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Factitious hypoglycemia

Factitious hypoglycemia
Author:
Adrian Vella, MD
Section Editor:
Irl B Hirsch, MD
Deputy Editor:
Katya Rubinow, MD
Literature review current through: Jan 2024.
This topic last updated: May 06, 2022.

INTRODUCTION — Factitious (or factitial) hypoglycemia occurs secondary to the surreptitious use of insulin or insulin secretagogues (sulfonylureas, meglitinides). The term factitious (or factitial) hypoglycemia has been used in medical parlance to imply covert human activity. The consideration of such a possibility often changes the patient-clinician relationship, leading the clinician to feel deceived and the patient to feel mistrusted. However, the pejorative connotation with which factitious illness has been encumbered requires softening because some patients with factitious disease suffer through no fault of their own. As an example, dispensing errors in the outpatient or inpatient setting can lead to inappropriate administration of hypoglycemic agents.

The clinical features, diagnosis, and treatment of factitious hypoglycemia will be reviewed here. Other causes of hypoglycemia are discussed elsewhere. (See "Hypoglycemia in adults without diabetes mellitus: Clinical manifestations, causes, and diagnosis" and "Insulinoma".)

ETIOLOGY OF FACTITIOUS HYPOGLYCEMIA — Factitious hypoglycemia results from the use of insulin or insulin secretagogues (sulfonylurea, meglitinides) but not from metformin or other insulin-sensitizing antidiabetic drugs [1-3]. Newer agents such as sodium-glucose co-transporter 2 (SGLT2) inhibitors have not been convincingly associated with hypoglycemia. Therapies that utilize the glucagon-like peptide 1 pathway should also not cause hypoglycemia, since insulin secretion stimulated by these agents is glucose-dependent (ie, insulin secretion is only stimulated above a certain threshold of glucose) [4,5].

Ingestion of an oral insulin secretagogue — The first reported case of factitious hypoglycemia related to a sulfonylurea was due to the surreptitious self-administration of chlorpropamide by a patient without diabetes [6]. Inappropriate manipulation of hypoglycemic tablets by a patient with diabetes is another cause of factitious hypoglycemia.

In addition to patients who knowingly take insulin secretagogue drugs, there are patients who, by taking a prescribed medication in good faith, have hypoglycemia because a sulfonylurea was mistakenly dispensed [7]. In most instances, confusion in dispensing the drug arose because of similarity in spelling between the intended medication and the sulfonylurea. The most common errors in early reports were the substitutions of Diabinese for Diamox [8,9] and of Tolinase for Tolectin; however, Diabinese (chlorpropamide) and Tolinase (tolazamide) are no longer used to treat diabetes [10].

Hypoglycemia in an older person whose spouse is being treated with a hypoglycemic tablet is generally due to a mix-up in medication. Hence, a medical history of the spouse/partner may be an important part of the initial evaluation, as are questions pertaining to how medication is prepared for dosing (eg, similar versus distinct pill boxes). It may also occur after ingestion of herbal products contaminated with sulfonylureas [11,12]. As an example, hypoglycemia has been reported after ingestion of illegal sexual enhancement drugs or herbal preparations (eg, Power 1 Walnut) contaminated with glyburide in amounts ranging from 13 to 100 mg per tablet [11]. In a case series from Singapore, seven patients who ingested such products were comatose secondary to prolonged neuroglycopenia, and four patients subsequently died [11,13].

Administration of insulin — Covert self-administration of insulin by a patient without diabetes and the inappropriate manipulation of insulin by a patient with diabetes are causes of factitious hypoglycemia.

Administration of a hypoglycemic agent by a caregiver to a child is an insidious form of child abuse [14,15]. In previous cases, the alleged perpetrator was the patient's caregiver who had ready access to insulin. (See "Medical child abuse (Munchausen syndrome by proxy)".)

Insulin has also been used to attempt suicide [16]. A review of 97 published cases found that completed suicide occurred in 17 [17]. In most cases, those attempting suicide were insulin-treated patients with diabetes. There was equal sex distribution within this series and a wide distribution of age, ranging from 20 to 70 years.

CLINICAL CHARACTERISTICS — Factitious hypoglycemia in nondiabetic patients who knowingly self-administer hypoglycemic agents or in diabetic patients who manipulate their doses for the purpose of causing hypoglycemia seems to be more common in women, occurs most commonly in the third or fourth decades of life, and, among nondiabetic subjects, is often found in those in health-related occupations [18-23]. In a population-based study of unexplained hypoglycemia in France, 7 (5 women, 2 men) of 56 cases had a detectable sulfonylurea in their plasma [24].

