Recurrent Hypoglycemia: When Diabetes Is Not the Cause

ABSTRACT: Most episodes of recurrent hypoglycemia occur in patients with diabetes mellitus and can be prevented by changes in medication, diet, or activity. However, persistent, unexplained hypoglycemia can indicate a potentially grave, often treatable, underlying disorder, such as insulinoma, or adrenal or pituitary insufficiency. Medication errors are another cause of unexplained hypoglycemia. A focused laboratory workup is essential; obtain a plasma or serum glucose level and serum insulin and C-peptide levels. Insulin levels should be suppressed (less than 6 μIU/mL) when the glucose level is below 60 mg/dL. “Normal” or high insulin and C-peptide levels suggest excessive endogenous insulin production.

Hypoglycemia is a common event that typically occurs in persons with diabetes mellitus. In this context, hypoglycemia usually results from an imbalance among diabetic therapy, level of activity, and dietary intake. Therefore, management of hypoglycemia has become “scripted”: glucose administration, followed by adjustments in insulin or oral medications or diet. The simplicity of this approach can be deceptive, however. Practitioners may underestimate the impact of other hypoglycemic disorders that are not the direct result of diabetes or its treatment regimen. In this setting, hypoglycemia can indicate a serious disturbance in glucose regulation and can recur with devastating consequences. Determining the cause of hypoglycemic “outliers,” therefore, is critical. The potentially life-threatening consequences of sudden, unexpected hypoglycemia may endanger not only the affected person but others as well (eg, hypoglycemia in a driver of a motor vehicle).

Here are 4 cases of hypoglycemia that occurred in persons without diabetes (Cases 1-4). The low blood glucose levels were recognized, but they were not evaluated fully at initial presentation. The episodes were then followed by potentially dangerous events. The appropriate workup and management of recurrent hypoglycemia is discussed in each case.

HYPOGLYCEMIA: A WORKING DEFINITION
Hypoglycemia may be defined as a clinical syndrome in which low serum glucose levels lead to symptoms and signs of neuroglycopenia (eg, an altered sensorium and seizures) and sympathoadrenal activation.¹ Glucose concentrations of 60 mg/dL or less may cause autonomic symptoms and those below 50 mg/dL may cause impaired brain function.¹

As a general rule, confirmed glucose values below 50 mg/dL deserve further evaluation, but suggestive symptoms without low serum glucose levels are not diagnostic. The Whipple triad summarizes the minimum criteria required for a true hypoglycemic disorder:

• Symptoms and signs consistent with hypoglycemia.
• A documented low serum glucose level at the time of the symptoms and signs.
• Resolution of symptoms and signs with correction of the hypoglycemia.

Case 1: Nondiabetic Woman With Recurrent Episodes of Hypoglycemia

Clinical background. A 36-year-old woman had 2 episodes of hypoglycemia. During the first episode, the glucose level was 12 mg/dL (capillary) and 26 mg/dL (serum); during the second episode, the capillary glucose level was 37 mg/dL, but the serum level was not correspondingly low. In both instances, she was treated with intravenous dextrose, and the hypoglycemic symptoms and signs resolved. Unfortunately, the resolution was only temporary. Although the patient was not known to have diabetes, further workup of the hypoglycemia was not pursued.

After the second episode, the patient was hospitalized. Several days later, she experienced cardiovascular collapse. Hypopituitarism with severe, secondary adrenal insufficiency was diagnosed on the basis of a morning plasma adrenocorticotropic hormone (ACTH) level of 5 pg/mL and a serum cortisol level of less than 1 μg/dL.

Case discussion. On admission, the patient’s thyroid-stimulating hormone (TSH) level was 6.11 μIU/mL (normal range, 0.5 to 5.0 μIU/mL) and the free thyroxine (T₄) level was 0.5 ng/dL (normal range, 0.9 to 2.4 ng/dL). These values were interpreted as discordant for a diagnosis of either primary hypothyroidism or the sick euthyroid syndrome (decreased thyroid function as a result of a non-thyroidal illness), but possibly consistent with secondary hypothyroidism. With a low free T₄ level of 0.5 ng/dL, the corresponding TSH level should be higher than 6.11 μIU/mL in a patient with primary hypothyroidism. Conversely, during secondary hypothyroidism, the TSH and free T₄ levels should both be low. In the setting of secondary adrenal insufficiency, the likelihood of concomitant secondary hypothyroidism is increased.

