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12 APUDomas: acute complications and their medical management
12 APUDomas: acute complications and their medical management J. PHILIPPE
APUD (amine precursor uptake and decarboxylation) cells constitute a family of endocrine cells distributed throughout the body and characterized by the ability to take up and decarboxylate amino acid precursors of biogenic amines. This property results in the synthesis of bioactive amines or polypeptide hormones. APUD cells are found in organs as diverse as the pituitary gland, peripheral autonomic ganglia, adrenal medulla, gastrointestinal tract, pancreas, lung, gonads and thymus. Endocrine tumours originating from cells characterized by the APUD properties have been referred to as APUDomas. The initial clinical manifestations of most of these tumours can be attributed to the overproduction of biogenic amines or hormones. Although many endocrine tumours can be classified as APUDomas, only those whose clinical manifestations may require emergency management are considered here, excluding insulinomas and tumours originating from the autonomic ganglia or adrenal medulla (see Chapters 2 and 7). ZOLLINGER-ELLISON SYNDROME Definition The Zollinger-Ellison syndrome (ZES) is usually the first manifestation of gastrin-producing tumours (gastrinomas) and is secondary to an increased gastrin production. ZES is characterized by severe gastric acid hypersecretion, which causes peptic ulceration and diarrhoea. The most serious acute complications are bleeding and bowel perforation. Gastrinomas occur rarely, the incidence being one new case/million/year. In two-thirds of the patients gastrinoma occur sporadically while the other cases are associated with other endocrine tumours, such as pituitary and parathyroid tumours in the context of the multiple endocrine neoplasia syndrome type I (MEN-l). In MEN-1 patients, hypercalcaemia due to hyperparathyroidism may aggravate the severity of gastric acid hypersecretion. Most gastrinomas are located in the pancreas or within the duodenal wall and are frequently multiple, particularly in MEN-1 patients. Only a minority of patients with gastrinomas (20-40%) may be cured by surgery as tumours 13ailli~re's Clinical Endocrinology and Metabolism-217 Vol. 6, No. 1, January 1992 Copyright © 1992, by Bailli~re Tindall ISBN 0-7020-1485-0 All rights of reproduction in any form reserved
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are either not found by imaging studies or not entirely removed at surgery or have already metastatisized. Indeed, at the time of diagnosis, about 50% of the patients have metastasis to the lymph nodes, liver or bones (for review see Maton et al, 1989a). Recently, visualization of enteropancreatic tumours in vivo after intravenous administration of a labelled somatostatin analogue has been reported (Lamberts et al, 1990). This new imaging technique which relies on the presence of somatostatin receptors on most of these tumours may become useful in localizing primary tumours and detecting metastases.
Clinical manifestations Most if not all of the symptoms due to localized gastrinomas are secondary to gastric acid hypersecretion. Indeed, increased gastrin production and hypergastrinaemia are responsible for thickening of the gastric mucosa, augmented parietal cell number and high gastric acid output. Both basal (normal <10mmol/h) and maximal acid output (normal values: 2050mmol/h) are elevated in patients with ZES (Maton et al, 1989b) with consequent peptic ulcerations of the oesophagus, stomach, jejunum and most frequently duodenum. Abdominal pain, characteristic of peptic ulcer, is the first complaint in most patients and usually originates from a single duodenal ulcer (Wolfe and Jensen, 1987), although multiple ulcers can be found in severe cases. Other common symptoms are due to reflux oesophagitis, watery diarrhoea, malabsorption and weight loss (Maton et al, 1989b). In these patients, gastric acid secretion can reach enormous volumes (up to 101) which will inactivate pancreatic enzymes, precipitate bile salts and damage the intestinal mucosa. The most dramatic complications, that are sometimes the initial manifestations, include intractable vomiting associated with pyloric stenosis, gastrointestinal bleeding and duodenal or gastric perforation. In rare cases, ectopic expression of adrenocorticotropin (ACTH) in gastrinomas can cause Cushing's syndrome (Maton et al, 1986).
Diagnosis ZES should be considered in any patient with persistent or recurrent peptic ulceration, severe oesophagitis, persistent diarrhoea or with any serious complications. The delay of 5.8 years between appearance of the first symptoms and definitive diagnosis indicates that ZES is not always considered in these situations (Kaplan et al, 1990). The most helpful screening test is measurement of fasting serum gastrin level (Wolfe and Jensen, 1987); normal gastrin levels virtually excludes the diagnosis of ZES, while elevated levels combined with high gastric acid output or low gastric pH should allow proper diagnosis (Figure 1). Localization of gastrinomas by CT scan and selective abdominal angiogram, although not often successful, should be attempted since complete resection of the tumour is associated with a 10-year survival rate in more than 90% of the patients, compared with much less favourable outcome when the tumour cannot be removed (Malagelada et al, 1983; Stabile and Passaro, 1985).
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Fasting serum gastrin < 150 pg/m~ ZES ruled out ] or 71 pmol/ i > 150 pg/ml
Basal acid output (BAO) ]or gastric pH pH>3.5or BAO < 5 mmol/h /
/
~
\
/ [ Achlorydria ]
pH<2or "~O> 15 mmoi/h
Gastric outlet obstruction Vagotomy Renal failure Bowel resection
[-~ • basal serum gastrin: > 1000 pg/m[ or >476 pmol/I • secretin test (2 U/kg i.v.): gastrin levels at -10, 0, 2, 5, 10min rise > 200 pg/ml or >50% increase over basal
Figure 1. Diagrammatic approach to Zollinger-Ellison syndrome.
Treatment of ZES
Management of acute complications Acute complications arise as a consequence of high gastric acid output. With availability of antagonists to histamine H2 receptors and H+-K + proton pump, acid output should be effectively controlled in most, if not all patients with ZES and acute complications prevented (Jensen, 1984; Maton et al, 1989c). Severe gastrointestinal bleeding and perforation are the most serious complications necessitating emergency surgery (for review see Miller, 1988). Diarrhoea and vomiting secondary to pyloric stenosis can lead to volume depletion, electrolyte disturbances and arrhythmias. In addition to their specific treatment, proper management of complications associated with gastric acid hypersecretion should include adequate control of acid output with H2 receptor or H+-K + proton pump antagonists (Saeed et al, 1989; Vinayek et al, 1990). Three H2 receptor antagonists are now widely available, both for intravenous (i.v.) and oral treatments and include cimetidine, ranitidine and famotidine, although famotidine has not been thoroughly evaluated in patients with ZES. A slow i.v. bolus injection of cimetidine (300 mg), ranitidine (150mg) or famotidine (20rag) should be followed by a constant infusion in 5% dextrose (starting at lmg/kg/h for cimetidine, 0.5 mg/kg/h for ranitidine and 0.1 mg/kg/h for famotidine). Acid output should be checked 3-4h later and, if greater than 10mmol/h (5 mmol/h for partially gastrectomized patients), infusion doses should be doubled until adequate control is obtained. Doses of 3 mg/kg/h cimetidine
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and 1 mg/kg/h ranitidine are sufficient in 70% of patients with ZES. Doses up to 7 mg/kg/h cimetidine and 4 mg/kg/h ranitidine have been given without significant side-effects (Maton, 1989a; Saeed et al, 1989), except in acutely ill patients or in patients with liver or kidney disease, where confusion and hallucinations have been reported. Furthermore, in patients with preexisting cardiac disease i.v. bolus injections should be slow (2-5 rain) since arrhythmias, asystole and hypotension can occur. Anticholinergic agents have been useful in cases where high doses of H2 receptor antagonists were not sufficient to control gastric acid output. However, in such situations, we recommend to switch to omeprazole. Omeprazole is the first antagonist directed at the H+-K + proton pump, thus acting at a very distal step of acid secretion. An initial i.v. injection of 60 mg should reduce acid output to less than 5 mmol/h within 24 h (Vinayek et al, 1990). A single dose is usually sufficient, although two divided doses are preferred, especially when large amounts (more than 60mg) are administered. Efficacy and convenient administration make omeprazole the drug of choice for the acute treatment of ZES. Intravenous administration of drugs is not only required for acute complications but also for patients unable to take oral medications (during elective surgery, chemotherapy or any cause of nausea and vomiting). Intravenous treatment should be continued for 24 h after the patient is able to resume oral medications. The total daily oral dose should correspond to 1.5 times the i.v. dose, but acid output should be checked. Surgical management of ZES is now mostly reserved for acute complications. Indications for total gastrectomy include severe and intractable gastrointestinal bleeding and perforation. Mortality during this emergency procedure is high (Miller, 1988).
