hypoglycemia in non diabetic patient diagnostic approach causes of hypoglycemia symptoms how to diagnosis

1. Hypoglycemia in
Adults Without
Diabetes Mellitus
Prepared by : Dr. Eman Hassona
Supervised by: Dr. Ahmed Alghazali

2. • Introduction
• Definition
• Physiologic response to Hypoglycemia
• Causes of Hypoglycemia
• Diagnostic approach of non diabetic hypoglycemia
• Management
• Admission criteria
Lecture Outline

3. • Hypoglycemia is a Medical Emergency.
• It signals an inability of the central nervous system to meet
its energy needs, as the glucose is the sole metabolic fuel for
the brain in physiologic condition
• Untreated hypoglycemia can result in permanent neurologic
damage and death.
• As a hypoglycaemia is an uncommon condition in
nondiabetic patients it represents a Diagnostic Challenge!!
Introduction

4. • Hypoglycemia is a clinical syndrome with diverse causes in
which low levels of plasma glucose eventually lead to symptoms
and Signs, and there is resolution of symptoms and signs when
plasma glucose concentration is raised .
• Specific value of hypoglycemia varies among and within
individuals over time.
• The onset of symptoms of hypoglycemia normally occur as
glucose levels fall below 55 mg/dL
What is Hypoglycemia?

5. Hypoglycemia diagnosis require
fulfillment of the……..

6. Why Whipple triad and not just cutoff?
• Glucose threshold for symptom is dynamic
• Lower in recurrent hypoglycemia
• Higher in hyperglycemia
• Low blood glucose may be artificial ?
• Similar symptoms can arise from other condition
• cardiac disease , hyperthyroidism, pheochromocytoma
• Medication and psychiatric disease.

7. Physiologic Response To Hypoglycemia In Normal Subjects

8. Physiologic Response Of Hypoglycemia

9. Symptoms And Signs Of Hypoglycemia

10. Hypoglycemia has Multiple
Classifications
Fasting OR
Postprandial
Insulin mediated
or non-insulin
mediated
Patient appears to be ill (or
medicated) or is seemingly well

11. Fasting
(postabsorptive)
After prolonged fasting
Causes include:
• Ethanol
• Critical illness (septic shock,
renal insufficiency, mechanical
ventilation,)
• Factitious hypoglycemia from
insulin or sulfonylurea
• Insulin autoimmune
hypoglycemia
• Insulinoma
• Malnourishment
• Cortisol deficiency
Reactive
(postprandial)
Follows last meal within 5 hours
Causes include:
• Post Roux-en-Y gastric bypass
• Ackee fruit poisoning
• Early type 2 DM
• Factitious hypoglycemia from
insulin or sulfonylurea
• Insulin autoimmune
hypoglycemia
• Insulinoma
• NIPHS
• Hereditary fructose
intolerance

12. Hypoglycemic disorders once thought to cause
exclusively postprandial or fasting hypoglycemia
have been observed in some cases to cause
hypoglycemia in the alternate state.
In a retrospective review of 237 patients with
surgically confirmed insulinoma;
• 21 percent reported both fasting and postprandial
symptoms and
• 6 percent reported only postprandial symptoms

15. Medicated or ill
individual
• Drugs
• Critical illness
• Hormonal deficiency
• Non islet cell tumor
• Malnourishment
Seeming well
individual
• Endogenous
hyperinsulinism
• A beta cell secretagogue,
such as a sulfonylurea
• Insulinoma
• NIPHS.
• Insulin autoimmune
hypoglycemia.
• Accidental, surreptitious, or
malicious hypoglycemia

16. Medicated or ill
individual
• Drugs
• Critical illness
• Hormonal deficiency
• Non islet cell tumor
• Malnourishment
Seeming well
individual
• Endogenous
hyperinsulinism
• A beta cell secretagogue,
such as a sulfonylurea
• Insulinoma
• NIPHS.
• Insulin autoimmune
hypoglycemia.
• Accidental, surreptitious, or
malicious hypoglycemia