A fundamental rule in the interpretation of endocrine laboratory results is the concept of “inappropriately normal” values. Hormone levels are always regulated in concert with feedback. Thus, they should never be interpreted in isolation. That is, they must be interpreted relative to the counter-regulating factors (eg, low thyroid function increases the TSH level in an attempt to stimulate the failing pituitary gland).

Outcome of this case. Because of this patient’s poor prognosis, she did not undergo imaging studies to further delineate her pituitary status. She had severe anoxic encephalopathy, necessitating ventilator dependence and enteral nutrition for life, and thus was not considered to be a candidate for any radical intervention even if a pituitary cause was uncovered. She was given medical treatment, which included oral glucocorticoids.

Take-home message. This case illustrates a life-threatening situation that was precipitated by secondary (pituitary ACTH-deficient) adrenal insufficiency. The previous episodes of  “unexplained hypoglycemia” were warnings that, at least initially, were not evaluated further. Unfortunately, the patient sustained severe, residual anoxic encephalopathy as a result of recurrent and prolonged hypoglycemia. Greater vigilance during her previous hypoglycemic episodes may have prevented this outcome. This case represents the most extreme example of the serious consequences of unrecognized, recurrent hypoglycemia. A review of patients with hypoglycemia as a result of Addison disease furnishes additional information.² Although the patients in this particular reference had diabetes, the workup for Addison disease, specifically related to hypoglycemia, is the same.
 

Case 2: Seizures in an Older Man With Rheumatoid Arthritis

Clinical background. Prednisone (Deltasone) was prescribed for joint inflammation in a 67-year-old man with rheumatoid arthritis. However, because of a pharmacy error, glyburide (DiaBeta) was dispensed inadvertently. Subsequently, he experienced 3 tonic-clonic convulsions, one of which was accompanied by a blood glucose level of 28 mg/dL. The discovery of the mislabeled medication bottle and the correction of the error eliminated the hypoglycemia and seizures. The patient had no permanent sequelae.

Case discussion. The key test in this patient demonstrated elevated levels of endogenous serum insulin during an episode of hypoglycemia. The serum glucose level was 40 mg/dL; serum insulin, 10 μIU/mL (fasting range, 5 to 20 μIU/mL); and serum C peptide, 2.0 ng/mL (range, 1.1 to 5.0 ng/mL). In this instance, the insulin and C-peptide results were both inappropriately “normal” (hypoglycemia should suppress insulin endogenous secretion). Therefore, both values were relatively increased and confirmed the endogenous secretion of insulin. A test for serum sulfonylureas was negative. Sulfonylurea measurements can be misleading, and in many instances do not return in time to affect appropriate treatment. A careful review of all the patients medications, prescription or otherwise, is critical. A CT scan of the pancreas was obtained in case an insulinoma (also associated with elevated insulin and C-peptide levels despite hypoglycemia) was present. No evidence of a pancreatic tumor was found.

Take-home messages. This case contains several important lessons:

• First, anyone can make an error in the complex environment of contemporary medical practice. Faulty systems lead to mistakes. The need for checks and counterchecks for things as simple as prescription medications can never be minimized.

• Second, review of a patient’s medication list, as well as the bottles and pills contained in them, is essential. Every effort should be made to obtain the list directly from the patient, and, if possible, the actual bottles and tablets should be examined and occasionally counted. In this case, the pharmacy records and the label on the bottle indicated prednisone, but the tablets inside were glyburide. Critical information was obtained by examining the patient’s medications directly.

• Third, mistakes are common. Hypoglycemia is more often related to medication errors than to a true endocrine phenomenon such as an insulinoma or Addison disease.

