Islet cell tumors (insulinomas) or islet hypertrophy (nesidioblastosis) are well-described causes of fasting hypoglycemia. The older medical literature, however, also lists exocrine pancreatic involvement as a cause of hypoglycemia [1]. In animal models, ligation of the pancreatic duct leads to atrophy of the exocrine pancreas with secondary hypertrophy of the endocrine portion of the pancreas (Herxheimer-Mansfield phenomenon) [1, 2]. In humans, this islet hypertrophic reaction to pancreatic fibrosis has been termed "pseudoneoplastic proliferation" [3] and can be seen in patients with pancreatic carcinoma, mucoviscidosis associated with cystic fibrosis [4], and chronic pancreatitis [5]. We describe a patient with recurrent severe hypoglycemia related to pancreatic fibrosis and secondary islet cell hypertrophy.

A 33-year-old woman was transferred from another hospital because of recurrent, severe hypoglycemia. The patient had a history of diabetes mellitus and had been receiving 40 U of neutral protamine Hagedorn (NPH) insulin each morning and 20 U each evening. During the 6 months before admission, she was able to discontinue insulin therapy completely but continued to have hypoglycemic episodes. Her medical history was remarkable for alcohol abuse (at 14 years of age, she began drinking 1 L of hard liquor and 1 case of beer per day) and drug abuse (marijuana, Quaaludes, and intravenous morphine). The patient also stated that she had a history of two previous episodes of pancreatitis. Results of physical examination were essentially normal.

Laboratory values at admission were the following: glucose, 124 mg/dL; C-peptide, 4.7 ng/mL (normal, 0.8 to 4.0 ng/mL); insulin, 37 µg/mL; cortisol, 16.4 µg/dL; and somatomedin C, 152 ng/mL (normal, 116 to 270 ng/mL). The patient was negative for the presence of sulfonylureas, and no insulin antibody screen was detected. The patient underwent a 72-hour fast under close observation. After 60 hours of fasting, hypoglycemia developed. The venous blood glucose level was 29 mg/dL, the insulin level was 24 µg/mL, the proinsulin level was 1.12 ng/mL (normal < 0.2 ng/mL), the C-peptide level was 3.6 ng/mL, and no sulfonylureas were detected. All imaging techniques had normal results. Because of the recurrent, severe symptomatic hypoglycemia, the patient underwent surgery. During surgery, no pancreatic masses were palpated, results of intraoperative ultrasonography were negative, and a two-thirds distal pancreatectomy was performed. The patient's blood glucose level became elevated after surgery; as a result, therapy with NPH insulin, 20 U each morning, was reinstituted.

The pancreas was serially sectioned at 2- to 3-mm intervals; no gross tumor was identified. Sections of pancreas showed diffuse hyperplasia of the islets of Langerhans. Marked fibrosis and atrophy of the acinar tissue surrounded these areas.

The mechanism responsible for the islet cell hyperplasia is unclear. Secretin, cholecystokinin, gastrin, and reactive hyperemia have all been implicated. Because an inflammatory process accompanies all of the diseases that lead to pancreatic exocrine atrophy, an inflammatory mediator may be involved. This process should be recognized as a potential cause of hypoglycemia because it can be treated surgically.