Oxford Medical Publications Oxford Handbook for the Foundation Programme

► Airway	Check airway is patent; consider manoeuvres/adjuncts
► Breathing	If no respiratory effort—CALL ARREST TEAM
► Circulation	If no palpable pulse—CALL ARREST TEAM
► Disability	If gcs ≤8—CALL ANAESTHETIST

►► Call for senior help early if patient deteriorating.

• Blood glucose is normally >3.5mmol/L

• Poorly controlled diabetics can have symptoms of hypoglycaemia with a glucose >3.5mmol/L.

Coma or low GCS with low glucose

GCS 15/15 with low glucose

• Give 15–20g of quick-acting carbohydrate (eg. 170–225mL Lucozade^®) or one glucose gel (eg GlucoGel^®) orally

• Monitor finger-prick glucose 1–2h until stable, aim for >5mmol/L

• If CBG remains <4.0 mmol/L despite 3× oral glucose, consider glucagon or IV glucose as above mentioned

• Once the patient has recovered, give a long-acting carbohydrate (eg toast, biscuits)

• Attempt to determine the cause of the hypoglycaemia (Box 10.1) and adjust diabetes treatment as appropriate.

► Box 10.1 Causes of hypoglycaemia

Hypoglycaemia

► Worrying features ↓gcs, recurrent episodes, loss of awareness,¹ non-diabetic, lacking insight, or unable to communicate symptoms.

Think about Most likely Excess insulin or oral hypoglycaemics in a diabetic or accidental dose in non-diabetic, alcohol; Other Dumping syndrome (DM or post-gastric surgery), liver failure, adrenal failure (Addison’s), pituitary insufficiency, sepsis, insulinoma, other neoplasia, malaria. Ask about Sweating, hunger, exercise, recent food, previous hypos and awareness,¹ usual blood sugars, seizures, weight loss, tiredness, anxiety, palpitations; PMH dm, gastric surgery, liver or endocrine disease; DH Insulin dose, oral hypoglycaemic dose, compliance; SH Alcohol, Occupation (eg commercial driver).

Obs hr, bp, rr, temp, gcs, recent and current blood glucose.

Look for Pale, sweating, tremor, slurred speech, focal neurology (can be severe, eg hemiplegia), ↓GCS, abdo scars (injection sites, lipodystrophy), pigmented scars, jaundice, spider naevi, hepatomegaly.

Investigations Finger-prick glucose If the result is unexpected ask for a repeat on a different machine and send a blood sample in a fluoride oxalate ( p. 531) tube for a laboratory glucose result. If not known to be diabetic send samples for fbc, u+e, lft, glucose, insulin, C-peptide, and cortisol, prior to correcting hypoglycaemia; do not let this delay treatment. Further investigations Hypoglycaemia is very rare in an otherwise healthy non-diabetic patient in the absence of alcohol. Consider ‘other’ causes listed previously (also see Box 10.2). For suspected insulinoma, the investigation of choice is glucose, insulin, and C-peptide levels at the time of hypoglycaemia or after a 72h observed fast. See OHCM10 p. 214.

Treatment Follow treatment for ‘Hypoglycaemia emergency’ ( p. 328). DM A single episode of mild hypoglycaemia should not prompt a change of medication. If the patient is having regular hypos then consider a dose reduction, especially if lack of awareness of hypoglycaemic episodes. Try to establish any diurnal pattern of hypos, then reduce appropriate insulin dose by 20%; consult BNF to reduce the doses of oral hypoglycaemics. Ensure the patient is aware of the sick day rules ( Box 10.7 p. 335). Alcohol Hypoglycaemia following alcohol will not reoccur after correction in the absence of further alcohol consumption. Once the patient’s blood sugars are stable they can be discharged. Dumping syndrome Fast passage of food into the small intestine (following gastric surgery or in severe diabetic autonomic neuropathy) can cause fluid shifts and rapid glucose absorption. Excessive insulin secretion results in rebound hypoglycaemia 1–3h after a meal. A diet low in glucose and high in fibre will improve the symptoms. Aim for frequent, smaller meals. Neoplasia If suspected, arrange appropriate imaging and referral

⇄ Box 10.2 Hypoglycaemia covered elsewhere

Addison’s/pituitary failure p. 337, p. 338	Sepsis p. 494
Acute liver failure p. 320

► Hyperglycaemia emergency

► Airway	Check airway is patent; consider manoeuvres/adjuncts
► Breathing	If no respiratory effort—CALL ARREST TEAM
► Circulation	If no palpable pulse—CALL ARREST TEAM
► Disability	If gcs ≤8—CALL ANAESTHETIST

►► Call for senior help early if patient deteriorating.

Diabetic ketoacidosis (DKA) ( p. 332.)

