Causes of Failed Initial Exploration for Hyperparathyroidism

HPT following a prior cervical or mediastinal exploration for hypercalcemia can be divided arbitrarily into persistent (defined as hypercalcemia recurring within 6 months after initial operation) or recurrent (hypercalcemia recurring after 6 months of normocalcemia following initial operation).2 3 The former denotes missed pathology and the latter refers to newly developed pathology. The distinction of these two categories has been loosely applied since it is possible that a physiologically...

Synthesis of Thyroid Hormone

After uptake into the follicular cells through the basal membrane (Fig. 1-2), inorganic iodide is rapidly oxidized. Thyroid hormones are then synthesized by the combination of iodine with tyrosyl residues within the protein thyroglob-ulin. This reaction is catalyzed by thyroperoxidase in two principal steps. In the first reaction, iodide reacts with FIGURE 1-2. Uptake of iodide into the follicular cell by active transport, with subsequent iodide oxidation, tyrosine iodination, and iodotyrosine...

Genetic Testing for Hereditary MTC

Germiine defects in the RET protooncogene are responsible for MEN 2A, MEN 2B, and FMTC.4143 RET encodes a transmembrane growth neurotrophic receptor with tyrosine kinase activity. In MEN 2A and FMTC, gain-of-function mutations within codons specifying cysteine residues in the extracellular ligand-binding domain of the RET gene product are most commonly found (see Table 15-2). In MEN 2B, a mutation is found in the intracellular tyrosine kinase domain. Changes in protein structure and function...

Diagnosis of Primary Hyperparathyroidism

The biochemical diagnosis of primary hyperparathyroidism is made by documenting an elevated serum PTH in a patient with hypercalcemia (serum calcium > 10.5 mg dL) without hypocalciuria. Patients with benign familial hypocalciuric hypercalcemia (BFHH) are also hypercalcemic and have an inappropriately high PTH. Virtually all patients with other causes of hypercalcemia have a suppressed serum PTH level. Patients with BFHH have elevated levels of PTH in the presence of hypercalcemia because of...

Clinical and Pathologic Characteristics

Although it may arise sporadically, MEN 2B more frequently occurs as a familial disorder inherited in an autosomal dominant fashion. MEN 2B is less common than MEN 2A. FIGURE 83-2. A diagram of the ret protooncogene demonstrating both highly conserved elements and sites of mutation known to be responsible for sporadic and familial medullary thyroid carcinoma (MTC) as well as the multiple endocrine neoplasia (MEN) 2 syndromes. Vertical bars within the diagram indicate sites of cysteine codons....

Pathology

Pancreatic endocrine tumors are commonly termed neuroendocrine tumors. However, some researchers indicate that it is unclear whether these tumors originate from the pancreatic islets.3 Pancreatic endocrine tumors may contain ductu-lar structures may produce hormones that are not produced by the normal pancreas, including gastrin and vasoactive intestinal polypeptide (VIP) and may produce more than one hormone.35 These findings suggest that pancreatic endocrine tumors originate from...

Surgical Treatment of Recurrent or Persistent Medullary Thyroid Cancer

Because of the lack of success reported for other modalities in the treatment of persistent or recurrent MTC, surgical FIGURE 15-5. A, Computed tomography (CT) of liver from patient with multiple endocrine neoplasia type 2A, recurrent medullary thyroid carcinoma (MTC), and elevated calcitonin levels. There is no evidence of liver metastases on the scan. B, Laparoscopic view of liver from the same patient showing multiple small raised whitish lesions on and just beneath the surface of the liver,...

Image Diagnosis of Medullary Cancer

All patients with a preoperative diagnosis of medullary cancer of the thyroid should be tested for a ret protoonco-gene germline point mutation and also be screened for pheochromocytoma and hyperparathyroidism (see other chapters regarding medullary thyroid cancer, pheochromocytoma, and hyperparathyroidism). Medullary cancer secretes calcitonin and carcinoembryonic antigen (CEA) and occasionally neuron-specific enolase, serotonin, chromogranin, gastrin-releasing peptide, substance P,...

Imaging of Metastases of Thyroid Cancer with Fluorine 18 Fluorodeoxyglucose

FDG is a D-glucose analog, which is converted in cells to FDG-6-phosphate by hexokinase. FDG-6-phosphate is metabolically trapped and accumulates in tissue where glucose-6-phosphatase is lacking. Metabolic trapping is the key factor responsible for the biodistribution of 18F-2-deoxyglucose.109 Because other enzymes that act on glucose-6-phosphate have only a negligible affinity for FDG-6-phosphate and membrane permeability is low, the rate of accumulation of FDG-6-phosphate is proportional to...

Molecular Carcinogenesis

The pathogenesis of radiation-induced thyroid cancer has not yet been elucidated. Gene rearrangements may play an important role in the process. Nikiforova and associates found that radiation-induced tumors had a 4 prevalence of BRAF point mutations and a 58 prevalence of RET PTC rearrangements, and sporadic papillary thyroid cancers demonstrated a 37 prevalence of BRAF point mutations and only a 20 prevalence of RET PTC rearrangements.34 Similarly, RET PTC3 rearrangement was found in...

NonMEN Familial Hyperparathyroidism and Parathyroid Cancer

Both parathyroid cancer and NMFH are rare parathyroid disorders. The association of these rare conditions suggests a common cause. Until 2002, 29 patients with NMFH and parathyroid cancer in 22 families were reported.16,21,23,27*33,35,43 Sixteen of these families have NMFH-JT or FIH-JT, and about one fourth of reported NMFH families have one or two affected members suffering from parathyroid cancer. Endocrinologists and surgeons should be aware of this association for proper management of these...