17. • Drugs are the most common cause of hypoglycemia .
• In addition to insulin, sulfonylureas, and meglitinides, other
drugs may also cause hypoglycemia
• excluding drugs used to treat diabetes and alcohol, 164
different drugs were associated with hypoglycemia
• Ethanol inhibits gluconeogenesis but not glycogenolysis.
Thus, alcohol-induced hypoglycemia typically follows a
several-day alcohol binge with limited ingestion of food,
resulting in hepatic glycogen depletion.
Drugs

19. Sepsis is a relatively common cause of hypoglycemia
because of cytokine-induced inhibition of
gluconeogenesis in the setting of glycogen depletion.
Chronic kidney disease The mechanism of
hypoglycemia is less clear, It likely involves impaired
gluconeogenesis, reduced renal clearance of insulin, and
reduced renal glucose production.
 severe liver failure, gluconeogenesis and glycogenolysis
are impaired.
Critical illness

20.  Malnutrition can cause hypoglycemia as a result
of substrate limitation of gluconeogenesis and
glycogenolysis in the setting of glycogen
depletion.
Hypoglycemia has been reported in patients with
anorexia nervosa
Malnourishment

21. • Hypoglycemia has been observed in a small number of
patients with large tumors of mesenchymal or epithelial
cell type (hepatoma, adrenocortical carcinoma,
carcinoid)
• Hypoglycemia usually occurs as a result of tumor
production of an insulin-like growth factor (e.g,
incompletely processed IGF-2)
• Endogenous production of insulin is appropriately
suppressed.
Non-islet cell tumors

22. • Should be considered when the cause of a hypoglycemic disorder is
not apparent
• Hypoglycemia can result from medical, pharmacy, or patient errors,
such as the mistaken use of a hypoglycemic tablet by an older spouse
of a patient with diabetes.
• It may also occur after ingestion of herbal products contaminated with
sulfonylureas
• Malicious hypoglycemia involves administration of an insulin
secretagogue or insulin to another person with the intent to cause
hypoglycemia
Accidental, Surreptitious, Or
Malicious Hypoglycemia

23. Medicated or ill
individual
• Drugs
• Critical illness
• Hormonal deficiency
• Non islet cell tumor
• Malnourishment
Seeming well
individual
• Endogenous
hyperinsulinism
• A beta cell secretagogue,
such as a sulfonylurea
• Insulinoma
• NIPHS.
• Insulin autoimmune
hypoglycemia.
• Accidental, surreptitious, or
malicious hypoglycemia

24. Endogenous hyperinsulinism is more likely in an otherwise overtly
well individual with no clinical clues to the common causes of
hypoglycemia.
 The diagnosis can be delayed for years
can be caused by the following:
1. A beta cell secretagogue, such as a sulfonylurea.
2. A beta cell tumor.
3. A functional beta cell disorder that can occur as a feature of the
noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS).
4. Insulin autoimmune hypoglycemia.
Endogenous Hyperinsulinism

25. • NIPHS is a very rare cause of endogenous hyperinsulinemic
hypoglycemia presenting in adulthood.
• Affected patients have primarily postprandial hypoglycemia
caused by diffuse islet cell hypertrophy and sometimes,
hyperplasia.
• This condition is often termed nesidioblastosis.
• NIPHS is less common than insulinoma
Noninsulinoma Pancreatogenous
Hypoglycemia Syndrome (NIPHS)

26. Autoantibodies directed against insulin receptors or
insulin itself may provoke hypoglycemia.
Anti-insulin receptor antibodies bind directly to and stimulate
insulin receptors and thereby mimic insulin action in tissues.
Anti-insulin antibodies bind circulating insulin and randomly
dissociate from insulin at inappropriate times, causing a sudden
rise in free insulin levels and subsequent hypoglycemia.
This disorder is observed most often in patients from Japan,
usually in association with other autoimmune diseases.
Insulin Autoimmune Hypoglycemia

27. Clinical Evaluation
Who Should Be Evaluated?
Only those patients
in whom Whipple
triad is documented
require evaluation
and management.
Patients with symptoms
of hypoglycemia but
normal plasma glucose
concentration at the
same time , no further
evaluation is needed.

