INTRODUCTION AND EPIDEMIOLOGY
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. Although most cases of HHS occur in the elderly, the incidence of HHS in children is increasing, with the common risk factors being obesity and African American race.1
The basic pathophysiology of diabetes is discussed in Chapter 223, “Type 1 Diabetes Mellitus,” and Chapter 224, “Type 2 Diabetes Mellitus,” and is also outlined in Figure 227-1. 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 stress hormones (catecholamines, growth hormone, glucagon, cortisol) that cause increased hepatic gluconeogenesis and glycogenolysis; and (3) osmotic diuresis followed by impaired renal excretion of glucose.2,3
Pathophysiology of hyperglycemic emergencies. HHS = hyperosmolar hyperglycemic state. [Reproduced with permission from Cardoso L et al: Controversies in the management of hyperglycaemic emergencies in adults with diabetes. Metabolism 68: 43, 2017 [PMID: 28183452]. Fig. 1. Copyright Elsevier.]
In patients 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, shifting 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 increases, the capacity of the kidneys to reabsorb glucose is exceeded, and an osmotic diuresis occurs with total body water losses that can exceed 20% to 25% of total body weight, or approximately 8 to 12 L in a 70-kg patient. During osmotic diuresis, significant urinary loss of sodium and potassium and more modest losses of calcium, phosphate, and magnesium occur. With ongoing volume losses, renal perfusion and glomerular filtration are reduced, and renal tubular excretion of glucose is further impaired.4
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 DKA; (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.5 Additionally, a greater proportion of ketosis-prone type 2 diabetes has been described in African American, Hispanic, and Asian populations.6