Vipoma syndrome

VIPoma Syndrome

GUENTER J. KREJS, M.D. Dallas,

Texas

From the Department of Internal Medicine, University of Texas Health Science Center at Dallas, Southwestern Medical School, Dallas, Texas. This work was supported by grants from the United States Public Health Service (MO-l -RR-00633) and from the Ruby D. Hexter Estate, Dallas, Texas. Requests for reprints should be addressed to Dr. Guenter J. Krejs, Department of Internal Medicine, Karl-Franzens University, Auenbruggerplatz 15, A-8036 Graz, Austria.

Since the description of the watery diarrhea syndrome by Verner and Morrison 29 years ago, clinical and experimental observations have elucidated the pathophysiology of this disease. Vasoactive intestinal polypeptide (VIP) is produced and released by a tumor of the pancreatic islets or by a tumor of neural crest origin such as a ganglioneuroma. Under normal conditions, current evidence suggests that VIP is a neurotransmitter in the central and peripheral nervous systems and particularly in the peptidergic nervous system. The low VIP plasma concentration observed in healthy subjects is viewed as a neuronal overflow since it has been impossible to ascertain any endocrine role for circulating VIP. Markedly elevated VIP plasma levels in the VlPoma syndrome lead to intestinal secretion with severe secretory diarrhea, resulting in hypovolemia, hypokalemia, and acidosis. These symptoms subside after successful tumor removal. Approximately 50 percent of patients have metastatic spread at the time of diagnosis. For these patients, a new and promising therapeutic modality is available in the form of a subcutaneously administered somatostatin analogue that relieves symptoms through potent inhibition of VIP release from tumor tissue. In 1957, Priest and Alexander [l] described a patient with islet-cell tumor and severe watery diarrhea and hypokalemia. The diarrhea responded to steroid therapy for a period of one year before it became intractable and resulted in the patient’s death. Just two years earlier, Zollinger and Ellison [2] had described the association of non-insulin-secreting islet-cell tumors of the pancreas with peptic ulceration, so this case was thought to be a variant of the Zollinger-Ellison syndrome. However, Verner and Morrison [3] of Duke University, North Carolina, first called attention to the syndrome of watery diarrhea, hypokalemia, and death from renal failure in association with islet-cell tumor. There are several synonyms for this syndrome (pancreatic cholera syndrome, Verner-Morrison syndrome, watery diarrhea, hypokalemia, hypochlorhydria syndrome, and VlPoma syndrome). The name pancreatic cholera was first used in a publication by Matsumoto and co-workers [4]. Pancreatic cholera syndrome is an appropriate name because the diarrhea results from intestinal secretion just as in Asiatic cholera; however, the term does not denote that some tumors are outside the pancreas. Bloom et al [5] first recognized that patients with this syndrome had elevated plasma levels and high tumor content of vasoactive intestinal polypeptide VIP.

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ON GASTROINTESTINAL

VASOACTIVE

INTESTINAL

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POLYPEPTIDE

In 1968, Said and Mutt [6,7] found that extracts of intestinal tissue, like lung tissue, contained vasoactive peptides. VIP was isolated in pure form in 1972 [8], and this was soon followed by elucidation of the amino acid sequence [9] and a report on the synthesis of VIP [lo]. VIP is a 28-amino-acid polypeptide with a molecular weight of 3,326. The amino acid sequence demonstrates similarities to those of secretin and glucagon [l I]. The concepts and understanding of the physiologic role of VIP have undergone considerable evolution in the past 19 years. Although VIP was initially characterized by Said and Mutt [6-81 as a vasoactive substance, it was later viewed as a candidate gastrointestinal hormone [12]. In 1976, when the peptide was demonstrated in neurons of the central and peripheral nervous systems, it soon became apparent that the major function of VIP may be that of a neuropeptide, neurotransmitter, or neuromodulator [13-161. VIP AND INTESTINAL

SECRETION

Makhlouf and Said [17] were the first to observe that VIP was capable of inducing intestinal secretion in dogs (their publication was, however, chronologically not the first to report intestinal secretion in response to VIP) [18]. Dogs equipped with Thiry-Vella loops of the proximal jejunum showed a dose-dependent increase in fluid secretion when VIP was given intravenously [17]. Numerous other investigators expanded these observations in both in vivo and in vitro models in different animal species (for a summary, see Table I in [19]). In canine experiments in our laboratory [20], we demonstrated active anion secretion in the small intestine in response to VIP. Water and ion secretion in perfused jejunal loops was associated with an increase in transmucosal potential difference. Chloride and bicarbonate were secreted against an electrochemical gradient. VIP-induced secretion was readily reversible when infusion of the peptide was discontinued. In vitro experiments have suggested that cyclic AMP is the second messenger mediating the secretory process induced by VIP [21-231. However, this view has recently been questioned when, in response to VIP, enterocytes were found to contain high concentrations of CAMP only at the villous tips and not in the crypts where secretion is believed to occur [24]. Other observations indicate that higher concentrations of VIP are needed to increase the CAMP concentration than to cause intestinal secretion, thus making the causal role of CAMP mediating VIP-induced secretion less clear [25,26]. VIPOMAS

After the first description of two cases by Verner and Morrison [3], the association of watery diarrhea and pancreatic tumor was discovered in other patients and led to the report of several series [27,28]. It was possible to distinguish these watery diarrhea 38

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cases from the cases in which diarrhea was caused by gastrinoma by the presence of low gastric acid secretion. It was clear that the mechanism of diarrhea was different in the two syndromes, since prevention of acid hypersecretion in patients with gastrinoma also abolished the diarrhea. In searching for a humoral mediator, Bloom et al (51 in 1973 found VIP-containing cells in tumor tissue as well as high VIP concentrations in the patients’ plasma [5]. Said and Faloona [29] confirmed these findings in 13 patients with pancreatic islet-cell tumor. Subsequently, there have been a number of case reports of this distinctly uncommon condition. At the University of Texas Health Science Center at Dallas, we have seen eight cases within the last 12 years [30-341. According to an Irish registry, gut endocrine tumors have a yearly incidence of 0.5 per 100,000 population. VlPomas can be expected at a yearly rate of one per 10 million population (Keith Buchanan, personal communication, 1986). CLINICAL