Adrenal Neoplasia and Hyperplasia

Thirty-five percent to 40 of MEN 1 patients harbor adrenocortical lesions, and these are clearly overrepresented in the MEN 1 syndrome.1517 Most lesions are hyperplastic, bilateral, and nonfunctioning. Aldosterone- and cortisol-secreting adenomas, however, have been reported.1517 Hypercortisolism in MEN 1 can be the result of an ACTH-secreting pituitary process, a cortisol-secreting adenoma carcinoma or, rarely, due to an adrenocorticotropic hormone (ACTH)- or corticotropin-releasing...

Adrenocortical Carcinoma

Adrenocortical carcinoma is a rare malignant disease with a dismal prognosis and an estimated incidence of 0.5 cases per 1 million individuals per year.45 Patients with nonfunctioning tumors have manifestations attributable to a large abdominal mass. Forty percent to 70 of adrenocortical carcinomas are secretory,4546 and these patients usually present with clinical features of hormone excess. The clinical features depend on the predominant excess steroid production glucocorticoid-secreting...

Advantages and Disadvantages

It is difficult to assess the advantages offered by minimally invasive parathyroid surgery because of the many different techniques considered minimally invasive. Similarly, conventional parathyroidectomy includes both bilateral and unilateral explorations. Furthermore, early sporadic reports of minimally invasive parathyroidectomy included only few cases that had inadequate follow-up and were not prospective studies. Possible advantages include cosmetic outcome and postoperative distress....

Assessment of Cure and Followup

Several reports suggest that at least one half of all Z-E syndrome patients explored, with the expectation to extirpate tumor and cure, continue to have hypergastrinemia postoperatively.84'96 Typically, a small duodenal gastrinoma or lymph node containing tumor has been excised, but an elevated serum gastrin level indicates that more tumor remains. A follow-up plan is needed for such patients. Should such a patient be re-explored or monitored Should re-exploration be done only when localizing...

Autoregulatory Mechanisms

The thyroid can also control its own stores of thyroid hormone by intrinsic autoregulatory mechanisms. These mechanisms are principally seen in response to alterations in iodide availability. For example, an excess of dietary iodide leads to autoregulated inhibition of iodide uptake into the follicular cells, whereas iodide deficiency results in increased iodide transport and uptake. Large doses of iodide have more complex effects, including an initial increase followed by a decrease in...

Benefits of Parathyroidectomy in Patients with Primary Hyperparathyroidism

Patients with untreated primary hyperparathyroidism have an increased risk of death from cardiovascular disease and cancers. This increased risk of death is similar in magnitude to that associated with smoking, and the risk appeared to correlate with parathyroid tumor size and the peak calcium level.17,18 Parathyroidectomy benefits most patients with primary hyperparathyroidism. Muscle strength and fine motor function19 as well as psychiatric symptoms20 improve within 1 month after...

Bone Disease

Although historically most patients with normocalcemic hyperparathyroidism were identified because of renal calculi, an increasing number of patients have recently been identified by screening patients for osteoporosis with dual-energy x-ray absorptiometry (DEXA) scans. Traditionally, hyperparathyroidism was associated with overt bone disease in a significant number of patients. This traditional bone disease was frequently symptomatic and associated with radiologic findings such as bone cysts,...

Causes of Goiter

Several mechanisms, including the interplay of intrinsic and extrinsic factors in the thyroid, cause goiter. The goitrogenic process involves genetic, environmental, dietary, endocrine, and other factors. The most common worldwide cause of endemic nontoxic goiter, as mentioned earlier, is iodine deficiency. In patients with sporadic goiter, the cause is usually unknown. Sporadic goiter is a result of environmental or genetic factors that do not affect the general population. The various types...

Childhood Thyroid Carcinoma

The nuclear accident at Chernobyl in 1986 refocused interest on radiation as a factor in the development of thyroid carcinoma.113122 Prior to 1950, irradiation was frequently used to treat acne, enlarged tonsils and adenoids, chronic sinusitis, and other benign conditions.115 External radiation was commonly used to irradiate enlarged thymuses in infants and young children. The latent period, the interval from exposure to the appearance of thyroid cancer, was assumed to be 10 years and increased...

Clinical Characteristics

Hurthle cells are large polygonal, eosinophilic cells with pleomorphic, hyperchromatic nuclei and fine granular, acidophilic cytoplasm, representing an abundance of mitochondria (Fig. 14-1). The individual cells are 10 to 15 pm in diameter and can vary in shape and size from small dumbbells to bizarre giant cells. Hurthle cell neoplasms are encapsulated collections of Hurthle cells (Fig. 14-2). Therefore, the presence of nonencapsulated Hurthle cells does not signify a neoplastic process,...

Clinical Features

The clinical manifestations of Cushing's syndrome usually begin gradually (Table 70-1). Patients frequently report increasingly severe asthenia, enhanced appetite, and weight gain. In premenopausal women, oligomenorrhea is common and may occur before any other apparent clinical change. Typically, these patients have centripetal obesity with moon face, fullness of the supraclavicular fat pads, and a buffalo hump. The limbs look thin in relation to the rest of the body, and muscular hypotrophy...

Clinical Manifestations

Most patients diagnosed with primary hyperparathyroidism today do not have the classic or historical clinical manifestations of this disorder such as osteitis fibrosa cystica, nephrolithiasis, nephrocalcinosis, peptic ulcer disease, gout, or pseudogout. The pentad of symptoms painful bones, kidney stones, abdominal groans, psychic moans, and fatigue overtones is more common, although most patients have few dramatic symptoms. The symptoms and other associated complications of primary...

Clinical Presentation

In sporadic MTC, tumors are usually single and unilateral. There is no family history and no other endocrinopathies are present. Sporadic MTC arises as a mass in the neck, and metastases to lymph nodes in the neck are usually present at the time of diagnosis. Familial forms of MTC are the multiple endocrine neoplasia (MEN) type 2A and 2B syndromes and the related disorder of familial non-MEN MTC (FMTC) (Table 15-1, Fig. 15-3).3'5 In these autosomal dominant...

