggests hyperparathyroidism because any other cause of hypercalcaemia should suppress the PTH.

• Elevated or high/normal 24-h urinary calcium excretion (normal: 2–8 mmol/24 h).

• Low bicarbonate 15–20 mmol/L (PTH excess causes a mild renal tubular acidosis).

• Moderately elevated ESR.

• Normochromic anaemia.

Familial hypocalciuric hypercalcaemia (FHH) is a benign, familial, autosomal dominant condition caused by a mutation of the calcium-sensing receptor in the kidney and parathyroid gland. It is not associated with renal calculi and is asymptomatic. It can be difficult to distinguish from asymptomatic primary hyperparathyroidism. A low urinary calcium suggests the diagnosis, which is confirmed by examining family members.

Treatment of primary hyperparathyroidism

Patients who are symptomatic or who have complications should all be referred for parathyroid surgery, whatever the serum calcium level.

Most authorities suggest that the majority of asymptomatic patients should also be treated surgically because they are at risk of developing complications, and should certainly be referred for specialist opinion.

Progress.

This patient had an uneventful postoperative recovery following her hysterectomy but did not want to consider any further surgery unless it becomes absolutely necessary. She is being followed with regular serum calcium levels.

Severe hypercalcaemia

Case history

A 72-year-old woman is referred with a diagnosis of ‘recurrent hyperparathyroidism’. She had a past history of primary hyperparathyroidism treated surgically 10 years previously and had been maintained on a low dose of oral calcium.

Three months prior to admission she had become generally unwell, weak and lethargic. She reported weight loss of 5 kg. The GP had performed blood tests: corrected calcium 3.5 mmol/L; urea 16 mmol/L; creatinine 150 µmol/L. Renal function was previously normal. The patient arrived dehydrated and vomiting. She was found to have a fungating breast carcinoma, which she had kept secret.

• Recurrence of hyperparathyroidism after surgical cure is unusual and suggests a familial cause of hyperparathyroidism (e.g. multiple endocrine neoplasia) or an alternative cause, e.g. breast cancer.

• Hypercalcaemia causes dehydration by creating a secondary type of nephrogenic diabetes insipidus. As calcium clearance is itself dependent on GFR, hypercalcaemia can rapidly decompensate in the presence of fluid depletion.

Management of this patient’s severe hypercalcaemia

Information

Severe hypercalcaemia is defined as: corrected calcium > 3.5 mmol/L or > 3.0 with evidence of dehydration.

• Aggressive rehydration with 0.9% saline 4–6 L over 24 h.

• Central venous pressure monitoring is usually necessary.

This is usually sufficient to bring calcium down to 3.0 mmol/L.

• Bisphosphonate: treatment of choice for hypercalcaemia of malignancies or of undiagnosed cause. 60–90 mg infusion of disodium pamidronate via a cannula in a large vein causes normalisation of serum calcium in 80% of patients after 48 to 72 h.

Other treatments:

• Glucocorticoids (e.g. prednisolone 60 mg daily is used in sarcoidosis or vitamin D toxicity).

• In life-threatening hypercalcaemia, haemodialysis may be necessary.

Progress.

This patient’s calcium level remained within the normal range for 2 weeks. She was referred to the Oncology Department for treatment of the breast cancer and was started on an oral bisphosphonate as skeletal secondaries were demonstrated.

Hypocalcaemia

Case history

Three days after a total thyroidectomy, a 32-year-old patient develops tingling and numbness around the mouth and in the extremities. She has become emotionally labile.

On examination tapping the facial nerve (Chvostek’s sign) her upper lip twitches. A serum calcium is 1.82 mmol/L corrected. How do you proceed?

Management

• The patient’s parathyroid glands might have been inadvertently removed. Before the plasma calcium result is available, an urgent assessment of the patient must be made to determine the severity.

Clinical features of hypocalcaemia

• Abnormal neurological sensations and neuromuscular excitability

• Numbness around the mouth and paraesthesia of the distal limbs

• Hyper-reflexia

• Carpal and pedal spasms

• Tetany contractions (may include laryngospasm)

• Generalised seizures

• Chvostek’s sign is elicited by tapping the facial nerve just anterior to the ear, causing ipsilateral contraction of the facial muscles (positive in 10% of normals).

• Trousseau’s sign is elicited by inflating a blood pressure cuff for 3 min at the level of systolic blood pressure. This causes mild ischaemia, unmasks latent neuromuscular hyperexcitability and carpal spasm is observed.

• ECG: prolonged QT interval.

