Dr. S.M.Sadikot.
Hon. Endocrinologist,
Jaslok Hospital and Research Centre,
Mumbai 400026

Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) or, as this is more popularly known, Hyperglycemic Hyperosmolar Non Ketotic state (HHNK), are the two most serious acute hyperglycemic complications of diabetes.

They continue to be important causes of morbidity and mortality among patients with diabetes in spite of major advances in the understanding of their pathogenesis and more uniform agreement about their diagnosis and treatment.

Although DKA is usually associated with people with Type 1 DM, it is also often seen in people with Type 2 DM. HHS is more typically seen in the older Type 2 patient.

The outcomes are especially poor in the absence of immediate and optimal management. The mortality associated with these disorders is still untenably high, and with DKA can reach almost 10% even in the best of hands. HHS has a mortality which approaches almost 50%.

Although for the purpose of discussion, these are considered separately as two entities, DKA and NKH should be thought of as a continuum of disease. At one extreme is pure DKA without hyperosmolarity of significant amount. As noted above these patients may present with more modest degrees of glucose elevation. At the other extreme is NKH with extreme elevations of glucose, and hyperosmolarity, but without significant ketosis (see table below). Finally, there are a range of patients who will have features of both.

It is due to this continuum, that a significant discussion about aspects of HHS has been dealt with in conjunction with the discussion on DKA. In fact. many leading authorities, feel that DKA and HHS presenting with a comatose state should be considered the opposite boundaries of a spectrum of presentations, rather than thinking of them as different disease states.

Diabetic Ketoacidosis (DKA)
DKA is a metabolic disorder consisting of three major abnormalities: elevated blood glucose level, high ketone bodies, and a metabolic acidosis with an elevated anion gap. Dehydration and hyperosmolarity may be present as well. There is no "typical" presentation and individual patients may present with a range of clinical findings not clearly meeting the above criteria.

Figure 1. The triad of DKA (hyperglycemia, acidemia, and ketonemia) and other conditions with which the individual components are associated.

PATHOPHYSIOLOGY
To understand what happens in DKA, it is helpful to understand the normal process of glucose metabolism.

Although the pathogenesis of DKA is better understood than that of HHS, the basic underlying mechanism for both disorders is a reduction in the net effective concentration of circulating insulin, coupled with a concomitant elevation of counterregulatory stress hormones (glucagon, catecholamines, cortisol, and growth hormone). Thus, DKA and HHS are extreme manifestations of impaired carbohydrate regulation that can occur in diabetes. Although many patients manifest overlapping metabolic clinical pictures, each condition can also occur in relatively pure form.

In patients with DKA, the deficiency in insulin can be absolute, or it can be insufficient relative to an excess of counterregulatory hormones. In HHS, there is a residual amount of insulin secretion that minimizes ketosis but does not control hyperglycemia. This leads to severe dehydration and impaired renal function, leading to decreased excretion of glucose. These factors coupled with the presence of a stressful condition result in more severe hyperglycemia than that seen in DKA. In addition, inadequate fluid intake contributes to hyperosmolarity without ketosis, the hallmark of HHS.

These hormonal alterations in DKA and HHS lead to increased hepatic glucose production and impaired glucose utilization in peripheral tissues, which result in hyperglycemia and parallel changes in osmolality of the extracellular space. The combination of insulin deficiency and increased counterregulatory hormones in DKA also leads to release of free fatty acids into the circulation from adipose tissue (lipolysis) and to unrestrained hepatic fatty acid oxidation to ketone bodies (ß-hydroxybutyrate [ß-OHB] and acetoacetate), with resulting ketonemia and metabolic acidosis. HHS on the other hand may be due to plasma insulin concentration inadequate to facilitate glucose utilization by insulin-sensitive tissues but adequate (as determined by residual C-peptide) to prevent lipolysis and subsequent ketogenesis, although the evidence for this is weak.

Under normal circumstances the body is able to maintain blood glucose within a narrow range during both these feeding and fasting states due to a complex interplay between insulin and certain counter regulatory hormones.

In the fed state, there is an abundance of glucose and insulin available. The glucose that is not immediately used is preserved in short and long term storage forms. The liver transforms glucose to glycogen through the actions of insulin. Insulin also promotes the formation of fat and protein - it is an anabolic protein. Insulin also prevents lipolysis (an opposite process), protein degradation, glycogenolysis (breakdown of glycogen into glucose), and gluconeogenesis (production of glucose from other sources in the liver).

After a meal has been absorbed, both glucose and insulin levels begin to fall. At this time events begin to occur to maintain a constant glucose level (and thus a constant supply of fuel for the brain and the rest of the body). The most important mechanism is hepatic glucose production - as glucose levels begin to fall, glycogen is broken down into glucose and released into the blood stream. Later, the liver may use other substances such as protein, amino acids, and ketone bodies to manufacture glucose and to release it into the circulation.

In the period between meals there is a relative insulin lack, which allows a mobilization of free fatty acids from adipose tissue. When this occurs, metabolism shifts slightly so that the lipids are used by peripheral tissues for energy rather than glucose. This allows the remaining glucose to be available to tissues such as the brain. It is important to be aware that brain cells are both insulin insensitive (they do not require insulin for transport of glucose into the cells) and primarily use glucose for energy. This means that the brain continues to use glucose as its fuel, even during fuel deprivation, starvation, and DKA.

Some of the fatty acids released are taken up by the liver and converted to ketones which can be oxidized in the brain to provide backup fuel should hepatic glucose production fail. These changes are typical of the post-prandial phase and would usually end at the next meal. If the fasting period is extended the ketone levels will begin to rise, but usually are limited by the fact that ketones stimulate insulin release which prevents further breakdown of adipose tissue. Obviously, in severe starvation conditions this mechanism can be overridden so that adipose stores can be used.

The counter-regulatory hormones (glucagon, cortisol, growth hormone, and epinephrine) promote this process and work in opposition to insulin. They promote catabolism - the breakdown of stored fuel. They promote lipolysis, gluconeogenesis, and glycogenolysis and increase the serum glucose level to prevent hypoglycemia.

Glucagon: promotes hepatic production of glucose and ketones,

Catecholamines: promotes hepatic glucose output (glycogenolysis), inhibits muscle glucose uptake, enhances fatty acid mobilization (lipolysis),