Download Evaluation of Recurrent Hypoglycemia

Evaluation of Recurrent Hypoglycemia
Endocrinology of Utah
Updated by Miriam Padilla, MD, CDE Nov 2015
Possible Causes of hypoglycemia:
1. Malnutrition/prolonged starvation
2. Liver or Kidney damage (liver produces 80% of glucose Kidneys produce 20% of glucose)
3. Iatrogenic- too much insulin or sulfonylurea
4. Insulinoma
5. Addison’s Disease or pan hypopituitarism or adrenal insufficiency where patient lacks cortisol
6. End stage diabetic patients will lack glucagon
7. Beta cell hyperplasia
8. Sepsis
9. Cystic fibrosis
10. Chronic pancreatitis
11. Chronic ETOH
12. Cirrhosis
13. Severe hyperthyroidism
14. Insulin autoimmune hypoglycemia (Ab to insulin, Ab to insulin receptor)
15. Post bariatric surgery
16. IFG-2 mediated hypoglycemia (Non-islet cell tumor)
17. Nesidioblastosis ( functional beta cell disorders): Non insulinoma pancreatogenous hypoglycemia
Work up for Hypoglycemia:
A.
Confirm Whipple's triad before embarking on extensive work-up
1. Glucose ≤50 mg/dL (2.77 mmol/L)
2. Clinical manifestations of hypoglycemia
3. Resolution of symptoms upon treatment of hypoglycemia
B.
Exclude identifiable systemic causes before proceeding
1. Hormone deficiencies
 Primary adrenal insufficiency
 Hypopituitarism with secondary adrenal insufficiency
2. Critical illness
 Severe renal, hepatic or cardiac failure
 Sepsis
3. Starvation
4. Drugs: salicylates, quinine, pentamidine, alcohol, accidental or surreptitious intake of insulin, and oral
hypoglycemia agents
C. Focus on insulin-related hypoglycemia (insulinoma, post-gastric bypass hypoglycemia, non-insulinoma
pancreatogenous hypoglycemia, anti-insulin antibodies, and antibodies against insulin receptor)
1. Measure glucose, insulin, pro-insulin, C-peptide, β-hydroxybutyrate, and glucose at the time of suspected
hypoglycemia
2. Measure blood levels of antibodies against insulin and against the insulin receptor
3. Obtain hypoglycemic agent screen panel
D. Focus on IGF-2-omas in patients with hypoglycemia with low insulin, C-peptide, pro-insulin, and βhydroxybutyrate levels
1. Measure levels of big–IGF-2: elevated level expected
2. Look for depressed levels of IGF-1, GH, and IGFBP-3, any of which would support the diagnosis
3. Measure total IGF-2: elevated level helpful; normal level is not exclusionary
4. Search for large tumors, especially in the thorax and retroperitoneum: large tumors supportive of diagnosis;
small tumors may or may not be related to hypoglycemia
Mayo Protocol to Evaluate Hypoglycemia:
- Fast for 72 hrs, patient may have water or drinks that are calorie free and caffeine free
- Check glucose Fingerstick every 6 hrs
- Once glucose concentration is <60 mg/dL, Collect blood for: insulin, c-peptide, proinsulin, beta hydroxybutyrate, glucose
- Check Insulin antibodies (this does not have to be measured during hypoglycemia)
- Fast is ended when either the glucose <45mg/dL, or 72 hours have passed or when the plasma glucose concentration is
less than 55 mg/dL (3 mmol/L) if Whipple's triad was documented on a prior occasion
- Ending the fast collect glucose, insulin, c-peptide, proinsulin, beta hydroxybutyrate, and sulfonylurea
- After the fast is completed and all blood work is drawn, Administer 1mg glucagon IV and measure plasma glucose 10, 20
and 30 minutes later
- Feed patient after the fast is completed
72 hour fast interpretation:
- Plasma insulin concentration of 3mU/mL when glucose <55mg/dL indicates excess inulin
- Plasma c-peptide > 0.2nmol/L consistent with hyperinsulinemia
- Plasma beta hydroxybutyrate is lower in insulinoma patients, BHOB level general 2.7mmol/L or less consistent with
insulinoma.