Information

Causes of tetany

In the presence of alkalosis:

• Hyperventilation

• Excess antacid therapy

• Persistent vomiting

• Hypochloraemic alkalosis, e.g. primary hyperaldosteronism

In the presence of hypocalcaemia: see below

How do you assess severity?

The symptoms and signs described above are a much better guide to prognosis than the absolute value of the plasma calcium. In the presence of a low calcium (corrected calcium less than 2.0 mmol/L), any of the above features should be taken as evidence that urgent treatment is required.

Causes of hypocalcaemia

• Hypoparathyroidism (primary, secondary or most commonly post-surgical)

• Renal failure (associated hyperphosphataemia)

• Vitamin D deficiency (giving rickets and osteomalacia)

• Pseudo-hypoparathyroidism (resistance to PTH)

• Severe magnesium deficiency (causes both reduced PTH secretion and resistance to PTH action)

• Acute pancreatitis

• Rhabdomyolysis.

How do you manage symptomatic hypocalcaemia?

The aim of acute management is not to return the calcium to normal but to ameliorate the acute manifestations of hypocalcaemia (Table 14.9).

Progress.

This patient’s serum calcium was normal on the 4th postoperative day and she made an uneventful recovery.

Information

Administration of alfacalcidol (0.5–1.0 µg), together with oral calcium gluconate, is used for chronic hypoparathyroidism with regular calcium monitoring.

Phaeochromocytoma (catecholamine crisis)

Phaeochromocytomas are rare catecholamine-producing tumours derived from neuroendocrine cells, usually involving the adrenal glands (90%) or elsewhere in the sympathetic chain (paragangliomas).

Case history

Three hours after a surgical procedure for colonic malignancy, a 62-year-old woman becomes hypertensive with tachycardia, inappropriate lactic acidosis and hyperglycaemia. When you review the notes you discover that she has a 3-cm adrenal mass seen on a CT scan preoperatively, which was felt to be an incidental finding by the surgical team. On further questioning, you determine that she has had a history of paroxysmal palpitations, flushing, sweating attacks and headaches for years.

This history and CT findings would be compatible with a phaeochromocytoma.

Phaeochromocytoma is known as the 10% tumour (see Information box). It can be diagnosed during routine screening of hypertensive patients (found in only 0.1% of hypertensive subjects), the investigation of unusual episodes or cardiac events of uncertain aetiology. Phaechromocytomas are usually associated with hypertension, ‘attacks’ and/or headache. They secrete adrenaline or noradrenaline (Fig. 14.6).

Figure 14.6 The synthesis and metabolism of catecholamines. DOPA, dihydroxyphenylalanine; COMT, catechol-O-methyl transferase; MAO, monoamine oxidase.

Information

Phaeochromocytoma – the 10% tumour

• 10% are bilateral

• 10% are extra-adrenal, usually around the sympathetic chain, when they are known as paragangliomas

• 10% are malignant

Associations

A family history is vital, particularly in young patients, and might reveal the following autosomal dominant conditions:

• Neurofibromatosis type I (neurofibromata, café au lait spots, Lisch nodules (iris hamartomas) and axillary freckling)

• von Hippel–Lindau disease (cerebellar haemangioblastomas, retinal haemangiomas and renal cell carcinoma)

• Multiple endocrine neoplasia type 2 (medullary thyroid carcinoma and hyperparathyroidism)

• Hereditary paraganglioma syndromes (phaeochromocytoma, carotid body tumour).

Diagnostic tests include

• U&Es: potassium often low, urea may be high if dehydrated

• Glucose: hyperglycaemia.

• Urinary catecholamines (adrenaline, noradrenaline and dopamine) are measured by most laboratories. Two sets of normal 24-h urinary catecholamines make a phaechromocytoma very unlikely.

• Plasma (heparinised) catecholamines (adrenaline, noradenaline and dopamine) are specific but not sensitive tests. The blood must be taken directly to the lab for centrifugation.

• MRI/CT scan of the adrenals should be delayed until biochemical diagnosis but are useful in localising the lesion.

• MIBG scan: MIBG (¹³¹I-metaiodobenzylguanidine) is taken up selectively by adrenal tissue and is useful for localisation of tumour, particularly in extra-adrenal sites.

How would you manage this case?

• Adequate fluid replacement with 1 L 0.9% saline intially over 1 hour, then 1 L 8-hourly, usually with CVP monitoring.

• Initiate oral alpha blockade: phenoxybenzamine 10 mg × 3 daily increasing gradually to 40 mg × 3 daily.

• When the blood pressure is controlled with phenoxybenzamine and a reflex tachycardia occurs, add propranolol 10–40 mg × 3 daily. Do not use Labetalol.