Clinical Presentation and Diagnosis

Goiter is classified according to the size of the thyroid gland on inspection and palpation, and the following grading system was proposed by WHO in I96032 Stage 0 no goiter Stage la goiter detectable only by palpation and not visible even when the neck is fully extended Stabe lb goiter palpable but visible only when the neck is fully extended Stage II goiter visible with the neck in the normal position palpation is not needed for diagnosis FIGURE 3-2. Classification of goiter size. 1, Stage la...

Criteria of Malignancy of Cortical Tumors

The criteria determining whether an adrenal neoplasm is benign or malignant are not precise. Currently, the only accepted criteria are metastasis, either synchronous or TABLE 69-1. Adrenal Surgery in Lille, France, during the Period January 1985 to December 1999 TABLE 69-1. Adrenal Surgery in Lille, France, during the Period January 1985 to December 1999 *54 malignant adrenal tumors 46 adrenocortical carcinoma, 8 others. *54 malignant adrenal tumors 46 adrenocortical carcinoma, 8 others....

Diagnosis

The limitations of a clinical diagnosis for insulinoma became apparent as early as 1935, when Whipple noted that 40 of explorations performed for insulinoma up to that time failed. Noting the numerous causes of hypoglycemia, Whipple set forth the strict diagnostic triad that bears his name (1) the signs and symptoms of hypoglycemia occur during periods of fasting or exertion (2) at the time of symptoms, blood sugar levels must be less than 45 mg dL and (3) symptoms are ameliorated by the...

Etiology of Primary Hyperparathyroidism

About 80 of patients with primary hyperparathyroidism have a single adenoma, 15 have hyperplasia of all four glands, and 5 have double adenomas.2 The cause of parathyroid adenoma or hyperplasia is not known. Head and neck irradiation increases the risk of primary hyperparathyroidism by 11 per centigray.3-4 Ten percent of parathyroid adenomas have a PRAD-1 oncogene (cyclin D gene activated by PTH promoter). Mutations in the calcium sensor protein appear not to be an important cause of primary...

Experience with Endoscopic Parathyroidectomy by the Lateral Approach

We developed the technique for endoscopic parathyroidectomy by the use of a lateral approach on the line of the anterior border of the SCM in 1998.13 Since then, over the course of 5 years (1998 to 2002), we operated on 528 patients with PHPT.34 An endoscopic approach was proposed for patients with sporadic PHPT, without associated goiter and without previous neck surgery, in whom a single adenoma was localized by means of sonography and sestamibi scanning. The procedure was performed by a...

Follicular Adenoma

Pathologic Features of Follicular Adenoma Follicular adenomas are benign tumors of the thyroid gland that grow in glandular or follicular patterns. They can occur in any portion of the thyroid and in any age group they are more common in young adults. Adenomas are usually solitary and less than 3 cm in size, although significant numbers of exceptions to these rules exist.6 The lesions tend to grow slowly within a capsule of surrounding compressed thyroid glandular tissue. Over time, they...

Goiter Growth

Goiters result from focal follicular cell hyperplasia at one or multiple sites within the thyroid gland. Iodine deficiency works synergistically with other causes of goiter but does not appear to change the basic mechanisms of goitrogenesis. There is a positive correlation between the total DNA content of the goiter and goiter weight. The increased amount of interstitial tissue and colloid formation usually contributes little to the total goiter growth. An intrinsically abnormal growth pattern...

Hiirthle Cell Thyroid Tumor

Hurthle cell thyroid tumors comprise 1 to 5 of all thyroid neoplasms and have been classified as variants of follicular thyroid tumors. They differ from follicular thyroid carcinomas by their inability to trap radioiodine and by FIGURE 36-6. Summary of chromosomal aberrations analyzed by comparative genomic hybridization in 15 Hiirthle cell adenomas and 13 Hiirthle cell carcinomas. the accumulation of mitochondria and eosinophilic cytoplasm on histology. They are also more likely to be...

Historical Aspects

The striking clinical malady of exophthalmic goiter, with its distinctive protruding eyes, tachycardia, nervousness, and enlarged thyroid, has been known for more than 150 years. Thyrotoxicosis was first described in 1786 by Parry, a physician in England, but was not reported until after his death in 1825. It was also noted by von Basedow and a handful of others.1 To this day, on the continent of Europe, it is known as Basedow's disease. In the English-speaking world it is named for Robert...

Historical Introduction

In 1869, Paul Langerhans showed that islands of characteristic cells are distributed throughout the pancreas and that these islands are richly innervated.1 After the demonstration that diabetes evolves after pancreatectomy,2 it was suggested in 1901 that the disease is caused by lack of a factor produced by these islets of Langerhans.3 Although several researchers were close to the discovery of insulin, the critical pieces of work in this area were performed by Banting, Best, MacLeod, and...

Illustrative Cases

A 44-year-old woman had persistent symptomatic hypercalcemia after two unsuccessful cervical explorations for primary HPT with removal of an enlarged left superior parathyroid gland and identification of all except ihe right inferior parathyroid gland. The diagnosis of persistent primary HPT was reconfirmed biochemically. Review of the previous pathology revealed a normal left superior gland. US of the neck revealed a 2- x 5.4- x 1.7-cm nodule posterior to the lower pole of the right lobe of...

Imaging Consequences

Because of the central location within the abdominal cavity and the vicinity of numerous viscera, plain films are rarely informative. Occasionally, a large adrenal mass may be suggested by the downward displacement of the kidney, but this appearance is rarely seen, and differentiation from renal, splenic, pancreatic, gastric, and retroperitoneal tumors requires further investigation. Calcification may be seen in the adrenal glands and can be idiopathic or result from neonatal causes...

Importance of LThyroxine Suppressive Therapy

Both the function and the growth of some metastatic thyroid tumors are under TSH control. It is a common observation that bone or lung metastases increase in size and take up radioiodine during periods of T4 withdrawal, whereas a reduction in size and lack of uptake are observed during periods of T4 therapy. Serum Tg, a marker of cell function, increases dramatically during hypothyroidism (see Fig. 17-1), whereas Tg levels return to low values during treatment with T4. In the classic article by...

