Etiology

Infection is the major precipitating factor, occurring in 30% to 60% of patients. Urinary tract infections and pneumonia are the most common infections reported.[1][9][2]

In many instances, the trigger is an acute illness, such as stroke, myocardial infarction, or other medical-surgical illnesses, or trauma that provokes the release of counter-regulatory hormones (catecholamines, glucagon, cortisol, and growth hormone) and/or compromises water intake.[1]

In elderly patients, being bed-ridden and having an altered thirst response compromise access to water and water intake, leading to severe dehydration and HHS.[16] HHS can be seen in postoperative patients with a known history of diabetes, especially postcardiac-bypass surgery or neurosurgery.[9][7][17]

Patients with pre-diabetes or diabetes who require total parenteral nutrition in their postoperative state and are not started on appropriate insulin therapy may also present with HHS.[9] A patient with a strong family history of diabetes is also at high risk of developing HHS on total parenteral nutrition therapy if not treated concomitantly with insulin.[9][18]

Rarely, endocrine disorders, such as hyperthyroidism and acromegaly, can lead to HHS.[9][19] In patients with concomitant diabetes, hypercortisolism leads to insulin resistance and promotes HHS development.[20] Ectopic production of adrenocorticotropic hormone has been associated with HHS.[21] Initiation of corticosteroids without adjustment of insulin doses or that of oral antidiabetic agents can trigger HHS.

Nonadherence to insulin or oral antidiabetic medication is found in 12% to 25% of patients admitted for HHS.[5][7] This association is much higher in urban African-American patients with diabetes, in whom nonadherence is the sole reason for HHS in 42% of cases.[10] Alcohol and cocaine abuse is a major contributing factor to nonadherence of diabetic therapy.

Corticosteroids, thiazide diuretics, beta-blockers, and didanosine have all been associated with HHS.[22][23][24][25][26] These drugs are thought to induce HHS by affecting carbohydrate metabolism.[8] Medications that have been associated with hyperglycemia but not with HHS include phenytoin and cimetidine.[27][28] Drug-induced hyperglycemia has been noted increasingly in HIV clinics; the drugs involved most commonly are megestrol, pentamidine, and corticosteroids.[29] The risk of severe hyperglycemia increases when using a combination of these medications.[30] Atypical antipsychotic medications (in particular, clozapine and olanzapine) have also been implicated in producing diabetes and hyperglycemic crises.[31][32]

Approximately 7% to 17% of patients have newly diagnosed diabetes.[10]

Pathophysiology

HHS is characterized by extreme elevations in serum glucose concentrations and hyperosmolality without significant ketosis. These metabolic derangements result from relative insulin deficiency and increased concentration of counter-regulatory hormones (catecholamines, glucagon, cortisol, and growth hormone).[1][16]

Although both HHS and diabetic ketoacidosis (DKA) are often discussed as distinct entities, they represent 2 points on the spectrum of metabolic derangements in diabetes. Approximately one third of patients with hyperglycemic crises present with a mixed picture of DKA and HHS.[5][6][33]

The pathogenesis of HHS is, however, not fully understood.[34] Measurable insulin secretion in patients with HHS is higher than in patients with DKA.[35][33] This higher insulin concentration is believed to be sufficient to suppress lipolysis and ketogenesis but inadequate to regulate hepatic glucose production and promote glucose utilization. This concept is supported by clinical studies. These studies have shown that the half-maximal concentration of insulin for antilipolysis is lower than for glucose use by peripheral tissues.[16][36] Another potential mechanism for the lack of ketosis in HHS involves the effect of hyperosmolality on inhibiting lipolysis, insulin secretion, and glucose uptake.[35]

A reduction in the net effective concentration of insulin owing to any etiology leads to impaired carbohydrate, lipid, and ketone metabolism in hyperglycemic crises. Decreased insulin results in increased gluconeogenesis, accelerated glycogenolysis, and impaired glucose utilization by peripheral tissues.[10][1]

Disturbances in hydration and electrolyte balance are of great importance in the pathogenesis of HHS. Because HHS evolves over several days, continued osmotic diuresis leads to hypernatremia, particularly in older patients with compromised renal function and/or inability to drink water to keep up with urinary losses. The resulting hypernatremia and hyperglycemia, coupled with inadequate water intake and excess water loss, result in profound volume contraction. Hypovolemia leads to a progressive decline in the glomerular filtration rate, which aggravates the hyperglycemic state.[1]

Counter-regulatory hormones, particularly epinephrine, are increased as a systemic response to infection. They induce insulin resistance, decrease insulin production and secretion, and increase lipolysis, ketogenesis, and volume depletion, thereby contributing to the hyperglycemic crises in patients with diabetes.[1]

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