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The Diabetes Institute and the Division of Surgical Oncology Eastern Virginia Medical School Norfolk, Virginia 23510
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Introduction |
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 Top Introduction Management of parathyroid...Management of islet-cell...References |
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). The main controversies in MEN-1 patients concern the management of
parathyroid disease and the various islet-cell hyperfunctioning
syndromes. The benign nature of hyperparathyroidism contrasts with the
malignant potential of gastrinomas and the lethal potential of organic
hyperinsulinism. The medical approach to each is, perforce, quite
different.
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Management of parathyroid disease |
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TopIntroductionManagement of parathyroid...Management of islet-cell...References |
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According to the Consensus Development Panel (5), to qualify for nonsurgical management, a patient must have a serum calcium that is only mildly elevated, no previous episodes of life-threatening hypercalcemia, and normal renal and bone status. Forgoing surgery requires conscientious follow-up and monitoring of mental status, depression, neuromuscular weakness, renal function and presence of kidney stones, peptic ulcer disease, and worsening hypercalcemia. A rise in calcium of more than 1.6 mg/dL, impairment of creatinine clearance, increasing calciuria, and renal stones on abdominal x-ray, as well as a loss of bone density of more than 2 SD for age- and sex-matched individuals are causes for surgical intervention. Patients must learn to avoid dehydration, immobilization, excess calcium intake, and loop or thiazide diuretics. They must immediately seek medical advice for any illness with potential for dehydration, e.g. vomiting and diarrhea. Hyportension must be treated aggressively. Estrogens may be of value in postmenopausal women, lowering calcium without stimulating parathyroid hormone secretion.
Unfortunately, persistence or recurrence of hypercalcemia after surgical resection is not uncommon. Some investigators have noted excellent results after subtotal parathyroidectomy, with long-term recurrence of hypercalcemia in only 16–30% of patients (6). However, persistence or recurrence of hypercalcemia has been noted in 40–80% of patients in other series. To minimize the risk of persistent or recurrent hypercalcemia, we favor an aggressive surgical approach, consisting of total parathyroidectomy and transcervical thymectomy, along with parathyroid autotransplantation into the forearm as described by Wells, et al. (7). Although this approach is associated with a somewhat higher incidence of hypoparathyroidism (5.6%), it can be managed with the use of oral calcium agents and vitamin D analogues as required. With the advent of ultrasound, venous sampling, angio-graphy, and Tc-99 m pertechnetate/Tc-99 m sestamibi imaging, improved localization of the 5% of cases not found by the surgeon at initial operation may be feasible (8). Using these techniques, surgically missed adenomas can be successfully localized in approximately 93% of cases, whereas only 60% of hyperplastic glands can be localized (9). Thus, double phase Tc-99 M (sestamibi) imaging is a promising technique of localization of parathyroid adenomas in MEN-1 patients, but localization of multiple hyperplastic glands, the rule in MEN-1, remains a challenge and dictates a need to examine conservative therapies for this subset of patients. Medical management is indicated for MEN-1 patients with hypercalcemia that persists or recurs after parathyroidectomy by an experienced endocrine surgeon. This applies particularly to patients in whom multiple surgical efforts have been unsuccessful.
The acute management of these patients is similar to patients with other causes of hypercalcemia (5). Avoidance of dehydration is a cornerstone of management. If the patient is symptomatic and dehydration is severe, then intravenous rehydration with normal saline is indicated. If the patient is on thiazide diuretics, these should be discontinued. Oral phosphate preparations have rather modest effects at best, and their use is limited by gastrointestinal toxicity including nausea and diarrhea.
Chronic therapy for hypercalcemia in surgical failures requires the same vigilance for confounding factors as discussed above under nonsurgical management. Unfortunately, the older agents have not proven effective for the treatment of hypercalcemia due to hyperparathyroidism. The results with the use of calcitonin alone have been disappointing. However, combination therapy with a bisphosphonate or plicamycin has been more successful. Plicamycin causes gastrointestinal, bone marrow, renal, and hepatic toxicities, which usually limit its duration of use. Whether or not agents such as the bisphosphonates (used successfully to treat the hypercalcemia of malignancy), Alendronate or Pamidronate will prove useful in patients with hypercalcemia caused by primary hyperparathyroidism that has been refractory to other measures, and in patients who are not candidates for surgery because of severe concurrent disease remains to be determined.
Parathyroidectomy is also beneficial in MEN-1 patients with hyperparathyroidism and gastrinoma. After successful parathyroidectomy in these patients, fasting serum gastrin levels and gastric acid secretion are frequently reduced, facilitating their management with lower doses of H2 receptor antagonists (10). For this reason, parathyroidectomy has been advocated as the initial procedure of choice in MEN-1 patients with primary hyperparathyroidism and gastrinoma. However, this is less of an issue since the development of more powerful antisecretory drugs such as omeprazole.