Incidence

Functioning adrenocortical neoplasms with clinical manifestations of hypersecretion occur in 4 cases per million and roughly half are adenomas and the rest carcinomas. Adrenocortical carcinomas at autopsy account for 2.5 cases per million. Hence, the suggested incidence of nonfunctioning adrenocortical carcinomas should be 0.6 to 1.7 cases per million.3 If these figures are matched with the prevalence of adrenal masses found incidentally (i.e., 0.6 to 1.3 of the ambulatory population), it is...

Indications

The indications for laparoscopic adrenalectomy are basically the same as those for open adrenalectomy, with few exceptions. These indications include the following 1. Functional adrenal cortical masses (1) Cushing's syndrome caused by benign cortisol-producing adenoma (2) Cushing's disease after failed pituitary surgery or after failure to control or find an ectopic adrenocorticotropic hormone (ACTH)-producing tumor (3) aldosterone-producing adenoma (Conn's syndrome) and (4) rare virilizing...

Indications for Transplantation with Cryopreserved Tissue

The indications for autotransplantation with cryopreserved tissue are straightforward persistent, permanent hypocalcemia in patients for whom cryopreserved tissue is available. There is no fully agreed-on definition of permanent hypocalcemia however, dependence on oral calcium and vitamin D TABLE 60-2. Clinical Success with Cryopreserved Parathyroid Autotransplants TABLE 60-2. Clinical Success with Cryopreserved Parathyroid Autotransplants Some patients may be included repeatedly in reports by...

Interpretation of the Fasting Test

A plasma insulin concentration of 6 (iU mL (36 pmol L) by radioimmunoassay (or 3 (iU mL by immunometric assay) when the plasma glucose concentration is below 45 mg dL (2.5 mmol L) indicates an excess of insulin and is consistent with insulinoma. Unfortunately, plasma glucose concentrations fall below 50 mg dL (2.8 mmol L) in some normal subjects and remain above 50 mg dL in an occasional patient with an insulinoma.16 Plasma C Peptide Concentrations. It is...

Intracellular Messengers Regulating Parathyroid Hormone Release

Regulation of hormone release involves translation of extracellular signals through interacting second messenger systems such as cytoplasmic Ca2+j, cAMP, and diacylglycerol production through phosphoinositol hydrolysis. It has been demonstrated that external calcium acts through all of these messenger systems of the parathyroid cell.31 Calcium interferes with parathyroid adenylate cyclase and cAMP-dependent protein kinases.32 This mode of action has been seen in many agents besides calcium and...

Intraoperative Palpation

Most insulinomas of the pancreas can be palpated by carefully exploring the pancreas at the time of surgery. The sensitivity of palpation is 75 to 95 in different studies and depends on the experience of the surgeon.23 Small tumors and those located in the pancreatic head and uncinate process are generally more difficult to palpate. The combination of IOUS and palpation has been reported to increase the sensitivity to 100 .42 Like IOUS, proper intraoperative palpation requires full mobilization...

Intraoperative Protocol Blood Sample Collection Time and Processing

In the operating room, a 14- or 16-gauge cannula is placed into an antecubital or other available peripheral vein. If not available, an arterial line can be used. This vascular access is maintained without heparin using a saline drip with extension tubing and a three-way stopcock at the head of the table. This allows blood sampling at the required intervals. Such access can also be used by the anesthesiologist as long as administered drugs are not collected with the blood samples used for PTH...

Islet Function

A key role for the pancreatic islets is to deliver an optimal amount of peptide hormones into the bloodstream to optimize carbohydrate metabolism. Of most importance in this respect is insulin, which facilitates the transport of glucose into insulin-dependent cells for storage as glycogen and fat with a concomitant reduction in blood glucose and free fatty acid levels as a consequence. One of the most important target organs for insulin action is the liver, in which at least 50 of the insulin...

Islet Nerves

The pancreatic islets are richly innervated by the autonomic nerves (see Fig. 78-1).1516 These nerves are postganglionic sympathetic nerves with their nerve cell bodies in the celiac ganglion, and postganglionic parasympathetic nerves with their nerve cell bodies in intrapancreatic ganglia. Preganglionically, the nerve impulses pass through the splanchnic and vagus nerves, respectively. The nerves primarily innervate the vessels, but some fibers also enter into the islets and terminate in close...

Laparoscopic Ultrasound

We used laparoscopic ultrasonography in 15 selected cases. In 1 patient it showed the location of a 0.7-cm aldosteronoma in an adrenal gland after open surgery failed to find the organ. In 2 patients, no adenoma was found, necessitating only biopsy and closure rather than adrenalectomy. In 2 patients with large masses (10 and 12 cm), no extra-adrenal or lymph node involvement was found. The masses were completely removed laparoscopically and proved to be histologically benign. In 1 patient,...

Localization of Persistent or Recurrent Medullary Thyroid Carcinoma

Computed Tomography and Ultrasonography A number of methods have been used to localize residual or recurrent disease in patients with persistent or recurrent calcitonin elevation after surgery for MTC. Careful physical examination may reveal adenopathy in the jugular and para-tracheal regions. Patients with advanced metastatic disease may acquire subcutaneous tumors of the trunk and extremities. Imaging studies that have been reported to be successful in localization include ultrasonography...

Medical Management versus Operation

Optimum treatment recommendations for patients with Z-E syndrome have undergone continuing change during the 40 years since Zollinger and Ellison reported on their first two patients, both of whom required a TG to control the complications of recurring peptic ulcer disease. These changes in Z-E syndrome management have come with a better understanding of the natural history and pathophysiology of Z-E syndrome, the RIA for gastrin, new imaging technologies that preoperatively and...

Men

The most common functional islet cell tumor in MEN 1 patients is the gastrinoma,22'27 34 MEN 1 patients account for approximately 30 of all patients with the ZES, and, even without a family history or other symptoms, all sporadic ZES patients should be evaluated for the possibility of MEN 1 and at least a serum calcium and prolactin level obtained. The surgical treatment of ZES in the MEN 1 patient has remained controversial because of a previously high failure rate in curing the...