Prevention of acute complications Control of gastric acid secretion should prevent most acute complications. Absence of symptoms is not a reliable parameter because it does not always correlate with suppressed acid production. It is thus necessary to lower acid output below 10 mmol/h (or 5 mmol/h in partially gastrectomized patients) throughout the day (Raufman et al, 1986; Maton et al, 1988); this can be assessed by measuring acid output just before the next dose of medication. Maintenance of gastric pH above 2 is an alternative (Vallot et al, 1983). In patients with severe peptic oesophagitis, these measures will not be sufficient since only 50% of strictures will heal when acid output is 1-10 retool/h; the majority of strictures will heal at an acid output below 1 mmol/h (Miller et al, 1990).
Medical options Both H 2 receptor antagonists (cimetidine, ranitidine, famotidine) and the antagonist of the proton pump (H+-K + ATPase), omeprazole, can be used in the chronic management of ZES. All H2 receptor antagonists can effectively lower acid output below 10mmol/h, although doses have to be individualized and periodically
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re-evaluated. However, differences in potencies, duration of action and side-effects exist between the different drugs. Famotidine is about 8-fold and 32-fold more potent than ranitidine and cimetidine, respectively (Howard et al, 1985). In addition, the duration of action of famotidine is about 1.3 times longer than either cimetidine or ranitidine; this may be of clinical value when doses have to be administered frequently. The major advantages of famotidine and ranitidine over cimetidine are their lack of antiandrogen effects (gynecomastia and impotence) and interference with hepatic drug metabolism (Wolfe and Jensen, 1987). To be effective in patients with ZES, doses of H2 receptor antagonists should be much higher than those recommended for the usual treatment of gastroduodenal ulcers. In recent studies, mean doses were 3.6g/day (range: 1.2-12.6g) for cimetidine, 1.2 g/day (range 0.45-6 g) for ranitidine and 0.25 g/day (range 0.05-0.8 g) for famotidine. Doses should be started at 300 rag, 150 mg and 40 mg every 6 h for cimetidine, ranitidine and famotidine, respectively, and doubled until acid output is below 10 mmol/h. When more frequent administrations are necessary, preference should be given to famotidine. Regular control of acid output is mandatory, as it is well established that many patients need increasing doses with time (Mignon and Bonfils, 1988). Whether this phenomenon reflects an increase in gastrin production induced by treatment, tumour progression, decreased sensitivity to treatment or delayed absorption remains to be determined. Although there is no major toxicity of H2 receptor antagonists, long-term usage may lead to hyperplasia of enterochromaffin cells and higher gastrin levels (Lehy et al, 1989). Indeed, rare cases of carcinoid tumours in patients with ZES and MEN-l, treated by H2 receptor antagonists, have been reported (Solcia et al, 1986). The implications of enterochromaffin cell hyperplasia are unknown. Omeprazole is the only available antagonist of the enzyme, H + - K + ATPase, which acts as a proton pump. It is a potent drug (50 mg is equivalent to 4 g of ranitidine) with a duration of action in excess of 48 h resulting in complete cessation of acid secretion. A once-a-day dose is generally sufficient, although up to 25% of patients may require two doses/24 h; daily doses range from 20 to 160 mg with a mean of about 70mg (Maton et al, 1989c). This is the treatment of choice for patients with severe oesophagitis since it can reduce gastric output below i mmol/h. There are no major toxic side-effects, although omeprazole may induce enterochromaffin cell hyperplasia. Carcinoid tumours have been reported in rat but not in man (Solcia et al, 1989). The long-acting somatostatin analogue, octreotide, is effective in controlling gastric acid output and, in a minority of patients can decrease or stabilize tumour growth. However, exceptions to this treatment have been reported. The exact role of octreotide in the management of ZES and gastrinoma is not clearly established, especially when considering its high cost and the efficacy of other treatments (Maton et al, 1989b).
Surgical options Total gastrectomy should only be considered for patients who are not
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compliant with drug treatment or whose basal acid output cannot be suppressed despite maximal medical management. Highly selective vagotomy should be reserved for the occasional patient with unusually high drug requirements. Vagotomy abolishes the cephalic phase of gastric acid secretion and can decrease basal acid output by 40% in patients with ZES. However, this procedure is not effective in many patients and its long-term effects on acid secretion have not been adequately assessed (Richardson et al, 1985). CARCINOID SYNDROME Definition
The carcinoid syndrome occurs at a frequency of about 3-4 cases/million/ year and results from the production and release of biologically active substances by carcinoid tumours. The cardinal manifestations are flushing, diarrhoea, asthma and endomyocardial fibrosis. Carcinoid tumours arise from enterochromaffin cells, principally of the gastrointestinal tract, pancreas and lungs, but occasionally of the thymus and gonads. Histochemical and functional heterogeneity of these cells may be related to their site of origin (embryonic foregut, midgut and hindgut), which may be of clinical relevance for the diagnosis and symptomatology of carcinoid tumours (Maton, 1988; Kvols, 1989). The carcinoid syndrome occurs in 6--18% of patients with carcinoid tumours and is seen most commonly with tumours originating from the jejunum, ileum and right colon (midgut origin) (Feldman, 1987). Patients with the carcinoid syndrome almost invariably have hepatic metastasis (95%). Bioactive substances synthesized within the liver are directly released into the systemic circulation bypassing hepatic inactivation. In contrast, substances released from the primary tumour into the portal circulation are efficiently metabolized by the liver. Clinical manifestations can also result from massive nodal metastasis which may rarely saturate the capacity of the liver or, in the absence of metastasis, from bronchial or ovarian carcinoids which release their products directly into the systemic circulation (Vinik et al, 1989). Clinical manifestations
Flushing is the most characteristic symptom that occurs in at least 75% of patients with the carcinoid syndrome. Frequency, duration and severity of flushing can vary from patient to patient. Episodes may occur spontaneously or be precipitated by foods, alcohol, exercise or stress. Diarrhoea is as common as flushing and may occur regularly shortly after meals or sporadically at any time. It may be sufficiently severe to lead to electrolyte abnormalities and volume depletion, especially when associated with Cushing's syndrome due to ectopic ACTH and/or CRF production by the carcinoid tumour. Heart disease caused by fibrosis of the endocardium is a late manifestation
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of the disease and occurs in a third of the patients. Endomyocardial fibrosis typically involves the right side of the heart with the potential consequences of pulmonic stenosis and tricuspid regurgitation. Rare patients may have more generalized fibrosis involving vessels, skin and retroperitoneum. Less common manifestations include asthma or wheezing and a pellagroid rash (secondary to the diversion of tryptophan for serotonin synthesis leading to reduced availability of tryptophan for synthesis of protein and nicotinamide) (Vinik et al, 1989). Mediators involved in the clinical manifestations of the syndrome have not been clearly identified. Serotonin production, however, is nearly always increased and may be responsible for diarrhoea, asthma and endomyocardial fibrosis. Potential mediators of the carcinoid flush include kallikrein, histamine, substance P, prostaglandins, dopamine and neurotensin (Norheim et al, 1986; Conlon et al, 1987). In patients with the carcinoid syndrome, the diagnosis can be established by measuring the urinary excretion of 5-hydroxyindolacetic acid (5-H1AA), a serotonin metabolite. A 24 h urinary excretion of more than 150 p~mol/1 is diagnostic. However, carcinoids arising from enterochromaffin cells derived from the foregut may produce 5-hydroxytryptophan rather than serotonin and have normal urinary values of 5-HIAA (Maton, 1988).
