A rare case of watery diarrhea, hypokalemia and achlorhydria syndrome caused by pheochromocytoma
© Jiang et al.; licensee BioMed Central Ltd. 2014
Received: 20 March 2014
Accepted: 21 July 2014
Published: 31 July 2014
A rare syndrome of watery diarrhea, hypokalemia and achlorhydria (WDHA) is usually caused by pancreatic endocrine tumors that secrete excessive vasoactive intestinal polypeptide (VIP). Here we report a rare case of WDHA caused by a pheochromocytoma.
A 45-year old male presented with persistent and progressive watery diarrhea for half a year, and was treated with dialysis due to azotemia, hypokalemia, hypercalcemia and metabolic acidosis. A right adrenal mass was found by ultrasonography, and Positron Emission Tomography-Computed Tomography (PET-CT) showed the tumor was hyper-metabolic. Levels of plasma normetanephrine (NMN) and serum chromogranin A (CgA) were significantly elevated. Immunohistochemistry analysis of the adrenal tumor was strongly positive for CgA, synaptophysin and VIP. The patient fully recovered from WDHA syndrome soon after surgery, as reflected in that diarrhea stopped, levels of plasma NMN, serum CgA, and electrolytes returned to normal thus no dialysis was needed. The patient remained disease free in a 12-months follow-up period.
We report an extremely rare case of pheochromocytoma causing WDHA syndrome and uremia, which the patient completely recovered from after tumor resection.
KeywordsVasoactive intestinal polypeptide Pheochromocytoma Hypercalcemia Bone metabolism
Vasoactive intestinal peptide (VIP) is a 28-amnio acid peptide that may cause secretory diarrhea when overproduced by activating adenylate cyclase. A rare syndrome of watery diarrhea associated with hypokalemia and achlorhydria (WDHA) due to hypersecretion of VIP was described initially by Verner and Morrison in 1958 . This syndrome is usually associated with pancreatic endocrine tumors (VIPomas), with only a few exceptions. In this report, we describe a case of WDHA caused by a VIP-positive pheochromocytoma. Surgical resection of the tumor relieved all the symptoms and normalized all the relevant biochemical characteristics in the patient.
A 45-year old man presented with persistent and progressive watery diarrhea for half a year. He was initially admitted to a local hospital because he suddenly lost consciousness, during which his blood pressure was unmeasurable. Emergency lab tests revealed elevated white blood cell count (WBC 21.4 × 109/L, N 86.4%), hypercreatinemia (Cr 647umol/L) and hypokalemia (K 2.9 mmol/L). Arterial blood gas tests indicated metabolic acidosis and hypoxia (pH 7.16, HCO3 10 mmol/L, PO2 70%). He was intubated, maintained on hemodialysis and treated with fluid and antibiotics intravenously. After his condition improved, he was transferred to our hospital for further diagnosis and treatment.
Follow up of electrolytes and hormones
Six month later
K + (mmol/L)
Ca2 + (mmol/L)
The patient underwent a combined surgery, which removed the adrenal mass and the left lobe of the thyroid gland simultaneously. The surgery was completed uneventfully. The patient’s BP and HR were stable during the resection of a 9 × 8 × 5 cm adrenal mass. The gross and microscopic appearance was the typical feature of pheochromocytoma, whereas the thyroid nodule appeared to be a benign adenoma. There was no evidence of medullary thyroid cancer.
After surgery, the patient’s symptoms relieved rapidly. Diarrhea stopped soon after surgery. Moreover, his daily urine increased gradually and serum Cr also lowered into a normal range without dialysis. Plasma NMN, serum PTH, calcitonin and electrolytes all were back to normal (Table 1). Osteocalcin and beta-CTX lowered significantly, while P1NP increased significantly (Table 1). Two weeks after surgery, the patient recovered completely and was discharged. Six months after surgery, a comprehensive follow-up check revealed no abnormalities in the relevant biochemical makers, except for a slightly high P1NP (Table 1). Till now, the patient has been followed for one year, showing no sign of recurrence.