Natural History of Treated Primary Hyperparathyroidism

In 1925, Mandl of Austria performed the first operation for primary hyperparathyroidism (PHPT).1 His patient had sustained a spontaneous thigh bone fracture and was immobilized. Three months after a parathyroid adenoma had been excised, the patient could walk with crutches. The effect of the operation was conspicuous. During the next 4 decades, most patients with PHPT continued to have obvious symptoms relieved by surgery. In the mid-1960s, the number of operations for PHPT started to increase...

Natural History of Untreated Primary Hyperparathyroidism

G ran kerstrom, MD Ewa Lundgren, MD In the early descriptions of patients with primary hyperparathyroidism (HPT), the disease was recognized as a rare disorder and was associated with severe incapacitating bone symptoms, prevalent renal stones, devastating muscular weakness, and often early death from renal failure. Since the introduction in the mid-1970s of automated equipment allowing routine measurements of serum calcium by multiphasic laboratory screening on liberal indications, primary HPT...

Nontoxic Multinodular Goiter Theories of Pathogenesis and Thyrocyte Regulation

The pathogenesis and hence the treatment of multinodular goiter are debatable. If a goiter were simply induced by uninhibited TSH stimulation, one might expect it to be a diffuse goiter. Early studies by Taylor suggested a natural progression from diffuse toward multinodular.104 Indeed, TSH levels are in general not elevated in sporadic goiters. Studer and Ramelli105 suggested that newly generated follicles involve thyrocyte clones that may retain the ability to concentrate iodine (hot nodules)...

The Molecular Biology of MEN

The gene responsible for MEN 1 was identified in 199729 and is located on chromosome 1 lql3. MEN I spans 9 kb of genomic DNA and consists of 10 exons containing an 1830-base pair coding region. MEN I encodes a 610-amino acid nuclear protein, referred to as menin.4'29'32 Menin is localized to the nucleus and interacts with the activating protein 1 transcription factor JunD and other proteins involved in transcription and cell growth regulation.3335 MEN1 mutations are spread over the entire...

Operative Technique

The lymph nodes in the central neck compartment are usually resected in continuity with the thyroid itself. The strap muscles are retracted laterally during the dissection. When the strap muscles inhibit exposure, they can be divided superiorly, since they are innervated from below. The technique of the total thyroidectomy has been described in previous chapters. As mentioned earlier, the central neck dissection puts the recurrent laryngeal nerve and the blood supply to the parathyroids at...

Operative Technique Laparoscopic Approach

Since the publication of the last edition of this text, a dramatic and exciting change in the overall approach to adrenalectomy has occurred. Whereas previously only a limited number of laparoscopic adrenalectomies had been reported in total,32 some involving significant bleeding33 and a few including removal of pheochromocytomas,32 34 laparoscopic adrenalectomy has become the accepted standard method, even to remove pheochromocytomas. Multiple advantages of the laparoscopic approach have been...

Overall Results and Prognostic Factors

Unfortunately, the intra- and postoperative mortality within 30 days of operation is about 10 .1,4 Most of the mortality occurs in poor-risk patients with stage III or IV disease undergoing an extensive resection, with an occasional death from pulmonary embolism after isolated adrenalectomy. A review of 548 patients with adrenocortical carcinomas from seven large series in the literature from 1980 to 1990,1 of whom 290 were operated on with curative intent, revealed the following 1. Overall...

Parathyroid

The treatment of surgically acquired and idiopathic hypoparathyroidism requires life-long treatment with vitamin D and oral calcium supplementation. This is not, however, a perfect physiologic replacement because, although it sufficiently regulates blood calcium and phosphate levels, it does not reverse the lowered urinary calcium reabsorption and excessive urinary calcium excretion, which may result in renal stones.25 Owing to the complexity of parathyroid hormone's metabolic interactions,...

Parathyroid Calcium Sensor Proteins

A calcium sensor protein on the parathyroid cell surface was identified by monoclonal antibodies generated by immunization with human adenoma cells.49 Such a monoclonal antibody abolished the calcium-regulated Ca2+ and PTH release of normal and pathologic parathyroid cells.50 51 The antibody blocked the calcium-induced Ca2+, transient intracellular calcium mobilization as well as the steady-state elevation resulting from calcium influx. Because the antibodies also competed with calcium binding...

Parathyroid Embryology and Developmental Abnormalities

The inferior parathyroid glands arise from the dorsal part of the P III. The thymus arises from the ventral portion of the same pouch. This common origin justifies labeling P III and thymus as parathymus. The dorsal part of the PIV gives rise to the superior parathyroids. The fate of the ventral portion of the P IV is little understood in humans. Gilmour4 regarded it as the origin of the thymus IV (rudimentary thymus IV), which rapidly undergoes involution. The fatty lobules sometimes found at...

Pathology of Tumors of the Thyroid Gland

Tumors of the thyroid gland can be problems for endocrinologists, surgeons, and pathologists. Carcinomas of the thyroid gland range from the innocuous occult papillary carcinoma to the extremely lethal anaplastic form. Approximately 12,000 new cases of thyroid cancers are discovered each year in the United States however, fewer than 1 of deaths caused by cancers are due to thyroid cancers.1 Because only 9 of patients affected by the disease die from it, malignant tumors of the thyroid gland are...

Pathophysiology of Endemic Goiter

Endemic goiter is the end result of the physiologic and morphologic changes in the thyroid gland as an adaptation to an insufficient supply of dietary iodine. When iodine intake is low, thyroid hormone synthesis is impaired. This impairment leads to an increased thyroidal clearance of iodide from the plasma and decreased urinary excretion of iodide, an adaptation toward iodine conservation. T3, being three to four times more potent than T4 but containing only three fourths as much iodine as T4,...

