EVALUATION OF HYPOGLYCEMIA

Andrew Maclennan, MD April 23, 2010 Morning Report

& Insulin Autoimmune Syndrome (Hirata disease)

SYMPTOMS OF HYPOGLYCEMIA

“Neuroglycopenic symptoms” Cognitive impairment, behavioral changes,

psychomotor abnormalities, coma, death “Neurogenic symptoms”

Tremors, palpitations, anxiety/arousal, sweating, hunger, paresthesias

WHO TO EVALUATE?

Whipple’s Triad: Symptoms consistent with hypoglycemia A low plasma glucose - measured with a

precise method (not a glucometer) Relief of symptoms after glucose level

normal

Allen Oldfather Whipple

DIAGNOSTIC APPROACH

Fast (overnight or post-prandial) 72 hr fast if initial fast is negative

End fast when glucose ≤45 mg/dL Pt has signs/sx of hypoglycemia 72 hours have elapsed glucose <55 mg/dL if Whipple's triad documented previously

Check Q6 hrs, more frequently when glucose < 60 mg/dL plasma glucose, insulin, C-peptide, proinsulin, BHOB, and oral

hypoglycemic agents At end of fast

IV glucagon and measure glucose 10, 20, and 30 minutes later Feed patient

WHAT TO MEASURE?

In symptomatic patients with hypoglycemia Insulin > 3 microU/mL is excess insulin; consistent w/ insulinoma

Caution! Glucose < 50 mg/dL in some normal subjects & >50 mg/dL in some patients with insulinoma.

Proinsulin > 5 pmol/L consistent w/ insulinoma Beta-hydroxybutyrate - Insulin is antiketogenic

BHOB levels lower in insulinoma patients than in normal subjects. C-peptide - distinguishes endogenous from exogenous hyperinsulinemia Sulfonylurea and meglitinide screen Glucose response to glucagon

Insulin is antiglycogenolytic and hyperinsulinemia permits retention of glycogen within the liver.

In insulin-mediated hypoglycemia, response to glucagon is release of glucose Normal patients have virtually exhausted hepatic glycogen stores after 72hrs and

can’t respond as vigorously. (Insulin & insulin receptor antibodies)

LOCALIZING STUDIES

Radiologic studies — CT, MRI, transabdominal US can detect most insulinomas

Arterial calcium stimulation — to distinguish between insulinoma and a diffuse process (islet cell hypertrophy/nesidioblastosis). Inject calcium gluconate into gastroduodenal, splenic

and superior mesenteric artery Sample hepatic vein for insulin Increased insulin secretion localizes area of

hyperfunctioning islets.

TREATMENT OF HYPERINSULINEMIC HYPOGLYCEMIC STATES

Insulinoma – surgical resection of tumor

Nesidioblastosis – partial or subtotal pancreatectomy

Antibodies to insulin receptors – immunosuppressants (poor response)

Antibodies to insulin – glucocorticoids (good response)

INSULIN AUTOIMMUNE SYNDROME

CLINICAL MANIFESTATIONS

Episodes of hyperinsulinemic hypoglycemia Often post-prandial, after exercise

Paradoxic hyperglycemia May occur after meal or oral glucose

challenge

EPIDEMIOLOGY

Extremely uncommon in West (58 case reports in non-Asian populations) 3rd leading cause of hypoglycemia in Japan

No sex preference Age > 40yrs Associated with rheumatologic disease

SLE, RA, May see positive ANA, anti DSDNA, RF

Association with medications Captopril, penicillamine, hydralazine, procainamide, INH,

penicillin G Meds with sulfhydryl group (especially methimazole)

PATHOPHYSIOLOGY

1. Insulin secreted after meal bound by antibodies (IgG)

2. Hyperglycemia persists causing more insulin secretion (results in high A1C over time)

3. As hyperglycemia abates, insulin-bound to antibodies is released, with inappropriately high insulin levels

4. Hypoglycemia results.

LABORATORY AND CLINICAL FINDINGS

Autoimmune Forms of Hypoglycemia.Lupsa, Beatrice; Chong, Angeline; Cochran, Elaine; MSN, CRNP; Soos, Maria; Semple, Robert; MB, PhD; Gorden, Phillip

Medicine. 88(3):141-153, May 2009.DOI: 10.1097/MD.0b013e3181a5b42e

REFERENCES

Lupsa BC et al, Autoimmune Forms of Hypoglycemia. Medicine, vol 88(3):141-153; May 2009.

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