Patients without diabetes — Patients without diabetes who have factitious hypoglycemia may present with a clinical syndrome that appears similar to insulinoma; as a result, many of them may undergo futile abdominal exploration and needless subtotal pancreatectomy in search of an insulinoma. The appropriate application and interpretation of available tests should preclude surgical exploration in them. (See 'Diagnosis' below.)

Patients with diabetes — Factitious hypoglycemia among patients with diabetes is probably more common than the incidence noted in published series [21,22,25-27]. Patients with diabetes are trained to modify doses of insulin for the purpose of achieving goal blood glucose values. In patients with factitious hypoglycemia, it can be difficult to distinguish between errors in insulin management and purposeful manipulation of insulin dosing.

Factitious hypoglycemia should be suspected in people with a prior diagnosis of diabetes who have experienced a "cure" and now have hypoglycemia. Alternatively, patients with diabetes and factitious hypoglycemia may appear to have brittle diabetes [28-30]. They typically have repeated episodes of hypoglycemia despite a reduction in dose or even cessation of insulin therapy. Although insulinoma is an extraordinarily rare event in patients with diabetes, several patients with diabetes have undergone needless pancreatic exploration and resection [31,32]. When truly deprived of access to hypoglycemic agents, diabetic patients with factitious hypoglycemia become hyperglycemic.

The identification of factitious disease as a cause of brittle diabetes requires three factors [29]:

A clinician who suspects the diagnosis

Examination of the brittle diabetic state in a controlled environment

Close patient follow-up to document manipulative behavior

Studies of patients with brittle diabetes have shown that psychological problems play a major role in the swings in blood glucose [29,30]. (See "Approach to the adult with brittle diabetes or high glucose variability".)

DIAGNOSIS — The possibility of factitious hypoglycemia should be considered in every patient undergoing evaluation for a hypoglycemic disorder, especially when the hypoglycemia has a random occurrence, ie, no relation at all to meals or fasting. All medications, including herbal preparations or other over-the-counter products, should be identified. The assistance of a pharmacist is desirable.

In persons for whom insulin or an oral insulin secretagogue has not been prescribed, the diagnosis of factitious hypoglycemia can usually be established by documenting the presence of hypoglycemia and by simultaneously measuring plasma:

Insulin

C-peptide

Proinsulin

Insulin secretagogues (sulfonylurea and meglitinides).

Insulin antibodies should be measured once. They do not have to be measured during an episode of hypoglycemia.

Performance of a 72-hour fast, which is primarily used to diagnose insulinoma, may be required in patients with factitious hypoglycemia should a spontaneous episode of hypoglycemia not be observed. However, the fast may be negative if the patient does not take the offending agent. (See "Hypoglycemia in adults without diabetes mellitus: Determining the etiology", section on 'Supervised fast for fasting hypoglycemia'.)

Insulin secretagogue — Factitious hypoglycemia caused by sulfonylureas or meglitinides biochemically mimics the insulinoma response since these drugs stimulate insulin secretion. Patients with insulinoma and insulin secretagogue-induced hypoglycemia can have plasma insulin, C-peptide, and proinsulin values above or within the normal overnight fasting range. These ranges, however, are too high for the low plasma glucose concentration. In such cases, the detection of sulfonylureas or meglitinides in the plasma confirms the diagnosis of factitious hypoglycemia (table 1) [33,34].

Exogenous insulin In individuals with factitious hypoglycemia caused by exogenous administration of insulin, plasma insulin values are high (often above 100 microU/mL), whereas plasma C-peptide and proinsulin values are low (table 1).

There are, however, caveats to the interpretation of plasma insulin values:

In hypoglycemia caused by synthetic insulin analogs (eg, glargine, detemir, lispro, aspart), insulin concentrations may be low, depending upon the insulin assay used. Clinical suspicion should guide subsequent testing of the sample obtained at the time of hypoglycemia against a panel of antibodies to insulin capable of detecting various analogs. (See 'Insulin measurements' below.)

In autoimmune hypoglycemia, both the plasma insulin and C-peptide concentrations can be very high, with plasma insulin levels often well above 1000 microU/mL (6000 pmol/L). In addition to the difference in C-peptide concentration (high with autoimmune hypoglycemia and low with exogenous insulin), the presence of insulin antibodies in high titers can distinguish insulin autoimmune hypoglycemia from exogenous insulin administration (table 1). The antibodies do not have to be measured during an episode of hypoglycemia. (See 'Anti-insulin antibodies' below.)

