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      Case Report: Irreversible Watery Diarrhea, Severe Metabolic Acidosis, Hypokalemia and Achloridria Syndrome Related to Vasoactive Intestinal Peptide Secreting Malignant Pheochromocytoma

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          Pheochromocytoma (PHEO) clinical manifestations generally mirror excessive catecholamines secretion; rarely the clinical picture may reflect secretion of other hormones. Watery diarrhea, hypokalemia and achlorhydria (WDHA) is a rare syndrome related to excessive secretion of vasoactive intestinal peptide (VIP).

          Clinical Case

          A 73-year-old hypotensive man affected by adrenal PHEO presented with weight loss and watery diarrhea associated with hypokalemia, hyperchloremic metabolic acidosis (anion gap 15 mmol/l) and a negative urinary anion gap. Abdominal computed tomography scan showed a right adrenal PHEO, 8.1 cm in maximum diameter, with tracer uptake on 68GaDOTA-octreotate positron emission tomography. Metastasis in lumbar region and lung were present. Both chromogranin A and VIP levels were high (more than10 times the normal value) with slightly elevated urine normetanephrine and metanephrine excretion. Right adrenalectomy was performed and a somatostatin analogue therapy with lanreotide started. Immunostaining showed chromogranin A and VIP co-expression, with weak somatostatin-receptor-2A positivity. In two months, patient clinical conditions deteriorated with severe WDHA and multiple liver and lung metastasis. Metabolic acidosis and hypokalemia worsened, leading to hemodynamic shock and exitus.


          A rare case of WDHA syndrome caused by malignant VIP-secreting PHEO was diagnosed. High levels of circulating VIP were responsible of the rapidly evolving clinical picture with massive dehydration and weight loss along with severe hyperchloremic metabolic acidosis and hypokalemia due to the profuse untreatable diarrhea. The rescue treatment with lanreotide was unsuccessful because of the paucity of somatostatin-receptor-2A on VIP-secreting PHEO chromaffin cells.

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          Most cited references 36

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          Vascular hyporesponsiveness to vasopressors in septic shock: from bench to bedside.

          To delineate some of the characteristics of septic vascular hypotension, to assess the most commonly cited and reported underlying mechanisms of vascular hyporesponsiveness to vasoconstrictors in sepsis, and to briefly outline current therapeutic strategies and possible future approaches. Source data were obtained from a PubMed search of the medical literature with the following MeSH terms: Muscle, smooth, vascular/physiopathology; hypotension/etiology; shock/physiopathology; vasodilation/physiology; shock/therapy; vasoconstrictor agents. Nitric oxide (NO) and peroxynitrite are crucial components implicated in vasoplegia and vascular hyporeactivity. Vascular ATP-sensitive and calcium-activated potassium channels are activated during shock and participate in hypotension. In addition, shock state is characterized by inappropriately low plasma glucocorticoid and vasopressin concentrations, a dysfunction and desensitization of alpha-receptors, and an inactivation of catecholamines by oxidation. Numerous other mechanisms have been individualized in animal models, the great majority of which involve NO: MEK1/2-ERK1/2 pathway, H(2)S, hyperglycemia, and cytoskeleton dysregulation associated with decreased actin expression. Many therapeutic approaches have proven their efficiency in animal models, especially therapies directed against one particular compound, but have otherwise failed when used in human shock. Nevertheless, high doses of catecholamines, vasopressin and terlipressin, hydrocortisone, activated protein C, and non-specific shock treatment have demonstrated a partial efficiency in reversing sepsis-induced hypotension.
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            Islet cell tumor and a syndrome of refractory watery diarrhea and hypokalemia.

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              The protean manifestations of pheochromocytoma.