Postoperative Adjuvant Therapy

Because of the excellent prognosis of most patients with low-risk papillary thyroid carcinoma, it has been difficult to demonstrate any benefit from adjuvant therapy in the form of radioiodine or TSH suppression therapy. Vickery,39 Cady,1'38 and their associates concluded that the usual course of low-risk papillary carcinoma treated by conservative surgery is generally so benign that further beneficial effects of radioiodine, thyroid suppressive treatment, or total thyroidectomy have never been...

Postoperative Care

Oral fluids are started on the day of surgery. Nasogastric tubes are unnecessary for most patients. If a Jackson-Pratt drain has been inserted at surgery, it is removed the next morning. Oral analgesics are provided to help patients tolerate the postoperative pain. However, during the first 12 hours, some patients require parenteral analgesia. The postoperative course is similar to that for laparoscopic cholecystectomy, except that some endocrine disorders necessitate hormonal support and...

Predictors of Thyroid Tumor Aggressiveness

The antecedents of attempts to predict thyroid cancer behavior date back to the 1930s, when the concept of lateral aberrant thyroid12 was established, because thyroid tissue appearing in lymph nodes in the neck was known to be associated with an innocent clinical behavior pattern in a vast majority of cases. As a result, these cases were considered to be not cancer but an arrested embryonic migration phenomenon, until Crile convincingly demonstrated small primary papillary cancers in such...

Preoperative Preparation

Patients undergoing adrenal surgery require thorough preparation. Such preparation is especially necessary when one uses an open approach. Venous thromboembolism is not uncommon postoperatively, so intermittent pneumatic compression of the legs or some other method of preventing deep venous thrombosis should be considered. Caution is necessary when using anticoagulants because of the risk of retroperitoneal hemorrhage postoperatively. A modified bowel prep using a clear liquid diet and...

Preoperative Tumor Localizing Techniques

Tumor-localizing techniques for gastrinoma have continued to evolve since Zollinger and Ellison's first report.1 Their first two Z-E syndrome patients had only barium swallows, demonstrating mucosal changes in the stomach and small bowel related to excess acid. In Ellison's 1956 report, the first reported series of ulcerogenic tumor patients, no tumors were identified preoperatively by any imaging technique, and the concept of preoperative localizing was not even mentioned. Abdominal plain...

Preventive Surgery for Multiple Endocrine Neoplasia Type 2 Gene Carriers

Individuals with MEN 2A, 2B and FMTC are virtually certain to acquire MTC at some point in their lives (usually before age 30 years). Therefore, at-risk family members who are found to have inherited the RET gene mutation are candidates for thyroidectomy regardless of their calcitonin levels. It has been shown in several series that RET mutation carriers often harbor foci of MTC in the thyroid gland even when stimulated calcitonin levels are normal.14'18-33'34'4547 In a series from Washington...

Recommendations for the Use of Thyroxine in the Nontoxic Multinodular Goiter

In practical terms, if TSH suppressive treatment is to be tried, it would be logical to give enough levothyroxine to reduce the TSH consistently to 0.5 mU L. If the goiter decreases in overall size or remains static (both clinically and by ultrasonography), treatment may be continued indefinitely in a low dose (perhaps in patients younger than 60 years), with periodic monitoring of TSH and thyroglobulin levels to assess the patient for the likelihood of functional anatomy. If the goiter...

Results of Unilateral Parathyroidectomy Original Approach

When patients are considered for unilateral parathyroidectomy, it is important to exclude familial HPT because these patients usually have multiple abnormal parathyroid glands. Patients who had previous operations in their neck for either parathyroid disease or thyroid disease are not candidates for unilateral parathyroidectomy because the functional parathyroid reserve cannot be evaluated. Identification of a normal parathyroid gland is easy in most instances, but occasionally it is difficult...

Screening and Diagnosis

Screening for MEN 2B should be reserved for a few well-defined populations (1) family members of known MEN 2B patients, (2) patients newly diagnosed with medullary thyroid carcinoma or pheochromocytoma, and (3) individuals exhibiting the characteristic phenotype of marfanoid habitus and mucosal neuromas. Screening is mandatory in these patients to maximize the opportunity to perform curative thyroidectomy or adrenalectomy, or both, before metastasis of the endocrine tumors. Screening of family...

Sensory Nerves

The endocrine pancreas is innervated by sensory afferent nerves as well as by the sympathetic and parasympathetic nerves.97 These sensory nerves seem to harbor CGRP and substance P as neurotransmitters.98 Both these neuropeptides inhibit insulin secretion.16 The role of these sensory nerves in the regulation of islet function has been examined with the use of the neurotoxin capsaicin, which destroys sensory nerves.98 Using a neonatal model with capsaicin treatment in mice, a sensory denervation...

Staging Surgical Indications and Preoperative Treatment

Adrenocortical carcinomas are classified according to stages described by MacFarlane and modified by Sullivan (Table 69-3). This classification has one major drawback (i.e., malignancy in stage I is based on histologic criteria only). Whether all of these tumors are malignant is unknown, and the assumption that all are malignant may lead to an overly optimistic affirmation of the results of surgery. All tumors at stage I, II, or III, whether diagnosed preop-eratively or intraoperatively, should...

Summary

Parathyroidectomy should be performed by surgeons with experience in this field. Patients with secondary HPT and hyperplasia are somewhat more difficult to manage than those with primary HPT because recurrent and persistent disease is more common. We believe that most patients with either primary or secondary hyperplasia are best managed with subtotal rather than total parathyroidectomy. Total parathyroidectomy with parathyroid autotransplantation, however, is useful in selected patients....

Surgical Approach to Primary Hyperparathyroidism Bilateral Approach

Surgery offers the only definitive treatment for patients with primary hyperparathyroidism.1 The success of parathyroidectomy depends on the skill and judgment of the surgeon. The best surgical approach should give the highest rate of cure with the lowest rate of complications. In this chapter, issues that influence surgical strategy are discussed. A strong case is made for surgeons to have a good understanding of the embryologic development of the parathyroid glands and to have experience in...