• 15L/minO₂ if SOB or sats <94%

• Call for senior help

• Establish venous access, take bloods:

• fbc, u+e, glucose, osmolality, hco⁻₃, bld cultures

• Check BP:

• if SBP<90mmHg, give 500mL 0.9% saline IV over 10–15min then recheck; if SBP <90, give further 500mL 0.9% saline IV over 10–15min and call ICU/critical care teams.

• if SBP ≥90, give 1L 0.9% saline IV over 60min

• Check finger-prick glucose and ketones (dipstick urine for ketones if capillary testing unavailable)

• Start a fixed rate insulin infusion of 0.1unit/kg/h IV (use 50units human soluble insulin eg Actrapid^® in 50mL 0.9% saline; max. rate 15unit/h)

• Venous blood gas; if pH <7.1 call ICU/critical care team

• Monitor glucose and ketones hourly, and venous hco⁻₃ and K⁺ at 60min and 2hrly thereafter (Box 10.3); remember K⁺ will fall unless replaced

• Further management p. 332; ECG, CXR, MSU to determine cause

• Reassess, starting with a, b, c …

► Box 10.3 Consider HDU admission in DKA for:

• Heart or kidney failure

• GCS <12, sats <92%

• SBP <90

• Young people, elderly, comorbidities, or pregnant

• Ketones >6mmol/L, hco⁻₃ <5mmol/L, pH <7.1

• K⁺ <3.5mmol/L, anion gap >16 p. 599

Hyperosmolar hyperglycaemic state (HHS) ( p. 332.)

► Box 10.4 Life-threatening precipitants of DKA/HHS

• Sepsis

• MI

• Trauma/surgery

• Other acute illness.

Hyperglycaemia

► Worrying features ↓GCS, ketonuria, acidosis, vomiting.

Think about ► Emergencies Diabetic ketoacidosis (DKA p. 332), hyperosmolar hyperglycaemic state (HHS p. 332); Common After sugary food, steroids, non-compliance with diabetic treatment, infection, or acute illness (in diabetics or severely unwell non-diabetics), new diagnosis of DM.

Ask about ‘Osmotic symptoms’ (thirst, polyuria, frequency, urgency), tiredness, weight loss, vomiting, rashes, breathlessness, cough, sputum, chest pain, abdo pain, dysuria; PMH dm; DH Insulin dose, oral hypoglycaemic dose, medication changes and compliance, steroids; SH Alcohol.

Obs Temp, rr, gcs, urine dip, BM, recent and current blood glucose, fluid balance.

Look for Volume status ( p. 394), sweet-smelling breath (ketones). Signs of infection Check skin thoroughly (including perineum and feet) for abscesses or rashes and injection site problems, look in mouth for dental infection, chest for poor air entry or creps, abdominal tenderness.

Investigations Finger-prick glucose (±ketones if available and suspect DKA) repeat if result unexpected; Urine dipstick Ketones, evidence of infection ( pp. 604–605); blds Send if patient is unwell, has persistent hyperglycaemia (over 48h), or has urinary ketones (type 1 dm), request fbc, u+e, lft, osmolality, pH/hco⁻₃ (venous), blood cultures; ABG Unnecessary unless concerns regarding respiratory status (venous pH adequate for DKA); ECG/CXR If treatment has been required.

Treatment A single episode of hyperglycaemia in an otherwise well patient is unlikely to suggest underlying pathology. dka takes hours to days to develop while HHS takes days to weeks.

Type 1 diabetes Check finger-prick glucose (±ketones if available) and urine. Glucose is usually high in dka but may be transiently normal soon after a dose of insulin. Assess volume status ( p. 394), check dipstick for ketonuria and check a venous blood gas for ph/hco⁻₃ (normal venous pH or absence of urinary ketones excludes DKA). If hyperglycaemia persistent, try to establish any diurnal pattern and ↑ appropriate insulin doses by 20% with close monitoring of blood glucose.

Type 2 diabetes Check finger-prick glucose and urine. The glucose must be raised for a diagnosis of HHS. If unwell, follow the treatment plan for HHS initially. Otherwise monitor glucose levels every 6h for 48h, increase oral/IV fluid intake, and reassess. dka can occur in type 2 diabetics who require insulin but it is very unusual (even low levels of residual insulin production inhibit ketogenesis). For persistent hyperglycaemia increase the dose of hypoglycaemic medication or consider starting/increasing insulin with frequent finger-prick glucose checks.

Non-diabetic patients New diabetics often present with dka/HHS; have a low threshold for starting treatment plans later in this section. Other triggers These can include steroids, pregnancy, and stress, eg severe illness or surgery.

