Differentiating Hypoglycemia from other diseases

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2]

Overview

Hypoglycemia should be differentiated from other causes of autonomic hyperactivity symptoms. Physicians should have history, signs and laboratory results sufficient to help them to identify the cause of hypoglycemia. Neonatal hypoglycemia should be differentiated from other causes of neurological symptoms in neonates such as sepsis, metabolic diseases: urea cycle disorders, and branched-chain organic acidemias, hyponatremia and neonatal asphyxia.

Differentiating Hypoglycemia from other Diseases

Differentiating Different Causes of Hypoglycemia from each other:

	Fating symptoms	Postprandial symptoms	Plasma insulin	C-peptide	proinsulin	Sulfonylurea in plasma	insulin or insulin receptor antibodies
Insulinoma	+	-	high	high	high	-	-
Oral hypoglycemia agent-induced	-	-	high	high	high	+	-
Autoimmune hypoglycemia	-	-	high	high	high	-	+
NIPHS*	-	+	high	high	high	-	-
Exogenous insulin	-	-	high	low	low	-	-
Non-islet cell tumors	-	-	low	low	low	-	-

*(NIPHS) non-insulinoma pancreatogenous hypoglycemia syndrome Differentials for Hypoglycemia on the basis of Laboratory findings:

Diagnoses	Laboratory Findings differentiating among causes of Hypoglycemia
	S.Glucose (mg/dL)	C Peptide (pmol/L)	S.Insulin (μU/mL)	S.Proinsulin (pmol/L)	S. Beta hydroxybutyrate	Glucose increase after glucagon(mg/dL)	Oral Hypoglycemic agent	Antibodies to Insulin
Normal/Fasting	<55	<200	<3	<5	>2.7	<25	-	-
Exogenous Insulin	<55	<200	>>3	<5	≤2.7	>25	-	-
Insulinoma	<55	≥200	≥3	≥5	≤2.7	>25	-	-
Nesidioblastosis
Post gastric bypass hypoglycemia (PGPH)
Insulin autoimmune hypoglycemia	<55	>>200‡	>>3	>>5‡	≤2.7	>25	-	+
Oral hypoglycemic agent	<55	≥200	≥3	≥5	≤2.7	>25	+	-
IGF¤	<55	<200	<3	<5	≤2.7	>25	-	-
‡ Free C-peptide and proinsulin concentrations are low ¤ IGF= Insulin Growth Factor, Increased pro-IGF-2, free IGF-2, IGF-2/IGF-1 ratio

Differentiating Hypoglycemia from other Diseases that Cause autonomic hyperactivity symptoms (tachycardia, hypertension):

Disease	Clinical Manifestation					Investigations
	Symptoms				Signs
	Tachycardia	Fever	Sweating	Headache
Anxiety disorders	+	-	+	+	Patient looks irritable Rapid pulse and may be irregular	Normal investigations
Pheochromocytoma	+	+	+	+	Tachycardia Strong rapid pulse High pulse pressure	Plasma fractionated metanephrines, 24-hour urinary fractionated metanephrines, catecholamines. Computed tomography: Radiological evaluation should follow lab tests to locate site of the tumorr.
Arrhythmia	+	-	-	-	Irregular pulse	ECG changes according to the cause
Hyperthyroidism	+	+	+	+	Hyperactive deep tendon reflexes Thyromegaly Exophthalmus	Level of thyroid-stimulating hormone (TSH) Levels of T4 and/or T3 in the blood Antibodies such as anti-TSH-receptor antibodies in Graves' disease

Differentiating Hypoglycemia from other Diseases that Cause Neurological Symptoms in Neonates:

Disease	History and symptoms					Investigations
	Family History	Lethargy and irritability	Improvement of symptoms with glucose intake	Fever	Hepatomegaly
Hypoglycemia	+	+	+	-	-	Blood glucose level
Sepsis	-	+	-	+	-	Blood cultures
Inborn errors of metabolism	+	+	-	-	+	Positive blood tests
Hyponatremia	-	+	-	-	-	Plasma sodium falls below 125 mEq/L
Perinatal asphyxia	+	+	-	-	-	MRI of acute brain injury confirms the diagnosis of encephalopathy

Differentiating Hypoglycemia from other Diseases that Cause Coma and Consciousness Alterations:

Diseases	Diagnostic tests				Physical Examination					Symptoms			Past medical history	Other Findings
	Na+, K+, Ca2+	CT /MRI	CSF Findings	Gold standard test	Neck stiffness	Motor or Sensory deficit	Papilledema	Bulging fontanelle	Cranial nerves	Headache	Fever	Altered mental status
Brain tumor		✔	Cancer cells	MRI		✔	✔	✔	✔	✔		✔		Cachexia, gradual progression of symptoms
Delirium tremens		✔		Clinical diagnosis		✔	✔		✔	✔	✔	✔	Alcohol intake, sudden withdrawal or reduction in consumption	Tachycardia, diaphoresis, hypertension, tremors, mydriasis, positional nystagmus,
Subarachnoid hemorrhage		✔	Xanthochromia	CT scan without contrast	✔	✔	✔	✔	✔	✔	✔	✔	Trauma/fall	Confusion, dizziness, nausea, vomiting
Stroke		✔	Normal	CT scan without contrast		✔	✔		✔	✔		✔	TIAs, hypertension, diabetes mellitus	Speech difficulty, gait abnormality
Neurosyphilis		✔	↑ Leukocytes and protein	CSF VDRL-specific CSF FTA-Ab -sensitive	✔	✔	✔	✔		✔		✔	Unprotected sexual intercourse, STIs	Blindness, confusion, depression, Abnormal gait
Viral encephalitis		✔	Increased RBCS or xanthochromia, mononuclear lymphocytosis, high protein content, normal glucose	Clinical assesment	✔	✔	✔		✔	✔	✔	✔	Tick bite/mosquito bite/ viral prodrome for several days	Extreme lethargy, rash hepatosplenomegaly, lymphadenopathy, behavioral changes
Herpes simplex encephalitis		✔		Clinical assesment			✔	✔	✔	✔	✔		History of hypertension	Delirium, cortical blindness, cerebral edema, seizure
Wernicke’s encephalopathy			Normal				✔	✔			✔		History of alcohol abuse	Ophthalmoplegia, confusion
CNS abscess		✔	↑ leukocytes >100,000/ul, ↓ glucose, ↑protein, ↑ red blood cells, and lactic acid >500mg	Contrast enhanced MRI is more sensitive and specific, Histopathological examination of brain tissue	✔	✔	✔		✔	✔	✔	✔	History of drug abuse, endocarditis, ↓ immune status	High-grade fever, fatigue, nausea, vomiting
Drug toxicity											✔	✔		Lithium, Sedatives, phenytoin, carbamazepine
Conversion disorder				Diagnosis of exclusion		✔		✔		✔	✔	✔		Tremors, blindness, difficulty swallowing
Electrolyte disturbance	↓ or ↑			Depends on the cause						✔		✔		Confusion, seizures
Febrile convulsion			Not performed in first simple febrile seizures	Clinical diagnosis and EEG					✔	✔	✔	✔	Family history of febrile seizures, viral illness or gastroenteritis	Age > 1 month,
Subdural empyema		✔		Clinical assessment and MRI	✔	✔	✔	✔	✔			✔	History of relapses and remissions	Blurry vision, urinary incontinence, fatigue
Hypoglycemia	↓ or ↑			Serum blood glucose HbA1c		✔				✔		✔	History of diabetes	Palpitations, sweating, dizziness, low serum, glucose