Chapter 7. Endocrine, electrolyte and renal

Diabetes mellitus 187

Thyroid and adrenal problems 197

Electrolyte imbalance 202

Renal dysfunction 209

DIABETES MELLITUS

Diabetes mellitus (DM) is a common disorder with a UK prevalence of approximately 4%. This figure is expected to increase as the population ages and obesity becomes more common.

Modes of presentation

Incidental evidence of complications

Patients not known to have diabetes may present to optometrists for eye testing with signs of diabetic retinopathy. Similarly, patients with proteinuria, or symptoms and signs of peripheral neuropathy should be investigated for undiagnosed DM. If this is confirmed, it is likely that the patient has had untreated DM for over 10 years.

Management of established DM

DM is essentially a self-managed condition and most patients will have received advice from healthcare professionals at the time of diagnosis. This advice may be forgotten or ignored. Therefore, hospital admissions present valuable opportunities to re-engage patients and update their knowledge. Most hospitals have diabetes healthcare teams to support this. Primary healthcare teams also have a key role in the education of patients with DM, especially those not requiring insulin.

Dietary measures

Dietary discretion is the cornerstone of good glycaemic control, whether medication is used or not. Patients should be encouraged to look closely at food labelling; avoiding products that have glucose or sugar as one of the first three ingredients. A refresher consultation with a dietician can also be beneficial.

Monitoring

Three measures are available: urine glucose testing, blood glucose testing and glycated haemoglobin.

Urine glucose self-testing

This is not as popular as blood glucose self-testing because of concerns regarding accuracy and cleanliness. However, persistently negative fasting urine glucose, checked once or twice a week, is a reasonable target for patients with type 2 DM if they would rather test urine than blood.

Blood glucose testing

Bedside or self-testing with blood glucose strips and meters is now exceedingly common in hospitals and the community. Boehringer Mannheim made the most widely used strips in the 1970s and 1980s. Hence the term BM is still used to describe bedside or self-testing with blood glucose strips. If used properly, these are exceedingly accurate, except when the blood glucose concentration is very low (<3.0 mmol/L).

It is crucial that patients understand that blood testing should be used to facilitate treatment adjustment and the optimization of their glycaemic control.

Glycated haemoglobin

Glycated haemoglobin (HbA1c) is a measure of glycaemic control over the preceding 2 months. The HbA1c is the main tool used to assess longer-term glycaemic control, but should not be thought of as simply an average blood glucose. Keeping it below 7% minimizes future microvascular complications and reduces morbidity and mortality. It reflects compliance with treatment, including diet, but can also be affected by stressful life events. Time trends are as important as one-off measurements.

Medication

You should be aware of the indications, side-effects and potential problems related to each of the drug classes used in the management of DM.

Metformin

This drug is used as first-line therapy in type 2 diabetics who are overweight or obese. Diarrhoea is the most common side-effect, but can be minimized by taking the tablets with food. The starting dose is 500 mg once daily, titrated to a maximum daily dose of 1 g 8-hourly, aiming for a fasting plasma glucose of 4–6 mmol/L. Metformin can be used in combination with both a sulphonylurea and glitazone if necessary, but should be stopped if the eGFR falls below 60 mL/min.

Sulphonylureas

These include gliclazide and glibenclamide and they are often used in non-obese type 2 diabetics with hyperglycaemic symptoms. The starting dose should be low, but then titrated to achieve a fasting plasma glucose of 4–6 mmol/L, e.g. gliclazide (40 mg daily titrated to 160 mg twice daily). Symptomatic hypoglycaemia (<3.0 mmol/L) usually necessitates a dose reduction and is an indication for treatment withdrawal in elderly patients with renal impairment.

Glitazones

Both rosiglitazone and pioglitazone are insulin-sensitizing agents used in type 2 DM. These drugs are usually added to metformin or a sulphonylurea when fasting plasma glucose levels remain >6 mmol/L at the maximum tolerated dosage. Glitazones should be started in low dose and, because it takes 6 weeks for the drug to achieve its optimal effect, dose titration should not be considered before then.

Glitazones should be avoided in patients with heart disease. Fluid retention is common. Liver function tests may become abnormal and should be monitored in the early stages of therapy.

