Introduction

Endocrinology testing usually involves a snapshot picture of function. Some hormone secretion is pulsatile, other hormones have diurnal variation and increase with sickness, protein binding can all make results less reliable. Dynamic testing provokes suspected underactive glands and suppresses suspected overactive glands and gives a better assessment of true function.

• About: acutely reduced adrenocortical function (glucocorticoids, mineralocorticoids). Insidious and subtle or acute and life threatening, provoked by illness, e.g. infection. Iatrogenic due to cessation of medically prescribed steroids. Adrenal cortex provides cortisol, sex hormones and mineralocorticoids. Increased demand during stresses (infection, trauma, illness). Never stop long-term steroids acutely. Ill patients need them even more.
  
• Types: primary: adrenal destruction or dysfunction. Low cortisol, high ACTH. Needs 90% adrenal destruction before detectable. Secondary: pituitary disease and ACTH insufficiency. Low ACTH and cortisol. Tertiary: impaired hypothalamic CRH release. Low CRH and ACTH and cortisol.

• Aetiology: adrenals produce 15–30 mg/day of cortisol and more when under stress. Endogenous production falls with chronic steroid therapy. 8–9 am normal is 110–520 nmol/L (4–19 mcg/dL), but midnight <140 nmol/L (5 mcg/dL). Cortisol – wound healing, BP, immune function, stress response. Adrenal failure causes low glucocorticoids and aldosterone. Failure to retain salt and water causes ↓BP. Pituitary releases increased ACTH/MSH with pigmentation.
  
• Clinical: subacute with fatigue, anorexia, weight loss, tiredness, diarrhoea, vomiting. Easily misattributed to virus, chronic fatigue or anorexia or depression. Abdominal pain, generalised weakness, precipitated by sepsis, surgery. Postural ↓BP, ↑HR, shocked, confusion, hypoglycaemia. In secondary disease (pituitary) K normal and no pigmentation and BP less affected. Loss of axillary and pubic body hair in females (loss of adrenal androgens). Pigmentation in gums, buccal mucosa, skin, pressure points, skin creases, scars (not in those with corticosteroid therapy). Hypoglycaemia is more common in secondary adrenal insufficiency. May also see Type 1 DM, RA, vitiligo, Hashimoto’s thyroiditis, coeliac, pernicious anaemia.

Investigations

• FBC: ↑eosinophils. U&E: low Na, high K, low HCO3, low Cl, low glucose, low or high urea, high Ca. K normal if due to pituitary hypofunction. ABG or venous gas: low HCO3 mild metabolic acidosis.
  
• Random plasma cortisol: at 8–9 am value >276 nmol/L is normal and >400 nmol/L makes adrenal insufficiency unlikely. Random cortisol <80–100 nmol/L makes diagnosis very likely unless patient on oral/inhaled steroids. If level between 100 and 400 nmol/L then perform a short synACTHen test.
  
• Short synACTHen test: give Synacthen 250 mcg IV or IM (1 vial). Check 30 min cortisol. Diagnosis excluded if cortisol at 30–60 min >500 nmol/L. Usually a flat response is seen. Treat on clinical evidence if result delayed. Some have relative adrenal insufficiency which manifests with acute illness, infection, bleed, surgery/trauma. A short synACTHen may show a muted response. They may need steroids in their acute phase when unwell and re-evaluate later. In a sick patient testing should never delay steroid replacement. The diagnosis can always be confirmed later post the acute phase.
  
• ACTH: (normal 4.4–22 pmol/L or 20–100 pg/ml) if cortisol low then check ACTH. ACTH >80 ng/L at 9 am with low cortisol confirms diagnosis.
  
• Renin/aldosterone: low aldosterone and renin is high. Plasma dehydroepiandrosterone (DHEA) and DHEA sulphate are low.
  
• Adrenal antibodies to 21-hydroxylase seen in 80% autoimmune disease.
  
• CXR/AXR: to look for active TB disease and classically small heart. Calcification.
  
• CT abdomen: may show enlarged necrotic glands with calcification. Small adrenals in autoimmune disease. Large with infection or metastases. Haemorrhage may be seen. Adrenal biopsy in selected cases.
  
• Plasma C26:0 fatty acids will detect adrenoleukodystrophy.

Differential

• Hypopituitarism: see Section 5.9 for pituitary assessment.
  
• Anorexia nervosa: normal/high cortisol, low LH, FSH. Fear of weight gain.

Management

• ABC and O2 as per BTS guidelines. 1 L NS over 30–60 min. Check for and manage any hypoglycaemia. Send random cortisol 10 ml in a heparinised tube. Do not delay glucocorticoids while awaiting laboratory results or attempt endocrine stimulation testing in acutely ill patients. Treat with suspicion alone and confirm later.
  
• Immediate: give HYDROCORTISONE 50–100 mg IV then IM every 6 h. Alternatively DEXAMETHASONE 4 mg IV OD. Once stable and able to take oral then start HYDROCORTISONE 20 mg 8 h and gradually wean down to 30 mg per day in divided doses, usually with a larger morning dose.
  
• Long term for life: HYDROCORTISONE (20–30 mg/day) 10 mg at 8 am, 5 mg at 1 pm, 5 mg at 4pm (avoid late as may cause insomnia). Later add FLUDROCORTISONE 50–200 mcg/day if postural ↓BP. Alternatives to hydrocortisone are PREDNISOLONE 2.5–5 mg OD. Double dose in times of stress/infection, see below.
  
• Relative adrenal insufficiency: suspected incidence in critical care patients as high as 77%. Management controversial. Trials conflicting. Has been shown that HYDROCORTISONE 50 mg IV 6 h may be beneficial for severe septic shock refractory to fluid resuscitation and vasopressors if given early (<8 h).
  
• Determine cause: investigate and treat for TB or HIV, malignancy, adrenal imaging, etc. Endocrine consult and follow up for advice and monitoring.
  
• Patient advice on sick day rules: double steroid dose if minor illness or unwell or physiological stress. Family should be aware. Patients should carry a steroid card to alert staff. Ensure know to never stop steroid. Aware that nausea and vomiting may be signs of a crisis and to seek help. Recommended to have an ampoule of HYDROCORTISONE for IM administration in the event of being unable to take oral.
  
• Prior to operative procedures patients should be given HYDROCORTISONE 100 mg IM then 50–100 mg IM 6 h until back on oral therapy.

• About: prolonged hypoglycaemia causes brain injury and death. Check capillary blood glucose and send lab sample in any confused or comatose patient. Treat any symptomatic blood glucose <4.0 mmol/L.
  
• Aetiology: causes neuroglycopaenia and neuronal dysfunction and increased sympathetic drive. Neurons do not need insulin to allow glucose to enter cells. High metabolising brain is dependent on a steady supply of glucose/ketones. Any shortfall in supply quickly leads to neuronal dysfunction.
  
• Clinical: sweating, trembling, palpitations, anxiety, blurred vision, hunger, headache. Lack of coordination, ataxia, stroke mimic – hemiparesis, confusion, aggression. Loss of inhibitions, convulsions, coma, brain damage, death, violence, agitation. Morning headache, night sweats, vivid dreams suggest nocturnal hypoglycaemia or nocturnal seizures.
  