Surgical Exposure of the Pancreas

Exposure of the pancreas in patients with islet cell neoplasms is preferably obtained through an upper midline or a bilateral subcostal incision. Intraoperative evaluation of patients with pancreatic islet cell neoplasms requires a meticulous examination of the entire pancreas for tumor masses that are frequently small (less than 2 cm) and multiple. The duodenum and peripancreatic lymph nodes are also carefully examined because they may be sites of extrapancreatic islet cell tumors. The liver...

Techniques

Although several approaches have been proposed as endoscopic parathyroidectomy, the most commonly used are the (1) endoscopic parathyroidectomy (Gagner, 1997),2 (2) video-assisted parathyroidectomy with external retraction (Miccoli, 1997),3,4 and (3) videoscopic parathyroidectomy by a lateral approach (Henry, 1998).5 Endoscopic parathyroidectomy was the first technique described for endoscopic parathyroidectomy. It uses steady gas flow, not exceeding 8 mm Hg pressure.6 A 5-mm endoscope (0...

Thyroid Stimulating Hormone Suppression and the Solitary Thyroid Nodule

Studies in this area are confusing in that they include a heterogeneous collection of goiters (such as nodules with functional autonomy or cystic degeneration), are frequently uncontrolled and poorly randomized, fail to establish compliance or consistent TSH suppression, and do not objectively evaluate nodule size and treatment response. Inclusion in a suppressive treatment arm relies on the absolute ability to distinguish a benign from a malignant nodule largely on the basis of accurate...

Thyroxine and Lipid Metabolism

There is an overall increase in hyperlipidemia in overt hypothyroidism, and there have been claims of higher mortality from ischemic heart disease in undertreated patients.63,64 In subclinical hypothyroidism the biologic efficacy of thyroid hormone replacement has been confirmed with observed changes in serum lipoprotein concentration, improvement in cognitive performance and indices of cardiac function, and reduction of subjective symptoms. The majority of patients show no fundamental changes...

Treatment Modalities

Patients with parathyroid carcinoma frequently present with symptomatic hypercalcemia. They need prompt treatment and correction of renal and cardiac dysfunction because of the metabolic consequences of the high serum calcium levels. Rehydration with saline and additional electrolytes, including magnesium, restores glomerular function and increases urinary excretion. Loop diuretics also increase urine calcium secretion, provided that the patient is well hydrated. Calcitonin is an osteoclast...

Troubleshooting for a Missing Parathyroid Gland

The enlarged parathyroid gland can remain undiscovered after routine exploration of the neck in some patients. Several of such classic situations are described next. It is of great importance to identify the normal parathyroid glands during the exploration of the neck because a parathyroid missed at its normal localization can indicate the site of the migrated enlarged parathyroid. Situation 1. Three normal parathyroid glands have been identified but the (right) upper parathyroid gland cannot...

Unusual Thyroid Cancers

Unusual thyroid cancers, including the intermediately differentiated carcinomas, account for only 10 to 15 of all primary thyroid neoplasms (Table 19-1). This unique group of neoplasms behaves differently than the more common type the well-differentiated thyroid cancers (WDTCs). They therefore present a challenge to both the surgeon and the endocrinologist-oncologist. Most of these cancers behave in an aggressive fashion and, at times, present as a medical emergency. Multimodality therapy is...

The Gut and Insulin Secretion

It has long been known that oral ingestion of glucose results in high levels of plasma insulin, although the increase in plasma glucose is only marginal.100'101 This is due to the action of gut hormones, called incretins, that are released into the circulation during meal intake and stimulate insulin secretion. The most important incretins are glucose-dependent insulinotropic polypeptide (GIP also called gastric inhibitory polypeptide) and GLP-1.102 103 GLP-1 is a 30-amino acid peptide produced...

Endocrine Pancreas and Type 2 Diabetes

From the previous discussions, it is clear that the endocrine pancreas is a complexly regulated organ that integrates incoming impulses of nutrient, hormonal, and neural nature. The endocrine pancreas converts these impulses to an optimal secretion of the islet hormones mainly for the regulation of carbohydrate homeostasis. An example of the consequences that follow derangement of the endocrine pancreas is type 2 diabetes. A primary event during the development of this disease is a reduced...

Glucose and Insulin Levels

Currently, the diagnosis of insulinoma is confirmed by demonstrating a circulating insulin level that is inappropriately high for the serum glucose level, measured at the time of hypoglycemia (Fig. 79-3). When a patient presents with symptoms of hypoglycemia (i.e., coma, convulsions, or other neurologic symptoms), blood samples should be taken for the determination of both insulin and glucose levels. Samples should be drawn as early as possible to avoid complications of hypoglycemia and before...

Measurement of Proinsulin and C Peptide

Proinsulin is the precursor molecule for insulin and is found in the rough endoplasmic reticulum of the beta cells in the pancreatic islets. As shown in Figure 79-2, the proteolytic conversion of proinsulin results in the formation of equimo-lar amounts of insulin and its connecting peptide, C peptide. In the presence of an insulinoma, there is an elevation of both proinsulin and C peptide.1015 Furthermore, proinsulin levels, which are usually less than 20 of the total immunoreactive insulin in...

Insulin Glucose Ratio

The insulin-glucose (I G) ratio provides a relationship between these two values that aids in the determination of the presence of an insulinoma. In a normal individual, the ratio is always less 0.4, but in patients with an insulinoma the ratio approaches 1.0 and may in some cases exceed 1.0. The I G ratio is important because as many as one third of patients with an insulinoma have insulin levels within normal limits when they have symptomatic hypoglycemia. FIGURE 79-3. Plasma insulin (in...