Diabetic ketoacidosis (DKA) ( oham4 p. 516.)²

Insulin deficiency resulting in ketosis→ acidosis and hyperglycaemia → dehydration due to osmotic diuresis. Typically seen following missed insulin treatments or infection in T1DM, or as a first presentation of T1DM.

Diagnose based upon presence of hyperglycaemia (≥11mmol/L), acidosis (venous pH <7.3 or hco⁻₃ <15mmol/L), and blood ketones ≥3mmol/L or ketonuria (≥2+). Stabilize the patient as shown p. 330, then:

• Continue IV insulin infusion and fluid rehydration (see ‘DKA fluids’)

• Monitor venous K⁺, pH, and hco⁻₃ after 1h, 2h, and then 2hrly using a venous sample on a gas analyser for rapid testing

• Monitor venous glucose and ketones hourly aiming for blood ketones to fall by >0.5 mmol/L/h and glucose by >3mmol/L/h

• If patient uses long-acting insulin continue at normal dose/time

• Continue fixed rate insulin infusion until ketones <0.6mmol/L and pH >7.3. At this point, convert to regular SC insulin if eating and drinking normally, otherwise use a sliding scale ( p. 333). See Box 10.5.

DKA fluids 0.9% saline is the most appropriate fluid replacement. A guide in adults would be to prescribe 1L over 1h, 1L over 2h, 1L over 2h, and 1L over 4h. If systolic BP <90mmHg on admission an initial 500–1000mL bolus must be carefully given under senior supervision. Since excess fluid replacement can lead to cerebral oedema, reassess frequently for signs of overload ( p. 394), and tailor to volume status and patient weight. Add 40mmol/L KCl after the first litre of fluid if the plasma k⁺ is 3.5–5.5mmol/L. Omit additional KCl if k⁺ >5.5; if k⁺ <3.5 seek senior review. Add a 10% glucose infusion at 125mL/h if glucose <14mmol/L but do not stop saline.

Box 10.5 Management tips in DKA/HHS

These patients require close monitoring. If severely ill, catheterize, consider admission to HDU or ICU, and an arterial and/or central line. If obtunded or persistent vomiting, keep NBM and pass NG tube. Dehydration and ↓GCS predispose to thromboembolism: give prophylactic LMWH ( pp. 420–421). Consider likely precipitants: poor compliance/incorrect insulin dose, alcohol, infections (may be asymptomatic—check blood cultures, MSU and CXR; low threshold for starting antibiotics), MI (check an ECG), CVA, surgery, pregnancy.

Hyperosmolar hyperglycaemic state (HHS) ( oham4 p. 524.)

Severe, uncorrected hyperglycaemia leads to dehydration, but in the presence of residual insulin production in T2DM, ketoacidosis does not develop. Previously referred to as hyperosmolar non-ketotic state (HONK). Diagnose based upon raised plasma osmolality³(typically >340 mOsmol/kg) with high glucose (typically >30mmol/L).

• Stabilize the patient as shown on the treatment plan p. 330, then:

• Continue IV fluid replacement based on clinical state and comorbidities (eg elderly with heart failure)

• Monitor u+e, glucose and osmolality every 2h. Be aware that hyperglycaemia will drive redistribution of water into the extracellular fluid, lowering serum Na⁺ concentrations (‘spurious hyponatraemia’)

• Commence IV insulin (fixed rate 0.05 units/kg/hr) only once glucose has stopped falling with IV fluids alone (unless i blood ketones at diagnosis)

Sliding scales

These allow strict monitoring and control of blood glucose levels. They are used in the treatment of diabetic patients requiring insulin whose oral intake is significantly disrupted (eg NBM, severe vomiting, or serious illness), and in critical illness, where good glycaemic control improves outcomes, eg post MI or on ICU, but are no longer used in the management of DKA or HHS where fixed-rate insulin infusions are advised.

Both the insulin infusion and appropriate IV maintenance fluids are prescribed on the infusions section of the drug card (Fig. 10.1). Use 0.9% saline or 5% glucose (with KCl as necessary), according to the blood glucose (use 0.9% saline if the glucose is running >11mmol/L).

Fig. 10.1 Prescribing insulin and fluids for a sliding scale.

Fig. 10.2 Example of sliding scale regimen (check local guidelines).

Fig. 10.3 Prescribing subcutaneous insulins.

If the patient remains hyperglycaemic despite the sliding scale (Fig. 10.2) then check the infusion pump and cannula; if no problems found, then increase infusion rates by 1.5–2-fold, and check venous pH (T1DM) or osmolality (T2DM). If the capillary blood glucose is <4mmol/L check that there is 5% glucose running, increase the fluid rate and/or glucose concentration (up to 10%); recheck glucose in 30min. If persistently <4mmol/L stop the sliding scale, and restart the infusion at half the doses once blood glucose >6mmol/L. If glucose <2 p. 328.