- After glucagon administration: Patients with insulin mediated hypoglycemia respond to glucagon by releasing glucose,
normal subject cannot respond as vigorously compared to insulinoma patients because insulin is antiglycogenolytic and
hyperinsulinemia permits retention of glycogen within the liver.- At the end of the fast insulinoma patients have an
increase in plasma glucose of 25mg/dL or more in 20-30 minutes whereas normal subjects have a smaller increment
- Proinsulin will be elevated in insulinoma >5 pmol/L
Confirmatory Testing:
Non Invasive Testing:
1. Transabdominal US
2. Spiral CT or MRI
3. To eval for insulinoma:111I-In-pentetreotide imaging or Fluorine-18-L-dihydroxyphenylalanine PET (18-F-DOPA PET)
Invasive Testing:
1. Selective arterial calcium stimulation test:
- Inject calcium gluconate into arteries supplying the pancreas with frequent checking of insulin levels
- A positive result is double or tripling of the basal hepatic venous serum insulin concentration (indicated hyperfunctioning
lesion)
- In Insulinoma – reponse is positive in one artery alone or two if lesion is fed by two arteries
- In pancreatogenous hypoglycemia syndrome – response is positive in multiple arteries (example in Diffuse hypertrophy
of islet cells or Nesideoblastosis)
2. Endoscopic Ultrasonography
3. Pancreatic biopsy to diagnose Nesidioblastosis
Treatment on Insulinoma or Non Islet Cell tumor :
1. Oral glucose and/or IV glucose or dextrose containing fluids
- Not a desirable long term strategy
2. Complete removal of tumor or reduction of tumor mass
- Surgical removal is the treatment of choice for insulinoma and Non Islet Cell tumors
3. Local Antitumor Therapy
- Selective embolization of tumor
- Localized Chemotherapy (example line streptozocin/doxorubicin or a temozolomide-based
regimen)
- Radiation Therapy
4. Glucocorticoids:
-
Dexamethasone, Hydrocortisone, Prednisolone, and Prednisone
Equivalent to Prednisone 30-60mg/d are most effective
stimulation of hepatic gluconeogenesis
inhibition of peripheral glucose uptake
mobilization of amino acids from extrahepatic sites
promotion of lipolysis with fatty acid release from adipose tissue
decrease production of IGF-2
5. Recombinant Human Growth Hormone
- stimulates hepatic gluconeogenesis and glycogenolysis
- Suppresses peripheral glucose uptake
dose required is very high and has only modest efficacy
- 3-12mg daily
- concern with long term tx of GH is potential to elevate levels of IGF-1 and insulin and undo
beneficial effects
- theoretical risk of stimulating growth of tumor itself
- Can lead to volume overload
6. Glucagon
-
Increases hepatic glucose output
Effect is short lived; best used as adjunctive therapy in setting of acute hypoglycemia
0.06-0.3 mg/hr IV continuous infusion
7. Somatostatin Analogues such as Octreotide or Lanreotide:
-
Works minimally in some intra abdominal hemangiopericytomas in combination with
glucocorticoids by reducing big IGF-2
Generally does not work in other NICTH because the somatostatin receptors, if present in tumor,
are usually non-functional inhibits GH secretion but in large doses also inhibits the secretion of
TSH, insulin, and glucagon
8. Diazoxide
-
given in divided doses of up to 1200 mg/day
Nondiuretic benzothiadiazine derivative initially used as an antihypertensive but found to have
hyperglycemic effect
inhibits pancreatic insulin release
Can lead to fluid retention, edema, and hirsutism
Not very successful
Post Treatment Surveillance for Insulinoma or Non-islet Cell Tumors:
●Three and six months postresection – History and physical examination, tumor markers, and computed
tomography (CT) or magnetic resonance imaging (MRI).
●Long-term – History and physical examination with tumor markers every 6 to 12 months for years one to three,
and as clinically indicated thereafter. Imaging studies are recommended only as clinically indicated.
References:
Dynkevich, Y. et all. Tumors , IGF-2, and Hypoglcemia; Insights From the Clinic, the Laboratory, and the Historical Archive. Endocrine Reviews,
December 2013, 34 (6): 798-826.
Bodnar, T. et all. Management of Non-islet Cell-Tumor Hypoglycemia: a Clinical Review. Journal of Clinical Endocrinology and metabolism. March
2014, 99 (3):713-722.
Service, John. Hypoglycemia in adults without diabetes mellitus: Diagnostic approach. UpToDate Oct. 2015.