LABORATORY TESTS

Insulin measurements — Some insulin assays detect only human insulin, whereas others detect both human insulin and synthetic insulin analogs (glargine, detemir, lispro, aspart) [35-37]. In addition, some assays have been developed to specifically measure synthetic insulin analogs (eg, lispro, aspart) or animal insulin (porcine, beef) without any crossreactivity with human insulin [38-40]. Assay specificity depends upon the selection of monoclonal antibody used for detection. Mass spectrometry-based assays allow rapid identification of human insulin and its synthetic or animal analogs [41-43]. It is important for the clinician to know which insulin assay is used and whether it measures human insulin, insulin analogs, or both. The clinician can discuss this with the director of the immunochemical testing facility to determine if additional testing with different assays is indicated.

Insulin secretagogue measurements — In all hypoglycemic patients, except those with type 1 diabetes (who have no residual endogenous insulin secretion), plasma should be obtained during a hypoglycemic episode for the measurement of sulfonylureas and meglitinides (nateglinide, repaglinide). It is important to ascertain that the assay used can reliably identify all of these compounds. The Department of Laboratory Medicine at the Mayo Clinic developed a liquid chromatography tandem mass spectrometry (LC/MS/MS) method that has proven to be highly sensitive for the detection of these compounds (sulfonylureas and meglitinides). Similar type assays are available in other countries [44,45]. Capillary electrophoresis (CE) and high-performance liquid chromatography (HPLC) assays are also available for detecting surreptitious abuse of sulfonylureas or meglitinides [46,47].

The misdiagnosis of insulinoma or insulin secretagogue factitious hypoglycemia is doubly injurious, depriving the patient of a potentially curative procedure (if the diagnosis of insulinoma is missed) [48] or leading to unnecessary surgery (if the diagnosis of insulin secretagogue use is missed).

C-peptide measurements — In hyperinsulinemic hypoglycemic patients, the distinction between an endogenous or exogenous source of insulin can be made by measuring plasma C-peptide in the sample used for the insulin determination (table 1) [49]. Isolated measurements of plasma glucose, insulin, and C-peptide are diagnostically useless. Interpretation of the value for any one of these substances is dependent upon the values of the other two. Insulin and C-peptide are secreted in an equimolar fashion [50]; as a result, the plasma concentrations of these two peptides parallel each other in patients with endogenous hyperinsulinemia.

In contrast, the plasma concentrations of the two peptides are inversely related in patients with exogenous insulin factitious hypoglycemia; plasma insulin is high (as long as the assay can detect the insulin or insulin analog used), while C-peptide is appropriately suppressed, usually close to the lower limit of detection of the C-peptide assay. This observation applies to both nondiabetic patients [19,22,51] and to those with type 2 diabetes [21,22,27]. Patients with type 1 diabetes are characteristically severely insulin deficient and have low or undetectable plasma concentrations of C-peptide. Although the C-peptide values in these patients cannot be further suppressed, confirmation that they are low during hypoglycemia eliminates any consideration of endogenous hyperinsulinism [26,52].

Anti-insulin antibodies — Historically, the presence of anti-insulin antibodies in nondiabetic patients or patients with diabetes who had never been treated with insulin was taken as evidence favoring the surreptitious use of insulin [22]. However, the syndrome of autoimmune hypoglycemia in which insulin antibodies are spontaneously generated has complicated this interpretation [33,53]. Patients with this disorder have high plasma titers of insulin antibodies and may have a history of autoimmune disease or exposure to sulfhydryl-containing drugs.

The detection of anti-insulin antibodies in insulin-treated patients is of no diagnostic utility, since they occur routinely. Human insulin generates antibodies in fewer patients and in lower titers (50 percent lower) than does purified porcine insulin [54].

The presence of anti-insulin antibodies can interfere with measurements of plasma insulin and C-peptide concentrations. As a result, plasma free insulin and C-peptide should be measured in these patients.

TREATMENT

Long term — The long-term treatment after the recognition of factitious hypoglycemia involves changing abnormal behavioral patterns to protect the patient from the consequences of hypoglycemia. Meetings for informing patients about their diagnosis may be more effective when they are a collaborative intervention by the attending clinician and psychiatrist together. Having the support of caregivers/family members is also important to mediating behavioral change. It is important to emphasize that the patient needs help, providing assurance that medical care and support is available. (See "Factitious disorder imposed on self (Munchausen syndrome)", section on 'Specific treatment' and "Factitious disorder imposed on self (Munchausen syndrome)", section on 'Prognosis'.)