• Another agent has been added to the armamentarium of treatment (dextrose and glucagon) for prolonged hypoglycemia resulting from over-ingestion of sulfonlyureas. That drug is octreotide. Prospective controlled trials have attested to its utility in this particular clinical situation.^3,4

Patient safety has become a paramount issue for primary care (Sidebar). In the 2009 Safety Standards published by the Joint Commission for the Accreditation of Hospitals, medication safety is prominent.⁵
 

CLINICAL MANIFESTATIONS

Serious hypoglycemia manifests with symptoms and signs related to sympathoadrenal activation and neuroglycopenia. Sympathoadrenal activation includes sweating, tachycardia, tachypnea, anxiety, tremulousness, and nausea. Neuroglycopenic symptoms and signs consist of altered vision, fatigue, dizziness, headache, confusion, mental status changes, seizures, coma, and potentially death. Not all symptoms or signs are present in each patient who has hypoglycemia. However, the pattern of an individual patient’s complications is usually consistent during repeated episodes.

DIAGNOSIS

When patients present with symptoms or signs of hypoglycemia or have a low blood glucose level, it is important to initiate a focused laboratory workup. This approach is imperative in those who are not known to have diabetes or in persons with diabetes who have not responded to appropriate attempts to remedy their hypoglycemia (adjustments in medications or diet, for example). Serum glucose values below 60 mg/dL, accompanied by a history of symptoms or signs consistent with hypoglycemia, suggest an underlying, nondiabetic hypoglycemic pathology. A glucose value below 50 mg/dL with hypoglycemic symptoms or signs mandates further investigation. Since the correlation of hypoglycemia, insulin, and C-peptide are critical, initiate diagnostic studies while the patient is hypoglycemic. Obtaining additional serum samples at the initial hypoglycemic presentation, especially in patients who are not known to have diabetes, can facilitate diagnostic testing. If the suspicion of a hypoglycemic disorder is sufficiently high and symptomatic episodes infrequent, a supervised 72-hour fast in consultation with an endocrinologist to confirm hypoglycemia and determine a specific cause may be warranted (Table). In the workup of hypoglycemia, the following laboratory studies should be included:

• A plasma or serum glucose level: Capillary glucose levels below 60 mg/dL are suggestive but not always reliable. A low plasma or serum glucose level should be confirmed on at least 2 more occasions.
• Serum insulin and C-peptide levels: Insulin levels should be suppressed (less than 6 μIU/mL) when the glucose level is below 60 mg/dL.
 

The presence or absence of insulin during episodes of hypoglycemia helps identify the specific cause. Insulin-induced hypoglycemia can then be further divided into those with inappropriate endogenous or exogenous sources of insulin based on the C-peptide levels, because C-peptide is found only with endogenous insulin secretion. Further workup is contingent on the results of these initial, focused laboratory studies. At this point, it is important to consult an endocrinologist because the causes discussed here are not common and may require specialized diagnostic and therapeutic interventions.

Case 3: Young Woman With Recurrent Seizures

Clinical background. A 24-year-old woman with new onset generalized seizures was hospitalized. An electroencephalogram and an MRI scan showed no neurological cause of the seizures. Hypoglycemia (serum glucose level, 30 mg/dL) was documented and treated but was not evaluated further. She later presented with another seizure and a blood glucose level of 20 mg/dL. Measurement of the adrenocorticotropic hormone (ACTH) level (1062 pg/mL) and the serum cortisol level (0.5 μg/dL) led to a diagnosis of primary adrenal insufficiency (Addison disease). The seizures ended after she received corticosteroid therapy.

Case discussion. Hypoglycemia was considered the probable cause of this patient’s seizure activity. The seizures and episodes of hypoglycemia occurred each time she experienced a flu-like illness. There appeared to be no relationship between seizure activity and meals, activity, or stress.

After further questioning, the patient reported that she had lost 87 to 95 lb over the past 2 to 3 years. A focused physical examination revealed the hyperpigmentation of Addison disease. (The Figure shows hyperpigmented gingiva in another patient with primary adrenal insufficiency). This patient’s insulin and C-peptide levels were undetectable-a finding consistent with the diagnosis of Addison disease. Because endogenous insulin secretion was not responsible for the hypoglycemia, it was suppressed. The culprit was a lack of adrenal production of steroids.
The ACTH level was markedly elevated because the pituitary was trying to stimulate a failing adrenal gland, but the cortisol level was extremely low. There was no response to cosyntropin (synthetic ACTH), 250 μg given intravenously. This workup confirmed the diagnosis of primary adrenal insufficiency.