FEATURES

OF THE VIPOMA

SYNDROME

The key feature of the disease is large-volume secretory diarrhea, with only 30 percent of cases recorded as having less than 3 liters of stool per day [35]. Our own experience in seven adult patients is listed in Table I. In secretory diarrhea, stool water is isotonic to plasma, stool electrolytes account for all the osmolality, and diarrhea persists during a fasting period [36]. For practical purposes, a stool volume of less than 700 ml per day rules out the syndrome [37]. Large amounts of potassium and bicarbonate are lost in the stool, resulting in hypokalemia, acidosis, and volume depletion. Steatorrhea is usually not present. In the few patients that have been studied appropriately [30-34, 381, intestinal water and ion secretion has been demonstrated by perfusion studies. Other clinical features of the VlPoma syndrome are listed in Table II. Achlorhydria and hypochlorhydria are often but not always present. Among 43 patients reviewed by Verner and Morrison [28], only 14 had histamine-fast achlorhydria, whereas another 16 had hypochlorhydria. Since gastric mucosal biopsy specimens have invariably revealed normal parietal cells even in achlorhydric patients, and since gastric hyposecretion has been corrected by resection of diarrheageriic tumors [38], it is likely that the tumor releases a gastric inhibitor. Although VIP infusion inhibits pentagastrin- and meal-stimulated acid secretion in dogs [39,40], short-term experiments in humans failed to show any suppressive effect of VIP on pentagastrin-induced acid secretion [41]. The effect of VIP on meal-stimulated secretion is, however, not known in humans. The species differences of VIP’s action on gastric secretion are further emphasized by the observation that VIP stimulates acid and pepsin secretion in cats [42]. Hypercalcemia has been reported in 50 percent of cases [28], but the mechanism is not clear. There appears to be a negative calcium balance with increased bone re82 (suppl

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sorption [43]. In organ cultures, VIP stimulates bone resorption [44]. Tetany in patients with pancreatic cholera syndrome is thought to be due to hypomagnesemia and may occur in the presence of hypercalcemia. Flushing is occasionally observed in these patients. In our VIP infusion experiments in healthy subjects (see following), flushing was invariably observed [45]. Some patients have circulatory disturbances with hypotension due to peripheral vasodilation, and severe hypertension may develop after tumor removal [46]. Glucose intolerance is also observed in about 50 percent of patients with the VlPoma syndrome. The diabetogenie effect of the secreted agent is also suggested by the observation that operative manipulation of the pancreatic tumor resulted in pronounced hyperglycemia in one patient [47]. In patients with the VlPoma syndrome, a family history of the disease is usually absent. However, the report of a father with multiple islet-cell adenomas and ZollingerEllison syndrome and his son with VlPoma syndrome and a parathyroid adenoma suggests that VIP-producing tumors may occur as part of the multiple endocrine neoplasia type I syndrome [48].

TABLE I

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Stool Weights in Seven Patients with Pancreatic Cholera Syndrome* StoolWeight (g psr day)

PatientNumber

*Patients University

Regular

Fasting

Diet

1 2 3 4 5 8 7

9,000 5,500 2,350 3,800 3,722 3,321 1,875

3,350 1,800 1,720 1,300 2,034 1,482 1,050

Mean

4,224

1,817

were studied at the General Clinical Research Center of the of Texas Health Science Center at Dallas, Dallas, Texas.

TABLE II

VlPoma Svndrome: Clinical Presentation Constant features Diarrhea Hypovolemia Acidosis Hypokalemia Variable features Achlorhydria or hypochlorhydria Hypercalcemia Hypomagnesemia Enlarged gallbladder Myopathy or nephropathy (hypokalemic) Rash Flushing Hyperglycemia Lacrimal gland hypersecretion and excessive tearing

VARIANTS OF VIPOMA SYNDROME Islet-Cell Hyperplasia. In Verner and Morrison’s [28] own later series, several patients without pancreatic tumor were included. It was stated that 20 percent of cases have islet-cell hyperplasia. In Said’s [49] series, 14 percent of patients with watery diarrhea syndrome had islet-cell hyperplasia. Several experts in the field refuse to accept pancreatic islet-cell hyperplasia as part of the spectrum of the VlPoma syndrome. Bloom and Polak [50] did not find elevated plasma VIP levels in any patient with islet-cell hyperplasia, and J. Fahrenkrug (Copenhagen, Denmark, personal communication) doubts that this combination exists. Many of the reports about such cases are difficult to interpret since the diagnosis of islet-cell hyperplasia is always poorly documented. A morphometric or other quantitative approach has not been used, and the diagnosis is based on the subjective judgement of a pathologist. A further problem arises from the fact that in the early days of the VIP radioimmunoassay, false-positive results were not uncommon. For instance, Said [51] had cautioned about the interpretation of plasma VIP levels since two of 25 healthy control subjects had elevated VIP levels at that time. I believe that it is open to question whether such an entity as islet-cell hyperplasia causing elevation of plasma VIP concentration really exists. VIP is not contained in normal pancreatic islet cells, and hyperplasia of these cells should not lead to VIP production unless a tumor (adenoma or carcinoma) is already present. High plasma VIP levels and life-threatening diarrhea can be present in infants with nesidioblastosis, but this disease represents microadenoma and not just islet-cell hyperplasia. Likewise, in adults, the disease has to be reclassified

ON GASTROINTESTINAL

as islet microadenomatosis or carcinomatosis, when watery diarrhea disappears after resection of a pancreas that contains enlarged islets with invasive features and VIPpositive cells on immunohistochemistry [52]. Ganglioneuroma, Neuroblastoma, Neuroflbroma, and Pheochromocytoma. Neural crest tumors are the fourth most common type of neoplasm in the pediatric age group (8 percent of cancers that develop before the age of 15) [53]. Many of these tumors secrete catecholamines that do not cause diarrhea (hypertension, flushing, fever). However, nearly 30 cases have now been described in which diarrhea was the presenting symptom. In these children, high circulating levels of VIP were found, the ganglioneuromas or neuroblastomas were shown to contain the peptide (immunofluorescence and tissue extract), and the diarrhea resolved after tumor removal [54-561. Secretory diarrhea and high plasma VIP concentration have also been found in a child with neurofibromatosis [571. Pheochromocytomas rarely cause diarrhea [58]. VIP production and release by such tumors has been demonstrated in rare cases that are indeed associated with diarrhea [59]. Since the adrenal medulla is of neural-crest oriThe American

