Recurrent Confusion and Seizures in an Adult Male

Qing Meng, MD, PhD; Gillian Luxton, MD, FCACB


Lab Med. 2004;35(8) 

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  1. Neurological symptoms, including confusion and seizures; markedly decreased random and fasting glucose; markedly increased insulin, C-peptide, proinsulin, and high sensitivity C-reactive protein (hsCRP); decreased RBC count, Hb, Hct, platelet count, MCV and MCH, with an increased RDW; prolonged INR; decreased iron, albumin, and A/G ratio; increased ALP and LD; slightly increased LH and FSH levels; decreased testosterone (Table 1 and Table 2).

  2. The explanation of this patient's most striking clinical and laboratory findings are complicated by his cancer. Neurological symptoms such as confusion and seizures, coupled with markedly decreased random and fasting glucose concentrations and markedly increased insulin, C-peptide, and proinsulin values, indicate that this patient has hypoglycemia. The low RBC, Hb, Hct, MCV, MCH, increased RDW, and low serum iron indicate iron deficiency anemia (IDA). Iron deficiency anemia may be related to the patient's poor nutrition, glucose malabsorption, or chemotherapy. Serum ferritin is a sensitive, but less specific, early marker for IDA because it can be increased in clinical conditions such as acute phase reaction and inflammation. When these conditions are present, a normal serum ferritin concentration can occur in individuals with severe IDA. An acute phase reaction in our patient is supported by the markedly increased hsCRP concentration. C-reactive protein is a positive acute phase reactant whose concentration is increased in individuals with an acute phase reaction. A total iron binding capacity (TIBC) within the limits of the (normal) reference interval does not eliminate the diagnosis of IDA because TIBC is a surrogate marker of transferrin, a negative acute phase reactant (ie, transferrin concentration decreases in individuals with an acute phase reaction). High transferrin saturation (>15%) may suggest coexistence of anemia of chronic disease (ACD) with IDA; however, IDA alone is not excluded because TIBC can be influenced by many physiological and pathophysiological conditions.[1] Low platelet count, prolonged INR, decreased albumin and A/G ratio, high ALP, LD, and AST suggest that the patient has chronic liver disease. Testicular tissue damage from tumor (seminoma) infiltration or chemotherapy could be the cause of the patient's low testosterone concentration. A low testosterone concentration stimulates the hypothalamus to secrete gonadotropin releasing hormone (GnRH) which acts on the anterior pituitary to increase the release of LH and FSH.

  3. Hypoglycemia (ie, a serum glucose concentration <50 mg/dL) can arise due to alimentary and endocrine problems, idiopathic, extrapancreatic, and pancreatic (eg, insulinomas) tumors, and miscellaneous causes, including fasting and malnutrition, hepatic and other diseases, as a side effect of diabetes treatment, treatment with various medications (eg, sulfonylureas and chemotherapeutic agents), and hormone or enzyme deficiencies. Malnutrition was not a severe problem for the patient because his serum albumin concentration was close to the lower limit of the reference interval and he denied any vomiting and diarrhea. Based on his increased liver function test values, he appeared to have a chronic hepatic injury, which could impair gluconeogenesis, increase depletion of glycogen stores, and cause hypoglycemia. Cancer chemotherapy is known to be associated with development of hypoglycemia. The findings of a low blood glucose concentration, coupled with markedly increased insulin, C-peptide, and proinsulin values, are consistent with insulin-induced hypoglycemia, which is usually due to an insulin-producing tumor.[2]

  4. Because the patient had a testicular tumor (seminoma) with metastases to the retroperitoneal and mesenteric areas, the pancreas might contain an insulin-secreting tumor or the testicular tumor itself might be secreting insulin. Rarely do non-pancreatic tumors secrete insulin, and there has been only 1 report of such a case involving an insulin-secreting small-cell carcinoma of the cervix.[3] Moreover, a tissue specimen resected from the patient's tumor was negative for insulin staining. In addition, the patient's markedly increased proinsulin and C-peptide values eliminated exogenous insulin as the cause of his hypoglycemia, while the patient's negative drug history, including lack of treatment with a sulfonylurea, ruled out the possibility of medication-induced insulin secretion. Based on the collection of these findings, the most likely source of this patient's markedly increased insulin concentration is a pancreatic insulinoma.