28. Idiopathic Postprandial Syndrome
Symptoms suggestive of hypoglycemia that occur after eating but
without biochemical evidence of hypoglycemia (absent Whipple’s
triad).
other etiologies for hypoglycemia-like symptoms (hyperthyroidism,
pheochromocytoma, and migraines) should be excluded.
Frequently, underlying anxiety, neuropsychiatric disease, or
situational stress reactions are the real culprits of idiopathic
postprandial syndrome, which the patient characterizes or self-
diagnoses as reactive hypoglycemia.

29. Review the patient's history in details, including:
• The nature and timing of symptoms (particularly in
relationship to meals),
• Existence of underlying illnesses or recent surgery
• Medications taken by the individual and by family
members
• Social history (ethanol intake and nutritional def)
History

30. • General condition: confused/lethargic, pallor/diaphoresis
• Vital signs: SBP&HR
• HEENT : Blurred vision , icterus( hepatic disease) and parotid
pain (due to endocrine causes)
• CVS: Tachycardia hyper/o tension &dysrhythmia
• Neurologic: coma , confusion, loss of coordination,tremor
,convulsion and diplopia
• Skin: diaphoretic and warm or show signs of dehydration
Physical Examination

31. Differs according to the patient situation and clinical suspicion
• CBC
• liver function tests
• BUN/Cr ,electrolyte
• morning cortisol level &(ACTH) stimulation testing
• Glucose
• Insulin
• C-peptide
• Beta-hydroxybutyrate (BHOB)
• Proinsulin
• Sulfonylurea and meglitinide screen
Laboratory Tests

32. • When a spontaneous hypoglycemic episode cannot
be observed, the recommendation is to formally
recreate the circumstances in which symptomatic
hypoglycemia is likely to occur.
• To reach the diagnosis you have to establish the
hypoglycemic episode either by prolonged fasting UP
to72h or mixed meal test.
How To Diagnose?

33. • If symptoms of hypoglycemia typically occur within five hours
after eating, patients should be evaluated in the postprandial
state (mixed-meal test).
• Mixed-meal Diagnostic Test, the patient consumes a non-liquid
meal that usually leads to symptoms and is then observed for up
to five hours .
• Samples are collected for plasma glucose, insulin, C-peptide, and
proinsulin prior to ingestion of the meal and every 30 minutes
thereafter for five hours.
Postprandial Evaluation

34. • If severe symptoms occur prior to five hours, samples for
the above lab tests should be collected before the
administration of carbohydrates (to assess for correction
of symptoms).
• All glucose samples are sent for analysis.
• The samples for insulin, C-peptide, and proinsulin should
be analyzed only in those samples in which plasma
glucose is <60 mg/dL (3.3 mmol/L).

35. • Normal individuals do not have symptomatic hypoglycemia
after a prolonged fast, because of a hormonally mediated
increase in glucose production and/or lipolysis and ketone
body production
• The prolonged fast will result in hypoglycemia only if there is
a defect in the ability to maintain normoglycemia due, for
example, to an excess of insulin, which inhibits endogenous
glucose production, as well as the transition to alternate
sources of fuel and subsequent ketone production.
Fasting Hypoglycemia

36. •Date the onset of the fast at the time of the last
intake of calories.
•Discontinue all nonessential medications.
•Allow the patient to drink beverages that are
calorie and caffeine free.
•Ensure that the patient is active during waking
hours.
72-Hour Fasting Test

37. Collect blood specimens for measurement
of plasma glucose, insulin, C-peptide,
proinsulin, and BHOB every six hours
until the glucose concentration is below
60 mg/dL (3.3 mmol/L); at this point, the
frequency of sampling should be
increased to every one to two hours.