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gin [60], it is not at all surprising that a tumor of this organ would be capable of producing a neurotransmitter such as VIP. A case of cutaneous mastocytoma secreting VIP has been reported in an eight-month-old child. The child did not have diarrhea, but had generalized flushing and apnea that may have been related to manipulation of the tumor [61]. VIP in Other Diseases. Mild plasma VIP elevations are found in patients with hepatic failure [62,63] and probably result from decreased peptide metabolism by the failing liver. In dogs with hepatic failure, a high VIP concentration can be found in cerebrospinal fluid, suggesting increased central nervous system release of VIP in the encephalopathic state [64]. VIP is also released during intestinal ischemia in experimental animals [65,66]. It is unknown whether this observation has any clinical relevance (such as impainent of the cardiovascular condition by VIP in such patients). In the report by Said and Faloona [29], six patients with primary bronchial carcinoma and watery diarrhea were described (five patients with high levels of VIP in the plasma). Although the combination of watery diarrhea and lung cancer has been observed by others [671, it has been questioned whether the VlPoma syndrome exists in association with bronchogenic carcinoma [37]. Such cases have not been seen in other large series [50,68]. On the other hand, since VIP is found in autonomic nerves of the lung [69], it is not surprising that some bronchogenic carcinomas may contain VIP. VIP AS MEDIATOR SYNDROME

OF PANCREATIC

CHOLERA

VIP appears to be the major mediator of this syndrome. However, a lively discussion on this question has continued until very recently [70,71]. The controversy had several reasons: 1. Not all patients with pancreatic islet-cell tumor and watery diarrhea have elevated plasma VIP levels. For instance, in the series of Ebeid and co-workers [72], only one of three patients had a high VIP concentration. 2. High VIP levels were reported in healthy subjects [29] and were found in other patients with diarrhea such as chronic laxative abusers [30]. However, re-analysis with an improved assay of some of the samples previously reported to have high VIP concentrations yielded normal results [73,74]. 3. Many of the pancreatic VlPomas produce other peptides. Levels of pancreatic polypeptide (PP) may be elevated in 75 percent of patients with islet-cell tumors [75]. In experimental animals, PP does not have a secretagogue effect on the intestine [76]. There is, however, at least one well-documented case in which the watery diarrhea syndrome was attributed to a PPoma [77] and one case of islet-cell hyperplasia exclusively composed of PP

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cells [78]. Neurotensin production has also been shown in VIPomas, resulting in high plasma concentrations of the peptide in such patients [79]. Occasionally, tumors produce gastrin, glucagon, insulin, and somatostatin [80,81]. Of interest is the association of calcitonin production with islet-cell tumors. Patients with VlPoma may have associated hypercalcitoninemia [31]. Since calcitonin itself is an established intestinal secretagogue [82,83], secretory diarrhea may be due in part to a high circulating concentration of this peptide. Furthermore, since indomethacin provides successful treatment in single cases [84], it is possible that prostaglandins may have a role in causing diarrhea in this syndrome [85]. Elevated levels of helodermin, first found in the venom of the gila monster [86,871, and peptide 7B2, a possible islet-cell growth factor, have also been found in plasma and tumor tissue of patients with VlPoma (Stephen Ft. Bloom, personal communication, 1986). Co-secretion of peptide histidine methionine (PHM), the human counterpart of peptide histidine isoleucine (PHI), has been found in patients with VIPomas. PHM concentration is high in plasma, and both VIP and PHM are present in the same tumor cells as indicated by immunocytochemistry [EE]. Peptide histidine methionine and peptide histidine isoleucine have effects on intestinal mucosa similar to those of VIP, but as secretagogues are 32 times less potent than VIP [89]. Peptide histidine methionine and VIP are peptides that have been cleaved from the same large molecular precursor, pre-pro VIP [go]. The evidence for VIP as the responsible secretagogue for pancreatic cholera syndrome comes from the following: (1) the fact that many of the symptoms in the VlPoma syndrome can be explained by the biologic action of VIP observed in experimental animals [91]; (2) clinical observations in patients with high circulating levels of VIP prior to removal of a tumor and normal VIP levels after surgery, with disappearance of the diarrhea [30,92]; and (3) VIP infusion experiments in humans carried out in our iaboratory showed intestinal water and ion movement changing from absorption to secretion while VIP plasma levels were achieved that were comparable to VIP concentrations in patients with the VlPoma syndrome [19,93]. Moreover, the syndrome can be mimicked in healthy subjects by prolonged (10 hours) VIP infusion (400 pmol/ kg/hour). Watery diarrhea (2.4 liters/IO hours) and metabolic acidosis [94,95] developed in all subjects. DIAGNOSIS

OF VIPOMA

SYNDROME

Analysis. Stool volumes are usually in excess of 1 liter per day, and diarrhea persists during fasting periods [30]; stool osmolality is equal to that of plasma, and stool electrolytes account for all the osmolality of stool water ([sodium + potassium] x 2 = measured osmolality) [36]. The osmotic gap may even be negative because of the

Stool

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1978 x

l

.

200aa : :

:. . .

tEJ=OPO~ED4OO- 7 i

-

-

-

-..-.W

-

‘i!Y

NORMAL

, Figure 7. Basal plasma 4fP levels from c&trol periods prior to VIP infusion in experiments described in [19] and [93], expressed as percentage of the upper limit of normal reported by the individual laboratories: A, Thomas M. O’Dorisio, Columbus, Ohio; 8, John H. Walsh, Los Angeles, California; C, Sarni 1. Said, Dallas, Texas (after 1980, OFlahoma City, Oklahoma); D, Jan Fahren rug and Ove B. Schaffalitzky de Muck+ 8 ell, Copenhagen, Denmark; E, Josef !Fischer and Richard F. Murphy, Bost 4, Massachusetts (after 1979, Cincih, R $i, Ohio); F, Stephen R. Bloom, LonTn, England. lop, the results from the Dapember 1978 shipment of plasma samples; bottom, results from the March 197$, shipment. In four of six laboratories, 10 $I 33 percent of basal samples from healthy control subjects were above the reported upper limit of normal (“false positive”).

