Differentials
hypoglycaemia due to non-diabetic drugs
SIGNS / SYMPTOMS
Drug-induced hypoglycaemia in people without diabetes is more common in those who are older and have underlying comorbidities.[42] Non-diabetic drugs that may cause hypoglycaemia include:[42]
Certain antibiotics, particularly sulfonamides and fluoroquinolones.
Beta-blockers. These can mask symptoms and signs of hypoglycaemia, which can predispose patients to severe, life-threatening hypoglycaemia.[63] Non-selective beta-blockers can also impair hepatic and renal release of glucose into the circulation, which can cause hypoglycaemia.[42]
Quinine.
Pentamidine.
Indometacin.
This list of drugs is not exhaustive, and you should consult a drug formulary for more information.
Alcohol can cause hypoglycaemia during and after consumption, particularly if the patient has not eaten recently.[3][4][17][37] In addition, alcohol-related liver disease can lead to hepatic insufficiency, which decreases gluconeogenesis.
INVESTIGATIONS
Alcohol-related hypoglycaemia is usually associated with elevated levels of beta-hydroxybutyrate, and low insulin and C-peptide levels.[42]
acute or chronic liver failure
SIGNS / SYMPTOMS
The patient may be asymptomatic, or have features of underlying liver disease, such as right upper quadrant pain, weight loss, pruritus, fatigue, or anorexia. Specifically, patients with acute liver failure will have jaundice and encephalopathy. The patient may also have a history of liver disease, or risk factors for liver disease.
INVESTIGATIONS
Elevated liver function tests (AST and ALT), coagulopathy.
chronic kidney disease
SIGNS / SYMPTOMS
The patient may have vague symptoms such as fatigue and oedema.
The patient may have a history of chronic kidney disease, and risk factors for renal impairment.
INVESTIGATIONS
Elevated urea and creatinine levels.
coeliac disease
sepsis
SIGNS / SYMPTOMS
Acute deterioration in a patient in whom there is clinical evidence or strong suspicion of infection.[88] Take into account that people with sepsis may have non-specific, non-localised presentations, such as feeling very unwell, and may not have a high temperature.[88]
INVESTIGATIONS
Blood or other body fluid cultures may be positive for the infectious organism.
White cell count elevated.
inanition
SIGNS / SYMPTOMS
The patient may have a history of eating disorders such as anorexia nervosa, mental health conditions, diseases causing malabsorption, alcohol and substance use disorders, or a period of starvation.[42]
INVESTIGATIONS
Clinical diagnosis.
primary adrenal insufficiency
SIGNS / SYMPTOMS
Features of primary adrenal insufficiency (Addison's disease) include progressive substantial fatigue and generalised weakness associated with mucocutaneous hyperpigmentation, hypotension and/or postural hypotension, and salt craving.
hypothyroidism
SIGNS / SYMPTOMS
Features include lethargy, fatigue, change in voice, cold intolerance, constipation, weight gain, skin changes, hair loss, and bradycardia.[92] If central hypothyroidism is present, there may also be features of hypopituitarism, including hypogonadism and secondary adrenal insufficiency.
INVESTIGATIONS
Inappropriately low, normal, or elevated thyroid-stimulating hormone, depending on the type of hypothyroidism.
Low free thyroxine (T4).
hypopituitarism
SIGNS / SYMPTOMS
The clinical manifestations of hypopituitarism are variable and dependent on the duration and degree of hormone deficiencies, as well as the age of onset. Key risk factors for hypopituitarism include pituitary tumours, apoplexy, surgery, or radiation; genetic disorders such as mutations of the PROP1 gene that cause familial hormone deficiencies; and hypothalamic disease.
INVESTIGATIONS
Results of investigations will depend on the underlying cause of hypopituitarism.
non-islet cell tumours (NICT)
SIGNS / SYMPTOMS
Also known as insulin-like growth factor-2 (IGF-2)-secreting tumours.[93][94]
There may be features of the underlying tumour. Tumours associated with NICT hypoglycaemia are hepatocellular carcinoma, fibrosarcoma, mesothelioma, adrenocortical carcinoma, stomach carcinoma, pancreatic carcinoma, medullary thyroid carcinoma, lymphoma, leukaemia, carcinoid syndrome.[95]
INVESTIGATIONS
Blood tests will show:[96]
Insulin level <3 microunits/mL
Pro-insulin level <5 picomol/L
C-peptide level <0.2 nanomol/L
Insulin-like growth factor 1 (IGF-1) level <100 nanograms/mL
Insulin-like growth factor 2 (IGF-2) level >275 nanograms/mL
IGF-2:IGF-1 ratio >3:1.