• Causes: drugs: insulin, sulphonylurea, meglitinides (not metformin), pentamidine, quinine, salicylates, acute alcohol, propranolol. Endocrine: Addison’s disease, growth hormone (GH) deficiency, hypopituitarism. Liver failure, insulinoma, chronic pancreatitis with a loss of glucagon activity. Worsening renal function increases insulin sensitivity.
  
• Not usually caused by: metformin, glitazones, thiazolidinediones, DPP-4 inhibitors, GLP-1 analogues. Starvation: those in fasts or famines or hunger-strikes do not usually succumb to acute hypoglycaemia.
  
• Impaired awareness of hypoglycaemia (IAH): acquired syndrome with insulin treatment. Diminished warning symptoms of hypoglycaemia. Increases vulnerability to severe hypoglycaemia. Prevalence increases with duration of diabetes and seen T1DM > T2DM.
  
• Investigations: high morning glucose may suggest overnight hypoglycaemia with stress response. Measure overnight 16 h fast levels of glucose and insulin to look for low glucose and high insulin suggestive of insulinoma. U&E, LFTs, cortisol, C-peptide which mirrors endogenous insulin production. Test if overnight blood glucose <4 mmol/L. Urine sulphonylurea screen in rare unexplained cases.

Management

• Hypoglycaemic symptoms: blood glucose <4 mmol/L treat with 10–20 g GLUCOSE as sugary soft drink or sugary tea or juice (not diet drink) or small carbohydrate snack only. Adults who are conscious but uncooperative but can swallow can give a small snack or 1.5–2 tubes Glucogel/Dextrogel squeezed into the mouth. If ineffective or oral intake unsafe consider GLUCAGON 1 mg IM/SC but if no response within minutes then 20–50 ml 50% GLUCOSE IV or equivalent must be given. Note: there may be a marked disparity between arterial and venous blood glucose which can lead to misdiagnosis of hypoglycaemia based on symptoms and misleadingly low venous levels when arterial levels are actually normal.
  
• Adults with suspected hypoglycaemia (check CBG and send venous blood sample) who are unconscious or fitting then check ABC + O2 and give 20–50 ml IV 50% GLUCOSE through a large vein and place in recovery position and manage as for status epilepticus (Section 11.16). If no venous access or no IV GLUCOSE then GLUCAGON 1 mg IM/SC. Glucagon may take up to 15 min to take effect because it mobilises glycogen from the liver and so it will be less effective in those who are chronically malnourished (e.g. alcoholics) or in patients who have had a prolonged period of starvation and have depleted liver glycogen stores, or in those with severe liver disease. In this situation, or if prolonged treatment is required, IV GLUCOSE is better. Once normoglycaemic, assess cause and make changes to diabetic regimen if needed. If there is any suspicion of adrenocortical insufficiency then HYDROCORTISONE 50–100 mg IV 8 h should be given and later investigated for hypoadrenalism. An insulin and C-peptide assay can be done where hypoglycaemia is unexplained and deliberate or accidental misuse of insulin suspected. Exogenous insulin causes a rise in insulin but not C-peptide. Endogenous insulin release is accompanied by C-peptide release. If hypoglycaemia confirmed with no obvious cause, then one should consider admission for further tests, e.g. a prolonged fast and other assessments of endocrine function.

• Clinical: asymptomatic, arrhythmias, muscle weakness, cramps, paraesthesia. ↓BP, ↓HR, cardiac arrest.
  
• Severity: mild (K 5.5–6.0 mmol/L) or moderate (K 6.1–6.5 mmol/L). Severe (K >6.5 mmol/L) or if ECG changes or symptoms.
  
• Investigations: U&E: repeat sample in case it is false, especially if ECG normal and high K inexplicable. AKI. FBC/LDH: haemolysis. CK: rhabdomyolysis. Venous/arterial blood gases: metabolic acidosis. ECG signs: peaked ‘tented’ T waves, widened QRS, sine waves, agonal rhythm and VT/VF.
  
• Causes (most commonly drugs – check drug chart) [can get falsely high result: haemolysed sample, laboratory or sampling error]: AKI, CKD, digoxin poisoning (poor prognostic sign). Rhabdomyolysis, tumour lysis syndrome, vigorous exercise, haemolysis, blood transfusion. Drugs: ACE inhibitors, AT2 blockers, spironolactone, eplerenone, amiloride, NSAIDs, ciclosporin, depolarising muscle relaxants, trimethoprim. Metabolic acidosis, Addison’s disease (pigmented, ↓BP, fatigue), Type 4 RTA (diabetes), hyperkalaemic periodic paralysis (AD familial).

Further management

• ABC. Assess ECG changes. Stop all potentially offending drugs or infusions immediately. This is easily overlooked. Ensure IV access, repeat any sample if surprise result. Start IV fluids. K >6.0 mmol/L or ECG changes needs telemetry and defibrillator available.
  
• Severe (K >6.5 mmol/L and/or ECG changes) then cardioprotect with CALCIUM GLUCONATE 10 ml 10%. Next give 50 ml of 50% GLUCOSE with 10 units of SOLUBLE INSULIN (moves K into cells) and consider SALBUTAMOL 10–20 mg in 4 ml saline nebulised with caution in those with IHD/arrhythmias. FUROSEMIDE 10–20 mg IV may be considered if not dehydrated. U&E needs to be repeated every 2 h and blood gas, capillary blood glucose for 6–12 h. The remainder need ECG and underlying cause to be found and close monitoring. These actions only lower K for 4 hours. If metabolic acidosis (low HCO3) consider either IV 500 ml 1.26% solution (75 mmol) over 60 min but caution with volume overload. Alternatively 50–100 ml 8.4% NaHCO3 by central line. Do not give calcium if likelihood of digoxin toxicity.
  
• Cation exchange resins, e.g. CALCIUM RESONIUM 30 g initially and then 15 g QDS PR/PO. PR route is possibly more effective than PO. When given rectally the calcium resonium must be retained for 9 h followed by irrigation to remove resin from the colon to prevent faecal impaction. Bowel perforation can be a rare complication.
  
• AKI assess and manage cause: renal referral needed. If AKI/CKD and refractory/severe hyperkalaemia despite treatment, then discuss suitability for haemodialysis/haemoperfusion. Adopt a ‘low potassium diet’, e.g. avoid chocolate, fruit juices. Ensure that any amiloride, spironolactone, ACE inhibitor, ARB or similar has been stopped. See AKI, Section 10.4.

Reference: Clinical Resource Efficiency Support Team (2005) Guidelines for the treatment of hyperkalaemia in adults (www.crestni.org.uk).

• About: major intracellular cation. In cardiac patients aim for a K of 4.0–5.0 mmol/L. Beware rapid administration of IV potassium can cause lethal arrhythmias. The IV rate of KCl administration should not exceed 20 mmol/h.
  
• Aetiology: the daily intake of potassium in the western diet is between 80 and 120 mmol. Low K reduces muscle and nerve excitability and enhances digoxin toxicity. Hypokalaemia and hypomagnesaemia often coexist, and treatment of hypokalaemia is unlikely to be successful without reversal of hypomagnesaemia.
  
