Hypoglycemia (Case 39)
Shadi Barakat MD
Case: The patient is a 35-year-old athletic woman who works as nurse. She has been healthy except for mild depression and anxiety that have not required treatment. She presents for evaluation of recurrent episodes of fatigue, palpitations, tremor, and sweating, without loss of consciousness, that started 4 weeks ago. Each episode lasted for a few minutes and subsided quickly after she ate a snack. Usually these episodes occurred at work shortly before lunchtime. During one of the episodes, she appeared confused and her co-workers tried to obtain a fingerstick glucose, but she refused, claiming that she would be fine. She blamed the episodes on her bad eating habits. She exercises every morning for 1 hour before coming to work, and she does not eat breakfast. For lunch she eats some steamed vegetables with a diet drink. Her coworkers were concerned about her and urged her to make an appointment for evaluation.
On exam, she is pleasant and in no apparent distress. Her height is 65 in. and her weight is 115 lb. (Her BMI is 19.) Her vital signs and the rest of her exam are negative for any abnormalities.
Differential Diagnosis
Medications (diabetic patients) | Alcoholic hypoglycemia | Non–insulin-secreting tumors |
Medications (nondiabetic patients) | Insulin-secreting tumors | |
Factitious administration of hypoglycemic agents | Counter-regulatory hormones deficiency |
Speaking Intelligently
Symptoms of hypoglycemia can be grouped as (1) adrenergic symptoms such as palpitations, tremor, and anxiety; (2) cholinergic symptoms such as sweating, hunger, and parasthesias; and (3) neuroglycopenic symptoms including behavioral changes, confusion, fatigue, seizure, and loss of consciousness. When asked to evaluate a patient like this, it is essential to document a measurement of the patient’s blood glucose while symptomatic. However, maintaining a broad differential diagnosis is important since other disorders may trigger autonomic and psychiatric symptoms when the blood glucose is normal.
PATIENT CARE
Clinical Thinking
• Reactive hypoglycemia is most commonly seen after abdominal surgeries including gastrectomy and roux-en-Y gastric bypass; in addition, it is often seen in thin, young healthy individuals and in patients with early diabetes or pre-diabetes who have insulin-secretory dysfunction.
History
• A social and psychiatric history.
• Symptoms that occur always in public and under stressful condition may indicate panic attacks.
• Any recent changes in the dosage, timing of administration of the medication, or patient activity.
Physical Examination
• Common signs of hypoglycemia include diaphoresis, tremor, and pallor.
• Heart rate and blood pressure are usually elevated.
• Transient focal neurological deficits occasionally occur.
• However, the physical exam is otherwise unremarkable between episodes.
Tests for Consideration
$18 | |
$96, $154, $334, $2086 | |
| Clinical Entities | Medical Knowledge |
Medications (Diabetic Patients) | |
Pφ | Medications are the most common cause of fasting hypoglycemia. Insulin causes hypoglycemia through its action of inducing glucose utilization. Sulfonylureas and meglitinides are secretagogues; they act by increasing insulin secretion from the pancreas. Some of them have active metabolites and long durations of action. |
Insulin-treated diabetic patients usually encounter hypoglycemia when the insulin dose exceeds their needs and is mostly seen when the dose is adjusted to better control high blood glucose. The insulin dose can also exceed the requirement in several other scenarios, such as when patients change their physical activity without adjusting the insulin dose, or when they fail to have a meal or a full meal after they administer a mealtime insulin dose. Also, it is not uncommon for hypoglycemia to occur as a result of the administration of a higher insulin dose by mistake, especially if the patient has a vision problem. Diabetic patients using sulfonylureas can encounter hypoglycemia in similar circumstances. Both insulin and sulfonylurea doses become higher than the requirement when the patient’s kidney function worsens. | |
Dx | Most diabetic patients can recognize and report their hypoglycemic symptoms. However, the physician should always check fingerstick blood glucose when possible before taking any action when hypoglycemic symptoms occur. Demonstration of Whipple triad is easy and confirms the diagnosis. |
Tx | Diabetic patients are almost always instructed to carry sugar tablets at all times and are educated to recognize and manage hypoglycemia. Most hypoglycemic episodes can be reversed by ingesting 15 g of sugar. Insulin-treated patients who present to the emergency department with hypoglycemia can be treated with IV dextrose and observation for the duration of action of the insulin they are using after other confounding factors such as sepsis and worsening kidney function, which will require inpatient management, have been ruled out. Insulin dose should be adjusted to prevent future events. Special attention should be paid to patients who are using a secretagogue. Sulfonylurea-induced hypoglycemia can be best described as severe, prolonged, and relapsing, and often requires stopping all hypoglycemic agents and instituting inpatient observation for 1 day or more. Keep in mind that one of the main reasons for nonadherence to medication in patients with diabetes is frequent episodes of hypoglycemia. See Cecil Essentials 70. |