Carcinoid crisis This is the most serious manifestation of the carcinoid syndrome and it can be lethal. It can occur spontaneously but more commonly be triggered by a diagnostic procedure, anaesthesia, surgery or following initiation of chemotherapy. Hypotension, hypertension, severe flushing, arrhythmia, confusion or coma are the principal signs. They may last for a few hours to several days. Management of carcinoid crises has been particularly difficult despite adequate fluid replacement and vasopressor administration (Kvols, 1989). Treatment of the carcinoid syndrome
Surgery Surgery may be considered as a curative or palliative treatment. Surgery may result in a cure in the presence of localized bronchial or ovarian carcinoid tumours. More commonly, surgery is palliative. The indolent behaviour of carcinoids and the poor results of chemotherapy are good reasons to consider a debulking procedure or removal of the primary turnout to alleviate both local (small bowel or bronchial obstruction, bleeding) and systemic manifestations.
Medical management Diarrhoea will often respond to codeine phosphate, loperamide or diphenoxylate. More specific measures should sometimes be considered, such as the use of antibiotics for bacterial overgrowth and cholestyramine for bile
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salt spillage. Asthma should be managed by [32-adrenergic agonists. When simple measures are not effective at controlling symptoms, alternative therapies must be sought. Three classes of drugs may be useful to control the carcinoid syndrome (Maton, 1988; Harris and Smith, 1982): 1. 2. 3.
The a-adrenergic antagonist, phenoxybenzamine 10-30rag/day, can control flushing. For flushing induced by gastric carcinoid, the use of diphenhydramine (50 mg every 6 h) and cimetidine (300 mg every 6 h) can be useful. Antagonists of 5-hydroxytryptamine receptors, such as cyproheptadine (4-8 mg every 6 h), ketanserin (20-40 mg every 12 h) and methysergide (3-9 mg every 12 h) can ameliorate the diarrhoea.
This list is not exhaustive and other medications, such as glucocorticoids may prove useful to decrease diarrhoea or flushing Moertel, 1983).
Somatostatin analogues Octreotide, a long-acting somatostatin analogue, ~s the most important recent advance in the treatment of the carcinoid syndrome. Somatostatin had previously been shown to control effectively acute symptoms of the carcinoid syndrome; with the availability of the long-acting octreotide, chronic management of these symptoms, even when severe, is now feasible. octreotide relieves diarrhoea, flushing and wheezing in 80-90% of the patients, this effect being associated with a 50% reduction in urinary 5-HIAA excretion. It is thus the most effective single medication. However, its effect on tumour mass is much less spectacular since shrinkage of the measurable mass by at least 50%, as assessed by CT scan, occurs in less than 20% of the patients (Maton, 1988; Kvols, 1989). Octreotide has also been successfully used to prevent or treat carcinoid crisis. All patients undergoing surgery, chemotherapy or hepatic arterial devascularization should receive octreotide at a dose of 200-250 txg every 6-8 h subcutaneously over a period of 48 h followed by a dose 1-2 h before the procedure. With this approach, initiation of chemotherapy can be done with full doses of cytotoxic drugs. For treatment of carcinoid crisis, in addition to the usual measures to control blood pressure and arrhythmias, octreotide should be administered i.v., 100-500 ~g, followed by a continuous infusion or s.c. injections every 4-6h (Kvols et al, 1987; Marsh et al, 1987; Roy et al, 1987). VIPOMAS Definition
Watery diarrhoea, hypokalaemia and achlorhydria (WDHA) characterize the syndrome associated with tumours releasing high amounts of vasoactive intestinal peptide (VIP). Most of these tumours arise from the pancreas but elevated levels of VIP can also be found with other tumours, such as
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pheochromocytomas, ganglioneuromas, neuroblastomas and bronchogenic carcinoma. When VIP was found in submucosa of the intestinal tract to stimulate chloride secretion in the lumen, it became apparent that VIP was a paracrine neuromodulator of intestinal function. In patients with high plasma VIP levels, intestinal secretions are potently stimulated and electrolyte absorption probably inhibited (Mekhjian and O'Dorisio, 1987). Clinical manifestations
Most of the manifestations of VIPomas can be explained by the elevated levels of VIP. The severe secretory diarrhoea and metabolic acidosis are the consequences of an increased intestinal secretion induced by VIP. VIP also inhibits gastric acid secretion causing achlorhydria and induces glucose intolerance by stimulating hepatic glycogenolysis. Hypokalaemia is the combined result of passive movement of K-- into the intestinal lumen and hyperaldosteronism secondary to volume depletion and VIP-induced hyperreninaemia. Flushing of the upper part of the body, hypercalcaemia and hypomagnesaemia can also be seen in a minority of patients (Mekhjian and O'Dorisio, 1987; O'Dorisio et al, 1989). Diagnosis is confirmed by an elevated fasting VIP plasma level (> 200 pg/ml), increased faecal weight (> 500 g/24 h) and persistence of diarrhoea despite prolonged fasting (Mekhjian and O'Dorisio, 1987). Treatment
The first objective of the treatment is to replace the important fluid losses resulting from diarrhoea; severe volume and electrolyte depletion accompanied by metabolic acidosis may often be the presenting symptoms. Intravenous fluids, such as NaC1 0.9% supplemented with KC1, are part of the management to correct hypotension, volume depletion and hypokalaemia. It is also critical to provide, once the acute symptoms are controlled, enough calories to reverse the catabolic state. Medical management Somatostatin is a potent inhibitor of VIP effects. It directly inhibits VIP release and decreases the VIP-induced chloride secretion. Both somatostatin and its analogue, octreotide, have been effective in controlling watery diarrhoea, although with advanced disease, increasing doses are often necessary. Along with the amelioration of the clinical symptoms, VIP levels often decrease, but rarely normalize. Owing to its efficacy in most patients, octreotide has become the treatment of choice for VIP-induced diarrhoea (Gaginella, 1990). Glucocorticoids, such as prednisone (60rag/d) have been extremely helpful in the past to treat severe diarrhoea; they inhibit VIP release and may decrease intestinal secretion and enhance absorption. They are still occasionally used when octreotide is not sufficient to control symptoms (Lennon et al, 1975; Benson et al, 1986).