• Surgery: hypotension commonly occurs intra-operatively when the tumour is removed, and this should be managed with blood, plasma expanders and inotropes as required. Inotropes should be used only when the patient is appropriately fluid replete. Expansion of intravascular volume 12 h before surgery significantly reduces the frequency and severity of postoperative hypotension.

• In emergency (hypertensive crisis) intravenous phentolamine (1–5 mg) should be used, but great care should be taken to adequately rehydrate the patient in order to prevent severe hypotension.

Progess.

This patient improved with α and β blockade and her blood pressure stabilised. She was referred to the Endocrine Department who, after further investigations, recommended surgical removal of the tumour.

Hypopituitarism

Pathophysiology

Deficiency of hypothalamic releasing hormones or of pituitary trophic hormones can be selective or multiple. Thus isolated deficiencies of GH, LH/FSH, ACTH, TSH and vasopressin are all seen, some cases of which are genetic and congenital and others sporadic and autoimmune or idiopathic in nature.

Multiple deficiencies usually result from tumour growth or other destructive lesions. There is generally a progressive loss of anterior pituitary function. GH and gonadotrophins are usually first affected. Hyperprolactinaemia, rather than prolactin deficiency, occurs relatively early because of loss of tonic inhibitory control by dopamine. TSH and ACTH are usually last to be affected.

Case history

A 60-year-old man is admitted with a sudden onset of explosive headache and a left third nerve palsy. CT scan showed no evidence of an intracranial haemorrhage. An LP showed a mild lymphocytosis.

Viral meningitis is suspected but his recovery is slow. He is noted to have small testes and a hypogonadal appearance. Six weeks later he is readmitted with weight loss and a chest infection. Endocrine screening shows a low 09:00 serum cortisol and undetectable serum testosterone.

Diagnosis.

Hypopituitary coma and apoplexy.

Pituitary apoplexy occurs with infarction or haemorrhage into an undiagnosed pituitary tumour. It produces severe headache with sudden visual field defects or ocular palsy. Axial CT scan can miss pituitary apoplexy but MRI usually shows the tumour.

Features of pituitary apoplexy

Pituitary infarction can be silent. Apoplexy implies the presence of symptoms:

• Headache occurs in 75% of cases (may be sudden onset, very severe, or mild)

• Visual disturbance (compression of optic tract, usually causing bitemporal hemianopia)

• Ocular palsy present in 40% of cases: unilateral or bilateral

• Nausea/vomiting

• Meningism

• Hemiparesis.

Clinically, pituitary apoplexy can be very difficult to distinguish from subarachnoid haemorrhage, bacterial meningitis, mid-brain infarction (basilar artery occlusion) and cavernous sinus thrombosis.

Initial investigation

An MRI of the pituitary reveals a tumour mass. Note: MRI will often reveal a pituitary tumour although it cannot distinguish between recent and old haemorrhage (CT might help).

A single clotted blood sample should be taken to measure cortisol, thyroid function, prolactin, growth hormone, testosterone (in men) and the gonadotrophin hormones.

Assessment of severity

The course of pituitary apoplexy is variable. Headache and mild visual disturbance can develop slowly and persist for several weeks. In the acute form, apoplexy might cause optic nerve compression, haemodynamic instability, coma and is potentially fatal. Neurosurgical advice should always be sought. Residual endocrine disturbance invariably occurs. Panhypopituitarism is the usual result. Table 14.10 shows the replacement therapy that is required.

Table 14.10 Replacement therapy for hypopituitarism

Axis	Usual replacement therapies
Adrenal	Hydrocortisone 15–40 mg daily (starting dose 10 mg on rising/5 mg lunchtime/5 mg evening) (Normally no need for mineralocorticoid replacement)
Thyroid	Levothyroxine 100–150 mcg daily
Gonadal
Male	Testosterone IM, orally, transdermally or implant
Female	Cyclical oestrogen/progestogen orally or as patch
Fertility	HCG plus FSH (purified or recombinant) or pulsatile GnRH to produce testicular development, spermatogenesis or ovulation
Growth	Recombinant human growth hormone used routinely to achieve normal growth in children Also advocated for replacement therapy in adults where growth hormone has effects on muscle mass and well-being
Thirst	Desmopressin 10–20 mcg 1–3 times daily by nasal spray or orally 100–200 mcg 3 times daily Carbamazepine, thiazides and chlorpropamide are very occasionally used in mild diabetes insipidus
Breast (prolactin inhibition)	Dopamine agonist (e.g. cabergoline 500 mcg weekly)

FSH, follicle-stimulating hormone; GnRH, gonadotrophin-releasing hormone; HCG, human chorionic gonadotrophin.

