Cholera and Pancreatic Cholera: Is VIP the Common Pathophysiologic Factor?

Background: Cholera remains a major global health problem, causing high output diarrhea leading to severe dehydration and shock in developing countries. We aimed to determine whether vasoactive intestinal polypeptide (VIP), the mediator of pancreatic cholera syndrome, has a role in the pathophysiology of human cholera. Methods: We conducted a prospective observational study of cholera cases hospitalized with severe dehydration. Plasma and stool water levels of VIP were measured just after admission, after complete rehydration (3–4 h), at 24 h post-rehydration and at discharge after diarrhea ceased. Results: In total, 23 cholera patients were examined between January and August 2018. The geometric mean of stool VIP (sVIP) and plasma VIP (pVIP) on admission were 207.67 and 8.34 pmol/L, respectively. pVIP values were all within the normal range (</= 30 pcmol/L); however, sVIP levels were very high at all timepoints, though less so just after rehydration. In multivariable GEE models, after adjustment for covariates, sVIP levels were significantly associated with duration of hospitalization (p = 0.026), total stool volume (p = 0.023) as well as stool output in the first 24 h (p = 0.013). Conclusions: The data suggest that VIP, which is released by intestinal nerves, may play an important role in human choleragenesis, and inhibitors of intestinal VIP merit testing for potential therapeutic benefits.

VIPomas

Vasoactive intestinal polypeptide (VIP) secreting tumours are rare neuroendocrine tumours. The associated syndrome was first described by Priest and Alexander in 1957. They reported a case that they thought to be a variant of the Zollinger–Ellison syndrome—a patient with an islet cell tumour associated with diarrhoea, peptic ulceration, and hypokalaemia (1). The following year, Verner and Morrison described a syndrome of profuse, refractory, watery diarrhoea with severe hypokalaemia and dehydration associated with a non-β‎-cell islet cell tumour (2). Historical terms for this syndrome have included ‘pancreatic cholera’ (as the diarrhoea is similar to the secretory diarrhoea observed in cholera) and the acronym WDHA (watery diarrhoea, hypokalaemia, and achlorhydria). However, these terms are inaccurate descriptions of a syndrome that can be associated with both extrapancreatic tumours and normal gastric acid secretion. In 1973, Bloom first connected the watery diarrhoea with an elevated plasma VIP level and an increased tumour content of VIP, suggesting the term ‘VIPoma syndrome’ (3). There followed a debate as to whether VIP was a marker for the syndrome or the causative agent for the diarrhoea. However, in 1983, Kane infused porcine VIP intravenously in healthy human subjects, achieving VIP levels similar to patients with VIPomas. Profuse watery diarrhoea developed within 4 h of infusion, providing evidence that VIP was indeed the mediator of the syndrome (4).