The patient’s thyroid-stimulating hormone (TSH) level was 50 μIU/mL; free thyroxine (T₄) level, 1.1 ng/dL; and triiodothyronine uptake, 26.6%. These values indicate primary hypothyroidism in addition to adrenal insufficiency (a low T₄ level despite an elevated TSH level). Markedly increased levels of antimicrosomal antithyroid antibodies suggested that an autoimmune disorder was responsible for the hypothyroidism. The presence of autoimmune primary hypothyroidism makes it likely that the primary adrenal insufficiency also had an autoimmune cause.

Take-home message. This case highlights the importance of the “degree” of hypoglycemia in a patient with seizures. Blood glucose levels below 55 mg/dL suggest that hypoglycemia is responsible for the seizures.
 

Case 4: Elderly Woman With Insulinoma

One of the most commonly discussed etiologies for non-diabetic hypoglycemia, insulinoma, has been conspicuous thus far by its absence. It is an uncommon cause of hypoglycemia, but nonetheless an important one. A recent Clinical Problem solving exercise in the New England Journal of Medicine describes the diagnostic approach and treatment of insulinoma.⁶

The patient was an 88-year-old woman who had a 1-year history of transient confusion that had increased in frequency. She was not taking oral hypoglycemic medications. Her history and physical examination were otherwise unremarkable. A random glucose and CT scan of the head were normal. Two months after initial workup, she suddenly became minimally responsive. Her blood glucose level was 40 mg/dL. She was treated with intravenous dextrose and glucagon and recovered. An inpatient fast was ordered and within 7 hours, she became dizzy, and lethargic. Her glucose was 43 mg/dL, her insulin level was 12 microIU/mL (normal, <3 microIU/mL), and her C-peptide was 2.9 ng/mL (normal, <0.6 ng/mL). She was treated again with dextrose. The working diagnosis was insulinoma. Finding the tumor producing insulin was more difficult, however. An MRI of the abdomen did not discover the tumor. An endoscopic ultrasound found a hypoechoic mass (1.2 cm in diameter) in the pancreatic body. It was surgically removed and the patient did not exhibit symptomatic hypoglycemia again.

This case highlights a new diagnostic modality that helps localize the tumor producing insulin-the endoscopic ultrasound. The preceding workup was consistent with that of our previous cases (Cases 1-3). 

Discussion
The 4 cases demonstrate the symptoms and signs of hypoglycemia in non-diabetic persons, each from a different cause. These etiologies for a symptomatic drop in glucose levels included hypopituitarism with secondary adrenal insufficiency, a prescribing error inadvertently administering a sulfonylurea, primary adrenal insufficiency (Addison disease), and an insulinoma. Each precipitating disease or insult, although not common, could have been suspected based on the presence of hypoglycemia in non-diabetic individuals. A sample of typical frequencies for some of the disorders discussed may be obtained with the reference provided.⁷

The essential aspect of diagnosis is suspicion when unexplained hypoglycemia results in mental status changes. Inappropriately elevated insulin and increased C-peptide level in the face of symptomatic, severe hypoglycemia is key to preventing a disastrous outcome, as in Case 1. Endoscopic ultrasound has assisted in uncovering the small tumors responsible for insulin oversecretion. Since insulinoma is a fascinating diagnosis, further references with more detail are provided.¹³ The use of this diagnostic modality and supervision of a controlled fast require subspecialty consultation.

The primary care physician remains the important contact point for the initial diagnosis of symptomatic hypoglycemia.    

SIDEBAR: Patient Safety-A Paramount Issue for Primary Care

Some additional comments regarding Case 2, the case involving medication prescribing error, are warranted. It is disconcerting to realize that more people in the US die of medical errors than motor vehicle accidents. As many as 10% to 20% of these aforementioned errors are the result of medicines.^8,9 Medication Reconciliation and explicit efforts to improve medication safety have become essential in this complex medical environment. Without access to the bottle of mistakenly dispensed sulfonylurea, the cause for Case 2’s hypoglycemia would have remained unknown. As the literature cautions, this particular medication error and consequent hypoglycemia are not uncommon.¹⁰ As a result, practice quality mandates serious attempts to make medication use as safe as possible.^11,12 

Table – Supervised 72-Hour Fast to Confirm Hypoglycemia¹

A prolonged fast should be done under the supervision of an endocrinologist. However, it is important to be comfortable with the basic principles of the test:

References:

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