LAUSR

I n 1996, Lucio Gullo coined the term “benign pancreatic hyperenzymemia” (BPH) for a condition characterized by a chronic increase of serum amylase, pancreatic isoamylase, lipase, and trypsin detectable in healthy people without any clinically or imaging-proven evidence of organic disease. Increased pancreatic enzymes levels are usually detected accidentally mainly as a result of screening tests in otherwise asymptomatic subjects. The exact incidence of the condition is unknown. The knowledge so far acquired on the BPH allowed for the identification of the following major laboratory and clinical features: (a) most often, the enzyme elevation is 2 to 4 times the normal range, but it can sometimes be much higher, increasing up to 15 times; (b) it occurs in adult and pediatric asymptomatic subjects, lacking any pancreatic or systemic diseases; (c) it persists over time with considerable fluctuations in serum enzyme concentration, including periods with normal values; (d) it can be either familial, when at least 1 family member shows the same abnormality, or sporadic; and (e) after the initial finding, the hyperenzymemia should be considered benign only after at least 2 years of follow-up, during which all imaging tests, that is, pancreatic computed tomography (CT) scans and/or magnetic resonance imaging/magnetic resonance cholangiopancreatography (MRCP), must be negative. Despite this progress, the finding of increased pancreatic enzymes raises the suspicion of an underlying pancreatic disease in most physicians. As a result, asymptomatic subjects undergo numerous, expensive, and often useless investigations increasing health care costs and patients' concerns. Thus, the aim of this brief review is to provide the general practitioners and gastroenterologists with an update on the clinical and diagnostic features of BPH to guarantee a proper management of these otherwise healthy subjects. When approaching a subject with a pancreatic hyperenzymemia, many potential causes should be considered and excluded, including a wide array of pancreatic (eg, acute and chronic pancreatitis, pancreatic cancer, pancreatic obstruction, drugs, viral hepatitis) and extrapancreatic disorders (eg, rheumatic diseases, cancers, hematologic disorders, infections, renal and chronic liver diseases). The reason why some subjects present with a higher level of pancreatic enzymes in the absence of identified diseases remains unknown. Cook et al proposed the existence of a direct, physiological, constitutive-like pathway from the trans-Golgi network to the basolateral cell membrane through which newly synthesized enzymes reach the circulation instead of the duodenum. It has been hypothesized that a defect in this pathway could be responsible for the increased passage of enzymes to the circulation (Fig. 1). In different studies, Gullo focused on potential underlying correlations with peculiar genetic background or mutations. A study investigated serum concentrations of pancreatic enzymes for 5 consecutive days in 42 patients with BPH. The enzyme concentrations remained elevated, albeit with wide fluctuations, for all 5 days in only 8 (19%) of the 42 subjects studied and normalized in most subjects (78.6%). This fluctuating behavior excluded persistent underlying anatomic alterations. It was also evaluated whether mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene or other genes, such as PRSS1 and SPINK1, that are mutated in chronic pancreatitis, may play an etiological role in this form of pancreatic hyperenzymemia. However, no correlation was ever established between these genes and BPH. Interestingly, the BPH has been described and observed also in the