641 J Clin Pathol: first published as 10.1136/jcp.56.9.641 on 27 August 2003. Downloaded from Best Practice No 173 Clinical and laboratory investigation of adult spontaneous hypoglycaemia R Gama, J D Teale, V Marks ............................................................................................................................. J Clin Pathol 2003;56:641–646 Adult spontaneous hypoglycaemia is not a diagnosis concentrations fall and glucagon secretion rises per se but a manifestation of a disease. Although rare, it on completion of glucose absorption. Homeostatic mechanisms to reverse hypogly- is important to identify spontaneous hypoglycaemia and caemia include stimulation of the sympathetic its causes because treatment may be preventative or nervous system, and counter-regulatory hormo- curative. Hypoglycaemia can occur as an nal responses. The net effect of these is to suppress insulin secretion, promote hunger, in- epiphenomenon in many serious diseases. It is sufficient crease glucose output by stimulating glycogenoly- to recognise the disease’s association with sis and gluconeogenesis, reduce peripheral tissue hypoglycaemia and then take appropriate action to glucose uptake, and provide alternative fuel sources by promoting lipolysis and ketogenesis. prevent the recurrence of hypoglycaemia. In investigating apparently healthy individuals, common CLINICAL MANIFESTATIONS OF pitfalls to avoid are: failure to recognise subacute HYPOGLYCAEMIA5–9 neuroglycopenia clinically; failure to document The symptoms of hypoglycaemia are stereotypical and manifested through alteration in cerebral hypoglycaemia adequately during symptoms; failure to metabolism, and are hence termed neuroglycope- measure pancreatic hormones, counter-regulatory nia. There are three distinct neuroglycopenic syn- hormones, and ketones in hypoglycaemic samples; dromes; acute, subacute, and chronic neuroglyco- penia. Acute neuroglycopenia, most commonly http://jcp.bmj.com/ failure to recognise pre-analytical and analytical associated with iatrogenic hypoglycaemia, is limitations of laboratory assays; and failure to abandon characterised by sweating, anxiety, tremor, palpi- obsolete and inappropriate investigations. Providing tations, tachycardia, pallor, diaphoresis, hunger, and paraesthesiae. Subacute neuroglycopenia is these caveats are met, appropriate laboratory and most commonly associated with spontaneous radiological investigations will almost always uncover hypoglycaemia and is also referred to as hypogly- the cause of spontaneous hypoglycaemia. caemic unawareness in patients with type 1 diabetes mellitus. It presents with episodic on September 27, 2021 by guest. Protected copyright. .......................................................................... disorientation, somnolence, personality changes, amnesia, and loss of consciousness. Clinical ypoglycaemia is not a diagnosis itself, but a features common to both acute and subacute manifestation of a disease process. Hy- neuroglycopenia include transient hemiplegia, poglycaemia has many causes (table 1), but H strabismus, hypothermia, hyperthermia, convul- in practice it is most commonly iatrogenic, and sions, and automatism. If untreated, these syn- the result of overtreatment of patients with dromes may progress to stupor, coma, and even diabetes with insulin or sulfonylureas. This article death as a result of cerebral oedema, but discusses the clinical and laboratory investigation fortunately this is rare because of the effective- of spontaneous (non-diabetic) hypoglycaemia in ness of counter-regulatory hyperglycaemic adults, which may be uncommon but important homeostatic mechanisms. Chronic neuroglycope- nevertheless, because often preventative or cura- nia, virtually confined to patients with insuli- See end of article for tive treatment is available. The investigation and noma or patients with diabetes who are over- authors’ affiliations treatment of neonatal and childhood hypoglycae- treated with insulin, is rare and presents with ....................... mia is covered elsewhere.12 insidious progressive mental illness resembling Correspondence to: personality disorders, schizophrenia, paranoid Dr R Gama, Clinical PATHOPHYSIOLOGY OF Chemistry, New Cross HYPOGLYCAEMIA3–5 Hospital, Wolverhampton, West Midlands The autoregulation of pancreatic insulin and glu- ................................................. WV10 0QP, UK; cagon secretion normally maintains circulating Abbreviations: [email protected] blood glucose between 3.5 mmol/litre and AIS, autoimmune insulin syndrome; β-OHB, β hydroxybutyrate; CSF, cerebrospinal fluid; GH, 10 mmol/litre. Insulin secretion, which is stimu- Accepted for publication growth hormone; IGF, insulin-like growth factor; IR-A, 14 February 2003 