Association of Rapid-Onset Type 1 Diabetes and Clinical Acute Pancreatitis Positive for Autoantibodies to the Exocrine Pancreas

A 24-year-old woman presented with epigastralgia on day 0. About 2 weeks before day 0, she had a low- grade fever for a few days. On day 3, she consulted a clinic, where hyperamylasemia (2.8 multiples of the upper normal limit) and swelling of the pancreas on ultrasonography were detected. The subject’s fasting plasma glucose (FPG) level was 85 mg/dl. Her serum insulin and C-peptide levels, as measured later with the frozen plasma, were 20.5 μU/ml and 7.7 ng/ml, respectively. On day 5, the subject’s serum amylase was 4.58 multiples of the upper normal limit. On day 6, her FPG level was elevated to 370 mg/dl and her urinary ketone showed +++. After treatment with intravenous administration of glucose, insulin, and ulinastatin (serine protease inhibitor) at the clinic, she was referred and admitted to Ohtsu Red Cross Hospital. The subject had no history of diabetes, pancreatitis, or alcohol consumption. Her BMI was 17.2 kg/m², her serum amylase was 3.22 multiples of the upper normal limit, and her serum elastase 1 was 1,400 ng/dl (range 100–400). The subject’s plasma glucose level was 329 mg/dl, and her HbA_1c was 4.9% (3.0–6.0). The serum C-peptide level was 0.2 ng/ml, the urinary C-peptide excretion rate was 4 μg/day, and the increment of serum C-peptide in response to intravenous administration of 1 mg of glucagon was not detectable, indicating severe impairment of insulin secretion. Islet cell antibody, anti-GAD antibody, and anti–IA-2 (tyrosine phosphatase–like protein) antibody were negative. Dynamic computed tomography showed swelling of the pancreas, with enhancement on the early phase. Magnetic resonance cholangiography and pancreatography examinations were normal. Virus antibodies showing acute infection with cytomegalovirus, Epstein-Barr virus, rubella virus, mumps virus, herpes simplex 1 and 2, herpes zoster virus, coxsackie B viruses, and rotavirus were all negative. The patient possessed HLA DQA1*0102 and DQB1*0602, the HLA types resistant to type 1 diabetes in Japanese individuals (1). Other HLA types in this case were A24, A33, B7, B44, Cw7, DRB1* 0101 and 1501, DQA1* 0101, and DQB1* 0501. The bentiromide test value on day 28 was 63.7% (73.1–90.1), showing mild exocrine dysfunction. Even after acute pancreatitis was remedied with ulinastatin, the subject remained insulin-dependent. In this case, it is unlikely that diabetes is secondary to classical pancreatitis, considering the severity of insulin deficiency with only mild exocrine dysfunction. Rather, this patient was diagnosed as an association of type 1B (idiopathic) diabetes and clinical acute pancreatitis. This association suggests a common etiopathogenesis in both exocrine and endocrine dysfunction, although the mechanism remains to be elucidated.

Simultaneous involvement of exocrine and endocrine pancreas has been reported in type 1 diabetic patients (2,3). Recently, a novel subtype of type 1 diabetes, characterized by a rapid onset, an absence of diabetes-related antibodies, and hyperamylasemia with lymphocytic infiltration in the exocrine pancreas, was postulated to be “nonautoimmune” fulminant type 1 diabetes (4). Our case subject showed characteristics, i.e., hyperglycemia with low HbA_1c, an absence of autoantibodies to the endocrine pancreas, and hyperamylasemia, that seem compatible with this entitiy. The relatively high levels of serum insulin and C-peptide for normoglycemia on day 3 appear to reflect the ongoing destruction of β-cells.

Serum levels of autoantibodies against human carbonic anhydrase II (ACA) and autoantibodies against lactoferrin (ALF), which are distributed in the pancreatic duct cells and the acinar cells, respectively, were measured using the solid-phase ELISA method, as previously described (5). ACA and ALF were positive in the present case subject.

It was reported that ACA and ALF were detected in patients with autoimmune pancreatitis, whereas they were not detected in any of the patients with alcoholic or gall stone–related pancreatitis (5). Although our present case was uncharacteristic of autoimmune chronic pancreatitis after completion of imaging studies and the clinical course (6,7), the presence of these antibodies suggests the involvement of autoimmunity against the exocrine pancreas.

We have recently demonstrated the presence of ACA and ALF in type 1 diabetic patients and proposed the concept of autoimmune exocrinopathy and endocrinopathy of the pancreas (8).

In conclusion, we reported the first case of an association of rapid-onset type 1 diabetes and clinical acute pancreatitis that tested positive for autoantibodies to the exocrine pancreas. Although known antibodies against the endocrine pancreas were not detected, autoimmunity, at least against the exocrine pancreas, was suggested.