Hypoglycemia

Hypoglycemia, or low blood glucose, has many causes, but it most commonly occurs in diabetic patients as a consequence of insulin therapy or other drugs. The onset of hypoglycemic symptoms depends largely on the individual's physiological adaptation mechanisms, although symptoms can start to occur when blood glucose falls below 70 mg/dL. Hypoglycemia manifests with autonomic symptoms (i.e., hunger, sweating, tachycardia) and neuroglycopenic symptoms (i.e., confusion, behavioral changes, somnolence). Since prolonged hypoglycemia can result in acute brain damage, changes in a patient's mental status should prompt immediate fingerstick blood glucose measurement and treatment. Treatment in patients who are still conscious consists of a fast-acting carbohydrate such as glucose tablets, candy, or juice. Unresponsive patients are treated with intravenous dextrose or intramuscular glucagon.

Diabetic patients ^[2][3]

Causes of hypoglycemia in diabetic patients
Insulin-related	Insulin excess Accidental overdose of insulin or noninsulin drugs (e.g., sulfonylureas, meglitinides) Wrongly timed medication Drug interactions Factitious disorder Reactive hypoglycemia Increased sensitivity to insulin Weight loss Increase in activity/exercise Decreased insulin clearance Renal failure
Glucose-related	Fasting/missed meals Chronic alcohol use Exercise
Acute illness	Sepsis Trauma Burns Organ failure

(Relative) overdose of insulin or a noninsulin drug is by far the most common cause of hypoglycemia.

Consider factitious disorder in patients with access to insulin and other diabetes medications (e.g., healthcare professionals), for whom there is no other obvious explanation for hypoglycemia.

Nondiabetic patients ^[2][3]

Causes of hypoglycemia in nondiabetic patients
Critical illness	Hepatic disease Renal failure Heart failure Malnutrition Sepsis Trauma Burns
Drugs that cause hypoglycemia [3]	Nonselective beta blockers Antimalarial drugs: quinine, chloroquine Antibiotics: sulfonamides, trimethoprim-sulfamethoxazole, fluoroquinolones Antifungal drugs: pentamidine, oxaline Analgesics: indomethacin, propoxyphene/dextropropoxyphene Antihypertensive drugs: ACE-inhibitors, angiotensin receptor antagonists Antiarrhythmics: cibenzoline, disopyramide Others: IGF-1, lithium, mifepristone, heparin, 6-mercaptopurine
Hormone deficiencies	Hypopituitarism Adrenal insufficiency
Endogenous hyperinsulinism or IGF	Insulinoma Noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS) Gastric bypass surgery (late dumping syndrome) Nonislet cell tumor hypoglycemia
Exogenous hyperinsulinism	Factitious disorder Accidental insulin use
Autoimmune causes	Insulin autoimmune syndrome (IAS) Anti-insulin receptor autoantibodies
Genetic and congenital disorders [4]	Congenital hypopituitarism Glycogen storage diseases Fructose intolerance

Threshold for symptoms

• Varies greatly; , but symptoms have usually occurred by the time serum glucose concentration is < 50 mg/dL (2.8 mmol/L)
• The threshold at which symptoms may appear in patients with chronic diabetes is especially variable due to hypoglycemia-associated autonomic failure (HAAF). ^[1]
  • Recurrent hypoglycemia → changes in the counterregulatory response (e.g., decreased epinephrine release) → lower glucose threshold needed to trigger symptoms → asymptomatic hypoglycemia
  • For this reason, the initial symptom of hypoglycemia in patients with HAAF is often confusion.
• The threshold can also vary due to medication: Beta blockers can mask signs of hypoglycemia.

Signs and symptoms

• Neurogenic/autonomic
  • Increased sympathetic activity: tremor, pallor, anxiety, tachycardia, sweating, and palpitations
  • Increased parasympathetic activity: hunger, paresthesias, nausea, and vomiting
• Neuroglycopenic
  • Agitation, confusion, behavioral changes
  • Fatigue
  • Seizure, focal neurological signs
  • Somnolence → obtundation → stupor → coma

Beta blockers can mask signs of hypoglycemia.

General diagnostic approach

1. Confirm low blood glucose (via fingerstick or BMP) and check for Whipple triad.
2. Rule out acute illness as a cause (e.g., infection, sepsis, burns).
3. Review the patient's medications to rule out medication as a cause (see drugs that cause hypoglycemia).
4. Perform diagnostic workup based on the leading differential diagnosis and whether the patient has diabetes or not.

If the Whipple triad is not confirmed, no further workup is indicated.