• Causes: thiazides and loop diuretics, Conn syndrome, Cushing syndrome. Severe diarrhoea (villous adenoma, fistulas, laxatives or a VIPoma). Alcohol abuse and Magnesium depletion. Renal tubular acidosis 1 and 2, nephrotoxic drugs, severe vomiting with metabolic alkalosis. Insulin therapy in setting of DKA, giving sodium bicarbonate, IV/nebulised salbutamol. Familial (low K) periodic paralysis, amphotericin B, gentamicin, levodopa. Congenital adrenogenital syndromes, Liddle, Bartter (alkalosis, hypocalciuria) and Gitelman syndromes.
  
• Clinical: mild: lethargy, weakness, paralysis, diarrhoea (as a cause). More severe hypokalaemia: muscle pains, rhabdomyolysis, paralytic ileus, palpitations (ectopics). Look for hypertension (Conn or Cushing syndrome). Check drugs: loop diuretics, thiazides.
  
• Investigations: U&E: K <3.5 mmol/L (severe K <2.5 mmol/L) with normal K 3.5–5.0 mmol/L. Look for a low magnesium. ECG: atrial/ventricular ectopics, arrhythmias, ST changes, U wave, T wave flattening. TFT: ↑FT4 and low TSH if hyperthyroid. HCO3 is low in RTA. Endocrine testing for Cushing or Conn syndrome. Blood gases may show a metabolic alkalosis.

Management (aim to keep K 4–5 mmol/L on CCU)

• Mild (3.0–3.4 mmol/L): give 50–100 mmol KCl over 24 h as oral/NG or IV replacement. Treat any hypomagnesaemia.
  
• Moderate (2.5–2.9 mmol/L): give 100 mmol KCl over 24 h as oral/NG or IV replacement. Treat any hypomagnesaemia.
  
• Severe (<2.5 mmol/L): replace in total 100–200 mmol KCl over 24 h. Give 40 mmol KCl in 0.5–1 L by infusion pump over 4 h. Max 10 mmol/h in ward area. May be repeated 2–3 times per day with twice daily monitoring. Treat any low Mg. Higher rates e.g. 20 mmol/h only given by infusion pump in critical care areas with close ECG/K monitoring.
  
• Cardiac arrest: if hypokalaemia is suspected to be a contributory factor then 10 mmol KCl over 5–10 mins and then commence infusion 40 mmol over 1 h. Treat any hypomagnesaemia.
  
• Oral/NG and IV replacement: one Sando-K tablet = 12 mmol KCl; 25 ml Kay-Cee-L = 25 mmol KCl. Avoid solutions more concentrated than 40 mmol in 1 L as they can cause phlebitis and pain. Use the largest peripheral vein available. Given by central line with close monitoring. K solutions should be given by infusion pump to avoid accidental high flow rates. Treat any hypomagnesaemia.
  
• NPSA recommends: a second practitioner should always check for correct product, dosage dilution, mixing and KCl concentrate and other strong potassium solutions.

References: Rastergar & Soleimani (2001) Hypokalaemia and hyperkalaemia. Postgrad Med J, 77:759. NPSA (2002) Potassium chloride concentrate solution. Patient Safety Alert.

• About: severe high Ca is a corrected calcium of >3.5 mmol/L or severe symptoms. 90% of hypercalcaemia is due to primary hyperparathyroidism (HPTHM) or malignancy. Severity of corrected calcium = measured [Ca] + ((40 – [albumin]) × 0.02). If <3.0 mmol/L: often asymptomatic and does not usually require urgent correction; 3.0–3.5 mmol/L: can be well tolerated but if symptomatic then prompt treatment is usually indicated; >3.5 mmol/L: requires urgent correction due to risk of dysrhythmia and coma.
  
• Aetiology: body contains 1–2 kg calcium, almost all of which is in bone. Total Ca (2.1–2.6 mmol/L) = free ionized (1.1–1.4 mmol/L) (active) + BOUND Ca. Calcium is bound to albumin, citrate and phosphate (inactive). A fall in serum albumin leads to a fall in measured total serum calcium.

Causes

• 1° HPTHM: ↑PTH and calcium often in an otherwise well patient. Symptoms may be minimal and patients otherwise appear well.
  
• Malignancy (low PTH): if undiagnosed often unwell with weight loss and other malignancy symptoms. Due to bone metastases (lung, breast, renal, thyroid and myeloma) or PTH-related peptide (squamous cell lung). Needs CXR. Symptoms usually marked. Myeloma screen.
  
• Sarcoidosis, TB, Lymphoma: ↑ectopic 1,25(OH)2D3.
  
• Drugs: thiazides, calcium, vitamin D, and lithium.
  
• Endocrine: Addison’s disease, hyperthyroid, phaeochromocytoma, acromegaly, MEN I / II.
  
• Familial hypercalcaemic hypocalciuria: autosomal dominant with increased PTH – it is important to identify patients with familial hypocalciuric hypercalcaemia to prevent a wrong diagnosis of 1° HPTHM.
  
• Milk-alkali syndrome: was seen with milk + excess antacids.
  
• Paget’s disease: with immobilisation. Usually calcium normal in Paget’s disease.
  
• 3° HPTHM: 2° HPTHM which becomes autonomous usually with CKD.

Clinical

• Constipation, N&V, confusion, depression, delirium even psychosis and coma. Polyuria and/or polydipsia, hypotonia, hyporeflexia, weakness +/− hyperreflexia and tongue fasciculation.
  
• Long-standing high Ca may cause band keratopathy. Peptic ulcer disease. Renal stones, pancreatitis. Can cause seizures and arrhythmias.
  
• Look for malignancy: weight loss, neck, respiratory, abdomen, breasts, lymph nodes, finger clubbing, chest signs.

Investigations

• FBC and U&E: ↑urea, ESR (myeloma/malignancy). TFT: hyperthyroid. Corrected calcium: measured [Ca] + ((40 – [albumin]) × 0.02). Phosphate: ↑in 3° HPTHM.
  
• ECG: a short QT interval, prolonged PR and risk of dysrhythmias. CXR: squamous cell carcinoma, sarcoidosis, TB.
  
• PTH level: a normal or high PTH in the setting of an ↑calcium is suggestive of 1° HPTHM. A low PTH suggests malignancy or sarcoid or other cause. Measure PTH-related peptide in malignancy.

Management (G5 = 5% glucose, NS = 0.9% saline)

• Emergency: if corrected calcium level >3.2 mmol/L and/or dehydrated start 3–6 L NS IV (125–250 ml/h) per day titrated to degree of fluid depletion (HR/BP).
  
• It may require HDU admission and central line insertion to avoid fluid overload and the risks of oedema in the elderly.
  
• In some patients with mild to moderate high Ca (corrected calcium <3.2 mmol/L) then admission may not be needed and if no heart or renal issues advise the person, provided there are no contraindications, to maintain good hydration by drinking 3–4 L of fluid per day. Encourage mobilisation and return if symptoms worsen. Monitor closely via next day ambulatory care clinic.
  
• BISPHOSPHONATES: after rehydration if the corrected calcium is >3.0 mmol/L and renal function is normal (rehydrate first for 12 h and repeat calcium) then IV PAMIDRONATE 30–60 mg at 40 mg/h. Lower dose in renal failure and GFR <20 ml/min. Alternatives, e.g. ZOLEDRONATE 4 mg IV infusion in NS over 15 min.
  