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Surgery Surgical treatment needs to be considered as a second step once the patient has been able to regain some weight. When the tumour can be localized (generally in the distal two-thirds of the pancreas), it can be curative. However, when metastatic disease is already present, a debulking procedure may be offered both to decrease symptoms and to increase the likelihood of responding to chemotherapy. MEDULLARY CARCINOMA OF THE THYROID Definition
Medullary carcinoma of the thyroid (MCT) originates from thyroid parafollicular C cells whose major secretory product is calcitonin. MCT may occur sporadically or b e inherited as a single disease or in the context of MEN-2. Severe diarrhoea and occasionally flushing may occur when metastases are present. The humoral substances responsible for these symptoms have not been clearly identified, although calcitonin, prostaglandins, serotonin and VIP have been implicated (Wells et al, 1985). Treatment of diarrhoea
Diarrhoea associated with MTC can be extremely severe and result in volume depletion, hypotension and hypokalaemia. Apart from the standard antidiarrhoeal agents which should be tried, bromocriptine and octreotide have been used successfully in a few patients (Emmertsen et al, 1981; Keeling and Basso 1988). Their efficacy in large-scale trials remains to be demonstrated. SUMMARY
APUDomas are rare tumours originating from a variety of endocrine cells localized in different organs. Acute complications from APUDomas usually result from the increased biosynthesis and release of bioactive amines or polypeptide hormones by the tumour. Less frequently, bleeding or compression by the tumour can occur requiring emergency surgery. Increased gastrin production by gastrinomas is the cause of ZES (peptic ulceration and diarrhoea) by gastrin effects on gastric acid secretion. Volume depletion, hypokalaemia, severe bleeding, duodenal perforation, oesophageal stricture and pyloric stenosis are the most dramatic complications. Treatment of these complications and their prevention has been facilitated by the availability of antagonists to H2 receptors and H + - K + proton pump. These medications should control acid output in every patient with ZES. Frequent manifestations of carcinoid tumours, VIPomas and medullary thyroid carcinomas are flushing and diarrhoea. Octreotide, a long-acting
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somatostatin analogue, has markedly changed the management of these patients, their symptoms decreasing in severity or disappearing in most cases. Octreotide has also been used with success in the prevention and treatment of the carcinoid crisis, a dreaded complication of carcinoid tumours. A better understanding of the pathophysiology of APUDomas has enabled new treatment designs which have considerably ameliorated the quality of life of patients affected by these tumours; efforts must be continued to affect their life expectancy. REFERENCES Benson GD, O'Dorisio TM, Ellison EC et al (1986) Control of watery diarrhea syndrome in a patient with a VIP-secreting tumor using SMS 201-995 and dexamethasone. Scandinavian Journal of Gastroenterology 119 (supplement 21): 170. Conlon JM, Deacon CF, Richter G et al (1987) Circulating tachykinins (substance P, neurokinin A, neuropeptide A) and the carcinoid flush. Scandinavian Journal of Gastroenterology 22: 95-105. Emmertsen K, Mosekilde L, Nielsen HE &Hansen HH (1981) Bromocriptine reduces diarrhea in medullary thyroid carcinoma. Hormone and Metabolic Research 13: 301-302. Feldman JM (1987) Carcinoid tumors and syndrome. Seminars in Oncology 14: 237-246. Gaginella TS, O'Dorisio TM, Fassler JE & Mekhjian HS (1990) Treatment of endocrine and nonendocrine secretory diarrheal states with Sandostatin. Metabolism 39 (supplement 2): 172-175. Harris AL & Smith IE (1982) Regression of carcinoid tumors with cyproheptadine. British Medical Journal 285: 475. Howard JM, Chremos AN, Collen MJ et al (1985) Famotidine, a new potent long acting histamine H2 receptor antagonist: comparison with cimetidine and ranitidine in the treatment of Zollinger-Ellison syndrome. Gastroenterology" 88: 1026-1033. Jensen RT (1984) Basis for failure of cimetidine in patients with Zollinger-Ellison syndrome. Digestive Diseases and Sciences 29: 363-366. Kaplan EL, Horvath K, Udekwu K et al (1990) Gastrinomas: a 42-year experience. World Journal of Surgery 14: 365-375. Keeling CA & Basso LV (1988) Iodine-131 MIBG uptake in metastatic medullary carcinoma of the thyroid. A patient treated with somatostatin. ClinicalNuclear Medicine 13: 260-263. Kvols LK (1989) Therapy of the malignant carcinoid syndrome. Endocrinology and Metabolism Clinics of North America 18: 557-568. Kvols LK, Maples WJ & O'Connell MJ (1987) Carcinoid crisis: successful treatment and prevention with somatostatin analogue (SMS 201-995). Proceedings of the American Society of Clinical Oncology 6: 96. Lamberts SWJ, Bakker WH, Reubi JC & Krenning EP (1990) Somatostatin-receptor imaging in the localization of endocrine tumors. New England Journal of Medicine 323: 1246-1249. Lehy T, Mignon M, Cadiot G e t al (1989) Gastric endocrine cell behavior in Zollinger-Ellison syndrome patients upon long-term potent antisecretory treatment. Gastroenterology 96: 1029-1040. Lennon JR, Sircus W, Bloom SR et al (1975) Investigation and treatment of a recurrent VIPoma. Gut 16: 821-824. Malagelada JR, Edis AJ, Adson MA et al (1983) Medical and surgical options in the management of patients with gastrinomas. Gastroenterology 84: 1524-1532. Marsh HM, Martin JK, Kvols LK et al (1987) Carcinnid crisis during anesthesia: successful treatment with a somatostatin analogue. Anesthesiology 66: 89-91. Maton PN (1988) The carcinoid syndrome. Journal of the American Medical Association 260: 1602-1605. Maton PN, Gardner JD &Jensen RT (1986) Cushing's syndrome in patients with the ZollingerEllison syndrome. New England Journal of Medicine 315: 1-5.