Stop a sliding scale once a patient is eating normally and able to resume normal diabetes medication. Give normal dose of SC insulin 30min before stopping the scale, unless rapid acting (eg Novorapid^®, Humalog^®) in which case give at same time as stopping the scale.

Prescribing insulin

Most hospitals have separate drug cards for prescribing insulin. Always specify the insulin formulation, and avoid using the abbreviation ‘U’ for units (since this can be misread as a zero). See Fig. 10.3 for an example.

Diabetes mellitus

Fasting plasma glucose ≥7.0mmol/L, or ≥11.1mmol/L 2h after a 75g oral glucose load ⁴or HbA_1c >48 mmol/mol (on one occasion if symptomatic or 2 occasions in no symptoms).

• Type 1 Autoimmune pancreatic β-cell destruction, resulting in dependence on exogenous insulin; typically presents in children or young adults

• Type 2 Relative insulin hyposecretion or resistance to effects, requiring drugs to potentiate insulin secretion or effects, or exogenous insulin; typically occurs in adults, especially if overweight

• Impaired glucose tolerance (IGT) HbA_1c 42–47mmol/mol or plasma glucose ≥7.8mmol/ L after OGTT, but <11.1mmol/ L; 20–50% progress to T2DM in 10yr

• Impaired fasting glucose (IFG) Plasma glucose ≥6.1mmol/L after an overnight fast, but <7.0mmol/L; lower risk of developing T2dm

• Gestational Any degree of glucose intolerance first detected during pregnancy ( p. 519); around 30% will progress to T2DM within 5yr.

Type 1 DM ( OHCM10 p. 206.)

Symptoms Tiredness, weight loss, thirst, polyuria, abdo pain, vomiting.

Signs Sweet-smelling breath, shock, abdominal pain (all suggest DKA).

Investigations Glucose testing as previously mentioned. Check venous hco⁻₃ and pH and urine (ketones) to exclude DKA. If uncertainty about type of diabetes, positive islet cell or glutamic acid decarboxylase antibodies, or low C-peptide levels all suggest T1DM. Check HbA_1C (see Box 10.6).

Treatment Resuscitate and investigate for dka; in the absence of DKA, a new diagnosis of T1DM does not necessitate admission, but the patient should be started on a suitable insulin regimen by an appropriately experienced individual (eg endocrine registrar or diabetes nurse specialist) with regular finger-prick glucose monitoring and prompt out-patient follow-up. For properties of some commonly used insulins p. 205. Chronic management p. 336. Involve diabetes team ASAP.

Box 10.6 HbA_1c

HbA_1c reflects non-enzymatic glycosylation of haemoglobin at a rate proportional to plasma glucose. Since erythrocytes (and hence haemoglobin) undergo slow but constant turnover, HbA_1c reflects plasma glucose control over the preceding 1–3 months and is a reliable predictor of diabetes complications. Target HbA_1c levels should be set with patient involvement, taking into account an individual’s risk profile, as well as tolerability of therapy. Initial targets in both T1DM and T2DM are 48mmol/mol (looser targets applied if frail elderly or treatment refractory), with treatment intensification in T2DM if levels rise to 58mmol/mol.⁵

Type 2 DM ( OHCM10 p. 206.)

Symptoms As for type 1, but can also present with diabetic complications, eg visual problems, neuropathy, mi, CVA, claudication.

Signs Foot ulcers, infections, peripheral neuropathy, poor visual acuity and retinopathy, evidence of cardiovascular disease.

Investigations blds Confirm diagnosis based upon plasma glucose testing ±OGTT ( pp. 334–336), HbA_1c (Box 10.6), U+E, lipid profile; ECG.

Treatment T2DM may initially be controlled by a healthy diet with minimal rapid-release carbohydrates (as found in sugary drinks or sweets) and weight loss. If medication required, uptitrate pharmacological agents (usually to triple therapy) before adding in insulin therapy (Table 10.1). Chronic management p. 336. See Box 10.7.