Insulinomas

Ninety percent of insulinomas are benign and are smaller than 2 cm in diameter. Ninety-nine percent are located in the pancreas. A variety of preoperative imaging modalities for the detection of insulinomas are currently available, such as US, CT, MRI, somatostatin receptor scintigraphy (SRS), and various invasive methods, including endosonography (ES), selective angiography (SA), selective portal venous sampling (PVS), and selective hepatic venous sampling after arterial stimulation (modified...

Physiologic Effects of Corticosteroids

Aldosterone regulates electrolyte excretion and the intravascular volume through its effects on the distal tubules and cortical collecting tubes of the kidney. It binds to a miner-alocorticoid receptor in the cytosol and moves into the nucleus to increase transcription.8 The early effect is to increase the Na absorption through the Na channels. Via changes in electrical potential across the renal tubule, K and H secretion are increased. This leads to an expanded intravascular volume and...

Clinically Inapparent Adrenal Mass Incidentaloma or Adrenaloma

Historically, the adrenal tumor that was discovered incidentally, usually during an imaging procedure such as computed tomography (CT), magnetic resonance imaging (MRI), or ultrasonography for symptoms unrelated to adrenal disease, (e.g., back pain) was called an incidentaloma.1 As more physicians (and patients on their own) ordered these easily available imaging studies for common diseases potentially related to adrenal pathology (and not the known syndromes), such as mild and nonparoxysmal...

The Goal of Evaluation

Although by definition the clinically inapparent adrenal masses appear nonfunctioning, on the basis of clinical and essential laboratory findings more and more investigators have shown that a high percentage of them may be subclinical functioning and or associated with other metabolic abnormalities. In a multicenter, retrospective evaluation of 1096 patients with adrenal incidentaloma, the work-up revealed that 9.2 had subclinical Cushing's syndrome, 4.2 had pheochromocytoma, and 1.6 had...

Diagnostic Procedures

When Cushing's syndrome is suspected and iatrogenic causes have been excluded, the diagnosis should be confirmed by both an overnight dexamethasone suppression test (1 mg of dexamethasone is given at 11 pm, and a plasma Cortisol measurement is obtained in the morning) and the 24-hour urinary free Cortisol measurement. When the dexamethasone suppression test is normal (plasma Cortisol < 50 mmol L) and the urinary free Cortisol is normal (< 135 nmol 24 hours), the patient does not have...

Environmental Radiation Exposure

As with the medical radiation exposure just described, environmental radiation exposure of the thyroid can be from external sources as well as internal ingestion of radioisotopes of iodine. The populations exposed are geographically related to discrete regional events involving either nuclear weapons or nuclear power plant accidents. The largest, best studied population exposed to acute external radiation from an environmental source includes survivors of the atomic bombs detonated at Hiroshima...

Radiation Exposure

The association between radiation exposure and increased risk of thyroid cancer was first recognized by investigators studying the increasing clinical problem of childhood thyroid cancer in the mid-20th century.5 6 The number of cases of thyroid cancer diagnosed and treated in children or adolescents was quite low only 18 cases of childhood thyroid cancer were reported in the medical literature before 1930 (Fig. 26-1).7 Duffy and Fitzgerald recognized an increased incidence of this disease and...

Environmentally Induced Goiter

Endemic goiter is discussed in Chapter 3. An inadequate adaptive mechanism of the thyroid to protect from severe iodine deficiency results in the development of goiter. These adaptive mechanisms include increased iodide clearance, increased production of triiodothyronine (T3) relative to thyroxine (T4), and increased mass of thyroid follicular cells.1 Pregnancy increases the need for iodine and T4, which results from significant transfer of thyroid hormone from the mother to the fetus and also...

Thyroid Stimulating Hormone Suppression and Miscellaneous Benign Goiters

Levothyroxine has been advocated for a variety of benign goitrous conditions, most notably in the follow-up of patients who have experienced irradiation to the head and neck in some cases of functionally autonomous nodules and in postpartum and neonatal goiter. Irradiation during childhood or adolescence for a range of benign conditions (tinea capitis, tonsillar and thymic enlargement, acne vulgaris, or head and neck vascular malformations) has been associated with a substantial increase in...

Incidence and Etiology

Carcinoma of the thyroid gland affects approximately 11,000 people in the United States each year, with a female-to-male ratio of nearly 3 1. It accounts for 90 of all endocrine malignancies and kills approximately 1300 people annually.5 In the United States, childhood thyroid carcinoma constitutes approximately 3 of all childhood cancers. Its incidence rate is three to five cases per million per year.6-7 Childhood DTC is so uncommon that even the largest referral centers in the United States...

Activating Oncogene G Proteins

The ras oncogene encodes a 21-kd protein (p21) that functions in signal transduction from receptor proteins belonging to the tyrosine kinase family of receptors. Three ras proteins (H, K, N) exist in an active state when they are anchored to the inner membrane and bound to guanosine triphosphate (GTP) and in a resting state when they are bound to guanosine diphosphate (GDP). Activating point mutations in the ras oncogene commonly occur in codons 12 and 13 in the GTP-binding domain and in codons...

Tumor Suppressor Genes

The p53 tumor suppressor gene is one of the most common genetic alterations observed in human cancers. The p53 gene, located on chromosome 17pl3, encodes a 53-kd nuclear phosphoprotein and functions as a key cell cycle regulator. p53 mutations lead to altered protein conformations that are nonfunctional and accumulate in the cell nucleus. A p53 mutation needs to occur in only one allele to lead to deregulated cellular growth. Most p53 gene mutations (98 ) occur in exons 5 through 8.643 p53...

Anaplastic Thyroid Carcinoma

Anaplastic thyroid carcinoma is an extremely aggressive cancer, with a median survival after diagnosis of just a few months.39 The outcome is so poor that the American Joint Committee on Cancer (AJCC) classifies all patients with this tumor as having stage 4 thyroid cancer. Fortunately, anaplastic thyroid carcinoma accounts for less than 2 of all thyroid carcinomas in the United States and has been decreasing in incidence.40-41 TABLE 36-4. Common Chromosomal Aberrations in 13 Hiirthle Cell...