38. 1. when the plasma glucose concentration is ≤45
mg/dL (2.5 mmol/L)
2. the patient has symptoms or signs of
hypoglycemia
3. 72 hours have elapsed
4. when the plasma glucose concentration is less
than 55 mg/dL (3 mmol/L) if Whipple's triad was
documented on a prior occasion
Test Endpoints And Duration

39. Three Steps Are Performed At The End Of The Fast
1. Collect samples for plasma glucose, insulin, C-
peptide, proinsulin, BHOB, and oral hypoglycemic
agents
2. 1 mg of glucagon is given intravenously and the
plasma glucose measured 10, 20, and 30 minutes later
3. The patient is fed.
Ending The Fast

40. Result
Interpretation

42. Result interpretation

44. • A 41-year-old woman was referred for evaluation of repeated episodes of
sweating, slurred speech, tremulousness, and confusion during the last nine
months that could be aborted by eating. On one occasion, she was
unresponsive to questions and thrashing about in bed. Capillary glucose
measured by emergency personnel was 31 mg/dL (1.7 mmol/L), and she
improved after intravenous glucose administration.
• After fasting for 24 hours, she became diaphoretic and confused. Serum values
at that time were as follows:
●Glucose – 32 mg/dL (1.8 mmol/L)
●Insulin – 6.5 microU/mL (39 pmol/L)
●C-peptide – 533 pmol/L
●Proinsulin – 84 pmol/L
What is your differential
diagnosis?

45. How To Differentiate?
• Insulin autoimmune hypoglycemia VS insulinoma ?
By the presence of insulin or insulin receptor antibodies
• NIPHS VS insulinoma?
NIPHS hypoglycemia occurs postprandially, two to four
hours after a meal. Fasting hypoglycemia, characteristic of
insulinoma

46. • Localizing studies should not be performed until
endogenous insulin-mediated hypoglycemia has been
demonstrated.
• In patients with endogenous insulin-mediated
hypoglycemia, the differential diagnosis includes
insulinoma, nesidioblastosis/islet-cell hypertrophy, oral
hypoglycemic agent-induced hypoglycemia, and insulin
autoimmune hypoglycemia
Localizing Studies

47. • Computed tomography (CT), magnetic resonance imaging (MRI),
and transabdominal ultrasonography can detect most insulinomas.
• Gallium Ga-68 DOTATATE PET/CT (a somatostatin-receptor-based
imaging modality) is an option when conventional imaging studies
do not identify an insulinoma.
• The choice of procedure depends upon which tests are available
and local radiologic skill.
• Transabdominal ultrasonography is our preferred initial test.
Radiologic Studies

48. • A negative imaging study does not exclude
insulinoma.
• If an insulinoma is not visible with initial imaging,
additional studies, such as endoscopic
ultrasonography (sometimes with fine-needle
aspiration biopsy of detected tumors) or selective
arterial calcium stimulation, are required.

50. Management
The treatment of hypoglycemic disorders
encompasses two distinct components:
1. Acute Intervention to prevent and minimize
neurological damage
2. Long Term Management of the underlying cause
to prevent the recurrence.

51. Acute Treatment
• The treatment for all hypoglycemia events is the
administration of glucose.
• Consider the ‘rule of 15s’ during therapy (i.e. 15 g of
carbohydrate will raise the glucose level about 15 mg/dl in
about 15 minutes).
• The route and amount of administration will depend on the
glucose level ,the patient’s level of consciousness and
available access.

52. • If the patient is conscious and able to drink and swallow
safely (ie, alert enough to do so and with gag reflex intact),
administer a rapidly- absorbed carbohydrate
• Quick source of sugar : 1 tablespoon of sugar ,1/2 cup of
juice or regular soda , 1 tablespoon of honey or corn
syrup.
• If the patient has altered mental status, is unable to
swallow, or does not respond to oral glucose
administration within 15 minutes, give an IV bolus of 12.5
to 25 g of glucose (25 to 50 mL of D50 ).

53. Practical Notes
• D50 is highly irritating and should be administered
through a large gauge needle into a large vein if
possible and followed by a saline flush.
• Alternative way : Larger volumes of less
concentrated dextrose in IV infusions (e.g. 125 ml of
20% dextrose D20 or 250 ml of 10% dextrose [D10])
may be used to minimize irritation.