Table 10.1 Medications for glycaemic control in T2DM^*

Class	Examples	Comment
Biguanides	Metformin	1st line for obese; ↑glucose uptake and ↓appetite; avoid if any renal failure
Sulphonylureas	Gliclazide	Add to metformin (1st line if metformin not suitable); ↑insulin secretion, but causes weight gain. Cautious use in the elderly due to risks of hypoglycaemia
Thiazolidinediones	Pioglitazone	2nd line if other drugs not tolerated or effective; ↓insulin resistance; avoid in heart failure
DPP-4 inhibitors	Sitagliptin	2nd line if other drugs not tolerated or effective; ↑insulin and ↓glucagon secretion
SGLT2 inhibitor	Dapagliflozin	2nd line if other drugs not tolerated or effective; blocks renal reabsorption of glucose and promotes urinary excretion of excess glucose
GLP-1 activators (given SC)	Exenatide, liraglutide	2nd line if other drugs not tolerated or effective, especially if ↑BMI; ↑insulin and ↓glucagon secretion
Insulin	Isophane (given SC)	Added eg if triple oral therapy insufficient (or if metformin not tolerated and dual therapy insufficient)
α-glucosidase inhibitors	Acarbose	Rarely used in current practice; ↓carbohydrate absorption; causes flatulence

*For more information, NICE guidelines are available at guidance.nice.org.uk/CG87

Box 10.7 Sick day rules

Educate diabetic patients about what to do if they are feeling unwell:

• Drink plenty of fluids

• If not eating, try milk, soup, fruit juice, or fizzy drinks instead

• Increase frequency of blood glucose monitoring to at least 4 times/day

• Seek medical attention if you cannot keep fluids down, becoming drowsy or confused, blood glucose <4mmol/L or persistently >20mmol/L

• If on insulin ►► This should never be stopped; hyperglycaemia can arise from intercurrent illness, regardless of calorie intake. Consider increasing insulin dose if blood glucose >13mmol/L even if unable to eat. Dipstick urine for ketones at least daily and seek medical attention if +ve

• If on tablets Continue regular diabetic medications providing calorie intake continues. Metformin may need to be stopped if becoming dehydrated: seek medical advice.

Long-term management of diabetes mellitus

Diabetes mellitus is associated with macrovascular (IHD, CVA, PVD) and microvascular (nephropathy, neuropathy, retinopathy) complications. Large, long-term studies show reductions in complications with control of risk factors; these should be assessed at least annually in a formal review.⁶,⁷

Education and lifestyle Ensure understanding and motivation for glycaemic control (including self-monitoring, medication compliance, and diet as well as assessing risk of hypoglycaemic unawareness). Modify risk factors for complications (physical activity, smoking cessation, foot care). Refer for education classes.

Glycaemic control Measure HbA1c (every 3–6mth) and adjust therapy accordingly (see Box 10.6); consider revising target if tight control unacceptable to patient based upon individual risk profile.

BP Aim for BP <140/80 (uncomplicated T2DM) or <135/85 (uncomplicated T1DM); if end-organ damage aim for BP <130/80 ( pp. 270–273). Use an ACEi as 1st line (plus diuretic or Ca²⁺ channel blocker if African-Caribbean descent).

Lipids Measure lipid profile and consider cardiovascular risk factors; in all T2DM age >40yr (except those judged to be very low risk) initiate statin therapy (primary prevention—atorvastatin 20mg) and assess response; in T1DM consider statin therapy in those with microalbuminuria, family history, age >35yr, or other high-risk features.

Nephropathy Test early morning urine albumin:creatinine ratio; if ≥2 repeated measurements show microalbuminuria (♂: >2.5mg/mmol, ♀: >3.5mg/mmol), tighten BP control, initiate ACEi and consider renal referral.

Retinopathy Arrange annual retinal screening; sudden loss of vision, rubeosis iridis, pre-retinal or vitreous haemorrhage, or retinal detachment require emergency ophthalmology review; new vessel formation requires urgent referral; pre-proliferative retinopathy, significant maculopathy, or unexplained change in visual acuity require routine referral.

Footcare Assess annually for ulcers, peripheral pulses, sensory function, and foot deformity. If ulcers present, refer urgently to a specialist diabetic footcare team. Those with previous ulcers, absent pulses or impaired sensation require referral to a footcare team for frequent review.⁸

Neuropathy Assess for autonomic neuropathy in the form of unexplained vomiting (gastroparesis—consider trial of prokinetic agents, eg metoclopramide), erectile dysfunction (offer phosphodiesterase-5 inhibitor, eg sildenafil), nocturnal diarrhoea, bladder voiding problems, or orthostatic hypotension. Neuropathic pain ⁹ requires oral neuropathic agent (eg gabapentin, amitriptyline, duloextine). Refractory or severe pain may require opioid analgesia and specialist pain service referral.

Pneumovax^® and yearly flu vaccines These should be offered to all patients.

Pituitary axis

Hypopituitarism

Failure of secretion may affect one or more anterior pituitary hormones.

Causes Damage to the hypothalamic–pituitary axis after surgery, irradiation, tumours, ischaemia, infection (eg meningitis), or infiltration (eg amyloidosis).

Symptoms and signs These are specific to each hormone lost, eg growth hormone (GH) loss: weakness, malaise, ↓cardiac output, hypoglycaemia; gonadotrophin (LH, FSH) loss: amenorrhoea, ↓libido, erectile dysfunction; TSH loss: hypothyroidism ( pp. 340–341); ACTH loss: glucocorticoid insufficiency ( p. 338).