Insulins

There are a variety of insulins available for use in the UK. These are life-saving treatments in type 1 diabetes, although more patients with type 2 diabetes are having insulin added to their regime to achieve better glycaemic control.

The choice of insulin for each patient is influenced partly by patient preference and partly by the duration of action. The normal daily starting dose of subcutaneous insulin in type 1 DM is 0.5 units/kg with a usual maintenance dose of 0.8 units/kg. Twice-daily dosing of an intermediate-acting insulin is commonly used, e.g. Mixtard 30®. Basal-bolus regimes combine a once-daily dose of long-acting insulin, e.g. Lantus®, and three pre-prandial doses of short-acting insulin, e.g. Novorapid®. In type 2 DM, patients are insulin resistant and may require higher doses.

Hypoglycaemia, both symptomatic and asymptomatic, is the most common side-effect and is an indication for specialist diabetic review. In general terms, insulin should never be stopped completely in patients with type 1 diabetes because of the risk of life-threatening ketoacidosis.

Complications of DM

Patients with type 1 and 2 DM have difficulty controlling blood glucose levels due to insulin deficiency and insulin resistance, respectively. This difficulty is exacerbated during intercurrent illness when stress-related insulin resistance develops, insulin doses may be omitted and the patient may be unable to eat and drink normally due to anorexia, nausea, vomiting or altered consciousness.

Diabetic ketoacidosis (DKA)

Type 1 diabetics are at risk of developing life-threatening ketoacidosis if insulin is omitted, or if insulin dosage is not increased during intercurrent illness. Patients with type 2 diabetes do not generally develop DKA, even if they have been started on regular insulin therapy because of poor glycaemia control.

Presentation

Patients may present with features of an intercurrent illness. Hyperglycaemic symptoms (polyuria, polydipsia) are often prominent, in addition to vomiting (due to gastroparesis), hyperventilation (Kussmaul’s, reflecting acidosis), significant dehydration and confusion. Abdominal pain is present in approximately 10% and is particularly common in children.

Assessment

An accurate assessment of intravascular volume is essential (see ‘Shock and fluid balance’, p. 250). Smell the patient’s breath for the ‘sweet’ odour of ketones. Look for evidence of a precipitating infection or other illness, e.g. chest or urine infection, MI, recent CVA. Request the following investigations in all patients with suspected DKA, but do not delay management; see below:

• FBC and Coag: a stress-related leucocytosis may occur in the absence of infection

• U&E and LFT: note Na ⁺, K ⁺ and renal function; remember that severe hyperglycaemia produces a technical error in Na ⁺ measurement; corrected Na ⁺ + measured Na ⁺ + 1.6 × ([plasma glucose (mmol/L) − 5.5]/5.5)

• glucose: may not be very high; see below

• ABG: determine the severity of any acidosis; severe cases (pH<7) should have early senior input

• urinalysis: ketones should be strongly positive; weak positive may reflect recent starvation

• ECG: look for evidence of myocardial infarction or arrhythmias, the latter may reflect electrolyte abnormalities; treat as per ‘Arrhythmias’, p. 132

• septic screen: CRP, blood cultures, CXR and urine cultures; other investigations should be directed by symptoms

• amylase: acute pancreatitis can accompany DKA in around 10%; amylase may be slightly elevated without pancreatitis.

Diagnosis

The diagnosis of DKA requires evidence of both:

• acidosis: as indicated by an elevated arterial hydrogen ion concentration (>50 nmol/L) or reduced arterial blood pH (<7.3), or a reduced venous bicarbonate (<15 mmol/L)

• ketosis: on either urinalysis or blood testing; beware other causes of acidosis in patients with diabetes, including lactic acidosis and salicylate poisoning.

Hyperglycaemia is very likely to be present, but is not essential for the diagnosis. DKA can occur with blood sugars as low as 10 mmol/L and the blood sugar may also be lowered if the patient has suspected the diagnosis themselves and administered a bolus of subcutaneous insulin recently. However, this will be insufficient to reverse the acidosis because of profound dehydration.

Management

The cornerstones of DKA management are intravenous fluid rehydration, insulin therapy and potassium replacement.

