Hypoglycemia

Karen Tordjman

Institute of Endocrinology

Tel Aviv Sourasky Medical Center

October 24, 2007

Hypoglycemia

• History• Recognition of hypoglycemia• Counterregulation• Incidence• Classification• Causes• Approach to the patient with hypoglycemia• Insulinoma• NIHPS

October 24, 2007

• 19th century: identification of hypoglycemia in some severe illnesses

• 1920’s: recognition of spontaneous symptoms similar to those seen with insulin Rx excess, “hyperinsulinism”

• 1927: 1st patient with hypoglycemia due to malignant islet cell tumor

• 1929: 1st successful surgical treatment of insulinoma• 1960’s: development of RIA proves hyperinsulinemia in

insulinoma• 1950-present: better understanding of physiology and

genetics of glucose metabolism and counterregulation allows identification of other causes of hypoglycemia

Hypoglycemia- History

October 24, 2007

• When should we suspect true hypoglycemia?When should we suspect true hypoglycemia?• Whipples’ triadWhipples’ triad

• Symptoms of hypoglycemia

• Low plasma glucose

• Relief of symptoms with glucose

Hypoglycemia- Recognition

October 24, 2007

• Symptoms of hypoglycemia• Neuroglycopenic: fatigue, drowsiness, difficulty

thinking and speaking, confusion, blurred vision, fainting

• Neurogenic-autonomic: Cholinergic: hunger, sweating, tingling Adrenergic: shakiness, palpitations,

nervousness

Hypoglycemia- Recognition

October 24, 2007

Hypoglycemia- Recognition

• Signs of hypoglycemiaSigns of hypoglycemia• Pallor, diaphoresis, tachycardia, elevated

BP, impaired cognition

October 24, 2007

• Biochemical evidenceBiochemical evidence• Unequivocal: fasting (post-absorptive) plasma

glucose<50 mg/dl• Suggestive: fasting 50-70 mg/dl• Postprandial: no good definition <50 mg/dl

Hypoglycemia- Recognition

• Artifactual causes of biochemical Artifactual causes of biochemical hypoglycemiahypoglycemia

• Prolonged sample standing, continued glycolysis

• Polycythemia, leukocytosis, leukemia

October 24, 2007

Hypoglycemia- Counterregulation

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Threshold for counterregulatory hormone secretion ~65-68 mg/dl

October 24, 2007

Hypoglycemia-Counterregulation

October 24, 2007

• Counterregulatory mechanisms are• Hierarchic• Redundant• Prolonged hypoglycemia due to failure of

hormonal counterregulation is very rare (T1DM excepted)

Hypoglycemia-Counterregulation

October 24, 2007

• Incidence of insulinoma: 4/106 person years (Olmsted county, Mayo Clinic)

• Hypoglycemia in adults is almost always due to drugs!

Hypoglycemia- General

October 24, 2007

Incidence and Scope of Hypoglycemia

• 1.2%-20% of adult inpatients• Marker of poorer outcome in elderly non diabetic

subjects• Type 1DM patients are 10% of the time in

hypoglycemia.• Average of 2 mild episodes/week, 1 severe/year• Hypoglycemia in T2DM~10% that in T1DM

October 24, 2007

Hypoglycemia- Classification

• Treated diabetic vs. no diabetes

• Fasting vs. postprandial

• Insulin-mediated (hyperinsulinemic) vs. non insulin-mediated

• Healthy- vs. ill-appearing patient

October 24, 2007

• Drugs• Ethanol (especially binge-drinking with no food)

• Salicylates

• Halidol, fluoxetine

• Fibrates

• Antibiotics: sulfonamides, fluoroquinolones (gatofloxacin)

• Surreptitious or erroneous administration of hypoglycemic agents: insulin or oral agents (mostly insulin-secretagogues)

Causes of Hypoglycemia in the Healthy-Appearing Patient

October 24, 2007

• Endogenous hyperinsulinemia• Insulinoma, very rare• Non Insulinoma Pancreatogenous Hypoglycemia

Syndrome: NIPHS. (1st report 1999, increasingly recognized, still extremely rare)

• Autoimmune, insulin autoantibodies, extremely rare

• Beta-cell stimulating autoAb, theoretical

Causes of Hypoglycemia in the Healthy-Appearing Patient

October 24, 2007

• Reactive (post-prandial) hypoglycemia• Post-gastric surgery hypoglycemia (to be

distinguished from earlier Dumping Synd. Sx)• Alimentary hypoglycemia (rapid glucose

absorbtion, enhanced incretin secretion, brisk and vigorous insulin response)

• NIPHS

Causes of Hypoglycemia in the Healthy-Appearing Patient

October 24, 2007

• Drugs are again the main offendersSame drugs, but also anti malarial, pentamidine

• Predisposing or causative illnesses• Starvation• Renal failure• Hepatic failure• Congestive heart failure• Sepsis• Hypopituitarism• Addison’s disease• Large mesenchymal tumors• Hematologic malignancies

Causes of Hypoglycemia in the Ill-Appearing Patient

October 24, 2007

Approach to the Patient with Hypoglycemia

• Establish the diagnosis of hypoglycemiaEstablish the diagnosis of hypoglycemia• Clinical suspicion (recurring neuroglycopenic

symptoms)• Hypoglycemia needs to be proven (venous

glucose<50 mg/dl, Whipple’s triad)

October 24, 2007

• Fasting hypoglycemiaFasting hypoglycemia• Document hypoglycemia after O/N fast if

possible• Prolonged fast if needed• Evaluate drugs and clinical condition• In case of emergency obtain: glucose, insulin,

C-peptide, SU, prior to treating

Approach to the Patient with Hypoglycemia

October 24, 2007

Approach to the Patient with Hypoglycemia

• Fasting hypoglycemiaFasting hypoglycemia• Measurable insulin: consider one of the

hyperinsulinemic conditions (C-peptide, SU screen essential)

• Insulin suppressed: search for potential drugs or/and clues to other conditions (tumors, chronic diseases, rare genetic metabolic dis.)