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Maton PN, Frucht H, Vinayek R et al (1988) Medical management of patients with ZollingerEllison syndrome who have had previous gastric surgery. A prospective study. Gastroenterology 94: 294-299. Maton PN, Gardner JD & Jensen RT (1989a) Recent advances in the management of gastric acid hypersecretion in patients with Zollinger-Ellison syndrome. Gastroenterology Clinics of North America 17: 308-315. Maton PN, Gardner JD & Jensen RT (1989b) Diagnosis and management of Zollinger-Ellison syndrome. Endocrinology and Metabolism Clinics of North America 18: 519-543. Maton PN, Vinayek R, Frucht H et al (1989c) Long-term efficacy and safety of omeprazole in patients with Zollinger-Ellison syndrome: a prospective study. Gastroenterology 97: 82%836. Mekhjian HS & O'Dorisio TM (1987) VIPoma syndrome. Seminars in Oncology 14: 282-291. Mignon M & Bonfils S (1988) Diagnosis and treatment of Zollinger-Ellison syndrome. In Piper D (ed.) Peptic ulcerations. BailliOre's Clinical Gastroenterology, vol. 2, pp 677-698. London: Bailli~re Tindall. Miller TA (1988) Emergencies in acid-peptic disease. Gastroenterology Clinics of North America 17: 303-315. Miller LS, Vinayek R, Frucht H et al (1990) Reflux esophagitis in patients with ZollingerEllison syndrome. Gastroenterology 98: 341-346. Moertel CG (1983) Treatment of the carcinoid tumor and the malignant carcinoid syndrome. Journal of Clinical Oncology 1: 727-732. Norheim I, Theodorsson-Norheim E, Brodin E & Oberg K (1986) Tachykinins in carcinoid tumors. Their use as a tumor marker and possible role in carcinoid flush. Scandinavian Journal of Clinical Endocrinology and Metabolism 63: 605-612. O'Dorisio TM, Mekhjian HS & Gaginella TS (1989) Medical therapy of VIPomas. Endocrinology and Metabolism Clinics of North America 18: 545-553. Raufman JP, Collins SM, Pandol S et al (1986) Reliability of symptoms in assessing control of gastric acid secretion in patients with malignant gastrinomas. Annals of Surgery 203: 352-359. Richardson CT, Peters MN, Feldman Met al (1985) Treatment of Zollinger-Ellison syndrome with exploratory laparotomy, proximal gastric vagotomy and H2 receptor antagonists: a prospective study. Gastroenterology 89" 357-367. Roy RC, Carter RF & Wright PD (1987) Somatostatin, anesthesia and the carcinoid syndrome. Perioperative administration of a somatostatin analogue to suppress carcinoid tumor activity. Anesthesia 42: 627-632. Saeed ZA, Norton JA, Frank WO et al (1989) Parenteral antisecretory drug therapy in patients with Zollinger-Ellison syndrome. Gastroenterology 96: 1393-1402. Solcia E, Gapella C, Sessa F et al (1986) Gastric carcinoid and related endocrine growths. Digestion 35 (supplement 1): 3-22. Solcia E, Rindi G, Havu N & Elm G (1989) Qualitative studies of gastric endocrine cells in patients treated long-term with omeprazole. Scandinavian Journal of Gastroenterology 24 (supplement 166): 129-137. Stabile BE & Passaro E Jr (1985) Benign and malignant gastrinomas. American Journal of Surgery 149: 144-148. Vallot T, Mignon M, Mazure R & Bonfils S (1983) Evaluation of antisecretory drug therapy in Zollinger-Ellison syndrome using 24-hour pH monitoring. Digestive Diseases and Sciences 28: 577-584. Vinayek F, Frucht H, London R et al (1990) Intravenous omeprazole in patients with Zollinger-Ellison syndrome undergoing surgery. Gastroenterology 96: 10-16. Vinik AI, McLeod MK, Fig LM et al (1989) Clinical features, diagnosis and localization of carcinoid tumors and their management. Gastroenterology Clinics of North America 18: 865-895. Wells SA, Dilley WG, Farndon JA, Leight GS & Baylin SB (1985) Early diagnosis and treatment of medullary thyroid carcinoma. Archives of Internal Medicine 145: 1248-1252. Wolfe MM & Jensen RT (1987) Zollinger-Ellison syndrome. New England Journal of Medicine 317: 1200-1209.
APUD (amine precursor uptake and decarboxylation) cells constitute a family of endocrine cells distributed throughout the body and characterized by the ability to take up and decarboxylate amino acid precursors of biogenic amines. This property results in the synthesis of bioactive amines or polypeptide hormones. APUD cells are found in organs as diverse as the pituitary gland, peripheral autonomic ganglia, adrenal medulla, gastrointestinal tract, pancreas, lung, gonads and thymus. Endocrine tumours originating from cells characterized by the APUD properties have been referred to as APUDomas. The initial clinical manifestations of most of these tumours can be attributed to the overproduction of biogenic amines or hormones. Although many endocrine tumours can be classified as APUDomas, only those whose clinical manifestations may require emergency management are considered here, excluding insulinomas and tumours originating from the autonomic ganglia or adrenal medulla (see Chapters 2 and 7). ZOLLINGER-ELLISON SYNDROME Definition The Zollinger-Ellison syndrome (ZES) is usually the first manifestation of gastrin-producing tumours (gastrinomas) and is secondary to an increased gastrin production. ZES is characterized by severe gastric acid hypersecretion, which causes peptic ulceration and diarrhoea. The most serious acute complications are bleeding and bowel perforation. Gastrinomas occur rarely, the incidence being one new case/million/year. In two-thirds of the patients gastrinoma occur sporadically while the other cases are associated with other endocrine tumours, such as pituitary and parathyroid tumours in the context of the multiple endocrine neoplasia syndrome type I (MEN-l). In MEN-1 patients, hypercalcaemia due to hyperparathyroidism may aggravate the severity of gastric acid hypersecretion. Most gastrinomas are located in the pancreas or within the duodenal wall and are frequently multiple, particularly in MEN-1 patients. Only a minority of patients with gastrinomas (20-40%) may be cured by surgery as tumours 13ailli~re's Clinical Endocrinology and Metabolism-217 Vol. 6, No. 1, January 1992 Copyright © 1992, by Bailli~re Tindall ISBN 0-7020-1485-0 All rights of reproduction in any form reserved
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are either not found by imaging studies or not entirely removed at surgery or have already metastatisized. Indeed, at the time of diagnosis, about 50% of the patients have metastasis to the lymph nodes, liver or bones (for review see Maton et al, 1989a). Recently, visualization of enteropancreatic tumours in vivo after intravenous administration of a labelled somatostatin analogue has been reported (Lamberts et al, 1990). This new imaging technique which relies on the presence of somatostatin receptors on most of these tumours may become useful in localizing primary tumours and detecting metastases.
Clinical manifestations Most if not all of the symptoms due to localized gastrinomas are secondary to gastric acid hypersecretion. Indeed, increased gastrin production and hypergastrinaemia are responsible for thickening of the gastric mucosa, augmented parietal cell number and high gastric acid output. Both basal (normal <10mmol/h) and maximal acid output (normal values: 2050mmol/h) are elevated in patients with ZES (Maton et al, 1989b) with consequent peptic ulcerations of the oesophagus, stomach, jejunum and most frequently duodenum. Abdominal pain, characteristic of peptic ulcer, is the first complaint in most patients and usually originates from a single duodenal ulcer (Wolfe and Jensen, 1987), although multiple ulcers can be found in severe cases. Other common symptoms are due to reflux oesophagitis, watery diarrhoea, malabsorption and weight loss (Maton et al, 1989b). In these patients, gastric acid secretion can reach enormous volumes (up to 101) which will inactivate pancreatic enzymes, precipitate bile salts and damage the intestinal mucosa. The most dramatic complications, that are sometimes the initial manifestations, include intractable vomiting associated with pyloric stenosis, gastrointestinal bleeding and duodenal or gastric perforation. In rare cases, ectopic expression of adrenocorticotropin (ACTH) in gastrinomas can cause Cushing's syndrome (Maton et al, 1986).
Diagnosis ZES should be considered in any patient with persistent or recurrent peptic ulceration, severe oesophagitis, persistent diarrhoea or with any serious complications. The delay of 5.8 years between appearance of the first symptoms and definitive diagnosis indicates that ZES is not always considered in these situations (Kaplan et al, 1990). The most helpful screening test is measurement of fasting serum gastrin level (Wolfe and Jensen, 1987); normal gastrin levels virtually excludes the diagnosis of ZES, while elevated levels combined with high gastric acid output or low gastric pH should allow proper diagnosis (Figure 1). Localization of gastrinomas by CT scan and selective abdominal angiogram, although not often successful, should be attempted since complete resection of the tumour is associated with a 10-year survival rate in more than 90% of the patients, compared with much less favourable outcome when the tumour cannot be removed (Malagelada et al, 1983; Stabile and Passaro, 1985).
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Fasting serum gastrin < 150 pg/m~ ZES ruled out ] or 71 pmol/ i > 150 pg/ml
Basal acid output (BAO) ]or gastric pH pH>3.5or BAO < 5 mmol/h /
/
~
\
/ [ Achlorydria ]
pH<2or "~O> 15 mmoi/h
Gastric outlet obstruction Vagotomy Renal failure Bowel resection
[-~ • basal serum gastrin: > 1000 pg/m[ or >476 pmol/I • secretin test (2 U/kg i.v.): gastrin levels at -10, 0, 2, 5, 10min rise > 200 pg/ml or >50% increase over basal
Figure 1. Diagrammatic approach to Zollinger-Ellison syndrome.