Fluids

Osmotic diuresis and insensible losses, largely related to hyperventilation, result in significant intravascular depletion; the average fluid deficit in DKA is around 10% of total body water (3–6 L). This should be replaced over the first 24 h; an appropriate regime is as follows:

• start with normal saline and switch to 5% dextrose once blood glucose falls below 12 mmol/L

• if the blood glucose rises after this switch, do not change back to saline; simply adjust the dose of insulin

• give the first and second litres of IV fluid over 1 h, the third litre over 2 h and all subsequent litres over 4 h, taking into consideration the risks of fluid overload and clinical response.

Insulin

Start an infusion of soluble insulin, e.g. 50 IU of Actrapid® insulin added to 50 mL of normal saline, as soon as the diagnosis is confirmed. An appropriate insulin prescription is provided in Table 7.1. This can be modified according to clinical response; aim for a fall in blood glucose of 3–6 mmol/L per hour. More rapid correction of blood glucose can lead to cerebral oedema.

**Table 7.1** An example insulin prescription for use in DKA
Blood glucose (mmol/L)	Insulin infusion rate (units/h)
>12	6
8.1–12	3 and change IV fluid to 5% dextrose
4.1–8	2
2.1–4	1 and contact doctor
<2	Stop and contact doctor

Improvement of glycaemic control should be accompanied by an improvement in acidosis. Intravenous insulin should be continued until the patient is eating and drinking normally and the acidosis and ketosis have resolved; SC insulin can then be restarted or introduced.

Potassium

All patients with DKA will be significantly K ⁺ depleted. Acidosis promotes H ⁺/K ⁺ exchange in the kidney and loss of the K ⁺ in the urine; K ⁺ is also lost during vomiting. Despite this, intravascular K ⁺ may appear normal or elevated initially. This reflects profound dehydration and catabolism of protein and glycogen stores, with or without renal impairment. K ⁺ replacement should be guided by serum electrolytes (Table 7.2). Omit K ⁺ from the first, rapidly infused, litre of normal saline, until serum levels are known.

**Table 7.2** K ⁺ replacement in DKA
Serum K ⁺ (mmol/L)	Amount of KCl (mmol/L) to add to each litre
>5.0	0
3.5–5	20
<3.5	40

Other general measures

• regular monitoring: DKA is a medical emergency and the patient should be transferred to the HDU, if available

• venous access: large-bore venous access should be obtained; if peripheral access is poor (common if recurrent admissions with DKA), the patient is shocked or has co-existing cardiac disease, consider whether a central line is required

• urinary catheter: if the patient is oliguric or has renal impairment, is old or has another disease that could make fluid overload a problem, consider inserting a urinary catheter and measuring hourly urine volumes

• conscious level: monitor GCS (see ‘GCS’, p. 11)

• anticoagulation: dehydration increases blood viscosity, and sepsis or other acute illness will result in fibrinolysis; all patients with DKA should receive prophylactic doses of LMWH, e.g. enoxaparin 40 mg SC (reduce to 20 mg if eGFR <60 mL/min)

• antiemetics: gastroparesis is common; give parenteral antiemetics, e.g. metoclopramide 10 mg 8-hourly, and keep the patient NBM for the first 6 h; consider the use of a NG tube if vomiting is persistent or conscious level is reduced

• antibiotics: should be given if there is evidence of infection; remember that a leucocytosis is common and does not necessarily reflect sepsis.

Monitoring

Rapid normalization of biochemistry, particularly sodium and glucose, can be dangerous. Therefore, careful monitoring is essential:

• check U&E, including venous bicarbonate, at baseline and again at 1, 2, 4, 6 and 12 h

• capillary blood glucose, using BM strips, should be measured hourly

• laboratory glucose should be measured 4-hourly

• an ABG should be checked at baseline, but needs to be checked again only if the patient’s clinical condition appears to be worsening.

Hyperosmolar non-ketotic coma

HONC occurs in type 2 diabetics; patients are often elderly and the mortality is much higher that than of DKA (approx. 40%). Blood glucose rises slowly and is often extremely high (>50 mmol/L). Severe dehydration and pre-renal failure are common, but ketoacidosis does not occur. Mortality correlates best with serum osmolality and there is a high frequency of thrombotic complications.

