The hyperosmolar hyperglycemic state (HHS) is characterized by progressive hyperglycemia and hyperosmolarity typically found in a debilitated patient with poorly controlled or undiagnosed type 2 diabetes mellitus, limited access to water, and commonly, a precipitating illness. A number of terms, including hyperosmolar hyperglycemic nonketotic state/coma/syndrome and nonketotic hyperglycemic coma, are used to describe HHS. The syndrome does not necessarily include ketosis or coma, and we will use the terminology adopted by the American Diabetes Association.1 Most cases of HHS occur in the elderly with comorbid organ or metabolic diseases, and about 70% of patients have been previously diagnosed as diabetics. However, the incidence in children is increasing, with the common risk factors being obesity and African American race.2
The basic pathophysiology of diabetes is discussed in Chapter 218, Type 1 Diabetes Mellitus, and Chapter 219, Type 2 Diabetes Mellitus. The development of HHS is attributed to three main factors: (1) insulin resistance and/or deficiency; (2) an inflammatory state with marked elevation in proinflammatory cytokines (C-reactive protein, interleukins, tumor necrosis factors) and counterregulatory hormones (growth hormone, cortisol) that cause increased hepatic gluconeogenesis and glycogenolysis; and (3) osmotic diuresis followed by impaired renal excretion of glucose.3
In a patient with type 2 diabetes, physiologic stresses combined with inadequate water intake in an environment of insulin resistance or deficiency lead to HHS. As serum glucose concentration increases, an osmotic gradient develops, attracting water from the intracellular space into the intravascular compartment, causing cellular dehydration. The initial increase in intravascular volume is accompanied by a temporary increase in the glomerular filtration rate. As serum glucose concentration increases, the capacity of the kidneys to reabsorb glucose is exceeded, and glucosuria and osmotic diuresis occur. During osmotic diuresis, significant urinary loss of sodium and potassium, as well as more modest losses of calcium, phosphate, and magnesium may occur. As volume depletion progresses, renal perfusion decreases, and the glomerular filtration rate is reduced. Renal tubular excretion of glucose is impaired, which further worsens hyperglycemia. A sustained osmotic diuresis may result in total body water losses that often exceed 20% to 25% of total body weight, or approximately 8 to 12 L in a 70-kg patient.
The relative lack of severe ketoacidosis in HHS is poorly understood and has been attributed to three possible mechanisms: (1) higher levels of endogenous insulin than are seen in diabetic ketoacidosis, which inhibits lipolysis; (2) lower levels of counterregulatory "stress" hormones; and (3) inhibition of lipolysis by the hyperosmolar state itself. Evidence of significant ketoacidosis in a patient thought to have type 2 diabetes should bring into question the possibility of variants of type 1 diabetes, such as latent autoimmune diabetes in adults.4 Additionally, a greater proportion of ketosis-prone type 2 diabetes has been described in black, Hispanic, and other populations.5,6 This growing body of evidence identifying ketosis-prone type 2 diabetes has prompted a call by some for ...