• Other steps: drugs: stop any calcium/vitamin D medication (this is often forgotten). FUROSEMIDE: should not be used until the patient is fully volume replaced if at all. Consider CALCITONIN 200 units every 6–12 h until calcium falls. Used rarely nowadays. PREDNISOLONE: useful if cause is lymphoma, myeloma, 25(OH)D3 toxicity or sarcoidosis. Steroids inhibit 1,25(OH)D3 production. Start at PREDNISOLONE 40 mg daily responding after 2–4 days. Parathyroidectomy: for 1° and 3° HPTHM. Indications in primary disease is for those with stones, renal impairment, bone disease, Ca >3.0 mmol/L and in younger patients. Monitoring may be appropriate for older patients with Ca 2.65–3.00 mmol/L.

References: NICE (2010) Hypercalcaemia, CKS. Society for Endocrinology (2013) Acute hypercalcaemia (www.endocrinology.org/policy).

• About: normal Ca 2.1–2.6 mmol/L. Total (bound + free) Ca <2.05 mmol/L. Check for and correct any hypomagnesaemia first. See Hypercalcaemia for pathophysiology.
  
• Aetiology: acidosis reduces protein binding sites and increases the amount of ionised Ca. Alkalosis increases protein binding sites and ionised Ca is lower, causing tetany.

Causes

• Low PTH: most common cause is post thyroidectomy with resultant low PTH which can be transient or permanent. Radiation or autoimmune damage.
  
• Low albumin: liver disease or the nephrotic syndrome.
  
• Renal failure: CKD-5 usually (failure of renal hydroxylation).
  
• Acute pancreatitis: seen with moderate to severe pancreatitis.
  
• PTH resistance: pseudohypoparathyroidism. GNAS1 mutation. Short stature, short metacarpals.
  
• High phosphate: phosphate binds calcium, which precipitates.
  
• Malabsorption: coeliac disease, Crohn’s disease, short bowel syndrome, CF or chronic pancreatic insufficiency.
  
• DiGeorge syndrome: hypoparathyroid with thymic aplasia.
  
• Miscellaneous: low Mg (diuretics, alcohol abuse), cinacalcet, tumour lysis syndrome, multiple blood transfusions, rhabdomyolysis, sepsis/toxic shock syndrome, hungry bone syndrome post correction of primary hypoparathyroidism; bisphosphonates, foscarnet.

Clinical

• Mild: asymptomatic. Chronic: cataracts, basal ganglia calcification, dry skin, pruritus.
  
• Moderate: numbness, paraesthesia, mild muscle weakness, wheezing. Positive Chvostek sign – tapping over facial nerve causes facial muscles to contract. Positive Trousseau sign – inflate BP cuff to 20 mmHg above SBP for 3–5 min – causes muscle spasm, and flexion of the wrist and metacarpal phalangeal joints can be observed with extension of the interphalangeal joints and adduction of the thumb (carpal spasm). More specific but less sensitive than the Chvostek sign.
  
• Severe: delirium, seizures, papilloedema, movement disorders, tetany, refractory ↓BP, or arrhythmias (needs IV calcium + magnesium).

Investigations

• FBC, U&E, LFTS: AKI, CKD. Determine estimated glomerular filtration rate (GFR). Ca, phosphate, PTH, 25(OH)D3, 1,25(OH)2D3: hypoparathyroidism: low calcium, high phosphate, low PTH. Pseudohypoparathyroidism: low calcium, high phosphate and PTH. Osteomalacia: calcium/phosphate low, ALP/PTH high, 25(OH)D3 low. CKD: high phosphate, ALP, creatinine, PTH high. 25(OH)D3 normal, 1,25(OH)2D3 low. In critically ill patients measure uncuffed sample.
  
• Parathyroid antibodies – autoimmune hypoparathyroidism.
  
• Magnesium <0.5 mmol/L typically results in symptomatic low Ca.
  
• Radiographs for Looser zone and osteomalacia and short 4th metacarpals in pseudohypoparathyroidism. ECG: a long QT interval. Amylase if pancreatitis considered.

Management (G5 = 5% glucose, NS = 0.9% saline)

• Mild/moderate: oral replacement, e.g. ADCAL D3 3 tablets BD or CALCICHEW Forte 2 tablets BD. Severe (<1.9 mmol/L and/or symptomatic at any level below reference range): give 10–20 ml of CALCIUM GLUCONATE over 15 min in 50–100 ml NS/G5. Then dilute 100 ml of 10% CALCIUM GLUCONATE (10 vials) in 1 L of NS or G5 and infuse at 50–100 ml/h. Monitor calcium.
  
• Treat any low Mg: IV MgSO4 2 g (8 mmol in 100 ml) over 20 min until symptoms have cleared. Mg avoided in CKD. PPI can cause a low Mg.
  
• Vitamin D: replace as required. Monitor calcium levels. Referral to endocrinology for complex patients, e.g. PTH resistance should be managed by specialists.

References: Hannan & Thakker (2013) Investigating hypocalcaemia. BMJ, 346:f2213. Acute Emergency Hypocalcaemia (2013) (www.endocrinology.com).

• About: may complicate long-standing often undiagnosed/untreated hypothyroidism. May be precipitated by an acute physiological stress event.
  
• Risk factors: mostly older females (mean age = 75) usually during winter. Usually long-standing primary thyroid failure but rarely pituitary failure.
  
• Causes: Hashimoto’s disease, post-thyroidectomy, radioactive iodine, antithyroid drugs. Drugs: lithium, amiodarone, iodine deficiency, thalidomide. Congenital, Infiltration of thyroid – haemochromatosis, amyloid, Riedel’s.
  
• Precipitants: look for infection/sepsis (chest/urine/encephalitis), GI bleed. Drugs (slow metabolism): alcohol, sedatives, tranquilisers, narcotics, amiodarone, lithium, beta-blockers. Lung disease, stroke, CCF, ACS, upper GI bleed, acute trauma/surgery/burns. Hypothermia, hypoglycaemia, noncompliance with thyroid replacement.
  
• Clinical: fatigue, increased weight, constipation and cold intolerance. Psychosis with delusions and hallucinations (‘myxoedema madness’). Hypothermia, generalised oedema, cool dry rough skin, sparse hair, macroglossia. Seizures, coma, ↓HR, ↓BP, hypoventilation. Abdominal distension/pain. Paralytic ileus, megacolon, old thyroidectomy scar. Goitre with Hashimoto’s disease, iodine deficiency.

Investigations

• FBC U&E: macrocytic anaemia, leukopenia, low Na, decreased GFR.
  
• Glucose: may be low, elevated CK/LDH, hyperlipidaemia. Short SynACTHen test if coexisting hypoadrenalism suspected.
  
• TFT: TSH >10 mU/L (low if pituitary disease), low FT4. TSH can be unreliable generally in acute illnesses and should at least be accompanied by a FT4. TFTs should be rechecked when patient is better. Sickness can cause deranged TFTs and this must always be considered.
  
• Thyroid autoantibodies (TPO Ab) in Hashimoto’s disease. CSF: ↓pressure, ↑protein.
  
• ABG: Type 2 RF may be seen. ECG: ↓HR, flattened T-waves, low QRS. TdP.
  
• CXR: cardiomegaly, pericardial and pleural effusion.
  