Presentation

The patient is usually known to have type 2 DM and will often present with confusion, polyuria, polydipsia and severe dehydration. Thrombotic complications (e.g. CVA, MI, DVT) and seizures are less common.

Diagnosis

Secured by significant hyperglycaemia in association with a calculated plasma osmolality >350 mmol/kg. Calculated osmolality = [2 × (calculated Na ⁺ + K ⁺) + urea + glucose]. For calculated Na ⁺, see p. 189.

Assessment

Look for evidence of precipitating infection or thrombotic complications, including a full neurological assessment; record the GCS. Check the following:

• glucose: usually >50 mmol/L

• U&E and LFT: remember hyperglycaemia will interfere with Na ⁺ measurement; see DKA section above for guidance on calculating corrected Na ⁺ concentration; otherwise, Na ⁺ may be underestimated, producing pseudohyponatraemia or masking significant hypernatraemia associated with dehydration

• calculate serum osmolality

• ABGs and urinalysis: ketoacidosis will not be present; lactic acidosis, a poor prognostic marker, may be present if the patient is grossly volume deplete or in renal failure

• FBC and Coag: leucocytosis may be present in the absence of infection

• ECG: look for evidence of myocardial infarction or arrhythmias; the latter may reflect electrolyte abnormalities (see ‘Arrhythmias’, p. 132)

• CXR

• septic screen, including CRP, blood and urine cultures; other cultures should be dictated by symptoms.

Management

The most important measures are cautious IV fluid rehydration, IV insulin therapy and thrombosis prophylaxis. In contrast to DKA, blood glucose should be normalized very slowly.

Fluids

The average fluid deficit is 8–10 L. Aim to replace this over 2–3 days. Avoid fluid overload, and in elderly patients or those with a history of cardiac disease consider inserting a central venous line to guide fluid prescription.

An appropriate IV fluid regime is as follows: give the first litre over 1 h, the second and third over 2 h and all subsequent litres over 6 h, until re- hydrated. Also take into consideration the risk of fluid overload and the clinical response. If the plasma Na ⁺ concentration is >160 mmol/L, consider using 0.45% saline for the first 3 L. Switch to 5% dextrose once the blood glucose is <15 mmol/L.

Insulin

Insulin prescription should aim to reverse hyperglycaemia slowly; therefore use a modified version of the DKA protocol, as provided in Table 7.3. Insulin can be stopped and oral hypoglycaemic agents restarted, or introduced, once the patient is eating and drinking again.

**Table 7.3** An example insulin prescription for use in HONC
Blood glucose (mmol/L)	Insulin infusion rate (units/h)
>22	6
17.1–22	4
15.1–17	3
11.1–15	3 and change fluid to 5% dextrose
7.1–11	2
4–7	1
<4	Stop and contact doctor

Potassium

Potassium will tend to fall as insulin moves it into cells. Replace K ⁺ as per management of DKA (Table 7.2).

Other measures

As indicated above, all patients should receive thrombosis prophylaxis, e.g. enoxaparin (40 mg SC daily; use 20 mg if eGFR <60 mL/min). Vomiting is common: manage with parenteral antiemetics, e.g. metoclopramide (10 mg 8-hourly). Where there is persistent vomiting, consider inserting a NG tube. Keep NBM for at least 6 h. Antibiotics should be given if there is evidence of infection. If there is confusion or a reduced GCS that does not improve with therapy, consider a CT brain scan to look for evidence of a recent CVA.

Hypoglycaemia

Hypoglycaemia is common in diabetics receiving insulin. Symptoms occur when the blood glucose falls below 3.0 mmol/L and are commonly categorized into:

• adrenergic symptoms: sweating, tachycardia, pallor and hunger

• neuroglycopaenic symptoms: morning headache, incoordination, inappropriate behaviour, confusion and coma.

Most patients will be able to easily recognize mild hypoglycaemia and reverse it by taking a sweet drink or item of food. If more severe hypoglycaemia develops despite this, or the patient has a poor awareness of hypoglycaemia, increasing neuroglycopenia will make it less likely that the patient will be able to take appropriate steps to manage the problem.