Laboratory

A

B

C

D

E

F

1979 l 5c7 #

K t 200-

. . .

R\~~~-‘m

- i

f

I Labomtory A

well-recognized phenometion that for pure electrolyte solutions the measured o&olality may be less than the value calculated from the’lonic constituents. Stool pH is often as high as 8.0 due to, colonic bicarbonate secretion. Search for Tumor. In sc++rchingfor a pancreatic or retroperitoneal tumor (ganglion@roma) sonography, computer tomographic scanning, nublear magnetic resonance, and angiography can be used./ If a liver-spleen scan, or any of the other imaging procedures, suggests liver metastases, then peritoneoscopy should be performed to obtain tumor tissue. In addition to a regular histologic examination, immunocytochemical and ; immunofluorescence studies allow identification of thei peptides that are contained in the secretory granules se+! on electron microscopy [98]. For these special studies, tissue specimens must be fixed in Bouin’s solution. Surgeons must particularly be aware

May 29, 1987

. 0.9 -...

&

‘iv NORMAL

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1 B

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f

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P

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I C

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7-

-:-

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F

of using this fixative, since they may unexpectedly encounter islet-cell tumors at laparotomy. The tissue specimens are also frozen in liquid nitrogen to allow radioimmunoassay of tissue extracts for peptide content to be performed. Plasma Levels of intestinal Secretagogues. The radioimmunoassay for VIP is certainly one of the more difficult assays. Particularly in the mid-1970s, technical imperfection with some of the assays had led to false-positive results. Subsequently, some patients had unnecessary exploratory laparotomy or partial pancreatectomy [30]. The VIP assay, like virtually all other radioimmunoassays, does not measure the concentration of VIP in plasma directly. The assay measures the ability of a patient’s plasma to inhibit binding of [1251]VlPby an antibody. A plasma concentration of 500 pmol/liter actually means

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198V 1982 % 200-

REPORTED-tlOO-

-

-

-

7

-

-

YE: NOKIL

j&&g I

Laboratory

A

#$I#& I

6

C

D

that the plasma sample inhibited antibody binding of [‘251]VIP to the same extent as 500 pmol/liter of native VIP. One key question is what substance besides VIP can inhibit binding of [1251]VIPor how specific is the assay? By now, all major VIP-radioimmunoassay laboratories have published information on the specificity of their assays [14,97]. It appears that the assays have been refined to such a degree that they provide reliable information. It must be kept in mind, however, that even an extremely low false-positive or false-negative rate would severely diminish the value of such an assay since the VlPoma syndrome is such a rare disease, whereas chronic diarrhea is common. We have assessed the validity of six currently available radioimmunoassays by sending the laboratories coded plasma samples from VIP infusion experiments and control samples from the same subjects before VIP infusion was begun. This validation and comparison of laboratories was performed three times, namely in 1978, 1979, and 1981. When we looked at the basal samples prior to VIP infusion, only two laboratories had consistently reported normal results (Jan Fahrenkrug and Ove B. Schaffalitzky de Muckadell, Copenhagen, Denmark; and J. Fischer and R. F. Murphy, Cincinnati, Ohio). All other laboratories “read” 10 to 33 percent of samples analyzed in 1978 and 1979 above the upper limit of normal reported for the individual laboratory. Furthermore, the assay in some laboratories fluctuated markedly between 1978 and 1979. In 1981 (and 1982 for Dr. Sami Said’s laboratory), all laboratories reported low values in all control samples and high values during VIP infusion [93] (Figures 1 and 2). Thus, for 1981 (and 1982, respectively), we can report that highly reliable radioimmunoassays for VIP are available in the following laboratories: Stephen R. Bloom, Lon-

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E

F

Figure 2. Shipment of additional samples in coded fashion to the six VIP radioimmunoassay laboratories described in the legend of Figure 1. Due to improvement of assays, all laboratories now show basal values for healthy control subjects below the upper limit of normal established for the individual laboratories. Only laboratory D had no “false-positive” results when tested on three occasions (Figure 1). Laboratory E had no falsepositive results at the first and last test, whereas results from the second shipment were not available due to relocation of that laboratory at that time (Figure 1).

don, England; Jan Fahrenkrug and Ove 8. Schaffalitzky de Muckadell, Copenhagen, Denmark; Thomas M. O’Dorisio, Columbus, Ohio; Sami I. Said, Dallas, Texas (since 1981, Oklahoma City, Oklahoma); Josef Fischer and Richard F. Murphy, Cincinnati, Ohio; and John H. Walsh, Los Angeles, California. The accuracy of a commercially available assay (BIO ASSAY Laboratories, Columbus, Ohio) is monitored by Dr. Thomas M. O’Dorisio’s laboratory. In search for other secretagogues, we routinely have plasma assayed for calcitonin and peptide histidine methionine. Since many of the pancreatic islet-cell tumors contain other peptides, such agents may serve as markers of endocrine pancreatic malignancy. Therefore, we also obtain radioimmunoassay results on our patients’ plasma for pancreatic polypeptide, glucagon, insulin, gastrin, neurotensin, somatostatin, gastric inhibitory polypeptide, motilin, and secretin. Such gastrointestinal hormone profiles can be obtained on a single plasma sample in the laboratories of Dr. Thomas M. O’Dorisio, Columbus, Ohio, or Dr. Stephen R. Bloom, London, England. In order to send samples, blood needs to be drawn in tubes on ice containing EDTA with aprotinin added to inhibit serum peptidases (aprotinin, Trasylol, 0.5 ml [5,000 kallikrein inactivator units] per 10 ml of blood). After immediate centrifugation in a refrigerated centrifuge, plasma is stored at -25°C or lower until sent in a frozen state on dry ice to the radioimmunoassay laboratory. Due to the limited availability of radioimmunoassays for helodermin and peptide 7B2, we have not yet been able to routinely test the plasma of patients with suspected or proven VlPoma syn- ,. drome. Some investigators have reported that selective venous sampling with anatomic mapping of peptide concentration may be helpful in the workup of patients with biologically