  5. Specific causes of a markedly decreased glucose concentration include: factitious, fasting, or reactive hypoglycemia, nesidioblastosis, or drug-, alcohol-, critical illness-, hormone deficiency-, autoimmune-, and tumor-induced hypoglycemia. Factitious hypoglycemia can occur in patients with psychiatric disturbances, a need for attention, and access to insulin. The triad of hypoglycemia, high immunoreactive insulin levels, and suppressed plasma C-peptide levels is pathognomonic of exogenous insulin administration. Exogenous insulin-induced hypoglycemia can be detected by an insulin:C-peptide ratio greater than 1.0. Fasting hypoglycemia is diagnosed from a blood sample that shows a blood glucose level of less than 50 mg/dL after an overnight fast, between meals, or after exercise. In reactive hypoglycemia (postprandial) symptoms appear within 4 hours after a meal. The cause(s) of reactive hypoglycemia are controversial. Some investigators have suggested that certain individuals may be more sensitive than others to the effects of epinephrine, which cause many of the symptoms of hypoglycemia.[4] Others believe that a deficiency in glucagon secretion leads to hypoglycemia.[5] Causes of reactive hypoglycemia include gastric surgery, because of the rapid passage of food into the small intestine, drugs, antibodies to insulin or the insulin receptor, and hereditary fructose-1,6-diphosphatase deficiency. Nesidioblastosis, or hyperplasia of the pancreatic islet cells, causes hyperinsulinemic hypoglycemia. It is predominantly a neonatal disorder, although cases in adults have been reported.[6] Drug-induced hypoglycemia can occur in diabetics taking certain drugs (eg, insulin) to control blood glucose levels, including inadvertent ingestion of sulfonylurea due to patient or pharmacist error. Other drugs associated with drug-induced hypoglycemia include haloperidol, salicylates, quinine, pentamidine, and sulfonamides. The patient was not an insulin-dependent diabetic, and he was not taking any drugs or medications. Alcohol-induced hypoglycemia results from chronic alcohol ingestion that can impair hepatic gluconeogenesis and glycogen storage that is aggravated further by the malnutrition that frequently accompanies chronic alcoholism. Critical illness-induced hypoglycemia can occur in individuals with renal failure or severe liver disease, such as drug-induced hepatitis and liver failure. Long-term starvation, as may occur in the eating disorder anorexia nervosa, can result in the depletion of substances needed in gluconeogenesis, resulting in hypoglycemia. Hormone deficiency-induced hypoglycemia can occur in certain disorders of the adrenal (eg, Addison's disease) and pituitary glands (eg, hypopituitarism) that result in a deficiency of key hormones that regulate glucose homeostasis. Hormone deficiencies cause hypoglycemia in children more frequently than in adults. Decreased blood levels of cortisol, growth hormone, glucagon, thyroxine, or epinephrine can lead to fasting hypoglycemia. Moreover, hypoglycemia with adrenal insufficiency should be accompanied by suppressed insulin levels. Laboratory tests for hormone levels establish the diagnosis. In this patient, cortisol, ACTH, and TSH levels were within the limits of the (normal) reference interval for these hormones. Autoimmune-induced hypoglycemia is a rare disorder caused by the interaction of endogenous antibodies with insulin or the insulin receptor. When this disorder occurs, laboratory testing demonstrates low plasma C-peptide and high plasma insulin concentrations. Tumor-induced hypoglycemia occurs in individuals with pancreatic (insulinomas) and extrapancreatic insulin-producing tumors that cause hypoglycemia by disproportionately raising the serum insulin level in relation to the blood glucose level. Insulinomas do not normally metastasize to other parts of the body. Nonpancreatic, non-insulin producing neoplasms can also cause hypoglycemia; however, in such cases, the tumor secretes factors [eg, insulin-like growth factors I (IGF I) and II (IGF II)] other than insulin, which, when elevated, cause hypoglycemia. The patient had an increased plasma insulin level and a low IGF I level, suggesting that his insulin-secreting tumor was of pancreatic origin.