Acute — The acute management of factitious hypoglycemia is similar to the management of hypoglycemia during the treatment of diabetes:

Patients with symptomatic hypoglycemia should ingest carbohydrates. Fifteen to 20 grams of oral glucose is typically sufficient. Glucose may be ingested in the form of tablets, juice, milk, other snacks, or a meal.

Treatment of severe hypoglycemia, when the patient is unconscious or unable to ingest carbohydrate, requires a subcutaneous or intramuscular injection of glucagon (0.5 to 1 mg).

Patients brought to the hospital can be treated more quickly by giving 25 g of 50 percent glucose (dextrose) intravenously (IV).

A subsequent glucose infusion (or food, if patient is able to eat) is often needed, depending upon the half-life of the drug causing the hypoglycemia.

The treatment of hypoglycemia is reviewed in more detail elsewhere. (See "Hypoglycemia in adults with diabetes mellitus", section on 'Reversing hypoglycemia'.)

The role of octreotide in hypoglycemia associated with therapeutic use of sulfonylureas is unclear. As an example, in a trial of adult patients with sulfonylurea-induced hypoglycemia, subjects who were randomly assigned to receive octreotide (a single subcutaneous dose of 75 micrograms) in addition to one ampule of 50 percent dextrose (IV) had significantly higher mean glucose values during the first eight hours of therapy than those who received only IV dextrose [55]. (See "Sulfonylurea agent poisoning".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypoglycemia in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Low blood sugar in people without diabetes (The Basics)")

SUMMARY AND RECOMMENDATIONS

Etiology – Factitious hypoglycemia results from the use of insulin or insulin secretagogues (sulfonylurea, meglitinides) but not from metformin or other insulin-sensitizing antidiabetic drugs. (See 'Etiology of factitious hypoglycemia' above.)

Clinical characteristics – Patients without diabetes who have factitious hypoglycemia may present with a clinical syndrome that appears similar to insulinoma. Patients with diabetes and factitious hypoglycemia may appear to have brittle diabetes; they typically have repeated episodes of hypoglycemia despite a reduction in dose or even cessation of insulin therapy. (See 'Clinical characteristics' above and "Insulinoma", section on 'Symptoms and misdiagnosis'.)

Diagnosis – Factitious disease should be considered in every patient evaluated for a hypoglycemic disorder, especially when the hypoglycemia has a random occurrence, ie, no relation at all to meals or fasting.

Patients without diabetes – In persons for whom insulin or an oral insulin secretagogue has not been prescribed, the diagnosis of factitious hypoglycemia can usually be established by assessing plasma glucose, insulin, C-peptide, proinsulin, and insulin secretagogues (sulfonylureas, meglitinides) during any episode of symptomatic hypoglycemia. Insulin antibodies should be measured once. A 72-hour fast may be necessary should a spontaneous episode of hypoglycemia not be observed. (See 'Diagnosis' above and "Hypoglycemia in adults without diabetes mellitus: Determining the etiology", section on 'Supervised testing'.)

-Due to insulin secretagogues – Nonsuppressed plasma concentrations of insulin and C-peptide and the presence of sulfonylurea or meglitinide indicate factitious hypoglycemia caused by use of an oral insulin secretagogue (table 1). (See 'Diagnosis' above and 'Insulin secretagogue measurements' above.)

-Due to insulin administration – Nonsuppressed plasma insulin and suppressed plasma C-peptide and proinsulin concentrations in the absence of measurable insulin secretagogues indicates factitious hypoglycemia due to insulin administration (table 1). It is important for the clinician to know which insulin assay is used and whether it measures human insulin, insulin analogs, or both. If insulin, proinsulin, and C-peptide concentrations are all be suppressed during hypoglycemia, clinical suspicion should guide subsequent testing of the sample obtained at the time of hypoglycemia against a panel of antibodies to insulin capable of detecting various analogs. (See 'Diagnosis' above and 'Insulin measurements' above.)

Patients with diabetes – In patients with diabetes who are treated with oral insulin secretagogues or insulin, confirmation of factitious hypoglycemia can be very difficult. It requires an assessment under controlled conditions, where they can be closely monitored and observed, with all blood glucose testing, food, and insulin being administered by the staff. (See 'Patients with diabetes' above and "Approach to the adult with brittle diabetes or high glucose variability".)

Treatment – The acute management of factitious hypoglycemia is similar to the management of hypoglycemia during the treatment of diabetes. The long-term treatment of factitious hypoglycemia involves changing abnormal behavioral patterns. (See 'Treatment' above and "Hypoglycemia in adults with diabetes mellitus".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges F John Service, MD, PhD, now deceased, who contributed to an earlier version of this topic.

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