Information

• Neurosurgical decompression via a trans-sphenoidal route is the definitive treatment for pituitary apoplexy

• Obtundation and visual deterioration are absolute indications for neurosurgery

• Patients without confusion or visual disturbance generally do well without surgery

Management of this patient’s acute hypopituitarism

• Diagnostic samples for cortisol, TFTs, prolactin (single plain venous sample).

• Hydrocortisone 100 mg (preferably IM) should be administered when the diagnosis is suspected.

• Administer glucose if the patient is hypoglycaemic.

• Investigate and treat his chest infection.

How do patients with hypopituitarism present?

• Patients present at times of stress (e.g. following a general anaesthetic) with hypoglycaemia due to the combination of a lack of GH, cortisol and thyroxine, all of which have a counter-regulatory effect on insulin.

• Post-partum infarction of the gland occurs following post-partum haemorrhage and vascular collapse during a difficult delivery (Sheehan’s syndrome). This diagnosis should be suspected with failure to lactate, amenorrhoea and general ill-health post-partum.

• Other features of hypopituitarism are non-specific and include tiredness, weakness, loss of body hair and loss of libido (sexual interest) and features of hypothyroidism.

• Note that patients with ACTH deficiency have no postural blood pressure drop and normal electrolytes, as adrenal mineralocorticoids (aldosterone) are unaffected.

Assessment of severity

The degree of hypopituitarism bears little relationship to the clinical state of the patient. In the absence of stress, patients with severe hypopituitarism might have few complaints. Examination of the testes in males might reveal small testes and women can demonstrate either amenorrhoea or inappropriately low post-menopausal gonadotrophins. Patients with mild hypopituitarism might become profoundly unwell at times of stress, such as during an intercurrent infection.

Causes

• Destruction of the pituitary gland by primary or metastatic tumour

• Ischaemic necrosis after post-partum haemorrhage

• Pituitary apoplexy

• Post-pituitary surgery or radiotherapy

• Primary empty sella syndrome.

Investigations of anterior pituitary function

• Baseline blood samples must be taken for cortisol, free thyroid hormone levels, testosterone LH, FSH, prolactin and growth hormone levels.

• Dynamic investigation of pituitary function can be deferred and the patient should be treated expectantly with hydrocortisone (e.g. 10 mg × 2 daily once stable).

• Imaging using CT with fine cuts through the pituitary or MRI is indicated to find any space-occupying lesion.

Progress.

This patient’s hypopituitarism improved without surgery and at 3 months his serum hormone levels were normal. He was evaluated further for possible treatment of his pituitary adenoma.

Diabetes insipidus

Transient diabetes insipidus (DI) often occurs following pituitary surgery because of vasopressin deficiency, and can also occur acutely following head injury. Consider DI if asked to see a patient with polyuria and polydipsia who has normal blood glucose. DI is also a cause of hypernatraemia.

Case history

You are called to see a patient who had a trans-sphenoidal hypophysectomy the day before for a non-functioning pituitary adenoma. He has made a good recovery from surgery but now complains of severe thirst and is passing large volumes of dilute urine. Results of his investigations:

• Urine SG (dipstick): 1.001.

This patient probably has transient diabetes insipidus.

How would you manage this patient?

• Ensure adequate access to water or commence IV glucose 5% and 0.18% saline to match urine output if the patient cannot drink enough.

• Make sure an accurate fluid balance chart is being maintained.

• If urine output > 200 mL/hour for 2 consecutive hours, check plasma and urine osmolality.

• DI is confirmed by the presence of a high plasma osmolality (> 290) in the presence of an inappropriately low urine osmolality (< 500 mOsmol/kg).

• Start desmopressin: adult dose 0.5–1.0 µg SC stat followed by 10–40 µg × 3 daily as an intranasal spray.

• If the plasma osmolality is low the patient might be over-drinking due to a dry mouth, and a low urine osmolality is appropriate. In this circumstance, administration of desmopressin will cause a further fall in plasma osmolality and can be dangerous.

Other causes of diabetes insipidus

Diabetes insipidus is either cranial (CDI) or nephrogenic (NDI) due to the inability of ADH to act on the kidney (Table 14.11).

Table 14.11 Cranial and nephrogenic causes of diabetes insipidus

Cranial DI	Nephrogenic DI
Hypothalamic tumour	Drugs:
Basal skull fracture	diuretics
Neurosarcoidosis	lithium
(other hypothalamic disease)	Hypercalcaemia
Idiopathic	Hypokalaemia
Infection Inflammatory	Kidney disease e.g. renal tubular acidosis
	Idiopathic