• Abdominal X-ray: ileus and distended bowel and faeces.

Management

• Supportive: look for precipitant. Admit to ITU to manage hypoventilation, ↓O2, ↓BP, hypoadrenalism and hypothermia. Give O2 and fluids/inotropes. Gradually rewarm if hypothermic. Overactive warming may vasodilate and drop the BP. Watch for arrhythmias and monitor electrolytes and ABG. Interpretation impaired if hypothermic. Avoid any sedatives or sedating analgesics. Metabolism and drug excretion reduced.
  
• Sepsis: have a low threshold for IV antibiotics as signs of sepsis may be concealed by hypothyroidism, e.g. fever and ↑HR.
  
• LEVOTHYROXINE (T4) loading dose 100–500 mcg IV once followed by 50–100 mcg OD IV until tolerating PO or via NG tube. T4 (a prodrug converted to T3) may provide a smoother and more gradual though slower onset of action than T3. Lower doses of T4, e.g. 25–50 mcg OD, may be advocated in elderly or those with cardiac disease.
  
• LIOTHYRONINE T3 is available and may be the choice of some. Recommended doses range from LIOTHYRONINE 2.5 to 20 mcg 8 hourly. Give T3 10 mcg bolus IV and then 10 mcg 8–12 hourly for 24–48 h and then start oral T4. Lower doses may be advocated in elderly or those with cardiac disease.
  
• HYDROCORTISONE 100 mg IV and then IM 8 h given for first few days and then tapered off. The rationale being possible hypopituitarism and adrenal insufficiency.
  
• Hypoglycaemia: glycogen is often depleted so hypoglycaemia may be seen and so glucose should be monitored. A glucose infusion should be considered.
  
• Poor prognosis associated with hypothermia, advanced age, ↓HR, ↓BP, MI/CCF. No indication for prescribing T4 or any preparation containing thyroid hormones to patients with thyroid blood tests within the reference ranges.

Reference: Wall (2000) Myxoedema coma: diagnosis and treatment. Am Fam Physician, 62:2485.

• About: rare and life-threatening condition due to excess T3/T4. 2% of those with hyperthyroidism. Mortality is quoted as 10–20%.
  
• Aetiology of T4/T3 excess: untreated or inadequately treated Graves’ disease is the commonest pathology. Toxic adenoma or multinodular goitre, thyroiditis, post-partum thyroiditis. Excessive T4 ingestion – deliberate or accidental. Recent amiodarone or intravenous iodinated contrast.
  
• Precipitant: recent minor/major illness or post radioactive iodine treatment. Post thyroid surgery or stopping treatment, e.g. carbimazole or propylthiouracil.
  
• Clinical: ↑HR, palpitations, AF, heart failure, weight loss, tremor, lethargic. Sweating and agitation, fever, hypo- or hyperactive delirium. Apathetic (more like hypothyroidism) in elderly, abdominal pain. Graves’ eye disease: proptosis, lid lag, chemosis, acropachy. Pretibial myxoedema, tender gland suggests thyroiditis. Goitre may be seen with Graves’ (bruit) or thyroiditis (tender).
  
• Differential: hyperactive or any form of delirium, septic shock, anticholinergic toxicity. Delirium tremens, acute pulmonary oedema, apathetic cases can be subtle.
  
• Investigations: bloods: FBC, U&E, ESR/CRP: ↑Ca. ECG: SR, sinus tachycardia, AF, ST/T wave changes, especially if IHD. TFT: ↑FT3 and FT4 and TSH <0.05 mU/L. Antibodies: thyroid peroxidase (TPO), thyroglobulin antibodies and TSH receptor antibodies (TRAb) in Graves’ disease whose level parallels disease activity. CXR if infection suspected. Blood cultures and CSF if obtunded. Echo: may show a transient rate-induced cardiomyopathy and reduced LV function. Increased 123I uptake in Graves’ compared with Hashimoto’s thyroiditis.

Management

• Start ABC. O2 as per BTS guidelines. Consider ITU/HDU. Start IV fluids and correct electrolytes. Antipyretics: use Paracetamol. Avoid ASPIRIN (displaces protein bound T4). Look/treat any sepsis: blood/urine/CSF (if indicated). Sedation: if very agitated then HALOPERIDOL 1–5 mg or LORAZEPAM 1–2 mg IV/IM or DIAZEPAM as needed. PROPRANOLOL 40–80 mg 12 h PO to rate control tachycardia/AF. Cardioversion futile until rendered euthyroid.
  
• Anticoagulate any AF as cardioembolic risk using LMWH acutely.
  
• Antithyroid drugs: CARBIMAZOLE 20 mg BD/TDS. PO/NG often with THYROXINE 75–100 mcg as block and replacement therapy. A smaller dose CARBIMAZOLE 15–40 mg may also be given and titrated against TSH. Alternative PROPYLTHIOURACIL 200 mg BD is an alternative and often preferred in pregnancy. PTU reduces T4 to T3 conversion.
  
• POTASSIUM IODIDE 15 mg 6 h PO or LUGOL’s iodine (8 mg iodine/drop): 10 drops (0.1–0.3 ml) PO/NGT every 8 h. Blocks organification of iodine. Reduces T4 to T3 conversion. Give after Carbimazole. This is the Wolff–Chaikoff effect.
  
• HYDROCORTISONE 100 mg 6 h IM/IV to prevent T4 to T3 also suppresses the autoimmune process.
  
• Plasmapheresis (PLEX): has been used to treat thyroid storm in adults.
  
• Thyroid eye disease (Graves’ orbitopathy) in 15%. Presents with proptosis (Grade 3), redness, pain, diplopia (Grade 4), swelling and oedema. Emergency – those unable to close eyes fully have high risk of corneal ulceration (Grade 5), reduced acuity (Grade 6). Need urgent specialist ophthalmic/thyroid referral. The rest need surveillance, smoking cessation and Sodium SELENITE 100 mcg 12 h and management of thyroid disease. Tape eyes closed overnight, artificial tears/lubricants for gritty eyes. High dose steroids: PREDNISOLONE 1 mg/kg/day and decompression surgery if sight is at risk. Once controlled refer for radioiodine or subtotal thyroidectomy. Radioiodine avoided if active eye disease as can worsen situation but prophylactic steroids may be given.
  
• Heart failure: chronic tachycardia causes a cardiomyopathy and so ECHO may be needed and anti-failure medications.
  
• Thyroiditis: usually self-limiting 1–2 months. Symptoms control with PROPRANOLOL 40 mg TDS. Malaise, fever, pain settles. PREDNISOLONE 20–40 mg/day may be given. May be transient hypothyroidism after. A post-partum thyroiditis may be seen in some women <6/12 post-delivery and associated with anti-TPO antibodies in half.

References: Perros et al. (2015) Management of patients with Graves’ orbitopathy: initial assessment, management outside specialised centres and referral pathways. Clinical Medicine, 15:173. Marcocci et al. (2011) Selenium and the course of mild Graves’ orbitopathy. N Engl J Med, 364:1920 (doi: 10.1056/NEJMoa1012985).