Investigations Tests of pituitary function include LH, FSH, TSH, paired with target organ hormones: testosterone/oestradiol, T₄, cortisol and insulin-like growth factor-1 (IGF-1, a marker of growth hormone secretion). Dynamic testing (eg short Synacthen^® test p. 585) is also informative. Generally, testing of pituitary function should be undertaken and interpreted with specialist advice.

Treatment Identify and treat underlying cause; appropriate hormone replacement may be required eg hydrocortisone ( p. 205) or thyroxine ( p. 207).

►► On the ward, the most important point is to ensure any patient with panhypopituitarism gets regular steroids (increased in acute illness and given IV if necessary) with early endocrinologist involvement ( p. 332).

Diabetes insipidus

Inability to form concentrated urine due to loss of either ADH secretion (neurogenic) or renal response (nephrogenic).

Causes Neurogenic idiopathic, brain tumour or metastases, head trauma, cranial surgery; Nephrogenic drugs (eg lithium), CRF, post-obstructive uropathy, ↑Ca²⁺, ↓K⁺.

Symptoms Polyuria, thirst (may be extreme).

Signs Dilute urine, clinically dehydrated ( pp. 394–397).

Investigations ↓urine osmolality (<400mOsmol/kg), ↑plasma osmolality, and ↑Na⁺. In the water deprivation test (fluid balance, weight, urine, and plasma osmolality recorded over 8h without fluids)—failure to concentrate urine (>600mOsmol/kg) confirms DI. Desmopressin (an Adh analogue) is then given—the production of a concentrated urine at this point implies neurogenic DI; failure to concentrate implies nephrogenic DI.

Treatment Identify and treat the cause. In neurogenic DI, intranasal desmopressin may be used regularly. In nephrogenic DI, bendroflumethiazide or NSAIDs may be used.

►► Omission of desmopressin in a patient with DI who is unable to drink (eg NBM,↓ GCS) is life-threatening. Pay attention to fluid balance in these patients.

Acromegaly

Hypersecretion of GH from a pituitary tumour drives soft-tissue and skeletal growth resulting in characteristic facial and body features.

Symptoms and signs Enlarged hands and feet, coarse facial features, prognathism, macroglossia; headache ±bitemporal hemianopia. Sweating, hypertension, and hyperglycaemia are markers of disease activity.

Investigations IGF-1 levels reflect GH secretion; OGTT and other tests of pituitary function under specialist guidance; pituitary MRI.

Treatment Transsphenoidal resection of pituitary tumour where possible; medical therapy includes somatostatin analogues (eg octreotide).

Adrenal disease

Cushing’s syndrome ( OHCM10 p. 224.)

Excess of glucocorticoids (eg cortisol); ‘Cushing’s disease’ when due to an ACTH-producing pituitary tumour. ACTH may also be produced ectopically, eg by small-cell lung cancers. Adrenal adenomas or carcinomas are ACTH-independent causes (and will suppress ACTH). A patient on steroids may become ‘Cushingoid’.

Symptoms Weight gain, depression, psychosis, tiredness, weakness, oligo- or amenorrhoea, hirsutism, impotence, infections, dm.

Signs Central obesity (buffalo hump), moon-face, water retention, ↑bp, thin skin, striae, bruising, peripheral wasting; hyperpigmentation only in Cushing’s disease or ectopic acth production.

Investigations ↑glucose, ↑24h urinary cortisol, plasma acth and 8am cortisol, dexamethasone suppression tests ( OHCM10 p. 225); imaging tests are problematic due to high rates of ‘incidentalomas’ on adrenal CT or pituitary MRI and are only done after biochemical confirmation of the diagnosis.

Treatment Localize and remove source of cortisol, eg transsphenoidal resection of pituitary adenoma, adrenalectomy for adrenal adenoma. If surgical treatment fails or unsuitable (eg ectopic ACTH from metastatic lung cancer), suppress steroidogenesis, eg with ketoconazole or metyrapone. If iatrogenic cause, try to taper steroid dose ( p. 179). Consider bone protection with bisphosphonate and vitamin D; monitor for ↑glucose.

Complications Osteoporosis, dm, infection, poor healing, infertility.

Adrenal insufficiency ( OHCM10 p. 226.)

Adrenal deficiency, typically seen upon abrupt withdrawal of long-term steroid therapy; 1° adrenal (Addison’s) disease includes autoimmune (commonest in UK), TB (commonest worldwide), metastases (eg lung, breast), Waterhouse–Friderichsen syndrome (sepsis and adrenal haemorrhage).