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active islet-cell tumors [98]. Although we have not utilized this method, we doubt that the benefit outweighs the invasiveness of the procedure as well as the fact that it is technically very difficult to perform. The venous sampling procedure can also be misleading, since abnormal tumor veins can drain in an unexpected direction, resulting in erroneous conclusions about tumor location. Intestinal Perfusion Studies. When available, intestinal perfusion studies may be helpful in the differential diagnosis of secretory diarrhea. Net luminal gain of water and electrolytes (secretion) can be demonstrated in segments of perfused small bowel (absorption in a control group) [30,31,38]. This method is particularly helpful in differentiating surreptitious laxative ingestion from VfPoma syndrome. Perfusion studies show normal results in laxative abusers [30,31].

Synonyms for this condition are pseudo-Verner-Morrison syndrome, pseudo-pancreatic cholera, and chronic idiopathic secretory diarrhea. By our arbitrary definition, these patients have had diarrhea for more than four weeks, the stool volume must be more than 750 g/24 hours, fecal analysis must be typical for secretory diarrhea, the diarrhea must persist during a period of fasting, surreptitious laxative ingestion must be ruled out, and there must be no evidence of the diseases that are known to cause chronic secretory diarrhea [36]. In many instances, the patients will have had no abnormal findings on exploratory laparotomy. Although some of our patients had elevated serum concentrations of VIP on one occasion, this probably represented laboratory errors as the assays were being perfected. Recently, all patients we have classified in this category have had normal serum concentrations of VIP and calcitonin. The pathophysiology of this syndrome has not been studied extensively except in a few patients. In these, reduced absorption or intestinal secretion has been noted by segmental perfusion of the small and/or large intestine [99]. By definition, of course, the cause of these abnormalities is unknown; abnormal neuroendocrine function that was not tested or an undiscovered chronic infection are two possibilities. It seems unlikely that this syndrome could be caused by deranged intestinal motility, but this possibility has not been adequately studied. Crude clinical tests of transit time have not suggested a motility disturbance in any of our patients. The severity of this syndrome varies widely. The prognosis is also highly variable. Some patients have seemingly endless severe chronic diarrhea, some have persistent diarrhea of moderate severity, and still others have a complete resolution of diarrhea after several months to a few years. Some patients gain remarkable benefits from opiate therapy. We have administered prednisone to several patients (the ones with a more severe condition), in doses of 60 to 80 mg per day, with a

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benefit seen in only one of five patients. One of our patients died and results of the autopsy were negative. Decisions about angiography and laparotomy in these patients are difficult. We would tend to perform these procedures in patients with more severe diarrhea, and to avoid them in patients with less severe diarrhea. We do not advocate reversal of segments of small intestine, but we do seriously consider (in patients in whom intravenous fluids are required) insertion of a jejunostomy feeding tube that can subsequently be used for infusion of glucosecontaining electrolyte solutions. It is important to recognize that patients may have severe secretory diarrhea that mimics most, if not all, of the clinical features of the VlPoma syndrome, and yet have no evidence of an endocrine tumor, surreptitious laxative ingestion, or of any other known cause of secretory diarrhea. This syndrome is much more common than VlPoma syndrome itself. The prognosis is variable, from a severe but self-limited illness of six weeks to a severe protracted illness that may last years and end fatally. Verner and Morrison [28] have recommended that if all diagnostic measures (including laparotomy) fail to reveal an endocrine tumor in patients with chronic severe diarrhea, at least 75 percent of the pancreas should be resected. The rationale behind this suggestion is that the cause of the diarrhea may be microadenomatosis of the pancreatic islets rather than an overt neoplasm, and that if the pancreas is left unresected, microadenomas might develop into islet-cell cancers. However, this progression has never been clearly documented. In three of our patients, pancreatic resection had no influence on the diarrhea [36]. Furthermore, the spontaneous remissions noted in some patients [99] suggest that some of the good responses to partial pancreatectomy [26] may have been fortuitous. On the basis of our experience with pancreatic cholera syndrome and chronic secretory diarrhea of unknown origin [99], we would suggest the following scheme of management in patients with large-volume (1 liter per day or more) and chronic (longer than four weeks) secretory diarrhea, but with no evidence of laxative ingestion or of an endocrine tumor by radiologic or sonographic techniques. If the plasma concentrations of endocrine tumor markers (VIP, calcitonin, pancreatic polypeptide) are normal or only mildly and inconsistently elevated, we would recommend treatment with nonspecific remedies such as oplates for a period of up to six months. Only if there is no adequate response to these remedies or if severe diarrhea recurs when symptomatic therapy is withdrawn at six months should exploratory laparotomy be performed. On the other hand, if the plasma concentration of endocrine tumor markers is consistently and definitely elevated, it seems reasonable to carry out exploratory laparotomy regardless of the response to nonspecific medical therapy. If a tumor is not found at surgery, then our tentative

PSEUDO-VIPOMA SYNDROME

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recommendation would be to do a “blind” distal pancreatectomy only in those patients in whom preoperative plasma concentrations of endocrine tumor markers were markedly and repeatedly elevated. NATURAL

HISTORY

OF VIPOMAS

The average duration of symptoms in the VlPoma syndrome is three years prior to diagnosis [271, and may range from two months to four years [loo]. Metastases (liver, lymph nodes) are present in 50 percent of patients at the time of diagnosis. Death occurs from renal failure or cardiac arrest in the setting of water and salt depletion and acidosis. The length of survival in patients with islet-cell tumors used to be less than one year from the time of diagnosis [l 01,102]. It appears that a better understanding of the pathophysiology, resulting in a better treatment design, and the introduction of cytotoxic chemotherapy have markedly improved the survival time. In our own series of eight patients, we have achieved two cures. Two other patients’ conditions are stable two and three years after diagnosis, with remaining tumor being treated with the somatostatin analogue. TREATMENT