Diabetic patients ^[1]

• Hypoglycemia in diabetic patients is almost always due to acute illness and/or medications (e.g., insulin) and further workup is generally not indicated.
• Initial workup if no obvious trigger identified:
  • Labs: CBC, BMP, LFTs, urinalysis
  • Imaging: X-ray chest
  • Infectious workup
  • Consider sulfonylurea and exogenous insulin levels.

Nondiabetic patients ^[2]

• Rule out acute illness and medication as a cause.
• Further diagnostic testing should only be pursued if the cause is not evident based on history and examination (and with the guidance of an endocrinologist).
• The goal is to determine if the hypoglycemia is due to hyperinsulinemia (e.g., insulinoma).

Laboratory studies

• The following labs should be obtained during a hypoglycemic episode (or 72-hour fast if no spontaneous hypoglycemic episode is documented):
  • Insulin antibodies
  • Sulfonylurea level (and any other oral antidiabetic agents)
  • β-hydroxybutyrate
  • Proinsulin
  • C-peptide
  • Glucose
  • Insulin
• Glucagon tolerance test (see below)
• Consider also: anti-insulin receptor antibodies, IGF-1/IGF-2, cortisol, glucagon, growth hormone

72-hour fast ^[2]

• Procedure: The patient fasts for 72 hours, only drinking noncaloric beverages, and all nonessential medications are discontinued.
  • Measure insulin, C-peptide, and glucose every 4–6 hours.
  • Once plasma glucose < 45 mg/dL or < 55 mg/dL with documented Whipple triad, obtain serum studies (see “Laboratory studies” above).
  • After serum studies have been obtained, continue with a glucagon tolerance test and end the fast.
  • This should be done on an inpatient basis and under the guidance of an endocrinologist.
• Limitations
  • Results may be inaccurate if the physiological glucose level is low.
  • Rarely, insulinomas may suppress insulin release in response to hypoglycemia.
  • Insulin levels can be artificially elevated in the presence of circulating anti-insulin antibodies.

The 72-hour fast is only necessary if a spontaneous hypoglycemic episode does not occur.

Glucagon tolerance test

• Procedure: After the 72-hour fast has ended, inject glucagon.
  • Measure serum glucose and insulin at baseline, then at 10, 20, and 30 minutes after glucagon injection.
• Normal response: rapid insulin response, up to 100 uU/mL; glucose peak at 20–30 minutes
• Insulinoma patients: exaggerated insulin response (exceeding 160 uU/mL); peak insulin at 15 minutes
• Limitations
  • Unreliable in patients with malnutrition, hepatic disease, and cirrhosis with portocaval anastomosis
  • Medication interference: diazoxide, hydrochlorothiazide, diphenylhydantoin, sulfonylureas, aminophylline
  • Patients with nonislet cell tumors can have insulinoma-like responses.
  • The glucagon tolerance test can induce nausea, vomiting, and hypoglycemia.
  • In 8% of insulinomas, the expected peak is not observed.

Interpreting the results of fasting labs and the glucagon tolerance test ^[2][1]

Serum levels	Hypoglycemia without hyperinsulinism	Hyperinsulinism (or ↑ IGF)
Glucose	Low	Low
Insulin	Low/normal	Elevated
Proinsulin, C peptide	Low/normal	Exogenous: low
		Endogenous: normal/high
β-hydroxybutyrate	Normal	Low
Glucose response to glucagon	Diminished response	Normal response

Nonsuppressed serum insulin concentrations with decreased serum C-peptide and proinsulin concentrations are consistent with exogenous insulin use.

Imaging

• Indications: labs consistent with endogenous hyperinsulinism (e.g., insulinoma) ^[5]
• Usually, combined imaging is required to confirm the diagnosis of insulinoma (CT scan and MRI )

• If the patient is conscious:
  • Oral glucose 15–20 g
  • Fast-acting carbohydrates (such as glucose tablets, candy, or juice)
• If the patient is unconscious (or unable to ingest glucose): ^[2]
  • IV dextrose
    • Subsequent dextrose infusions (D5NS or D10NS infusion) may be needed to maintain glucose levels.
    • Monitor glucose every 2 hours and titrate infusion to maintain serum glucose > 100 mg/dL.
  • IM glucagon : if neither oral or IV routes of administering glucose are feasible
  • Monitoring
    • Recheck POC glucose after 15 minutes.
    • Consider ICU admission with hourly glucose monitoring if hypoglycemia is refractory.

Suspected severe hypoglycemia should be treated immediately, without waiting for the results of blood glucose testing!