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Management of islet-cell hyperfunction |
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TopIntroductionManagement of parathyroid...Management of islet-cell...References |
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Gastrinoma is the most common islet-cell neoplasm in patients with MEN-1. The management of patients with MEN-1 and gastrinoma is primarily medical. Because of the diffuse nature of the adenomas, which are frequently small and undetectable, cure is seldom achieved surgically. These patients may also have multiple duodenal wall gastrinomas, similar to patients with sporadic disease (12). In most patients, medical management using H2 blockers and/or the potent inhibitor of the gastric acid proton pump, omeprazole, can effectively control acid hypersecretion. The dosage of H2 blockers required to control acid hypersecretion varies from patient to patient. The use of omeprazole either alone or together with H2 blockers has supplanted the need for the high doses of H2 blockers often required in the past. The usual dose of omeprazole is 80 mg per day, but can vary between 60 and 120 mg per day (13). Relief of symptoms alone is insufficient to judge the adequacy of the dose of H2 blockers and/or omeprazole. Control of gastric acid hypersecretion must be confirmed by direct measurement. Omeprazole is currently the drug of choice in the management of gastrinoma. Use of the long-acting somatostatin analogue octreotide has had variable results and frequently does not result in a decrease of serum gastrin levels. The hope that arrest of growth of tumor cells and reduction of hyperplasia would be induced by the analogue of somatostatin has, unfortunately, not materialized.
Security with medical management of hypergastrinemia was based upon the notion that the incidence of malignancy in gastrinoma patients with MEN-1 was relatively low compared with patients with sporadic gastrinomas. With improvements in the management of MEN-1 patients, it has become apparent that the incidence of malignancy may indeed be higher than the 7–12% originally described for this syndrome (4). In a recent report, the incidence of malignancy was 47%, which is similar to that of patients with sporadic gastrinoma (11). Thus, although gastric acid secretion can be controlled medically in most patients, the safety of long-term usage of powerful antisecretory medications has not been established, and the fear of long-term malignancy is real (13). In addition, persistent hypergastrinemia is associated with a variety of undesirable effects, including gastric enterochromaffin-like (ECL) cell proliferation and the development of gastric carcinoid tumors (14). For these reasons, we believe that surgical exploration is justified in highly selected MEN-1 patients. Even with an abnormality on an imaging study, namely angiography or octreoscan, it cannot be assumed that the tumor visualized is the source of gastrin excess; hyperfunction of the radiographic abnormality must be demonstrated before surgery. An anatomically localized source of gastrin can sometimes be identified using transhepatic portal venous sampling (THPVS), selective intraarterial injection of secretin combined with angiography and sampling of hepatic vein gastrin levels (15), as well as other techniques. We have found localized sources of gastrin in about 25% of MEN-1 patients using THPVS (16). Enucleation or resection in such patients may offer excellent palliation, and occasionally, cure. Particular attention must be paid to the duodenum, as it may be a site for a missed gastrinoma in MEN-1 patients (17).
Unfortunately, cure is seldom achieved in MEN-1 patients with gastrinoma. In a recent series of 19 MEN-1 patients, 17 underwent abdominal operations, including pancreatic resection or tumor enucleation. Only one of these patients was biochemically cured (17). In another series, only 1 of 29 MEN-1 patients who survived surgical exploration was biochemically cured (11). Our early results were somewhat better, with surgical resection achieving a biochemical cure in 4 out of 6 MEN-1 patients. Our long-term data show that surgical resection has produced a reduction in serum gastrin in 10 of 11 (91%) patients, but produced a cure with negative secretin tests in only 3 of 11 MEN-1 patients (17). This may be the result of very careful patient selection using THPVS and careful duodenal exploration including duodenotomy. Patients with diffuse or multiple sources of gastrin secretion should not undergo surgical exploration. Despite the difficulty in achieving surgical cure, MEN-1 patients have a better prognosis than patients with sporadic gastrinoma, with 20-yr survival rates of 58%, compared with 31%, in the latter (18). Thus we believe that the primary form of management in these patients is medical, with surgery reserved for those patients who are good surgical risks and in whom a well-defined source of gastrin is identified. The hope that radioactive octreotide could be used ablatively has thus far not materialized. However, the identification of multiple subtypes of somatostatin receptors on endocrine tumors promises renewed vigor in the search for new medical treatments for these tumors.