The most effective method of treating a VlPoma is total excision. Unfortunately, this is often not possible either because of metastases or because of the fact that a benign tumor has grown too large and involves vital structures. Approximately half of the pancreatic tumors are re-

sectable, with the other half having evidence of metastases at the time of diagnosis. Debulking of the tumor may be beneficial, and hepatic arterial embolization may be applicable in the setting of liver metastases. Ligation of the hepatic artery is unsuccessful due to formation of anastomoses. Slow embolization with fine particles first followed by larger particles seems to damage the metastases while liver function remains unimpaired (metastases seem to rely on an arterial source of perfusion) [loo]. VlPomas are often sensitive to streptozocin (streptozotocin). The remission rate is higher than 90 percent and may last for years [102-1061. Dacarbazine and 5-fluorouracil have also been found effective [107]. Individual case reports have suggested that indomethatin [106], lithium carbonate [log], trifluoperazine [l lo], phosphate buffer [92], clonidine [l 111, metoclopramide [112], loperamide [113], and steroids [31] may stop or lessen the severity of the diarrhea. Of interest is the observation that somatostatin is capable of inhibiting pathologic secretion in the human intestine [114]. Ruskone et al [115] were the first to show a beneficial effect of native somatostatin in a patient with VlPoma syndrome. Domiciliary subcutaneous use of the somatostatin analogue (SMS 201-995) has now been successfully employed in a series of patients [33,34,1161 161, and in some there was a suggestion of tumor mass regression after use of the analogue for several months [33,117]. Whether newly developed VIP antagonists may have therapeutic potential is not known at this time [119,120].

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WM: Vasoactive intestinal peptide secreting tumors of childhood. Am J Dis Child 1980; 134: 21-24. Carson DJ, Glasgow JFT, Ardill J: Watery diarrhoea and elevated vasoactive intestinal polypeptide associated with a massive neurofibroma in early childhood. J Royal Sot Med 1980; 73: 89-72. Loehry CA, Kingham JG, Whorwell PJ: Watery diarrhea and hypokalaemia associated with phaeochromocytoma. Postgrad Med J 1975; 51: 416-419. Cooperman AM, Desantis D, Winkelmann, E, Farmer R, Eversman J, Said SI: Watery diarrhea syndrome. Two unusual cases and further evidence that VIP is a humoral mediator. Ann Surg 1978; 187: 325-328. Pearse PGE, Polak JM: The diffuse neuroendocrine system and the APUD concept. In: Bloom SR, ed. Gut hormones, 1st ed. Edinburgh: Churchill-Livingstone, 1978; 33-39. Weslev JR Vinik Al. O’Dorisio TM. Glaser B. Fink A: A new syndrome.of symptomatic cutaneous mastocytoma producing vasoactive intestinal polypeptide. Gastroenterology 1982; 82: 963-967. Hunt S, Vaamonde CA, Rattassi T, Berian MG, Said SI, Papper S: Circulating levels of vasoactive intestinal polypeptide in liver disease. Arch Intern Med 1979; 139: 994-996. Henriksen JH, Staun-Olsen P, Fahrenkrug J, Ring-Larsen H: Vasoactive intestinal polypeptide (VIP) in cirrhosis: arteriovenous extraction in different vascular beds. Stand J Gastroenterol 1980; 15: 787-792. Ebeid AM, Smith A, Escourrou J, Murray MS, Fischer JE: Increased immunoreactive vasoactive intestinal peptide in the cerebrospinal fluid (CSF) of dogs and monkeys in hepatic failure. J Surg Res 1978; 25: 538-541. Modlin IM, Bloom SR, Mitchell S: Plasma vasoactive intestinal polypeptide (VIP) levels and intestinal ischaemia. Experientia 1978; 34: 535-536. Bateson PG, Buchanan KD, Parks TG: Massive release of vasoactive intestinal peptide during prolonged intestinal ischaemia (abstr). Eur Surg Res 1980; 12: 87. Luey K, Scobie BA: Watery diarrhoea (WDHA) syndrome associated with carcinoma of the lung. Aust NZ J Med 1976; 6: 490-491. Fahrenkrug J, Schaffalitzky de Muckadell OB: Verner-Morrison syndrome and vasoactive intestinal polypeptide (VIP). Stand J Gastroenterol 1979; 14: 57-60. Dey RD, Shannon WA, Said SI: Localization of VIP-immunoreactive nerves in airways and pulmonary vessels of dogs, cats, and human subjects. Cell Tissue Res 1981; 220: 231238. Ginsberg AL: The VIP controversy. Stephen R. Bloom vs. Jerry D. Gardner. Dig Dis 1978; 23: 370-376. Unwin RJ, Calam J, Peart WS: VlPoma and watery diarrhea. N Engl J Med 1982; 307: 377-378. Ebeid AM, Murry P, Hirsch H, Wesdrop RIG, Fischer JE: Radioimmunoassay of vasoactive intestinal peptide. J Surg Res 1976; 20: 355-360. Said SI: Author’s reply re: intractable diarrhea. Gastroenterology 1978; 75: 153. Said SI: Vasoactive intestinal polypeptide (VIP) as a mediator of the watery diarrhea syndrome. World J Surg 1979; 3: 559563. Polak JM, Bloom SR, Adrian TE, Heitz P, Bryant MG, Pearse AGE: Pancreatic polypeptide in insulinomas, gastrinomas, VlPomas and glucagonomas. Lancet 1976; I: 328-330. Wu ZC, O’Dorisio TM, Cataland S, Mekhjian HS, Gaginella TS: The effects of pancreatic polypeptide and vasoactive intestinal polypeptide on rat ileal and colonic fluid transport, in vivo. J Dig Dls Sci 1979; 24: 625-630. Lundqvist G, Krause U, Larsson LI, et al: A pancreatic polypeptide-producing tumour associated with the WDHA syndrome. Stand J Gastroenterol 1978; 13: 715-718. Tomita T, Kimmel JR, Friesen SR, Mantz FA: Pancreatic poly-

