TYPE 1

Insulin-dependent diabetes mellitus (IDDM) has a peak incidence in the young, rising from 9 months to 14 years and declining thereafter. In 25% of patients the presentation is with ketoacidosis, especially in those under 5 years of age.¹ Usually the fasting plasma glucose is > 7.8 mmol/l and glucose and ketones may be present in the urine. In the asymptomatic patient with equivocal fasting plasma glucose an impaired glucose tolerance test may be demonstrated.

TYPE 2

Non-insulin-dependent diabetes mellitus (NIDDM) is prevalent in the elderly but can occur at any age. Truncal obesity is a risk factor and there is ethnic variation in susceptibility. Diagnosis is often delayed and may be incidental from blood or urine sugar screening.² It may present with classical symptoms, as a diabetic emergency, with complications of organ damage or vascular disease.

EPIDEMIOLOGY

Diabetes mellitus affects about 6% of the world’s population and is set to rise to 300 million sufferers by 2025.³ Most of these (97%) will have type 2 diabetes but the resources required to treat the complications of type 1 diabetes are such that health-care costs are equivalent between the two groups. The annual incidence of DKA is 4.6–8 episodes per thousand patients with type 1 diabetes and in the USA it has been estimated that about $1 billion is spent each year in treating DKA. HHS represents approximately 1% of primary admissions to hospital with diabetes as compared with DKA. An interplay of both genetic and environmental factors contributes to disease development. In type 1 diabetes there is some evidence for genetic susceptibility, but environmental factors play a greater part. It varies across race and regions, being highest in northern Europe and the USA and lowest in Asia and Australasia.⁴ Genetic factors in type 2 diabetes are evidently crucial, with a concordance between monozygotic twins approaching 100%.

PATHOGENESIS

Normal carbohydrate metabolism depends upon the presence of insulin (Figure 50.1). However, different tissues handle glucose in different ways; for example, red blood cells lack mitochondria and therefore lack pyruvate dehydrogenase and the enzymes involved in β-oxidation, whereas liver parenchymal cells are able to perform the full range of glucose disposal (Figure 50.2). Both DKA and HHS result from a reduction in the effect of insulin with a concomitant rise in counterregulatory hormones such as glucagon, catecholamines, cortisol and growth hormone. Hyperglycaemia occurs as a consequence of three processes: (1) increased gluconeogenesis; (2) increased glycogenolysis; and (3) reduced peripheral glucose utilisation. The increase in glucose production occurs in both the liver and the kidneys as there is a high availability of gluconeogenic precursors such as amino acids (protein turnover shifts from balanced synthesis and degradation to reduced synthesis and increased degradation). Lactate and glycerol also become available due to an increase in skeletal muscle glycogenolysis and an increase in adipose tissue lipolysis respectively. Lastly, there is an increase in gluconeogenic enzyme activity, enhanced further by stress hormones. Whilst hepatic gluconeogenesis is the main mechanism for producing hyperglycaemia, a significant proportion can be produced by the kidneys.⁵ What is unclear is the temporal relationship of these changes, although an increase in both catecholamines and the glucagon/insulin ratio are early features.⁶

Figure 50.1 Sources and fate of acetyl coenzyme A (CoA). *Pyruvate conversion by pyruvate dehydrogenase (PDH) is essentially irreversible, therefore no net conversion of fatty acids to carbohydrates can occur. TCA, tricarboxylic acid.

Figure 50.2 Glucose metabolism within hepatocyte. (1) Glucose transport: GLUT-1. (2) Hexokinase phosphorylation. (3) Pentose phosphate pathway (hexose monophosphate shunt). (4) Glycolysis. (5) Lactate transport out of cell. (6) Pyruvate decarboxylation. (7) Tricarboxylic acid (TCA) cycle. (8) Glycogenesis. (9) Glycogenolysis. (10) Lipogenesis. (11) Gluconeogenesis. (12) Glucose-6-phosphate (G-6-P) hydrolysis and release of glucose. (13) Glucuronidation.

Decreased insulin and increased adrenaline (epinephrine) levels activate adipose tissue lipase, causing a breakdown of trigylcerides into glycerol and free fatty acids (FFAs). Once again glucagon is implicated, as hepatic oxidation of FFAs to ketone bodies is predominantly stimulated by its inhibitory effect on acetyl-coenzyme A (CoA) carboxylase. The resultant reduced synthesis of malonyl-CoA causes a disinhibition of acyl-carnitine synthesis and subsequent promotion of fatty acid transport into mitochondria, where ketone body formation occurs. Both cortisol and growth hormone are capable of increasing FFA and ketone levels and once again the exact contribution of insulin deficiency or stress hormone increase to ketogenesis is undetermined. As ketone bodies are comparatively strong acids, a large hydrogen ion load is produced due to their dissociation at physiologic pH. The need to buffer hydrogen ions depletes the body’s alkali reserves and ketone anions accumulate, accounting for the elevated plasma anion gap.