• About: pituitary macroadenoma (>1 cm) undergoes infarction +/– haemorrhage. Get urgent CT head. Seen in 1% of pituitary tumours. Apoplexy may be precipitated by anticoagulants or surgery. Rare in pregnancy. The pituitary is shaped like a 6 and releases at least 6 important hormones: ACTH, (MSH), GH, Prolactin, TSH, LH, FSH. May need urgent neurosurgical referral to preserve vision and steroids for any secondary adrenal insufficiency.
  
• Aetiology: rapidly growing tumour outgrows blood supply or compresses its own blood supply. Expanding mass arising from the sella turcica can compress optic nerve and chiasma. Pituitary vascular supply from the inferior hypophyseal branch of the internal carotid artery. Result is hypopituitarism with secondary hypoadrenalism, hypothyroid, hypogonadism, etc. Secretory pituitary tumour has 3 effects: hormone excess, space occupying (headache), hypofunction of other hormones.
  
• Clinical: pre-existing adenoma and severe headache +/− eye signs, coma. ↓BP with secondary hypoadrenalism. Ophthalmoplegia, bitemporal superior quadrantanopia and loss/reduced visual acuity. Horner’s syndrome. Palsy of II, III, IV and VI and V1 (lateral wall cavernous sinuses). Look for signs of prolactinoma, acromegaly and Cushing’s syndrome.
  
• Differentials: SAH, bacterial/viral meningitis, brainstem infarction (eye signs/Horner’s), cavernous sinus thrombosis.

Investigations

• Bloods: FBC, U&E, LFT, clotting screen. Hormones: prolactin, GH (can be zero between pulses in normals so also check IGF-1), TSH and FT4, ACTH and cortisol, LH/FSH and testosterone or oestradiol. Commonest tumours secrete prolactin/GH. However, most pituitary tumours that undergo apoplexy are endocrinologically silent. If suspected hypopituitary and ACTH and GH low these can be stimulated with hypoglycaemia induced by an insulin tolerance test. If GH high and acromegaly suspected attempt to suppress with OGTT. These tests and results are assessed in the post-acute phase.
  
• CT head: acutely, haemorrhage in an existing pituitary tumour, subarachnoid bleed or ischaemic with no haemorrhage.
  
• MRI/A pituitary: more sensitive after 24 h showing blood, tumour, pituitary ring sign from central necrosis. MRA shows close vascular anatomy.
  
• Formal visual fields assessment as early as possible (when clinically possible) looking for a bitemporal superior hemianopia suggesting optic chiasmal compression from below.

Management

• HYDROCORTISONE 200 mg IV bolus and then 100 mg IM/IV 6 h to manage acute period. Adequate IV fluid replacement with NS.
  
• Urgent MRI/A (or CT/A if MRI not possible) and discussion with local neurosurgical and endocrine team.
  
• CABERGOLINE or other dopamine agonist may be sufficient in non-visually impaired prolactinoma and suffices in 80% and can rapidly reduce tumour size. Need for urgent surgery decided by a neurosurgeon with endocrinologist. Stop and reverse any coincidental anticoagulation.
  
• Neurosurgery: If vision is at risk or cranial nerve or other pressure effects then consider urgent trans-sphenoidal surgical decompression to reduce pressure on local structures. Complications include damage to local structures, especially the carotid arteries laterally. GH secreting tumours are less common than prolactinoma and more likely to need surgery / Octreotide / Pegvisomant / Radiotherapy.
  
• Endocrine review: long-term pituitary hormone replacement may be needed with Thyroxine, Hydrocortisone, etc. Remember to titrate to the T4 not the TSH. Posterior pituitary function rarely affected with even a large macroadenoma so if diabetes insipidus is seen consider inflammatory cause or metastases. Long term imaging shows an empty sella.

Reference: Rajasekaran et al. (2011) UK guidelines for the management of pituitary apoplexy. Clinical Endocrinology, 74:9.

• About: low serum Na with ↓serum osmolality causes intracellular movement of water and cerebral oedema, progressive coma and seizures. Rapid uncontrolled normalisation can lead to permanent neurological deficits.
  
• Pathophysiology: normal Na 135–145 mmol/L. Plasma osmolality is 275–295 mOsm/kg. Any rise in osmolality leads to ADH release and free water retention. ADH causes free water retention and lowers serum osmolality. ADH acts on renal V2 receptors.

Different scenarios

• Salt level fixed and water excess: ↑ADH release (SIADH) fails to excrete water, excess IV Dextrose/Glucose, potomania, water from prostate irrigation, ADH release to pain, opiates, surgery.
  
• Excess salt loss and water loss: diuretics, tubular disorders, surgical drains, Addison’s disease.
  
• Salt loss but water level constant: compensated diuresis, Addison’s disease.

Assessment

• Severity: mild: 125–130 mmol/L: no symptoms or mild lethargy. Not uncommon in elderly. Moderate: 115–125 mmol/L: headache, nausea, cramps, confusion. Severe: <115 mmol/L: confusion, seizure, delirium, coma, cerebral oedema and brain herniation.
  
• Clinical: assessment: is patient hypervolaemic, euvolaemic or hypovolaemic/dehydrated? Dehydrated: oliguria, low lying/standing BP, heart rate, thirst, poor skin turgor, weight. Fluid overloaded: peripheral and/or pulmonary oedema, basal crepitations, S3, ↑JVP. Fluid balance shows water taken orally or IV Glucose suggests water overload. Salt losses: surgical drains and NG tube may suggest shows excessive salt losses +/– water losses. Euvolaemic: meningitis, brain injury or small cell lung tumour or pneumonia suggests SIADH.

Types

• Hypovolaemic hyponatraemia: reduced ECF with low BP, dehydrated, renal or GI or burns or other losses or overdiuresis. Divide into renal losses (urine Na >20 mmol/L): diuretics (renal salt loss + ADH stimulation and free water retention), salt-losing nephropathy, RTA, cerebral salt wasting (SAH), Addison’s disease, and non-renal losses (urine Na <10 mmol/L: gastrointestinal losses, burns, pancreatitis, 3rd space losses. Avoid Na retention and so urine Na <10 mmol/L, and the urine may be low volume and hyperosmolar. Needs fluid and Na replacement if normal renal function then salt retention possible so correction should be simpler. Manage underlying cause of losses. Well patient: increase salt intake with slow sodium 80 mmol/day or slow IV NS. If vomiting then simply match losses with IV NS with 20 mmol KCl per litre. If slow to respond or encephalopathic then consider 500 ml of 3% over 6–12 h depending on urgency and response to replacement. Test and treat for any concerns of adrenal insufficiency. Try to limit increases <10–12 mmol/day.
  
• Euvolaemic hyponatraemia (increased ICF and ECF no oedema): causes include thiazide diuretics, SIADH, hypothyroidism, acute porphyria, adrenal insufficiency, Guillain–Barré syndrome. Dilutional hyponatraemia. Avoid excessive hyponatraemic water intake (runners, ecstasy users, potomania). Correct cause. Increase salt intake with slow sodium 80 mmol/day. Consider IV NS. Give 3% NS if urgent correction needed but bring levels up slowly. IV HYDROCORTISONE if hypoadrenalism. Stop thiazides. Try to limit improvements to less than 10 mmol/day.
  