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peptide cell hyperplasia with and without watery diarrhea syndrome. J Surg Oncol 1980; 14: 11-20. Blackburn AM, Bryant MG, Adrian TE, Bloom SR: Pancreatic tumours produce neurotensih. J Clin Endocrinol Metab 1981; 52: 820-822. Long RG, Bryant MG, Mitchell SJ, Adrian TE, Polak JM, Bloom SR: Clinicopathological study of pancreatic and ganglioneuroblastoma tumours secreting vasoactive intestinal polypeptide (VIPomas). Br Med J 1981; 282: 1767-1771. Long RG, Bryant MG, Yuille PM, Polak JM, Bloom SR: Mixed pancreatic apudoma with symptoms of excess vasoactive intestinal polypeptide and insulin: improvement of diarrhoea with metoclopramide. Gut 1981; 22: 505-511. Gray TK, Bieberdorl FA, Fordtran JS: Thyrocalcitonin and the jejunal absorption of calcium, water, and electrolytes in normal subjects. J Clin Invest 1973; 52: 3084-3088. Gray TK, Brannan P, Juan D, Morawski SG, Fordtran JS: Ion transport changes during calcitonin-induced intestinal secretion in man. Gastroenterology 1976; 71: 392-398. Jaffe BM, Kopen DF, DeSchryver-Kecskemeti K, Gingerich RL, Greider M: Indomethacin-responsive pancreatic cholera. N Engl J Med 1977; 297: 817-821. Rask-Madsen J, Bukhave K: Prostaglandins and chronic diarrhoea: clinical aspects. Stand J Gastroenterol 1979; 14: 7378. Naruse S, Yasui A, Kishida S, et al: Helodermin: synthesis, existence, and biological actions in mammals. Can J Physiol Pharmacol, Supplementum Gastrointestinal Hormones 1986: 23. Christophe J, Robberecht P, Cauvin A, et al: Mammalian and lizard helodermin and helodermin-like peptides, new members of the vasoactive intestinal peptide-peptide histidine isoleucine-secretin family. Can J Physiol Pharmacol, Supplementum Gastrointestinal Hormones 1986: 28. Bloom SR, Christofides ND, Delamarter J, et al: Diarrhoea in VlPoma patients associated with cosecretion of a second active peptide (peptide histidine isoleucine) explained by single coding gene. Lancet 1983; II: 1163-l 165. Krejs GJ: Comparison of the effect of VIP and PHI on water and ion movement in the canine jejunum in vivo. Gastroenterol Clin Biol 1984; 8: 868. Dimaline R, Vowles L: Alternative processing pathways for preprovasoactive intestinal peptide in stomach and intestine of man and rat. Can J Physiol Pharmacol, Supplementum Gastrointestinal Hormones 1986: 148. Said SI: VIP overview. In: Bloom SR, Polak JM, eds. Gut hormones, 2nd ed. Edinburgh: Churchill Livingstone, 1981; 379-384. VanDyk D, lnbal A, Kraus L, Grifel B, Ravid M: The watery diarrhea syndrome with hypercalcemia-a symptomatic response to phosphate buffer. Hepatogastroenterology 1981; 28: 58-59. Krejs GJ, Fordtran JS, Bloom SR, et al: Effect of VIP infusion on water and ion transport in the human jejunum. Gastroenterology 1980; 78: 722-727. Kane MG, O’Dorisio TM, Krejs GJ: Intravenous VIP infusion causes secretory diarrhea in man. N Engl J Med 1983; 309: 1482-l 485. Krejs GJ, Kane MG, O’Dorisio TM: VIP and the pancreatic cholera syndrome. N Engl J Med 1984; 310: 1465-1466. Krejs GJ, Orci L, Conlon JM, et al: Somatostatinoma syndrome: biochemical, morphological and clinical features. N Engl J Med 1979; 301: 285-292. Pandian MR, Horvat A, Said SI: Radioimmunoassay of VIP in blood and tissues. In: Said SI, ed. Vasoactive intestinal peptide. New York: Raven Press, 1982; 35-50. Kingham JGC, Dick R, Bloom SR, Frankel RJ: VIPoma: localisation by percutaneous transhepatic portal venous sampling. Br Med J 1978; 2: 1682-1883. Read NW, Read MG, Krejs GJ, Hendler RS, Davis G, Fordtran

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JS: A report of five patients with large-volume secretory diarrhea but no evidence of endocrine tumor or laxative abuse. Dig Dis Sci 1982; 27: 192-201. Bloom SR, Polak JM: VIPomas. In: Said SI, ed. Vasoactive intestinal peptide. New York: Raven Press, 1982; 457-468. Schein PS, DeLellis RA, Kahn CR, Gorden P, Kraft AR: Islet cell tumors: current concepts and management. Ann Intern Med 1973; 79: 239-257. Kahn CR, Levy AG, Gardner JD, Miller JV, Gordon P, Schein PS: Pancreatic cholera: beneficial effects of treatment with streptozotocin. N Engl J Med 1975; 292; 941-945. Charleux H: Syndrome de Verner Morrison, cholera endocrine au vipome? La Nouv Presse Med 1982; 11: 859-862. Gage1 RF, Constanza ME, Delellis RA, et al: Streptozotocin treated Verner-Morrison syndrome. Plasma vasoactive intestinal peptide and tumour responses. Arch Intern Med 1976; 136: 1429-1435. Obert K, Bostrom H, Fahrenkrug J, et al: Streptozotocin treatment of a pancreatic tumour producing VIP and gastrin associated with Verner-Morrison syndrome. Acta Med Stand 1979; 206: 223-227. Broder LE, Carter SK: Pancreatic islet cell carcinoma. II. Results of therapy with streptozotocin in 52 patients. Ann Intern Med 1973; 79: 108-118. Moertel CG, Hanley JA, Johnson LA: Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. N Engl J Med 1980; 303: 1189-l 194. Powell DW, Field M: Pharmacological approaches to treatment of secretory diarrhea. In: Field M, Fordtran JS, Schultz SG, ed. Secretory diarrhea. Baltimore: Waverly Press, 1980; 187-209. Pandol SJ, Korman LY, McCarthy DM, Gardner JD: Beneficial effect of oral lithium carbonate in the treatment of pancreatic cholera syndrome. N Engl J Med 1980; 302: 1403-l 404. Donowitz M, Elta G, Bloom SR, Nathanson L: Trifluoperazine reversal of secretory diarrhoea in pancreatic cholera. Ann Intern Med 1980; 93: 283-285.