October 24, 2007

• Postprandial hypoglycemiaPostprandial hypoglycemia• True condition very uncommon• Suspect with appropriate story and timing• Check out gastric surgery• OGTT not appropriate (10th percentile<47 mg/dl, no

symptoms)• Mixed meal (no standardization), documentation of

Whipple’s triad• Subject patients with postprandial hypoglycemia to

prolonged fast to R/O insulinoma

Approach to the Patient with Hypoglycemia

October 24, 2007

• Treatment of postprandial hypoglycemiaTreatment of postprandial hypoglycemia• Low carbohydrate high protein diet• Frequent feeding -glucosidase inhibitor (prandase) All unproven Surgery for NIHPS

Approach to the Patient with Hypoglycemia

October 24, 2007

• Clinical clues• Recurrent neuroglycopenic symptoms with fast or

upon exercise in healthy-appearing patient

Approach to the Patient with Suspected Insulinoma

• Diagnosis• Demonstrated fasting hypoglycemia with Whipple’s triad• If necessary patient is subjected to inpatient prolonged fast• Relative hyperinsulinemia with commensurate C-peptide (and proinsulin)• Lower OH-butyrate(<2.7 mM), good response to glucagon (>25 mg/dl)• Increased chromogranin A• Negative SU screen

October 24, 2007

• Issues with prolonged fast• Hypoglycemia possible in normal individuals but no

Whipple’s triad

• Because of lower threshold for symptoms in subjects with insulinoma

• Biochemical determination of hypoglycemia in the lab (not glucometer)

• Goal reached within 12 h in 35%, 24 in 75%, and 48h in 92%, essentially 100% within 72 h.

• No need for a stimulatory test!

Approach to the Patient with Suspected Insulinoma

October 24, 2007

• US, CT, MRI, often small and difficult to visualize but will demonstrate metastasis in malignant insulinoma (5-10%), 60-70% sensitive

Localization of Insulinoma

October 24, 2007

Localization of Insulinoma

October 24, 2007

• US, CT, MRI, often small and difficult to visualize but will demonstrate metastasis in malignant insulinoma (5-10%), 60-70% sensitive

• Octreoscan positive in 50%

Localization of Insulinoma

October 24, 2007

Localization of Insulinoma

October 24, 2007

• US, CT, MRI, often small and difficult to visualize but will demonstrate metastasis in malignant insulinoma (5-10%), 60-70% sensitive

• Octreoscan positive in 50%• Arteriography obsolete (poor accuracy)• Endoscopic US (positive ~90%)

Localization of Insulinoma

October 24, 2007

Localization of Insulinoma

October 24, 2007

Localization of Insulinoma

• US, CT, MRI, often small and difficult to visualize but will demonstrate metastasis in malignant insulinoma (5-10%), 60-70% sensitive

• Octreoscan positive in 50%• Arteriography obsolete (poor accuracy)• Endoscopic US (positive ~90%)• Intraoperative US, yield 98%

October 24, 2007

Localization of Insulinoma

October 24, 2007

Localization of Insulinoma

• US, CT, MRI, often small and difficult to visualize but will demonstrate metastasis in malignant insulinoma (5-10%), 60-70% sensitive

• Octreoscan positive in 50%• Arteriography obsolete (poor accuracy)• Endoscopic US (positive ~90%)• Intraoperative US, yield 98%• Selective arterial calcium stimulation

October 24, 2007

Localization of Insulinoma

Selective arterial calcium stimulation

October 24, 2007

April 10, 2006

Localization of Insulinoma

Selective arterial calcium stimulation

An insulinoma was excised from the tail, patient was cured

• >450 histologically proven cases

• Age ~50 y(8-85)

• F/M (58/42)

• MEN-1 7.6%

• Malignant insulinoma 5.8%

Insulinoma - The Mayo Clinic Experience 1927-2005

October 24, 2007

• Intraoperative glucose monitoring

• Intraoperative palpation/US

• Enucleation if possible (~60%)

• Distal pancreatic resection/splenectomy (~36%)

• Whipple’s operation rarely needed

• Laparoscopic surgery still under study

Insulinoma – Surgical Treatment

October 24, 2007

• Diazoxide• Verapamil• Chemotherapy (adria/STZ, 60% response rate)• Octreotide for symptomatic relief (SST2r in ~50%)• Somatostatin-receptor targeted therapy

(investigational)• New modalities based on molecular biology of tumors

(tyr-kinase receptors present, potential for inhibitors)

Insulinoma – Medical Treatment

Insulinoma in the Ferret

Insulinoma is the most common neoplastic disease in the ferret, followed by adrenocortical tumors

Zuki lived with recurring insulinoma for 4 years and lived a full and active life till age 7 1/2.

October 24, 2007

• First reported in 1999, increasingly diagnosed• Represents ~4% of endogenous hyperinsulinemia• Men > women• Post prandial neuroglycopenic symptoms• Usually fast negative, mixed meal positive• Insulin levels lower than in insulinoma• Negative imaging• SACS positive• Not tumor, islet cell hyperplasia and nesidioblastosis• Curable with surgery

NIPHS

April 10, 2006

NIPHS-Pathology

October 24, 2007

Thank you!