Symptoms Tiredness, lethargy, weight loss, weakness, dizziness, depression, abdo pain, diarrhoea or constipation, vomiting, myalgia.

Signs Vitiligo, postural hypotension, hyperpigmentation of creases, scars, and mouth (buccal).

Investigations ↓Na⁺, ↑K⁺, ↑urea, may have abnormal fbc and lft. If suspected perform short Synacthen^® test: order 250micrograms Synacthen^® from pharmacy, once this arrives send a blood sample for cortisol and ACTH levels, give the Synacthen^® im/IV ( p. 585); repeat cortisol levels in 30min. Addison’s is excluded if initial, or 30min cortisol is >550nmol/L.

Treatment Hydrocortisone 20–30 mg/day in divided doses to mimic normal circadian rhythm. May also need fludrocortisone (50–200micrograms PO OD) if electrolytes deranged or postural hypotension. ► If unwell, double dose of oral steroids for during of illness. If vomiting, needs IV/IM hydrocortisone—100mg stat and seek medical attention.

► Addisonian crisis Shock, ↓gcs, or hypoglycaemia in a patient with Addison’s disease or stopping long-term steroid therapy. Resuscitate according to pp. 488–489, send bloods for cortisol levels, and give hydrocortisone (200mg IV STAT, then 100mg IV/8h) and broad-spectrum antibiotics (eg Tazocin^® 4.5g iv); seek urgent endocrinologist advice.

Hyperaldosteronism ( OHCM10 p. 228.)

Excess aldosterone secretion, resulting in Na⁺ and water retention; typically from an adrenal adenoma (Conn’s syndrome), or adrenal hyperplasia.

Symptoms Thirst, polyuria, weakness, muscle spasms, headaches.

Signs Hypertension (especially if refractory to multiple antihypertensive agents or young age of onset).

Investigations ↓K⁺, normal or ↑Na⁺, metabolic alkalosis; measure plasma renin and aldosterone together after 30min supine (postural changes affect renin secretion). Ideally the patient should be off all antihypertensives apart from α-blockers. ↑Aldosterone with ↓renin supports the diagnosis; consider CT abdo (but beware ‘incidentalomas’: abnormal CT findings, such as a small adrenal mass of no clinical significance).

Treatment Spironolactone; if adenoma, surgical resection may be attempted after 4wk medical therapy once electrolytes and BP controlled.

Secondary hyperaldosteronism This occurs when renal perfusion is decreased, leading to high renin secretion. Common causes include diuretics, heart failure, liver failure, and renal artery stenosis. Features are similar, but aldosterone:renin ratio will not be high. Manage with spironolactone or acei.

Phaeochromocytoma ( OHCM10 p. 228.)

Catecholamine (eg noradrenaline) production from tumours with in the adrenal medulla, or more rarely extra-adrenal source. Consider in those with drug-resistant or young-onset hypertension, or typical symptoms.

Symptoms Episodic anxiety, sweating, facial flushing, chest tightness, breathlessness, tremor, palpitations, headaches, abdo pain, vomiting, or diarrhoea.

Signs Episodic hypertension.

Investigations Plasma and urine (24h collection) metanephrines. Imaging if biochemistry positive.

Treatment Surgical resection of tumour can safely be performed only after adrenoreceptor blockade. α-blockers (eg phenoxybenzamine) are given prior to β-blockers (eg propranolol) to avoid hypertensive crisis of unopposed α-adrenoreceptor stimulation. See Box 10.8.

► Box 10.8 Cautious prescribing needed

Many drugs can precipitate a crisis in a patient with phaeochromocytoma. Think before prescribing and if in doubt, seek advice. Put a warning on the patient’s drug charts to alert prescribers. Common culprits are opioids, β-blockers, dopamine-receptor antagonists, and steroids.

Thyroid disease

Hyperthyroidism

Hypermetabolic state driven by excess thyroxine.

Causes Graves’ disease (50–60%; agonistic autoantibodies to TSH receptor), toxic multinodular goitre (15–20%), subacute thyroiditis (15%; self-limiting, with painful granulomatous infiltrates as de Quervain’s thyroiditis, or painless lymphocytic infiltrates), toxic adenoma (5%), amiodarone (either due to excess iodine or drug induced thyroiditis), excess exogenous replacement.

Symptoms Weight loss, agitation, anxiety, psychosis, sweating, heat intolerance, diarrhoea, tremor, oligomenorrhoea.

Signs Thin, ↑hr, irregular pulse, warm hands, tremor, goitre ±nodules, lid lag, lid retraction, muscle weakness; Specific to Graves’ disease Exophthalmos, ophthalmoplegia, pretibial myxoedema, thyroid acropachy.