Without prompt intervention irreversible cognitive impairment can result. Therefore, family members or healthcare professionals will be required to administer mucosal glucose solutions, e.g. Hypostop®, or glucagon (SC, IM or IV). Where available, e.g. in hospitalized patients, an IV bolus of 50 mL of 20% dextrose should be given. Fifty per cent dextrose should be avoided because of the risk of extravasation-associated skin necrosis.

Common reasons for hypoglycaemia include poor carbohydrate intake, excessive insulin or unaccustomed exercise. The onset of renal impairment, hypothyroidism or hypopituitarism should also be considered.

Following a significant episode of hypoglycaemia the patient and healthcare team should attempt to modify any factors that contributed to the event. This might include withdrawal of a long-acting sulphonylurea in an elderly patient, or a reduction in the dose of subcutaneous insulin in a young type 1 patient.

Microvascular complications

These include diabetic retinopathy, nephropathy and neuropathy which all result from a diffuse microvascular injury affecting the retina, glomerulus and intraneural capillaries, respectively. The hallmark of this process is thickening of the capillary basement membrane and increased vascular permeability. The risk of developing microvascular complications is closely related to inadequate glycaemic control.

Diabetic retinopathy

This represents a common cause of adult blindness in developed countries. Patients are often asymptomatic until the condition is advanced or maculopathy develops. Therefore, regular screening by either fundoscopy or retinal photography is essential as early retinal photocoagulation is an effective treatment; see below. Diabetic retinopathy is classified as follows:

• background (or non-proliferative): venous dilatation and microaneurysms, blot haemorrhages and exudates (leakage of plasma from abnormal capillaries)

• pre-proliferative: venous beading and increased tortuosity (indicating capillary non-perfusion), clusters of microaneurysms, multiple cotton wool spots (these are important to identify, being representative of areas of retinal ischaemia due to arteriolar occlusions) and macular, or perimacular, exudates or haemorrhages

• proliferative: visible new vessel formation on the retina (neovascularization); may be associated with pre-retinal haemorrhage, gliosis (deposition of fibrous tissue anterior to the retina) and retinal detachment

• maculopathy: exudates, haemorrhage, oedema or cotton wool spots on, or around, the macula.

The prognosis and need for specialist referral is dependent on the stage and extent of the process (Table 7.4). Retinal photocoagulation is indicated for severe non-proliferative retinopathy and all proliferative retinopathies. This has been shown to reduce visual loss by 85% (reduced to 50% if maculopathy present).

**Table 7.4** Prognosis and indication for specialist referral in diabetic retinopathy
Type	Prognosis	Management
Background	No immediate threat to sight	Optimize glycaemic, BP and lipid control and other risk factors, e.g. smoking, alcohol; fundoscopy surveillance every 6 months; refer if rapid progression
Pre-proliferative	Sight-threatening	Optimize risk factors and refer; avoid rapidly lowering blood glucose as this may worsen retinopathy
Proliferative	Sight-threatening	Optimize risk factors and refer
Maculopathy	Sight-threatening	Optimize risk factors and refer

Diabetic nephropathy

This is a common cause of end-stage renal failure (ESRF). Renal abnormalities progress from thickening of the glomerular basement membrane and expansion of matrix material in the mesangium to nodular deposits in the glomeruli and eventual glomerulosclerosis and heavy proteinuria. The chance of a type 1 diabetic developing nephropathy over 20 years is approximately 30%. Particular risk factors include poor glycaemic control, long duration of diabetes, associated hypertension, ethnicity (more common in Asians) and the presence of other microvascular complications.

Treatment of established nephropathy is often unrewarding and frequently requires renal replacement therapy. Therefore, screening and prevention, or at least amelioration, are essential. Microalbuminuria (urinary albumin 3–30 mg/24 h) is an important predictor of progression to diabetic nephropathy, especially in type 1 diabetics in the first 10 years following diagnosis. After this, and in type 2 diabetics (who tend to be older), microalbuminuria may be explained by other vascular diseases. Progression to albuminuria (urinary albumin 30–300 mg/24 h), especially if associated with hypertension, is likely to reflect diabetic nephropathy.