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McArthur KE, Anderson DS, Durbin TE, Orloff MJ, Dharmsathaphorn K: Clonidine and lidamidine to inhibit watery diarrhea in a patient with lung cancer. Ann Intern Med 1982; 96: 323-325. Seif FJ, Sadowski P, Heni F, Fischer R, Bloom SR, Polak JM: Das vasoaktive intestinale Polypeptide Beim Verner-Morrison Syndrom. Dtsch Med Wochenschr 1975; 100: 399. Yamashiro Y, Yamamoto K, Sato M: Loperamide therapy in a child with VIPoma-associated diarrhoea. Lancet 1982; I: 1413. Krejs GJ: Peptidergic control of intestinal secretion-studies in man. In: Bloom SR, Polak JM, eds. Gut hormones, 2nd ed. Edinburgh: Churchill Livingstone, 1981; 516-520. Ruskone A, Rene E, Chayvialle JA, et al: Effect of somatostatin on diarrhea and small intestinal water and electrolyte transport in a patient with pancreatic cholera. Dig Dis Sci 1982; 27: 459-466. Maton P, O’Dorisio TM, Howe BA, et al: Effect of a long-acting somatostatin analogue (SMS 201-995) in a patient with pancreatic cholera. N Engl J Med 1985; 312: 17-21. Kraezlin ME, Ch’ng JLC, Wood SM, Carr DH, Bloom SR: Longterm treatment of a VlPoma with somatostatin analogue resulting in remission of symptoms and possible shrinkage of metastases. Gastroenterology 1985; 88: 185-l 87. Edwards CA, Cann PA, Read NW, Holdsworth CD: The effect of somatostatin analog SMS 201-995 on fluid and electrolyte transport in a patient with secretory diarrhoea. Stand J Gastroenterol 1986; 21 (suppl) 119: 259-261. Waelbroeck M, Robberecht P, Coy DH, Camus J-C, DeNeef P, Christophe J: Interaction of growth hormone-releasing factor (GRF) and 14 GRF analogs with vasoactive intestinal peptide (VIP) receptors of rat pancreas. Discovery of (N-AcTyr’,D-Phe*-(1 -29)ONH2 as a VIP antagonist. Endocrinology 1985; 116: 2643-2649. Pandol SJ, Dharmsathaphorn K, Schoeffield MS, Vale W, Rivier J: Vasoactive intestinal peptide receptor antagonist (4CI-D-Phe’,Leu”)VIP. Am J Physiol 1986; 250: G553G557.

Discussion Dr. Stephen R. Bloom: From a clinical viewpoint, we have not found the same degree of correlation as you have between improvement in diarrhea with SMS 201-995 and the suppression of plasma VIP concentrations. We often find that although plasma VIP levels do not decrease substantially, the diarrhea stops. So clinically, SMS 201995 appears to act indirectly on the gut as well as on the output of VIP. One explanation for this may be that the output shifts from active molecular forms to inactive molecular forms. The plasma concentration of PHM is five times higher than that of VIP in patients with VIPoma. Although PHM may be less active, it has a much longer half-life. PHM may play a more important role, depending on whether the ratio of VIP action to PHM action is as high in humans as in your experimental dog preparation. Dr. Guenter J. Krejs: We have studied two patients receiving SMS 201-995 and one given native somatostatin.

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In all three, we could explain observed changes in intestinal transport by the reduction in plasma VIP levels. This is based on a dose-response curve of VIP infusion and water and ion transport in the small intestine of healthy volunteers. As will be discussed, SMS 201-995 does affect the motility of the normal intestine. Possibly in a nonsteady state, prolonged transit time may play a role in decreasing the diarrhea in these patients. This raises the possibility of using SMS 201-995 to treat other conditions of intractable large-volume diarrhea. Dr. Bernard Jaffe: I also think that SMS 201-995 must have an effect on the end organ. In carcinoids, for example, diarrhea stops with administration of the analogue, without any change in hormone levels. I think it is now well accepted that in carcinoid intestinal secretion, SMS 201995 has an end organ effect. Certainly, the analogue effects secretion, and possibly motility too.

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Dr. Krejs: That is right, but in many patients with carcinoid, diarrhea is controlled by loperamide or other pure anti-motility drugs. This suggests that the anti-motility effect of somatostatin may play a role. Dr. Walter Dyck: Is there any suggestion that plasma VIP levels are elevated in patients who abuse laxatives? Dr. Krejs: I am aware of three or four patients who were abusing laxatives and had a high VIP concentration in the plasma, but I think the initial patients were observed before the assays had been refined. Actually, we saw a number of laxative abusers, who were referred to us because of diarrhea and high VIP levels. However, their high VIP levels could not be confirmed when the assays were repeated in different laboratories using improved radioimmunoassay techniques. But one or two patients did, indeed, have high VIP levels associated with laxative abuse. The cause remains unexplained. Dr. Bloom, would you please comment on this observation of laxative abuse and elevated VIP levels? Dr. Bloom: At our United Kingdom tumor service, about

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100 assays have been performed each week. We’ve been doing this for at least the past 10 years. In that time, a vast number of patients with various types of diarrhea have been examined for the presence of a VIPoma. We have not found one case of an elevated VIP level due to laxative abuse. We also did not find any VIP elevation in the so-called pseudo-Verner-Morrison syndrome. We did identify six patients with elevated VIP levels associated with diarrhea whose high VIP measurements were falsepositive because they were not the right molecular size for VIP. The assay (at least with our particular antibody) can be misled by high molecular-weight VIPs. Since PHM is co-produced with VIPs, PHM is now also measured. Also, we found that in none of the cases of falsely elevated VIP levels was the PHM concentration high. Since the VIPs were in the void volume of the column, we suspect that they are like macroamylasemia-in other words, the pep tide is not properly processed so it circulates for a long time. The VIP output is normal, but it is not cleared through the circulation because of its large molecular size.

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