Peptide Histidine-Methionine Immunoreactivity in Plasma and Tissue from Patients with Vasoactive Intestinal Peptide-Secreting Tumors and Watery Diarrhea Syndrome

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Abstract
The presence of peptide histidine-methionine (PHM)-like peptides has been determined in plasma and tumor specimens from patients with vasoactive intestinal peptide (VlP)-secreting tumors and the watery diarrhea syndrome. All patients had strikingly elevated plasma concentrations of PHM immunoreactivity (median, 1800; range, 500–6800 pmol/liter; n = 12), which were higher than those of VIP (median, 235; range, 50–580 pmol/liter). In patients with other endocrine and nonen-docrine pancreatic tumors, plasma PHM concentrations were not significantly different from normal (median, 20; range, 5–60 pmol/liter; n = 28). Plasma samples from patients with diarrhea due to other illnesses also had PHM concentrations that were not significantly different from normal (median, 40; range, 10–80 pmol/liter; n = 23). The gel chromatographic profiles of plasma and tumor extracts from patients with VIP-secreting tumors revealed the presence of at least two molecular forms that reacted with an antiserum directed to the N-terminus of PHM (SY1). The later peak (Kav, 0.50–0.53) corresponded in position to synthetic PHM and also reacted with the PHM-specific antiserum (SY2). The earlier peak (Kav, 0.30–0.37), not reactive with antiserum SY2, corresponded to a large molecular form of PHM-like immunoreactivity previously identified as the predominant form in normal human stomach and plasma, though not in the rest of the intestinal tract. The neuroendocrine nature of the tumors was confirmed by the demonstration of immunostaining with a battery of antisera to neuroendocrine markers. Immunocytochemistry revealed the presence of both VIP and PHM in tumor cells. The presence of high circulating concentrations of PHM-like immunoreactivity in patients with VIP-secreting tumors, as measured with a PHM N-terminus-directed antiserum, SYl, suggests that use of this type of antiserum may provide valuable information in the diagnosis of such tumors. The contribution of the PHM-like peptides to the features of this syndrome is not known.