Further investigation specific to the underlying tumour will be required.
insulinoma
SIGNS / SYMPTOMS
An insulinoma is an insulin-secreting tumour.[93][94]
It is difficult to clinically distinguish hypoglycaemia due to insulinoma from diabetic hypoglycaemia because the patient typically presents in a similar manner, with typical neuroglycopenic symptoms that improve quickly with administration of glucose.[93][94]
INVESTIGATIONS
48-hour supervised fast may demonstrate:
Whipple's triad (biochemical hypoglycaemia, symptoms consistent with hypoglycaemia, and reversal with carbohydrate replacement), and
Inadequately suppressed insulin levels (>3 micro-IU/mL) or, in some instances, inadequately suppressed pro-insulin levels (≥5 picomol/L).[97]
There has been some debate as to whether a 48-hour fast under observation is adequate in rendering a diagnosis, and the full 72-hour supervised fast has been found to identify individuals with an insulinoma not identified by 48-hour fast.[98]
72-hour hour fast may show:[99]
Insulin >5 milli-IU/L (>36 picomol/L)
C-peptide >0.6 nanograms/mL (>0.2 nanomol/L)
Insulin:C-peptide ratio <1.0
Pro-insulin >20 picomol/L
Absence of sulfonylurea metabolites in plasma or urine
CT or MRI will determine exact location of an insulinoma, its relationship to vital structures, and any metastases.[99]
non-insulinoma pancreatogenous hypoglycaemia (NIPHS)
post total pancreatectomy with islet auto-transplantation (TP-IAT)
SIGNS / SYMPTOMS
Clinical history of hypoglycaemia occuring after TP-IAT.[102]
INVESTIGATIONS
Clinical diagnosis.
post gastric bypass surgery
SIGNS / SYMPTOMS
Gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea, belching) or vasomotor symptoms (e.g., shock, syncope, near-syncope, palpitations, dizziness, desire to lie down, diaphoresis).[100]
Patients may have had bariatric surgery for treatment of obesity; Roux-en-Y gastric bypass surgery is most common.[100]
INVESTIGATIONS
Low blood glucose after a carbohydrate load (oral glucose tolerance) or meal.
dumping syndrome
SIGNS / SYMPTOMS
Gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea, belching) or vasomotor symptoms (e.g., shock, syncope, near-syncope, palpitations, dizziness, desire to lie down, diaphoresis).[100]
Dumping syndrome occurs in patients who have had gastric surgery; hypoglycaemia is related to abnormal transport of food to the small intestine. Use the Dumping Symptom Rating Scale, which is a self-assessment questionnaire, to assess the likelihood of dumping syndrome.[100]
INVESTIGATIONS
Low blood glucose after a carbohydrate load (oral glucose tolerance) or meal.
rapid gastric emptying
SIGNS / SYMPTOMS
Gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea, belching) or vasomotor symptoms (e.g., shock, syncope, near-syncope, palpitations, dizziness, desire to lie down, diaphoresis).[100]
INVESTIGATIONS
Low blood glucose after a carbohydrate load (oral glucose tolerance) or meal.
insulin autoimmune syndrome
SIGNS / SYMPTOMS
Extremely rare condition, apart from in Japan and other Asian countries.[103] Usually spontaneously resolves.[103] There may be a past medical history of other autoimmune diseases.[103]
INVESTIGATIONS
Elevated insulin antibody levels in the absence of exposure to exogenous insulin; elevated insulin receptor antibody levels.[103]
accidental, surreptitious, or malicious hypoglycaemia, including Munchausen syndrome by proxy
SIGNS / SYMPTOMS
Accidental, surreptitious, or malicious hypoglycaemia due to administration of insulin or insulin secretagogues should be considered as part of history and examination.[104]
INVESTIGATIONS
Diagnosis of exclusion.
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