Medications (Nondiabetic Patients) | |
Pφ | Although insulin and secretagogues cause hypoglycemia in diabetic patients through the action of insulin on glucose metabolism, other non-antihyperglycemic medications can cause hypoglycemia by different mechanisms. Large doses of salicylates can cause hypoglycemia by inhibiting glucose production. Sulfonamides and quinine can stimulate insulin production. Pentamidine causes dysglycemia and is considered toxic to β-cells. Patients can develop hypoglycemia, diabetes mellitus, or hypoglycemia initially and diabetes later. Disopyramide, cibenzoline, and fluoroquinolones (particularly gatifloxacin) have all been reported to cause hypoglycemia. |
TP | Patients are usually being treated for diseases such as malaria, Pneumocystis jirovecii pneumonia, other infections, or arrhythmias. Patients are usually symptomatic, or the hypoglycemia is documented during fingerstick blood glucose determination. Patients being treated with quinine may present with severe hypoglycemic coma. |
Dx | Diagnosis can be established by the Whipple triad in patients who are being treated with one of the medications that is known to cause hypoglycemia. |
Tx | Rapid correction of blood glucose with IV dextrose is very important in the acute setting. Glucagon can also be used. Patients should be monitored closely for up to 3 days for recurrence of hypoglycemia. They should be educated about recognizing the symptoms of hypoglycemia and should keep sugar tablets with them at all times. Pentamidine-treated patients should be monitored for the development of diabetes. Diazoxide can be used as an outpatient regimen in patients whose medical condition necessitates continuing the offending agent. See Cecil Essentials 70. |
Alcoholic Hypoglycemia | |
Pφ | Ethanol blocks gluconeogenesis and causes hypoglycemia. |
TP | Individuals with ethanol-induced hypoglycemia manifest a variety of neurologic signs. Coma, seizures, and hemiparesis have been described. They may also manifest adrenergic signs and symptoms, such as tachycardia and tremor. However, the repeated exposure to ethanol may deplete the catecholamine stores, resulting in absence of the adrenergic response to hypoglycemia. Most of these patients are chronic alcoholics who present a few days after binge drinking with little food intake. Ethanol-induced hypoglycemia is not related to the degree of ethanol-induced liver damage. |
Hypoglycemia should be suspected in any comatose and/or alcoholic patient. Fingerstick and analysis for blood glucose should be routinely done. A low blood glucose level establishes the diagnosis. A urine dipstick is usually positive for ketones. | |
Tx | Patients usually respond immediately to IV glucose infusion and do not require prolonged periods of infusion or observation so long as they can maintain modest carbohydrate intake. In alcoholic patients, physicians should always remember to replace thiamine, along with the infusion of glucose, to avoid the serious side effect of further depleting thiamine stores. See Cecil Essentials 70. |
Insulin-Secreting Tumors (Insulinoma) | |
Pφ | Though β-cell tumors (insulinomas) are the most common of the pancreatic endocrine neoplasms, they are very rare. The incidence was estimated as low as 4 per 1 million per year. They occur in both genders and have been described in persons from 8 to 82 years of age. They are most often found within the pancreas as a single small (<2 cm) encapsulated tumor. Rarely, they arise from ectopic pancreatic tissues. It is estimated that 10% of insulinomas are malignant. |
TP | Insulinoma should be suspected in patients who present with Whipple triad who are not being treated with insulin and/or hypoglycemic agents. A typical patient will be a middle-aged and otherwise healthy individual who presents with episodes of hypoglycemia symptoms. |
Dx | Considering how rare insulinomas are, it is important to keep in mind the wide differential diagnosis, especially the factitious use of insulin or secretagogues. Patients should be observed during fasting for symptoms of hypoglycemia. Sometimes it is necessary to admit the patient to the hospital for a prolonged period of fasting for 48–72 hours. Once symptoms are observed, blood should be drawn and sent for blood glucose, insulin, and C-peptide levels. A high insulin-to-glucose ratio, in the presence of a negative assay for the presence of secretagogues, makes the diagnosis more likely. The next step is localization of the tumor using transabdominal ultrasonography or spiral CT. Endoscopic ultrasonography, arteriography, and arterial stimulation with hepatic venous sampling can be used to localize the tumor if the first two modalities are unsuccessful. The preoperative studies, along with intraoperative ultrasonography and palpation, can identify 98% of all tumors. |
Management is surgical by excision of the tumor or tumors. Resection is also indicated for isolated metastatic tumors. In patients who fail surgery, diazoxide can be used. Somatostatin analogues can be effective in diazoxide-refractory symptomatic patients. See Cecil Essentials 70. | |
Non–Insulin-Secreting Tumors | |