Treatment of ZES
Management of acute complications Acute complications arise as a consequence of high gastric acid output. With availability of antagonists to histamine H2 receptors and H+-K + proton pump, acid output should be effectively controlled in most, if not all patients with ZES and acute complications prevented (Jensen, 1984; Maton et al, 1989c). Severe gastrointestinal bleeding and perforation are the most serious complications necessitating emergency surgery (for review see Miller, 1988). Diarrhoea and vomiting secondary to pyloric stenosis can lead to volume depletion, electrolyte disturbances and arrhythmias. In addition to their specific treatment, proper management of complications associated with gastric acid hypersecretion should include adequate control of acid output with H2 receptor or H+-K + proton pump antagonists (Saeed et al, 1989; Vinayek et al, 1990). Three H2 receptor antagonists are now widely available, both for intravenous (i.v.) and oral treatments and include cimetidine, ranitidine and famotidine, although famotidine has not been thoroughly evaluated in patients with ZES. A slow i.v. bolus injection of cimetidine (300 mg), ranitidine (150mg) or famotidine (20rag) should be followed by a constant infusion in 5% dextrose (starting at lmg/kg/h for cimetidine, 0.5 mg/kg/h for ranitidine and 0.1 mg/kg/h for famotidine). Acid output should be checked 3-4h later and, if greater than 10mmol/h (5 mmol/h for partially gastrectomized patients), infusion doses should be doubled until adequate control is obtained. Doses of 3 mg/kg/h cimetidine
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and 1 mg/kg/h ranitidine are sufficient in 70% of patients with ZES. Doses up to 7 mg/kg/h cimetidine and 4 mg/kg/h ranitidine have been given without significant side-effects (Maton, 1989a; Saeed et al, 1989), except in acutely ill patients or in patients with liver or kidney disease, where confusion and hallucinations have been reported. Furthermore, in patients with preexisting cardiac disease i.v. bolus injections should be slow (2-5 rain) since arrhythmias, asystole and hypotension can occur. Anticholinergic agents have been useful in cases where high doses of H2 receptor antagonists were not sufficient to control gastric acid output. However, in such situations, we recommend to switch to omeprazole. Omeprazole is the first antagonist directed at the H+-K + proton pump, thus acting at a very distal step of acid secretion. An initial i.v. injection of 60 mg should reduce acid output to less than 5 mmol/h within 24 h (Vinayek et al, 1990). A single dose is usually sufficient, although two divided doses are preferred, especially when large amounts (more than 60mg) are administered. Efficacy and convenient administration make omeprazole the drug of choice for the acute treatment of ZES. Intravenous administration of drugs is not only required for acute complications but also for patients unable to take oral medications (during elective surgery, chemotherapy or any cause of nausea and vomiting). Intravenous treatment should be continued for 24 h after the patient is able to resume oral medications. The total daily oral dose should correspond to 1.5 times the i.v. dose, but acid output should be checked. Surgical management of ZES is now mostly reserved for acute complications. Indications for total gastrectomy include severe and intractable gastrointestinal bleeding and perforation. Mortality during this emergency procedure is high (Miller, 1988).
Prevention of acute complications Control of gastric acid secretion should prevent most acute complications. Absence of symptoms is not a reliable parameter because it does not always correlate with suppressed acid production. It is thus necessary to lower acid output below 10 mmol/h (or 5 mmol/h in partially gastrectomized patients) throughout the day (Raufman et al, 1986; Maton et al, 1988); this can be assessed by measuring acid output just before the next dose of medication. Maintenance of gastric pH above 2 is an alternative (Vallot et al, 1983). In patients with severe peptic oesophagitis, these measures will not be sufficient since only 50% of strictures will heal when acid output is 1-10 retool/h; the majority of strictures will heal at an acid output below 1 mmol/h (Miller et al, 1990).
Medical options Both H 2 receptor antagonists (cimetidine, ranitidine, famotidine) and the antagonist of the proton pump (H+-K + ATPase), omeprazole, can be used in the chronic management of ZES. All H2 receptor antagonists can effectively lower acid output below 10mmol/h, although doses have to be individualized and periodically
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re-evaluated. However, differences in potencies, duration of action and side-effects exist between the different drugs. Famotidine is about 8-fold and 32-fold more potent than ranitidine and cimetidine, respectively (Howard et al, 1985). In addition, the duration of action of famotidine is about 1.3 times longer than either cimetidine or ranitidine; this may be of clinical value when doses have to be administered frequently. The major advantages of famotidine and ranitidine over cimetidine are their lack of antiandrogen effects (gynecomastia and impotence) and interference with hepatic drug metabolism (Wolfe and Jensen, 1987). To be effective in patients with ZES, doses of H2 receptor antagonists should be much higher than those recommended for the usual treatment of gastroduodenal ulcers. In recent studies, mean doses were 3.6g/day (range: 1.2-12.6g) for cimetidine, 1.2 g/day (range 0.45-6 g) for ranitidine and 0.25 g/day (range 0.05-0.8 g) for famotidine. Doses should be started at 300 rag, 150 mg and 40 mg every 6 h for cimetidine, ranitidine and famotidine, respectively, and doubled until acid output is below 10 mmol/h. When more frequent administrations are necessary, preference should be given to famotidine. Regular control of acid output is mandatory, as it is well established that many patients need increasing doses with time (Mignon and Bonfils, 1988). Whether this phenomenon reflects an increase in gastrin production induced by treatment, tumour progression, decreased sensitivity to treatment or delayed absorption remains to be determined. Although there is no major toxicity of H2 receptor antagonists, long-term usage may lead to hyperplasia of enterochromaffin cells and higher gastrin levels (Lehy et al, 1989). Indeed, rare cases of carcinoid tumours in patients with ZES and MEN-l, treated by H2 receptor antagonists, have been reported (Solcia et al, 1986). The implications of enterochromaffin cell hyperplasia are unknown. Omeprazole is the only available antagonist of the enzyme, H + - K + ATPase, which acts as a proton pump. It is a potent drug (50 mg is equivalent to 4 g of ranitidine) with a duration of action in excess of 48 h resulting in complete cessation of acid secretion. A once-a-day dose is generally sufficient, although up to 25% of patients may require two doses/24 h; daily doses range from 20 to 160 mg with a mean of about 70mg (Maton et al, 1989c). This is the treatment of choice for patients with severe oesophagitis since it can reduce gastric output below i mmol/h. There are no major toxic side-effects, although omeprazole may induce enterochromaffin cell hyperplasia. Carcinoid tumours have been reported in rat but not in man (Solcia et al, 1989). The long-acting somatostatin analogue, octreotide, is effective in controlling gastric acid output and, in a minority of patients can decrease or stabilize tumour growth. However, exceptions to this treatment have been reported. The exact role of octreotide in the management of ZES and gastrinoma is not clearly established, especially when considering its high cost and the efficacy of other treatments (Maton et al, 1989b).