Investigations TSH used as screening test—if ↓ then measure fT₄ (free thyroxine, ie active, not bound to plasma proteins); antithyroid peroxidase (TPO) antibodies positive in Graves’ and other forms of thyroiditis (TSH receptor antibodies more specific for Graves’ but not routinely measured); ECG

to exclude af; USS Thyroid, or nuclear scintigraphy may help localize lesion and assess uptake.

Treatment Symptom relief with propranolol 40mg/6h (or rate limiting calcium channel blocker if asthmatic); suppress thyroid function using carbimazole in dose titrated to TFTs, or with thyroxine in ‘block and replace’ approach. Other options include radioiodine ablation or surgical resection.

Complications CCF, AF, ophthalmopathy, osteoporosis.

►► Thyrotoxic storm This is caused by infection, severe illness, recent thyroid surgery or radioiodine. Tachycardia, ±af, fever, agitation, confusion, or coma with ↑fT₄ or ↑T₃. Resuscitate as required ( pp. 488–489) and get senior help. Propranolol (suppresses sympathetic response, blocks T₄ to T₃ conversion and alleviates symptoms), propylthiouracil (inhibits T₃/T₄ production and T₄ to T₃ conversion and hydrocortisone (reduces iodine uptake and inhibits T₄ to T₃ conversion) are the main treatments. Carbimazole (inhibits T₃/T₄ production) has a slower onset of action but may be preferred to propylthiouracil since it has a longer duration of action and is less hepatotoxic.

Hypothyroidism

Common and insidious; characterized by insufficient thyroxine release (see Box 10.9).

Causes Hashimoto’s thyroiditis (autoimmune destruction), resolution stage of subacute thyroiditis, drugs (eg amiodarone, lithium), iatrogenic (post surgery or radioiodine), iodine deficiency (commonest worldwide). See also Box 10.10.

Symptoms Fatigue, lethargy, weight gain, hair loss, depression, confusion, dementia, cold intolerance, constipation, menorrhagia, infertility.

Signs Obese, bradycardia, ↓temp, cold/dry hands, macroglossia, jaundice, pitting oedema, goitre, peripheral neuropathy, slow relaxing reflexes.

Investigations ↑TSH, ↓fT₄; +ve thyroid autoantibodies.

Treatment Levothyroxine (T₄): 50micrograms/24h PO, gradually titrated up into range 50–150micrograms/24h based upon monthly TFTs until TSH in normal range; yearly tft once stable. Beware of worsening underlying ischaemic heart disease: consider propranolol 40mg/6h PO to prevent ↑HR.

Complications Angina from treatment, myxoedema coma.

Box 10.9 Subclinical thyroid disease

Patients with normal fT₄ and T₃ but ↑ or ↓TSH have subclinical (hypo/hyper) thyroid disease. Although some will progress to frank hypo/hyperthyroidism, there is no management consensus. Positive autoantibodies increase likelihood of progression to overt thyroid dysfunction. Threshold for treatment lower if patient symptomatic. Recheck TFTs after 3mth; if TSH grossly ↑ or ↓ (eg >10 or <0.1mU/L) then consider levothyroxine/carbimazole or surveillance.

↓TSH and ↓fT₄ suggests ‘sick euthyroidism’ in systemic illness—recheck after recovery.

⇄ Box 10.10 Thyroid disease covered elsewhere

Parathyroid disease p. 403

¹ Loss of early autonomic symptoms warning of mild hypoglycaemia (eg tremor, sweating) seen in those with longstanding DM and frequent hypoglycaemic episodes.

² Joint British Diabetes Societies guidelines at http://www.diabetologists-abcd.org.uk/JBDS/JBDS_IP_DKA_Adults_Revised.pdf

³ Plasma osmolality may be estimated as 2×([Na⁺] + [K⁺])+ urea + glucose while awaiting a formal lab measurement.

⁴ In the presence of diabetes symptoms, a random plasma glucose ≥11.1mmol/L may be considered diagnostic; in the absence of symptoms, all tests should be repeated on a separate occasion.

⁵ Ie ≈6.5% (48mmol/mol) and ≈7.5% (58mmol/mol). Since 2009 HbA1c levels have been reported by NHS labs as mmol per mol (of haemoglobin without glucose attached) but previous units of % were reported in key trials, used in guidelines and still permeate the consciousness of some older patients and clinicians.

⁶ For NICE guidelines on management of T1DM see guidance.nice.org.uk/NG17

⁷ For NICE guidelines on management of T2DM, see guidance.nice.org.uk/NG28

⁸ For NICE guidelines on footcare in T2DM, see guidance.nice.org.uk/NG19

⁹ For NICE guidelines on neuropathic pain, see guidance.nice.org.uk/CG173

Chapter 10

Endocrinology

► Hypoglycaemia emergency