Pφ | Several case reports have described patients with non–islet cell tumors with severe hypoglycemia and without hyperinsulinism. The proposed mechanisms of hypoglycemia include the following: inhibition of gluconeogenesis, replacement of the liver and the adrenal tissue with tumors, and excessive utilization of glucose in the skeletal muscles or by the tumors that was linked in most cases to increased secretion of incompletely processed insulin-like growth factor II (IGF-II). |
TP | Non–islet cell tumor-induced hypoglycemia has been described in patients with a wide variety of tumors and was reported in association with carcinomas of the breast, colon, esophagus, lung, ovary, pancreas, and prostate, as well as other tumors such as carcinoid, hepatoma, lymphoma, multiple myeloma, meningioma, and mesothelioma. These tumors are usually large in size, with an average weight of 2–4 kg. |
Dx | It is usually easy to establish the diagnosis of hypoglycemia in patients with a known history of a tumor that is known to cause hypoglycemia. Further workup to determine the mechanism is not necessary. |
Tx | Treatment should be directed to the underlying malignancy, along with correction of hypoglycemia in the acute setting. Patients who respond well to glucagon and who continue to experience hypoglycemia can be treated with a continuous glucagon infusion. See Cecil Essentials 70. |
Counter-Regulatory Hormones Deficiency | |
Pφ | The first self-defense mechanism against hypoglycemia is to decrease insulin secretion. This is usually followed by increased secretion of hormones that counteract the action of insulin on glucose, attempting to return the serum glucose levels to normal. These counter-regulatory hormones are glucagon, epinephrine, cortisol, and growth hormone. |
Most of the patients are diabetics on treatment, and they present with other illnesses depending on the organ system involved. Diabetic patients with cirrhosis are a good example and are frequently encountered in acute care facilities. Hypoglycemia due to anterior pituitary insufficiency is seen in neonates and infants more than adults. Patients with adrenal insufficiency present with signs and symptoms of Addison disease. They are extremely sensitive to fasting of any period of time; patients with Addison disease may lack the adrenergic signs and symptoms when they develop hypoglycemia. | |
Dx | Clues to the diagnosis can be obtained by taking a good history and by performing a thorough physical exam. Addison disease patients present with hypotension and hyperpigmentation of the skin and the mucous membranes, along with specific electrolyte imbalances (specifically hyperkalemia). A patient with a history of chronic hepatitis or chronic ingestion of alcohol who presents with ascites should be monitored for hypoglycemia, especially if he or she is a diabetic on treatment. When counter-regulatory hormones deficiency is suspected, appropriate hormonal studies should be ordered. The cosyntropin stimulation test with measurements of cortisol is a very good method for evaluating patients with suspected adrenal insufficiency. |
Tx | Hypoglycemia secondary to endocrine deficiencies is a medical emergency. In the acute setting, rapid correction of plasma glucose using 50 mL of 50% dextrose should be done as soon as the diagnosis is suspected. Patients should be monitored closely for recurrence. The preferred IV fluids are 5% dextrose in normal saline. Glucagon can also be used to correct hypoglycemia. Parenteral hydrocortisone should be administered immediately if Addisonian crisis or hypopituitarism is suspected. Treatment should be directed to the underlying disease. Doses of hypoglycemic agents should be adjusted as needed. See Cecil Essentials 70. |
Factitious Administration of Hypoglycemic Agents | |
Pφ | Although this is an induced hypoglycemia, it represents a psychological pathology that warrants treatment. Patients with factitious disorder deliberately induce or falsify illness for the sole reason of playing the sick role. There is no secondary gain from faking the disease in factitious disorder. Stress, personality disorder, and psychodynamic factors have been described as factors in the pathogenesis of factitious disorder. |
The typical patient with factitious disorder who uses hypoglycemic agents is a female in the third or fourth decade, nondiabetic, health-care worker, or the family member of a diabetic patient. It has also been described in diabetic patients on treatment. Some patients present with a confabulated history describing symptoms of hypoglycemia, while others actually administer a hypoglycemic agent and develop signs and symptoms of hypoglycemia. | |
Dx | The diagnosis should be suspected in all patients undergoing workup for hypoglycemia, especially when the episodes happen randomly in relation to meals. An elevated insulin level with a low level of C-peptide confirms the administration of an exogenous source of insulin. Elevated insulin and C-peptide levels, with positive serum assay for sulfonylureas and/or meglitinides, confirm the use of secretagogue to induce hypoglycemia. However, the diagnosis is more difficult to establish if the patient is a diabetic on treatment. Insulin concentrations > 100 µU/mL suggest factitious use of hypoglycemic agents, since insulin levels are rarely >100 µU/mL in patients with insulinomas. |
Tx | No specific therapy for factitious disorder has been established. Management should be directed to correcting the hypoglycemia and protecting the patient from self-harm or harmful procedures. See Cecil Essentials 70. |