               W Manger (2009)
              The treacherous and deceptive nature of pheochromocytoma makes it crucial to detect and treat it promptly; otherwise it will almost certainly be fatal from cardiovascular complications or metastases. Hypertension occurring in patients with pheochromocytomas is sustained in about 50% and paroxysmal in the remainder; however, many patients remain normotensive. Hypertension attacks may be precipitated by physical activity, postural changes, anxiety, certain foods or wine, some drugs, operative procedures, etc. Cardinal manifestations are paroxysmal hypertension, headache, palpitations +/- tachycardia, inappropriate sweating; anxiety, tremulousness, pallor (rarely flushing), chest and abdominal pains; nausea and vomiting often occur. Hypercatecholaminemia manifestations are more common and pronounced when paroxysmal hypertension occurs, but persons with familial pheochromocytoma may be asymptomatic. Protean manifestations of pheochromocytoma may simulate many conditions, some of which may have elevated plasma and urine catecholamines and their metabolites. Baro-reflex failure, postural tachycardia syndrome, sleep apnea, carcinoid, renal failure, and pseudopheochromocytoma may be diagnostic challenges. The history, physical examination, biochemical testing (after eliminating interfering drugs, when possible) for plasma and urinary metanephrines can usually establish or exclude presence of pheochromocytomas. Occasionally a clonidine suppression test is needed to differentiate neurogenic from pheochromocytic hypertension. Manifestations suggesting hypercatecholaminemia without hypertension are highly atypical of pheochromocytoma. Pheochromocytoma may present as panic attacks, pre-eclampsia, cardiomyopathy, infection with fever and leucocytosis, diabetes, migraine, shock, Cushing's syndrome, multiple organ failure with lactic acidosis, neurological manifestations, transitory electrocardiogram abnormalities, constipation, intestinal obstruction, visual impairment, convulsions, etc. The key to diagnosis is always to think of pheochromocytoma in the differential diagnosis of hypertension.

                Author and article information

                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                17 March 2021
                : 12
                1 Internal Medicine and Secondary Hypertension Center, Ospedale Sant’Anna di Castelnovo Ne’ Monti, Azienda Unità sanitaria Locale – IRCCS di Reggio Emilia , Reggio Emilia, Italy
                2 Centro Ipertensione Arteriosa e Studio Malattie Cardiorenali, S.S. Fisiopatologia Medica, Clinica Medica Generale e Terapia Medica , Parma, Italy
                3 Pathology Unit, Department of Medicine and Surgery, University Hospital of Parma , Parma, Italy
                4 Pathology Unit, Ospedale Sant’Anna di Castelnovo Ne’ Monti, Azienda Unità sanitaria Locale – IRCCS di Reggio Emilia , Reggio Emilia, Italy
                5 High Care Internal Medicine Unit, Ospedale Sant’Anna di Castelnovo Ne’ Monti, Azienda Unità sanitaria Locale – IRCCS di Reggio Emilia , Reggio Emilia, Italy
                6 Molecular Biology Laboratory, Ospedale Sant’Anna di Castelnovo Ne’ Monti, Azienda Unità sanitaria Locale – IRCCS di Reggio Emilia , Reggio Emilia, Italy
                7 Histology and Histopathology Unit, Dental School, University of Parma , Parma, Italy
                Author notes

                Edited by: Antongiulio Faggiano, Sapienza University of Rome, Italy

                Reviewed by: Ronald De Krijger, Princess Maxima Center for Pediatric Oncology, Netherlands; Fady Hannah-Shmouni, National Institutes of Health (NIH), United States

                *Correspondence: Aderville Cabassi, aderville.cabassi@ 123456unipr.it

                †These authors have contributed equally to this work

                This article was submitted to Cancer Endocrinology, a section of the journal Frontiers in Endocrinology

                Copyright © 2021 Negro, Verzicco, Tedeschi, Campanini, Zanelli, Negri, Farnetti, Nicoli, Palladini, Santi, Cunzi, Calvi, Coghi, Gerra, Volpi, Graiani and Cabassi

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 3, Tables: 0, Equations: 0, References: 37, Pages: 6, Words: 3047
                Funded by: Università degli Studi di Parma 10.13039/501100004770
                Case Report


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