Insulinoma is the second most common pancreatic islet-cell tumor in patients with MEN-1. However, the management of insulinoma in MEN-1 patients differs significantly from that of gastrinoma in several important respects. Unlike gastrinoma, these tumors occur exclusively in the pancreas. Although these patients also have hyperplasia or multiple adenomas, the source of insulin hypersecretion is usually solitary (19) and is usually easily identified using THPVS or selective intraarterial secretion of calcium combined with sampling of hepatic vein insulin levels. Although hyperinsulisim in MEN-1 patients may also be caused by microadenomas, ß-cell hyperplasia, or nesidioblastosis, these have been uncommon in our experience (20). Hyperplasia and multiple adenomas can be distinguished from single adenomas on the basis of the insulin response to secretin (21). Because the medical management of hyperinsulinism is usually less than satisfactory, we believe that a surgical approach with enucleation and/or resection of the functional tumor or region should be performed as indicated. Some have advocated a more aggressive approach with distal subtotal pancreatectomy combined with enucleation of all adenomas in the pancreatic head. In one such study, cure was achieved in 17 of 18 patients (22). We have found such an approach unnecessary in most patients. Surgical cure is possible in most MEN-1 patients with insulinoma. Nonetheless, careful long-term follow-up is required, as some patients will develop hyperinsulinism from metastatic disease or from another insulinoma.
Medical management is indicated for the occasional patient in whom a single source of hyperinsulinism cannot be identified, for patients who are extremely poor surgical risks, or for patients who have failed surgical management. Management is similar to that of patients with sporadic insulinoma (4). Dietary measures include more frequent meals with snacks. Slowly absorbable forms of carbohydrates including starches, bread, potatoes, and rice are recommended. During hypoglycemic episodes, rapidly absorbable forms of glucose, such as those contained in fruit juices, are indicated. The most commonly used medications include diazoxide and natriuretic benzothiadiazines. Diazoxide promotes hyperglycemia by directly inhibiting insulin release and by indirectly enhancing glycogenolysis, in part the result of sympathetic activation. The dose of diazoxide required to manage the hypoglycemia of insulinoma typically ranges from 150–600 mg per day. Edema can be relieved by a thiazide or loop diuretic, which enhances the action of diazoxide. Nausea has been noted at higher doses, and hypertrichosis can occur with long-term treatment.
Other medications that have been used upon occasion for the management of hyperinsulinism include calcium channel blockers, propranolol, Dilantin, glucocorticoids, and glucagon. Propranolol should be used with extreme caution because it can mask the adrenergic symptoms of hypoglycemia and inhibit muscle glycogenolysis, potentially resulting in neuroglycopenia. The use of octreotide has had variable results that are not easily predictable. Routine use of octreotide is generally not recommended in these patients. However, if use of octreotide is necessary, then it should be used with extreme caution, as anecdotal reports suggest that it may induce severe hypoglycemia if the insulinoma lacks somatostatin receptors, and suppression of counterregulatory hormones, namely glucagon, hGH, ACTH, and epinephrine occurs. The use of ß-cell poisons such as streptozotocin, so effective in causing diabetes in animals, has not been greeted favorably because of general toxicity.
Finally, the usefulness of measuring pancreatic polypeptide (PP) levels in patients with MEN-1 has been questioned. Friesen and Kimmel (23) have suggested that an elevated level of PP in an MEN-1 patient indicates the presence of an islet-cell tumor and that such a patient should undergo pancreatic exploration.. However, PP levels may become elevated with increasing age, diabetes, chronic renal failure, pancreatitis, other pancreatic tumors, and other causes. Elevated PP levels are associated with islet-cell hyperplasia alone. Also the adenoma that is secreting PP may not be related to the clinical syndrome. We have not found measurement of PP levels to be particularly useful in the management of MEN-1 patients and do not feel that these patients should be subjected to surgical exploration solely on the basis of an elevated PP level, as frequently in this setting no tumor will be found (4). Others have also questioned the usefulness of measuring PP levels in patients with MEN-1. In the study of Langstein et al. (24), nearly half of MEN-1 patients with islet-cell tumors did not have elevated PP levels, and in those with elevated PP levels, measurement of post-operative levels did not reliably predict resection of the tumor. However, an elevated PP level in a patient with a pancreatic tumor should raise the flag for possible MEN-1.
We cannot deny that surgery remains the mainstay of management of patients with MEN-1 in most instances. With the identification of genes involved, cases will be recognized earlier in family members, dictating a need for better forms of medical therapy and surveillance. Hopefully, new pharmacotherapeutic agents as potent as the proton pump inhibitors for gastric acid secretion will surface on the horizon and expand the role of the clinical endocrinologist in medical treatment of patients.
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References |
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TopIntroductionManagement of parathyroid...Management of islet-cell...References |
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