  6. Most likely diagnosis: Hypoglycemia due to a pancreatic insulinoma. Hypoglycemia with highly elevated insulin, C-peptide, and proinsulin strongly suggests that this patient had hyperinsulinemia due to an insulin-secreting pancreatic insulinoma. This diagnosis was confirmed by ultrasound, octreotide scan, and surgical findings, which indicated the presence of an insulinoma in the head of the pancreas. The patient was unusual in that he presented with only neuroglycopenic symptoms of hypoglycemia.[7] An insulinoma is a neuroendocrine tumor, derived mainly from pancreatic islet cells, that produces excessive amounts of insulin and is the most common type of tumor causing hypoglycemia. In healthy individuals, insulin and C-peptide are secreted in equimolar amounts because they are both derived from the same inactive precursor molecule, proinsulin. Some insulinomas secrete additional hormones, such as gastrin, 5-hydroxyindole acetic acid (5-HIAA), ACTH, glucagon, hCG, and somatostatin. Insulinomas are the most common pancreatic endocrine tumor. The incidence of insulinomas in the United States population is about 1 to 4 per million people, and women are slightly more affected than men (male:female ratio = 2:3). Moreover, these tumors may secrete insulin in short bursts, causing wide fluctuations in blood glucose levels. About 90% of insulinomas are benign, while malignant insulinomas are often seen in patients with multiple endocrine neoplasia (MEN).[1] The pathogenesis of, and particularly the genetic changes that occur in, neuroendocrine tumors is not fully understood. In individuals with an insulinoma, symptoms vary widely; however, in general, they are characterized by central nervous system (headache, confusion, blurred vision, personality changes, seizures), cardiovascular (tachycardia, palpitations), GI (hunger, nausea, belching), and adrenergic effects (weakness, sweating, anxiety, tremulousness, nervousness). A diagnosis of hypoglycemia should not be made unless a patient meets the criteria of Whipple's triad: (1) low blood glucose concentration with (2) typical symptoms of hypoglycemia that are (3) alleviated by glucose administration.[8] The diagnosis of insulinoma is normally established by the laboratory findings of low plasma glucose, inappropriately elevated levels of insulin and C-peptide, and to a lesser degree, high levels of proinsulin.[2] The biochemical diagnosis of insulinoma is established in 95% of patients during prolonged fasting (up to 72 h) when the following laboratory test results are found in patients not on sulfonylurea therapy: serum insulin levels of 10 mU/mL or more [(normal) reference interval: <6 mU/mL], glucose levels of less than 40 mg/dL [(normal) reference interval: 70-110 mg/dL], C-peptide levels exceeding 2.5 ng/mL [(normal) reference interval: <2 ng/mL), and proinsulin levels greater than 25% (or up to 90%) that of the immunoreactive insulin level. Moreover, an insulin (mU/mL) to plasma glucose (mg/dL) ratio of >0.3 is diagnostic of an insulinoma. In patients with an insulinoma, this ratio rises during fasting as seen in this patient whose insulin to glucose ratio was 1.4 (Table 2). Stimulation tests are no longer recommended in the diagnostic workup of patients suspected of having an insulinoma. The intravenous administration of tolbutamide, glucagon, or calcium can be hazardous to the patient by inducing prolonged and refractory hypoglycemia. Moreover, an oral glucose tolerance test (OGTT) should not be used for evaluating a patient suspected of having hypoglycemia. Imaging studies, including computed tomography (CT) scan, magnetic resonance imaging (MRI), transabdominal ultrasonography, or arteriography is performed only after the diagnosis of insulinoma has been established biochemically. The sensitivity of these imaging techniques is low particularly when the insulinomas are small (< 2 cm).

  7. The initial treatment of hypoglycemia depends on the patient's symptoms. It may be helpful for patients to eat snacks, drink orange juice, swallow glucose tablets, or eat candy to raise their blood sugar level. If the symptoms are more severe, intravenous glucose administration or an injection of glucagon may be needed. In any event, treatment of a patient with signs and symptoms of hypoglycemia should not be withheld while waiting for a laboratory glucose values. For the long term, treatment of hypoglycemia may involve the use of an insulin inhibitory drug and surgical removal of the tumor (insulinoma). Diazoxide, a direct inhibitor of insulin secretion, which can increase hepatic glucose output and decrease cellular glucose uptake, may be indicated in patients with an insulinoma. Because insulinoma resection is curative in approximately 90% of patients with hypoglycemia due to an insulinoma, such surgery is currently the therapy of choice. After starting diazoxide therapy, the patient had no further episodes of severe hypoglycemic reactions, such as loss of consciousness or seizures. His blood glucose levels improved; however, they were still lower than normal. Subsequently, the patient underwent surgery and recovered well. Following surgery, he had no symptoms of hypoglycemia and all previously abnormal laboratory test values returned to values within the normal reference interval for each test.


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