Surgical options Total gastrectomy should only be considered for patients who are not
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compliant with drug treatment or whose basal acid output cannot be suppressed despite maximal medical management. Highly selective vagotomy should be reserved for the occasional patient with unusually high drug requirements. Vagotomy abolishes the cephalic phase of gastric acid secretion and can decrease basal acid output by 40% in patients with ZES. However, this procedure is not effective in many patients and its long-term effects on acid secretion have not been adequately assessed (Richardson et al, 1985). CARCINOID SYNDROME Definition
The carcinoid syndrome occurs at a frequency of about 3-4 cases/million/ year and results from the production and release of biologically active substances by carcinoid tumours. The cardinal manifestations are flushing, diarrhoea, asthma and endomyocardial fibrosis. Carcinoid tumours arise from enterochromaffin cells, principally of the gastrointestinal tract, pancreas and lungs, but occasionally of the thymus and gonads. Histochemical and functional heterogeneity of these cells may be related to their site of origin (embryonic foregut, midgut and hindgut), which may be of clinical relevance for the diagnosis and symptomatology of carcinoid tumours (Maton, 1988; Kvols, 1989). The carcinoid syndrome occurs in 6--18% of patients with carcinoid tumours and is seen most commonly with tumours originating from the jejunum, ileum and right colon (midgut origin) (Feldman, 1987). Patients with the carcinoid syndrome almost invariably have hepatic metastasis (95%). Bioactive substances synthesized within the liver are directly released into the systemic circulation bypassing hepatic inactivation. In contrast, substances released from the primary tumour into the portal circulation are efficiently metabolized by the liver. Clinical manifestations can also result from massive nodal metastasis which may rarely saturate the capacity of the liver or, in the absence of metastasis, from bronchial or ovarian carcinoids which release their products directly into the systemic circulation (Vinik et al, 1989). Clinical manifestations
Flushing is the most characteristic symptom that occurs in at least 75% of patients with the carcinoid syndrome. Frequency, duration and severity of flushing can vary from patient to patient. Episodes may occur spontaneously or be precipitated by foods, alcohol, exercise or stress. Diarrhoea is as common as flushing and may occur regularly shortly after meals or sporadically at any time. It may be sufficiently severe to lead to electrolyte abnormalities and volume depletion, especially when associated with Cushing's syndrome due to ectopic ACTH and/or CRF production by the carcinoid tumour. Heart disease caused by fibrosis of the endocardium is a late manifestation
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of the disease and occurs in a third of the patients. Endomyocardial fibrosis typically involves the right side of the heart with the potential consequences of pulmonic stenosis and tricuspid regurgitation. Rare patients may have more generalized fibrosis involving vessels, skin and retroperitoneum. Less common manifestations include asthma or wheezing and a pellagroid rash (secondary to the diversion of tryptophan for serotonin synthesis leading to reduced availability of tryptophan for synthesis of protein and nicotinamide) (Vinik et al, 1989). Mediators involved in the clinical manifestations of the syndrome have not been clearly identified. Serotonin production, however, is nearly always increased and may be responsible for diarrhoea, asthma and endomyocardial fibrosis. Potential mediators of the carcinoid flush include kallikrein, histamine, substance P, prostaglandins, dopamine and neurotensin (Norheim et al, 1986; Conlon et al, 1987). In patients with the carcinoid syndrome, the diagnosis can be established by measuring the urinary excretion of 5-hydroxyindolacetic acid (5-H1AA), a serotonin metabolite. A 24 h urinary excretion of more than 150 p~mol/1 is diagnostic. However, carcinoids arising from enterochromaffin cells derived from the foregut may produce 5-hydroxytryptophan rather than serotonin and have normal urinary values of 5-HIAA (Maton, 1988).
Carcinoid crisis This is the most serious manifestation of the carcinoid syndrome and it can be lethal. It can occur spontaneously but more commonly be triggered by a diagnostic procedure, anaesthesia, surgery or following initiation of chemotherapy. Hypotension, hypertension, severe flushing, arrhythmia, confusion or coma are the principal signs. They may last for a few hours to several days. Management of carcinoid crises has been particularly difficult despite adequate fluid replacement and vasopressor administration (Kvols, 1989). Treatment of the carcinoid syndrome
Surgery Surgery may be considered as a curative or palliative treatment. Surgery may result in a cure in the presence of localized bronchial or ovarian carcinoid tumours. More commonly, surgery is palliative. The indolent behaviour of carcinoids and the poor results of chemotherapy are good reasons to consider a debulking procedure or removal of the primary turnout to alleviate both local (small bowel or bronchial obstruction, bleeding) and systemic manifestations.
Medical management Diarrhoea will often respond to codeine phosphate, loperamide or diphenoxylate. More specific measures should sometimes be considered, such as the use of antibiotics for bacterial overgrowth and cholestyramine for bile
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salt spillage. Asthma should be managed by [32-adrenergic agonists. When simple measures are not effective at controlling symptoms, alternative therapies must be sought. Three classes of drugs may be useful to control the carcinoid syndrome (Maton, 1988; Harris and Smith, 1982): 1. 2. 3.
The a-adrenergic antagonist, phenoxybenzamine 10-30rag/day, can control flushing. For flushing induced by gastric carcinoid, the use of diphenhydramine (50 mg every 6 h) and cimetidine (300 mg every 6 h) can be useful. Antagonists of 5-hydroxytryptamine receptors, such as cyproheptadine (4-8 mg every 6 h), ketanserin (20-40 mg every 12 h) and methysergide (3-9 mg every 12 h) can ameliorate the diarrhoea.
This list is not exhaustive and other medications, such as glucocorticoids may prove useful to decrease diarrhoea or flushing Moertel, 1983).
Somatostatin analogues Octreotide, a long-acting somatostatin analogue, ~s the most important recent advance in the treatment of the carcinoid syndrome. Somatostatin had previously been shown to control effectively acute symptoms of the carcinoid syndrome; with the availability of the long-acting octreotide, chronic management of these symptoms, even when severe, is now feasible. octreotide relieves diarrhoea, flushing and wheezing in 80-90% of the patients, this effect being associated with a 50% reduction in urinary 5-HIAA excretion. It is thus the most effective single medication. However, its effect on tumour mass is much less spectacular since shrinkage of the measurable mass by at least 50%, as assessed by CT scan, occurs in less than 20% of the patients (Maton, 1988; Kvols, 1989). Octreotide has also been successfully used to prevent or treat carcinoid crisis. All patients undergoing surgery, chemotherapy or hepatic arterial devascularization should receive octreotide at a dose of 200-250 txg every 6-8 h subcutaneously over a period of 48 h followed by a dose 1-2 h before the procedure. With this approach, initiation of chemotherapy can be done with full doses of cytotoxic drugs. For treatment of carcinoid crisis, in addition to the usual measures to control blood pressure and arrhythmias, octreotide should be administered i.v., 100-500 ~g, followed by a continuous infusion or s.c. injections every 4-6h (Kvols et al, 1987; Marsh et al, 1987; Roy et al, 1987). VIPOMAS Definition
Watery diarrhoea, hypokalaemia and achlorhydria (WDHA) characterize the syndrome associated with tumours releasing high amounts of vasoactive intestinal peptide (VIP). Most of these tumours arise from the pancreas but elevated levels of VIP can also be found with other tumours, such as
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pheochromocytomas, ganglioneuromas, neuroblastomas and bronchogenic carcinoma. When VIP was found in submucosa of the intestinal tract to stimulate chloride secretion in the lumen, it became apparent that VIP was a paracrine neuromodulator of intestinal function. In patients with high plasma VIP levels, intestinal secretions are potently stimulated and electrolyte absorption probably inhibited (Mekhjian and O'Dorisio, 1987). Clinical manifestations
Most of the manifestations of VIPomas can be explained by the elevated levels of VIP. The severe secretory diarrhoea and metabolic acidosis are the consequences of an increased intestinal secretion induced by VIP. VIP also inhibits gastric acid secretion causing achlorhydria and induces glucose intolerance by stimulating hepatic glycogenolysis. Hypokalaemia is the combined result of passive movement of K-- into the intestinal lumen and hyperaldosteronism secondary to volume depletion and VIP-induced hyperreninaemia. Flushing of the upper part of the body, hypercalcaemia and hypomagnesaemia can also be seen in a minority of patients (Mekhjian and O'Dorisio, 1987; O'Dorisio et al, 1989). Diagnosis is confirmed by an elevated fasting VIP plasma level (> 200 pg/ml), increased faecal weight (> 500 g/24 h) and persistence of diarrhoea despite prolonged fasting (Mekhjian and O'Dorisio, 1987). Treatment
The first objective of the treatment is to replace the important fluid losses resulting from diarrhoea; severe volume and electrolyte depletion accompanied by metabolic acidosis may often be the presenting symptoms. Intravenous fluids, such as NaC1 0.9% supplemented with KC1, are part of the management to correct hypotension, volume depletion and hypokalaemia. It is also critical to provide, once the acute symptoms are controlled, enough calories to reverse the catabolic state. Medical management Somatostatin is a potent inhibitor of VIP effects. It directly inhibits VIP release and decreases the VIP-induced chloride secretion. Both somatostatin and its analogue, octreotide, have been effective in controlling watery diarrhoea, although with advanced disease, increasing doses are often necessary. Along with the amelioration of the clinical symptoms, VIP levels often decrease, but rarely normalize. Owing to its efficacy in most patients, octreotide has become the treatment of choice for VIP-induced diarrhoea (Gaginella, 1990). Glucocorticoids, such as prednisone (60rag/d) have been extremely helpful in the past to treat severe diarrhoea; they inhibit VIP release and may decrease intestinal secretion and enhance absorption. They are still occasionally used when octreotide is not sufficient to control symptoms (Lennon et al, 1975; Benson et al, 1986).