• Hypervolaemic hyponatraemia (increased ICF and ECF, oedema): ascites, ↑JVP, CCF, cirrhosis, nephrotic syndrome, renal disease: hyperaldosteronism, diuretic-induced renal salt loss. Dilutional hyponatraemia so the key is fluid restriction to 500–1000 ml per day and diuresis of free water by inducing diabetes insipidus or blocking ADH. In exceptions 3% saline 500 ml over 6–12 h may be given. Saline may be given with FUROSEMIDE to aid water loss. DEMECLOCYCLINE 300 mg BD or TOLVAPTAN 15 mg OD for several days may be used to get rid of free water by inducing a nephrogenic diabetes insipidus.
  
• Spurious hyponatraemia (normal osmolality) may be due to high triglyceride, protein or glucose.

Investigations

• FBC, U&E, urine Na excretion, glucose, urine and plasma osmolality. In acute correction the U&E should be checked every 2–4 h. TFT: check TSH and cortisol levels. CXR: infection/tumour. Short synACTHen if adrenal failure considered (low BP, ↓BP, pigmentation).
  
• SIADH: urine inappropriately concentrated when dilute serum and often >100 mOsm/L with hyponatraemic plasma osmolarity. Osmolality = 2 Na + glucose + urea (all in mmol/L).

Management

• Rises in Na should be actively managed not to exceed 12 mmol/24 h or 18 mmol/48 h. Acute hyponatraemia can be corrected more quickly and more safely than chronic hyponatraemia.
  
• ABC + supportive: if fitting or low GCS and cerebral oedema then ITU with full support and consider urgent management with hypertonic saline. Manage seizures as per status epilepticus. CT scan if any concern as to cause of coma. General principles depend on likely cause. Principles: what is the volume status? If severe low Na been present for less than 48 h then can be reversed more quickly and vice versa. Aim for improvement of 12 mmol/day and not immediate normality. Assess fluid balance, osmolality and urinary osmolality, volume and salt loss. Monitor Na closely and frequently and clinical state. Try to break it down into hypo-, eu-, hyper-volaemia, though some have mixed. Chronic hyponatraemia (>48 h) should have the sodium corrected much more slowly. A target of 120 mmol/L attained over 24–48 h depending on baseline should resolve acute symptoms.
  
• SIADH: excessive free water retention. Low serum osmolality and ↑urine osmolality (>100 mOsm/kg) and urine Na >30 mmol/L where hypopituitarism, hypoadrenalism, hypothyroidism, renal insufficiency and diuretic use have been excluded. Check and stop any causative drugs and look for other causes (malignancy, ecstasy (MDMA often combined with excess water), CNS disorders, drugs, lung disease, nausea, postoperative pain, HIV, infections, Guillain–Barré syndrome, acute porphyria). Fluid restriction to 800 ml/day is needed. See above for managing severe hyponatraemia.
  
• Drug treatments: Demeclocycline, Conivaptan and Tolvaptan antagonize effects of ADH by different mechanisms to cause free water loss. If euvolaemic: DEMECLOCYLINE 150–300 mg 6 h can be given to induce NDI and lose free water. Conivaptan or Tolvaptan may also be used. They may also be used with hypervolaemic/euvolaemic hyponatraemia, e.g. TOLVAPTAN 15 mg (up to 60 mg/day) for short periods. Need to watch for rapid rises in Na which can result in neurology. Specialist use. Fluid status should be monitored frequently and the patient should be encouraged to drink freely.
  
• Adrenal insufficiency should be treated as per Addisonian crisis with IV NS and steroids. See Section 5.1.
  
• Rapid correction can lead to central pontine demyelination now called osmotic demyelination syndrome: manifests after 2–3 days as brainstem symptoms of dysarthria, dysphagia, seizures, coma, quadriparesis and can be seen on MRI. Classically seen in malnourished alcoholic with rapid correction. Exact treatment regimens are difficult because multiple factors are involved, but an effort to increase serum osmolality with either NS, or hypertonic saline if volume must be restricted, must be done carefully and cautiously with regular checking of status and bloods; if seizures and coma then more urgency may be applied. Comatose or fitting hyponatraemic patients are best managed in an HDU/ITU setting. It is certainly a time to enlist expert experienced help.

• About: most often free water loss or no access to water. Occasionally excessive salt. Mild hypernatraemia Na >145 mmol/L; severe hypernatraemia >160 mmol/L. Mortality can be up to 50% in elderly patients. Correct slowly at <12 mmol/day. Most often due to an impaired access to water or loss of free water greater than can be replaced by drinking or other routes.
  
• Aetiology: ↑serum osmolality causes water to leave cells and cells to shrink. A small rise in osmolality detected by osmoreceptors causes desire to drink. Hypernatraemia occurs where there is limited access to water, e.g. lost in the desert or stuck in a side room and too confused or comatose to drink, or water not to hand.
  
• Causes: water/hypotonic fluid loss or impaired water intake. Polyuria with excess free water loss unmatched by water intake: high Ca, low K, cranial and nephrogenic diabetes insipidus, diabetic ketoacidosis, HONK. Simple dehydration + fever especially older people + impaired access to water. Water losses due to burns, sweat, vomiting, severe diarrhoea. Renal fluid losses: nephropathy, myeloma, obstructive uropathy, adult polycystic kidney disease. Excessive sodium intake: mild hypernatraemia with Conn or Cushing syndrome. Salt poisoning, ingestion of seawater, salt tablets, IV NaHCO3, hypertonic saline.
  
• Clinical: dehydration, thirsty, agitation, ataxia, progressively obtunded and comatose. ↓BP, thready pulse, sunken eyes, low BP, coma and seizures.
  
• Investigations: FBC, U&E, Ca, K, glucose: exclude AKI, high glucose, high Ca, low K. ↑serum and urine osmolality (>600 mOsmol/kg) unless renal concentrating issue or diabetes insipidus. CT/MRI head if suspect cranial diabetes insipidus. Urine volume and osmolality: diabetes insipidus > 3 L/day of a dilute urine despite dehydration.
  
• Management: determine cause: this is fundamental and key. Investigate for free water loss. Assess renal concentrating function and serum and urine osmolality and look for high glucose and calcium or low K which can cause polyuria. May just be failure to match normal losses as listed above in Causes.
  
• Fluid replacement: no definite treatment plan. Cautious rehydration if cardiac disease or elderly. Treat and look for a cause if not obvious. Encourage oral fluids. Consider IV G5 slowly with administration guided by plasma Na and urine output. This can be alternated with NS, to avoid too rapid a fall in plasma osmolality which can cause cerebral oedema. Can use a mixture of both. Volume replacement may be up to 4 L/day. Titrate to clinical response. Do not change [Na] by more than 12 mmol/day. Oral fluids may be given as long as losses are replaced and fluid balance maintained.
  
• Risk of VTE: administer VTE prophylaxis with Enoxaparin or equivalent.
  
• Diabetes insipidus (> 3 L/day of dilute urine despite dehydration) with thirst, headache: nephrogenic: fluid replacement, look for cause, e.g. lithium, correct electrolytes and paradoxically may need to give thiazide diuretics. Cranial: look for cause, replace losses. Consider DESMOPRESSIN 5–20 mcg nasal spray or tablets. Watch for hyponatraemia and fluid retention. Endocrine review.

• About: phosphate <0.8 mmol/L. Severe if phosphate <0.4 mmol/L.
  
• Causes: critically ill, DKA (insulin moves phosphate into cells), refeeding syndrome, malabsorption, vomiting or renal loss.
  