lated by glucose absorption, returns to basal anti-insulin receptor antibodies; IRI, immunoreactive insulin; ....................... values within two to four hours as glucose NICTH, non-islet cell tumour hypoglycaemia www.jclinpath.com 642 Gama, Teale, Marks Although typical, symptoms of hypoglycaemia are non- Table 1 Common causes of adult spontaneous specific. Acute and subacute neuroglycopenia can only be con- J Clin Pathol: first published as 10.1136/jcp.56.9.641 on 27 August 2003. Downloaded from hypoglycaemia fidently confirmed when Whipple’s triad is fulfilled; namely, Pancreatic neuroglycopenic symptoms, a low blood glucose, and symp- Insulinoma toms relieved by raising blood glucose to or above normal. Non-insulinoma pancreatogenic hypoglycaemia (NIPH) Brain glucose transporter activity adapts to circulating Nesiodioblastosis glucose; it is upregulated and downregulated by hypoglycaemia Pluriglandular syndrome and hyperglycaemia, respectively. This could, in part, explain Multiple endocrine neoplasia type 1 why chronically hyperglycaemic patients may experience Non-islet cell tumour hypoglycaemia neuroglycopenia at higher glucose concentrations and chroni- Insulin-like frowth factor II secreting tumours (for example, mesenchymal tumours, haemangiopericytomas, carcinomas of the cally hypoglycaemic patients may experience it at lower glucose liver, stomach, and adrenals) concentrations when compared with normal healthy subjects Lymphoma, myeloma, and leukaemias Metastatic cancer INVESTIGATION OF HYPOGLYCAEMIA7–11 Autoimmune hypoglycaemia The investigation of hypoglycaemia involves an index of Autoimmune insulin syndrome (AIS) suspicion, confirmation, or exclusion of hypoglycaemia and its Anti-insulin receptor Pancreatic Graves disease aetiology if it is confirmed. Spontaneous hypoglycaemia should be considered in anyone who presents with an episode Reactive (alimentary) hypoglycaemia Post-gastric surgery or episodic subacute neuroglycopenia, even if there may be an Alcohol provoked reactive hypoglycaemia alternative explanation for his or her symptoms. It is desirable Idiopathic that a blood sample should be collected when the patient is AIS symptomatic—first, to confirm or refute hypoglycaemia and NIPH second, if confirmed, it offers the ideal and sometimes only Drug induced opportunity to uncover its underlying aetiology. Insulin Often, however, patients referred for a medical opinion are Sulfonylurea Repaglinide asymptomatic when seen in the outpatient clinic, at which Salicylates time their blood glucose concentration is usually unhelpful. In Paracetamol this situation, the options are to attempt to provoke a Quinine hypoglycaemic attack, or to obtain a blood sample during Haloperidol symptoms for laboratory measurement of glucose concentra- Disopyramide β Blockers tions. Provocation of a hypoglycaemic attack involves fasting, Pentamadine with or without exercise, when fasting hypoglycaemia is sus- Many others pected, or giving a carbohydrate rich mixed meal when Dietary toxins reactive hypoglycaemia is suspected. Other provocative tests Alcohol are of limited value in the initial investigation of hypoglycae- Unripe ackee nuts mia because of poor diagnostic specificity and sensitivity. The Mushrooms causing acute liver failure intravenous tolbutamide test has been used to provoke Organ failure hypoglycaemia, but is no longer available in the UK. The L http://jcp.bmj.com/ Severe liver disease leucine test, intravenous glucagon test, and selective arterial Endstage renal disease and renal dialysis pancreatic calcium stimulation test may each have a limited Congestive cardiac failure Acute respiratory failure role in the differential diagnosis of hypoglycaemia, but not in its initial investigation.11 Endocrine disease Generalised or selective hypopituitarism and hypothalamic Obtaining a blood sample during symptoms entails training insufficiency the patient, relative, or friend to collect a capillary blood sam- Adrenal failure and cortisol resistance ple into a suitable capillary tube or on to specially prepared 5 Hypothyroidism filter paper for later laboratory blood glucose measurement, on September 27, 2021 by guest. Protected copyright. Postoperative removal of phaeochromocytoma and if hypoglycaemia is confirmed further investigation is Inborn errors of metabolism obligatory. Glycogen storage disease Hereditary fructose intolerance Provocation tests Galactosaemia Carnitine deficiency Overnight fast Disorders of gluconeogenesis Most patients with episodic spontaneous hypoglycaemia will Disorders of mitochondrial β oxidation have at least one overnight fasting (18 hours) plasma glucose Miscellaneous concentration of < 2.5 mmol/litre, when measured on three Sepsis separate occasions.9 The hypoglycaemic episodes