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Surgery Surgical treatment needs to be considered as a second step once the patient has been able to regain some weight. When the tumour can be localized (generally in the distal two-thirds of the pancreas), it can be curative. However, when metastatic disease is already present, a debulking procedure may be offered both to decrease symptoms and to increase the likelihood of responding to chemotherapy. MEDULLARY CARCINOMA OF THE THYROID Definition
Medullary carcinoma of the thyroid (MCT) originates from thyroid parafollicular C cells whose major secretory product is calcitonin. MCT may occur sporadically or b e inherited as a single disease or in the context of MEN-2. Severe diarrhoea and occasionally flushing may occur when metastases are present. The humoral substances responsible for these symptoms have not been clearly identified, although calcitonin, prostaglandins, serotonin and VIP have been implicated (Wells et al, 1985). Treatment of diarrhoea
Diarrhoea associated with MTC can be extremely severe and result in volume depletion, hypotension and hypokalaemia. Apart from the standard antidiarrhoeal agents which should be tried, bromocriptine and octreotide have been used successfully in a few patients (Emmertsen et al, 1981; Keeling and Basso 1988). Their efficacy in large-scale trials remains to be demonstrated. SUMMARY
APUDomas are rare tumours originating from a variety of endocrine cells localized in different organs. Acute complications from APUDomas usually result from the increased biosynthesis and release of bioactive amines or polypeptide hormones by the tumour. Less frequently, bleeding or compression by the tumour can occur requiring emergency surgery. Increased gastrin production by gastrinomas is the cause of ZES (peptic ulceration and diarrhoea) by gastrin effects on gastric acid secretion. Volume depletion, hypokalaemia, severe bleeding, duodenal perforation, oesophageal stricture and pyloric stenosis are the most dramatic complications. Treatment of these complications and their prevention has been facilitated by the availability of antagonists to H2 receptors and H + - K + proton pump. These medications should control acid output in every patient with ZES. Frequent manifestations of carcinoid tumours, VIPomas and medullary thyroid carcinomas are flushing and diarrhoea. Octreotide, a long-acting
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somatostatin analogue, has markedly changed the management of these patients, their symptoms decreasing in severity or disappearing in most cases. Octreotide has also been used with success in the prevention and treatment of the carcinoid crisis, a dreaded complication of carcinoid tumours. A better understanding of the pathophysiology of APUDomas has enabled new treatment designs which have considerably ameliorated the quality of life of patients affected by these tumours; efforts must be continued to affect their life expectancy. REFERENCES Benson GD, O'Dorisio TM, Ellison EC et al (1986) Control of watery diarrhea syndrome in a patient with a VIP-secreting tumor using SMS 201-995 and dexamethasone. Scandinavian Journal of Gastroenterology 119 (supplement 21): 170. Conlon JM, Deacon CF, Richter G et al (1987) Circulating tachykinins (substance P, neurokinin A, neuropeptide A) and the carcinoid flush. Scandinavian Journal of Gastroenterology 22: 95-105. Emmertsen K, Mosekilde L, Nielsen HE &Hansen HH (1981) Bromocriptine reduces diarrhea in medullary thyroid carcinoma. Hormone and Metabolic Research 13: 301-302. Feldman JM (1987) Carcinoid tumors and syndrome. Seminars in Oncology 14: 237-246. Gaginella TS, O'Dorisio TM, Fassler JE & Mekhjian HS (1990) Treatment of endocrine and nonendocrine secretory diarrheal states with Sandostatin. Metabolism 39 (supplement 2): 172-175. Harris AL & Smith IE (1982) Regression of carcinoid tumors with cyproheptadine. British Medical Journal 285: 475. Howard JM, Chremos AN, Collen MJ et al (1985) Famotidine, a new potent long acting histamine H2 receptor antagonist: comparison with cimetidine and ranitidine in the treatment of Zollinger-Ellison syndrome. Gastroenterology" 88: 1026-1033. Jensen RT (1984) Basis for failure of cimetidine in patients with Zollinger-Ellison syndrome. Digestive Diseases and Sciences 29: 363-366. Kaplan EL, Horvath K, Udekwu K et al (1990) Gastrinomas: a 42-year experience. World Journal of Surgery 14: 365-375. Keeling CA & Basso LV (1988) Iodine-131 MIBG uptake in metastatic medullary carcinoma of the thyroid. A patient treated with somatostatin. ClinicalNuclear Medicine 13: 260-263. Kvols LK (1989) Therapy of the malignant carcinoid syndrome. Endocrinology and Metabolism Clinics of North America 18: 557-568. Kvols LK, Maples WJ & O'Connell MJ (1987) Carcinoid crisis: successful treatment and prevention with somatostatin analogue (SMS 201-995). Proceedings of the American Society of Clinical Oncology 6: 96. Lamberts SWJ, Bakker WH, Reubi JC & Krenning EP (1990) Somatostatin-receptor imaging in the localization of endocrine tumors. New England Journal of Medicine 323: 1246-1249. Lehy T, Mignon M, Cadiot G e t al (1989) Gastric endocrine cell behavior in Zollinger-Ellison syndrome patients upon long-term potent antisecretory treatment. Gastroenterology 96: 1029-1040. Lennon JR, Sircus W, Bloom SR et al (1975) Investigation and treatment of a recurrent VIPoma. Gut 16: 821-824. Malagelada JR, Edis AJ, Adson MA et al (1983) Medical and surgical options in the management of patients with gastrinomas. Gastroenterology 84: 1524-1532. Marsh HM, Martin JK, Kvols LK et al (1987) Carcinnid crisis during anesthesia: successful treatment with a somatostatin analogue. Anesthesiology 66: 89-91. Maton PN (1988) The carcinoid syndrome. Journal of the American Medical Association 260: 1602-1605. Maton PN, Gardner JD &Jensen RT (1986) Cushing's syndrome in patients with the ZollingerEllison syndrome. New England Journal of Medicine 315: 1-5.
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