• Clinical: muscle weakness, ileus, cardiac failure, rhabdomyolysis.
  
• Management: for mild loss replace orally with Phosphate-Sandoz tablets up to 6 tablets per day. More severe deficiency then replace with IV PHOSPHATE 10–12 mmol given in 250 ml NS or G5 over 12 h. Watch serum calcium. Treat any vitamin D deficiency. May precipitate low Ca.

• Aetiology: renal reuptake inhibited by PTH. Retained in renal failure.
  
• Investigations: U&E, phosphate > 1.4 mmol/L.
  
• Causes: AKI/CKD, (pseudo+) hypoparathyroidism, tumour lysis syndrome, rhabdomyolysis. Usually causes calcium deposition.
  
• Management: volume expansion, with IV NS if renal function normal, and gut phosphate binders such as calcium carbonate.

• Causes: Mg <0.75 mmol/L. Malnourished patients or (loop) diuretics, alcoholism, diarrhoea, laxative abuse, malabsorption, pancreatitis, Gitelman’s syndrome, DKA, severe burns, PPI. Mild Mg <0.7, moderate Mg <0.5, severe Mg <0.3 mmol/L.
  
• Clinical: weakness, tremor, carpopedal spasm, ataxia, hyperreflexia, adrenal insufficiency, confusion, fits, TdP. Daily intake is 15 mmol.
  
• Investigations: U&E: low Mg, low K often, ECG: 1st degree heart block, T wave flattened, widened QRS, ventricular arrhythmias, TdP. [1 g MgSO4 = 4 mmol MgSO4.] High urine Mg suggests renal problem (Gitelman’s syndrome).
  
• Management: severe symptomatic give IV MAGNESIUM SULFATE 2 g (8 mmol) over 15–30 min. Replace with IV Mg 50 mmol (12 g) in 1 L of NS or G5 in the first 24 h. Mild/asymptomatic moderate can have up to 50 mmol/L day given as Maalox 10–20 ml qds (10 ml Maalox = 6.8 mmol Mg) but may cause diarrhoea. Also replace other electrolytes K/Ca if low. Amiloride can reduce Mg urine loss in some.

• Causes: Mg >1 mmol/L. Cause is large MgSO4 doses mistakenly given, e.g. pre-eclampsia or with impaired renal excretion.
  
• Clinical: reduced reflexes, weakness, cardiac arrest. May be seen in obstetric practice when Mg given as tocolytic or pre-eclampsia.
  
• Investigations: U&E, Mg symptomatic >2 mmol/L.
  
• Management: STOP Mg infusion. Give 10–20 ml of 10% CALCIUM GLUCONATE as per hypocalcaemia. Haemodialysis for renal failure. IV FUROSEMIDE + IV fluids can aid excretion. GLUCOSE and insulin can also be given (as for high K). Cardiac arrest – maintain CPR whilst giving calcium/IV fluids.

• About: increased lactic acid due to tissue hypoperfusion or drugs or mitochondrial toxicity from NRTIs /other causes.
  
• Aetiology: impaired glycolytic metabolism increases lactate and reduces pH. l-lactate is endogenous; d-lactate from gut bacteria.
  
• Type A lactic acidosis (tissue hypoxia): severe sepsis, diabetes, pancreatitis, malignancy, shock, LVF, renal and liver failure, respiratory failure, carbon monoxide, severe anaemia, local hypoperfusion, e.g. limb ischaemia or bowel ischaemia.
  
• Type B lactic acidosis (no tissue hypoxia): alcohol, iron, salicylates, isoniazid, metformin, zidovudine. Inborn errors of metabolism, thiamine deficiency, pyruvate dehydrogenase dysfunction, cyanide, exercise, seizures.
  
• Clinical: Kussmaul’s breathing, ↓BP, sepsis, shock, hypoxia. Do they have AIDS and on NRTIs, e.g. fatigue, nausea, aches, weight loss?
  
• Investigations: FBC, U&E: anaemia, AKI, lactate >4 mmol/L with sepsis/metabolic acidosis. ABG: hypoxia, hypercarbia may be seen. With mitochondrial dysfunction, e.g. cyanide, oxygen not extracted and so venous oxygen levels maintained. Metabolic acidosis: low HCO3 may not be seen even with a modest rise in lactate. Anion gap: is increased [Na+K] – [Cl+HCO3] >12 mmol/L.
  
• Management: ABCs, oxygen, resuscitate, supportive. Determine and treat cause. Stop causative drugs. Lactate is a useful marker of poor prognosis requiring expert and rapid intervention. Manage as per shock guidance or sepsis guidance. Dialysis can be considered in severe cases. Get expert help before considering an infusion of 500 ml isotonic 1.26% bicarbonate.

• About: deficiency of an enzyme in the haem biosynthesis pathway with overproduction of porphyrin precursors. Haem made from succinyl-coA + glycine by 8 enzymic steps in cytoplasm and mitochondria. Drugs can induce some of the initial steps in the pathway precipitating acute attacks. Acute attacks may occur with: acute intermittent porphyria, variegate porphyria, hereditary coproporphyria.
  
• Clinical: diagnosis often known. Often a family history is available. Episodes of neuropathic abdominal pain, back pain, constipation. ↑HR, hypertension. Women > men aged 20–40. Look for precipitants: fasting, infection, surgery, drugs.
  
• Drug precipitants: sulphonamides, rifampicin, OCP, anaesthetic agents, barbiturates, alcohol, some ACE inhibitors, carbamazepine, dapsone, furosemide, methyldopa, theophylline, some NSAIDs. Check any new drug in BNF.
  
• Investigations: FBC, U&E: urea, ↑LFTs: bloods as indicated with signs. Increased porphobilinogen (PBG) and ALA: urine darkens to port wine on standing and goes pink with Ehrlich’s reagent, which remains despite chloroform. Urine PBG analysis to confirm an acute attack of porphyria or for monitoring known patients can be carried out at UK Porphyria centres. Collect a random 10 ml urine sample in a plain tube, check the tube is labelled with patient details, and protect from light by wrapping in foil or a brown envelope. Sample request card should state ‘urine for porphobilinogen quantitation’ for a patient with known porphyria, or ‘urine for porphobilinogen screening test’ for a patient without a previous diagnosis of porphyria. Refrigerate the sample prior to analysis. Follow local laboratory guidance.
  
• Management: supportive: hydration, pain relief, rest, increased carbohydrate intake oral or IV dextrose. Referral to specialist for individual enzyme assays and further tests. If conservative management not effective then consider administering an IV haem infusion. Recommend HAEM ARGINATE 3 mg/kg (to a maximum of 250 mg) once daily for four consecutive days which shortens attacks with less risk of complications. Haem arginate replenishes the body’s haem stores. Through negative feedback this inhibits ALA synthase, thus reducing the production of porphyrins and their precursors, ALA and PBG.

Reference: NAPS section for Medical Professionals (www.cardiffandvaleuhb.wales.nhs.uk/national-acute-porphyria-service-naps); also www.porphyria.org.uk.

Related posts:

– Gastroenterology emergencies – Hepatobiliary emergencies – Haematological emergencies – Dermatological emergencies – Emergency drugs (use with BNF) – Ophthalmological emergencies

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