54. • For inpatients with hypoglycemia, D50 mixed with
equal parts of water can also be given through a
feeding tube if available.
• Failure of the hypoglycemia to correct within 15
minutes following one dose of glucose should lead
to administration of a second dose, and
occasionally a third, But failure thereafter should
prompt the clinician to consider other interventions

55. If IV access is not available, or is delayed, glucagon
1mg IM (or SC) can be administered, but its action is
short lived.
However, glucagon may not be effective in cases
where gluconeogenesis is defective, such as in
cases of extreme fasting, liver failure, alcohol
induced hypoglycaemia or adrenal insufficiency
because of glycogen depletion.

56. Maintenance Therapy
 Response may be transient and should be followed by careful glucose
monitoring and oral or intravenous glucose administration
patients should receive an additional form of glucose along with
protein (e.g. milk, cheese and crackers) to replenish hepatic glycogen
stores.
If the hypoglycemic episode is expected to be prolonged or recurrent
(e.g. due to long acting insulin or sulfonylurea), especially in the
elderly or in patients with renal impairment). an IV infusion of 5-10%
dextrose (D5 or D10) should be commenced and continued as
necessary.

57. Long Term Management
Insulinoma: surgery, octreotide ,diazoxide
Autoimmune hypoglycemic conditions may be treated with either
glucocorticoids or immunosuppressants, but these disorders may
be self-limited.
 Offending drugs can be discontinued or their doses reduce
Ethanol induced hypoglycemia: Thiamine 12mg/kg (IV) at bolus
dose before initiation of glucose treatment
Adrenal insufficiency: glucocorticoid replacement
Dumping syndrome: smaller more frequent meals , avoid simple
sugars
Factitious hypoglycemia: psychiatric ,CBT

58. Common Medication Treatment
Options for Serious Hypoglycemia
Alpha glucosidase inhibitors (acarbose, miglitol) delay the
digestion of ingested carbohydrates, resulting in lower blood
glucose concentrations after meals.
 Acarbose has been used to lessen the hyperinsulinism in post
Roux-en-Y gastric bypass hypoglycemia
Calcium channel blockers may be helpful in patients with
hypoglycemia by inhibiting glucose stimulated insulin secretion
from the pancreatic β cells;

59. Diazoxide is a direct inhibitor of insulin secretion
• It can help improve symptoms of hypoglycemia caused by increased insulin
secretion in patients awaiting surgery or those with nonresectable disease
and may be indicated in some cases of insulinoma or overdosage with oral
(PO) hypoglycemic agents.
• Dose 5mg/kg/day
• Hyperglycemic effect starts within 1 hour, lasting a maximum of 8 hours if
the patient's renal function normal.
• Patients with refractory hypoglycemia may require high
dosages(15mg/kg/day).
Diazoxide

60. (synthetic Somatostatin analogue)
• This agent Inhibits insulin secretion in high doses, but may not be as
effective as diazoxide
• Various regimens are described but 50mcg 6-8 hourly administered
IV/SC commonly used.
• Its effective in reducing hypoglycemia in 50%patient with insulinoma
Streptozocin Antineoplastic agents has a high affinity for
neuroendocrine cells, inhibits cell proliferation, and is cytolytic.
Octreotide

61. • A first-in-class GLP-receptor blocker, significantly
reduced hypoglycemia in patients with refractory post-
bariatric hypoglycemia.
• Still in phase 2 trial.
• As the pathophysiology of post-bariatric hypoglycemia
appears to be an exaggerated GLP-1 response that leads to
abnormal insulin secretion and symptomatic
hyperinsulinemic hypoglycemia.
Avexitide

64. • No obvious cause
• Oral hypoglycemic agent
• Long acting insulin
• Persistent neurologic deficit
• Recurrent hypoglycemia during observation
• An obvious cause is found and treated
• The hypoglycemic episode is reversed rapidly
Admission Criteria
Discharge criteria

65. References