By contrast HHS does not share the ketogenic features of DKA and it is of interest in what ways these two conditions differ. Reduced levels of FFAs, glucagon, cortisol and growth hormone have been demonstrated in HHS relative to DKA, although this is by no means a consistent observation. However, the presence of higher levels of C-peptide in HHS (with lower levels of growth hormone) relative to DKA suggests there is just enough insulin present in HHS to prevent lipolysis but not enough to promote peripheral glucose utilisation.⁷

Hyperosmolarity, which is a prominent feature of HHS, is caused by the prolonged effect of an osmotic diuresis with impaired ability to take adequate fluids. It has been shown that, even when well, patients who have suffered from HHS have impaired thirst reflexes. However the hyperosmolarity seen in about one-third of patients with DKA results from a shorter osmotic diuresis and to variable fluid intake due to nausea and vomiting – often ascribed to the brainstem effects of ketones.

Interestingly, hyperglycaemia, with or without ketoacidosis, leads to a significant increase in proinflammatory cytokine production, which resolves when insulin therapy is commenced.⁸ This has led others to postulate a wider beneficial anti-inflammatory effect attributable to insulin therapy.

CLINICAL PRESENTATION

DKA and HHS represent the two extremes of presentation due to the absolute or relative deficiency of insulin. However, up to one-third of cases can present with mixed features.⁹ DKA develops over a shorter time period whereas HHS appears more insidiously (Table 50.1). Polyuria, polydipsia and weight loss are experienced for a variable period prior to admission and, in patients with DKA, nausea and vomiting are also common symptoms. Abdominal pain is commonly seen in children and occasionally in adults and may mimic an acute abdomen. Dehydration presents with loss of skin turgor, dry mucous membranes, tachycardia and hypotension. Mental obtundation occurs more frequently in HHS than DKA as more patients, by definition, are hyperosmolar and the presence of stupor or coma in patients who are not hyperosmolar requires consideration of other potential causes for altered mental status.¹⁰ However, loss of consciousness is not a common presentation with DKA or HHS (< 20%). Most hospitalisations are caused by infection (29%) or non-compliance with medication (17%) in previously diagnosed diabetics; however, in some patients it is the first presentation with undiagnosed diabetes (17%).¹¹ Given that there is a high likelihood of concurrent infection, most patients have a normal or low temperature and most patients also have a leukocytosis, whether there is infection present or not.

Table 50.1 Comparison of DKA and HHS

DIABETIC KETOACIDOSIS

DKA tends to occur more often in patients with type 1 diabetes. Rapid, deep breathing due to acidosis (Kussmaul breathing) may be present, as may the breath odour that is characteristic of ketones, which is somewhat like nail polish remover. A history of insulin therapy omission is common, and patients using continuous insulin delivery devices are particularly at risk due to the use of short-acting insulin which provides no insulin reserve if the pump fails. Diagnostic criteria include pH < 7.3, HCO₃⁻ <15 mmol/l and blood glucose >14 mmol/l. Increasing acidaemia, ketonaemia and deteriorating conscious level indicate increasing severity. Blood glucose per se is not a good determinant of severity and euglycaemic ketoacidosis is possible, depending on the hepatic glycogen stores prior to the onset of DKA – a patient who has not been eating well in the recent past may well have a minimally elevated blood glucose. A high amylase is frequently seen and may be extrapancreatic in origin. It should be interpreted cautiously as evidence of pancreatitis.

HYPEROSMOLAR HYPERGLYCAEMIC SYNDROME

HHS is more often seen in patients with type 2 diabetes and the dominant feature is hyperosmolarity (> 320 mosmol/kg). HHS is typically observed in elderly patients with NIDDM, although it may rarely be a complication in younger patients with IDDM, or those without diabetes following severe burns,¹² parenteral hyperalimentation, peritoneal dialysis or haemodialysis. Patients receiving certain drugs, including diuretics, corticosteroids, β-blockers, phenytoin and diazoxide, are at increased risk of developing this syndrome. HHS may be caused by lithium-induced diabetes insipidus.¹³ Not only may mental obtundation occur but occasionally focal neurological features or seizures are present.

MANAGEMENT

Intensive care unit admission is indicated in the management of DKA, HHS and mixed cases in the presence of cardiovascular instability, inability to protect the airway, altered sensoria, the presence of acute abdominal signs or symptoms suggestive of acute gastric dilatation.