The effect of VIP on bone metabolism has not been established, although it was reported that VIP receptors are expressed by both osteoblasts and osteoclasts [14, 15]. The present case has provided the first clinical evidence that VIPoma is associated with a dysfunction of bone metabolism, as exemplified by the increase of osteocalcin, P1NP and most significantly, beta-CTX (Table 1). After surgery, beta-CTX subsided, and P1NP rose significantly (Table 1), suggesting a shift from bone resorption toward bone formation. It is very interesting to note that another patient with VIPoma, who was diagnosed recently in our hospital, has shown a very similar pattern of changes in bone metabolism before and after surgery (Jiang et al., unpublished data). It has been reported that WDHA syndrome is often accompanied by hypercalcemia . The current case showing a dysfunction of bone metabolism suggests a direct effect of VIP on osteoclasts, which should be considered as the underlying mechanism of hypercalcemia in the patients with VIPoma.
The most impressive finding of this case is the miraculous recovery of renal function after surgical treatment. To our knowledge, this is the first case of VIP-secreting pheochromocytoma with such a high level of Cr that hemodialysis was needed. In considering that the diarrhea and dehydration lasted for several months, pre-renal azotemia was suspected initially. As such, chances for recovery would be slim. But after surgical removal of the adrenal mass, serum Cr decreased dramatically together with a gradual increase in urine volumes, and dialysis was no longer needed. Another interesting finding in this case is that, despite extremely high level of NMN, the patient had no hypertensive symptoms. Such a typical characteristic of pheochromocytoma was probably masked by the vasodilative effect of VIP and severe dehydration due to diarrhea.
Because both NMN and calcitonin were elevated, multiple endocrine neoplasia type 2 (MEN2) was suspected in the initial diagnosis. Upon investigation, the patient had no relevant family history and the histology of thyroid specimen did not support the diagnosis of MEN2. It should also be mentioned that NMN was significantly elevated in the present case, whereas pheochromocytomas in MEN2 typically produce epinephrine, leading to elevated MN [16, 17]. Moreover, a fast screening of genomic DNA in our patient’s sample failed to identify any common RET gene mutations. We have also performed sequencing on the whole coding region of RET using cDNA from thyroid tissues of our patient, and no mutation was identified. Based on these investigations, along with the patient’s clinical manifestations, we could exclude the possibility of MEN2. So far, the only genetic manifestation of pheochromocytoma associated with WDHA syndrome was found being a NF1 gene mutation, with two cases reported in the literature [8, 18]. A pheochromocytoma secreting calcitonin has been previously reported in a MEN2A patient bearing a triple RET gene mutation . Yet the reason for the elevated calcitonin in this case remains unknow, as the IHC for calcitonin was negative in both pheochromocytoma and the thyroid nodule of the patient.
In conclusion, the current report describes a very rare case of WDHA syndrome caused by a VIP-positive pheochromocytoma. It is also the first case of WDHA that progressed to uremia relying on hemodialysis, and yet recovered completely after surgical removal of the pheochromocytoma. In addition, this was also reported for the first time that a VIP-positive pheochromocytoma had significant effects on bone metabolism in the patient.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
Watery diarrhea, hypokalemia and achlorhydria
Vasoactive intestinal polypeptide
Positron emission tomography-computed tomography
Standardized uptake value
Procollagen type 1 aminoterminal Propeptide
Cross-linked C-terminal telopeptide of type 1 collagen
Multiple endocrine neoplasia type 2
Neurofibromatosis type 1.
We thank Prof. Pu Xia for critical reading of the manuscript. This work was supported by the National Natural Science Foundation of China (grant number: 81100557) and the Specialized Research Fund for the Doctoral Program of Higher Education (SRFDP) (grant number: 20110073120086). We are grateful to the patient who participated in this study.
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