The Endocrine System - Past Paper

1114 C H A P T E R 24 The Endocrine System In the Zollinger-Ellison syndrome, hypergastrinemia gives rise to excessive...

1114 C H A P T E R 24 The Endocrine System In the Zollinger-Ellison syndrome, hypergastrinemia gives rise to excessive gastric acid secretion, which in turn causes peptic ulceration (Chapter 17). The duodenal and gastric ulcers are often multiple; although they are identical to those found in the general population, they are often unresponsive to therapy. In addition, ulcers may occur in unusual locations such as the jejunum; when intractable jejunal ulcers are found, Zollinger-Ellison syndrome should be considered. Clinical Features Treatment of Zollinger-Ellison syndrome involves control of gastric acid secretion by use of H+K+-ATPase inhibitors and excision of the neoplasm. Total resection of the neoplasm, when possible, eliminates the syndrome. Patients with hepatic metastases have a shortened life expectancy, with progressive tumor growth leading to liver failure, usually within 10 Figure 24.41 Pancreatic endocrine neoplasm (“islet cell tumor”). The neoplastic cells are monotonous and demonstrate minimal pleomorphism years. or mitotic activity. There is abundant amyloid deposition, characteristic of an insulinoma. Clinically, the patient had episodic hypoglycemia. Other Rare Pancreatic Endocrine Neoplasms α-cell tumors (glucagonomas) are associated with increased It is important to note that there are many other causes of serum levels of glucagon and a syndrome consisting of hypoglycemia besides insulinoma. The differential diagnosis mild diabetes mellitus, a characteristic skin rash (necrolytic includes such conditions as abnormal insulin sensitivity, migratory erythema), and anemia. They occur most fre- diffuse liver disease, inherited glycogenoses, and ectopic quently in perimenopausal and postmenopausal women production of insulin by certain fibromas and fibrosarcomas. and are characterized by extremely high plasma glucagon Depending on the clinical circumstances, hypoglycemia levels. induced by self-injection of insulin should also be considered. δ-cell tumors (somatostatinomas) are associated with diabetes mellitus, cholelithiasis, steatorrhea, and hypochlorhydria. Zollinger-Ellison Syndrome (Gastrinoma) They may be very difficult to localize preoperatively. High plasma somatostatin levels are required for diagnosis. Marked hypersecretion of gastrin usually has its origin in VIPoma induces a characteristic syndrome (watery diarrhea, gastrin-producing tumors (gastrinomas), which are just as hypokalemia, achlorhydria, or WDHA syndrome) that is caused likely to arise in the duodenum and peripancreatic soft by release of vasoactive intestinal peptide (VIP) from tissues as in the pancreas (so-called gastrinoma triangle). the tumor. Some of these tumors are locally invasive There has been lack of agreement regarding the cell of origin and metastatic. A VIP assay should be performed on of these tumors, although it seems likely that endocrine all patients with severe secretory diarrhea. Neural crest cells of either the gut or the pancreas could be the source. tumors, such as neuroblastomas, ganglioneuroblastomas, Zollinger and Ellison first called attention to the association and ganglioneuromas (Chapter 10), and pheochromocy- of pancreatic islet cell lesions, hypersecretion of gastric tomas (see later) can also be associated with the VIPoma acid and severe peptic ulceration, which are present in syndrome. 90% to 95% of patients. Pancreatic carcinoid tumors producing serotonin and an atypical carcinoid syndrome are exceedingly rare. Pancreatic polypeptide-secreting endocrine tumors present MORPHOLOGY as mass lesions as even high plasma levels of this hormone fail to cause symptoms. More than half of gastrin-producing tumors are locally Some pancreatic and extrapancreatic endocrine tumors invasive or have already metastasized at the time of produce two or more hormones. In addition to insulin, diagnosis. In approximately 25% of patients, gastrinomas arise glucagon, and gastrin, pancreatic endocrine tumors may in conjunction with other endocrine tumors, as part of the MEN-1 produce ACTH, MSH, ADH, serotonin, and norepineph- syndrome (see later). MEN-1-associated gastrinomas are frequently rine. These multihormonal tumors are to be distinguished multifocal, while sporadic gastrinomas are usually single. As with from the MEN syndromes (discussed later), in which a insulin-secreting tumors of the pancreas, gastrin-producing tumors multiplicity of hormones is produced by tumors in several are histologically bland and rarely show marked anaplasia. different glands. Adrenal Glands The adrenal glands are paired endocrine organs consisting structure, and function. In essence, the cortex and medulla are of a cortex and a medulla, which differ in their development, two glands packaged into one structure. The adrenal cortex  Adrenal glands 1115 has three zones. Beneath the capsule is the narrow layer of Secretion of ectopic ACTH by nonpituitary tumors accounts zona glomerulosa. An equally narrow zona reticularis abuts for about 5% to 10% of ACTH-dependent Cushing syn- the medulla. Intervening is the broad zona fasciculata, which drome cases. In many instances, the responsible tumor is makes up about 75% of the total cortex. The adrenal cortex a small-cell carcinoma of the lung, although other neoplasms, synthesizes three different types of steroids: (1) glucocorticoids including carcinoids, medullary carcinomas of the thyroid, (principally cortisol), which are synthesized primarily in the and PanNETs, have been associated with the syndrome. In zona fasciculata and to a lesser degree in the zona reticularis; addition to tumors that elaborate ectopic ACTH, occasion- (2) mineralocorticoids, the most important being aldosterone, ally a neuroendocrine neoplasm may produce ectopic CRH, which is generated in the zona glomerulosa; and (3) sex steroids which, in turn, causes ACTH secretion and hypercortisolism. (estrogens and androgens), which are produced largely in the As in the pituitary variant, the adrenal glands undergo zona reticularis. The adrenal medulla is composed of chromaffin bilateral cortical hyperplasia, but the rapid downhill course cells, which synthesize and secrete catecholamines, mainly of patients with these cancers often limits the extent of the epinephrine. Catecholamines have many effects that allow adrenal enlargement. This variant of Cushing syndrome is rapid adaptations to changes in the environment. more common in men and usually occurs in the 40s and 50s. Primary adrenal neoplasms, such as adrenal adenoma (~10% to 20%) and carcinoma (~5% to 7%) are the most common underlying causes of ACTH-independent ADRENAL CORTEX Cushing syndrome. The biochemical sine qua non of ACTH- independent Cushing syndrome is elevated serum levels of Diseases of the adrenal cortex can be conveniently divided cortisol with low levels of ACTH. Cortical carcinomas tend into those associated with hyperfunction and those associated to produce more marked hypercortisolism than adenomas with hypofunction. or hyperplasias. Recent large-scale gene-sequencing studies have helped define the molecular features of adrenocortical Adrenocortical Hyperfunction (Hyperadrenalism) carcinomas, including recurrent activating mutations of beta-catenin (CTNNB1) and inactivating mutations of TP53, The syndromes of adrenal hyperfunction are caused by over- MEN1, and PRKAR1A. Interestingly, PRKAR1A mutations are production of the three major hormones of the adrenal cortex observed in both adrenocortical adenomas and carcinomas, as (1) Cushing syndrome, characterized by an excess of cortisol; well as in micronodular hyperplasia (see earlier), suggesting (2) hyperaldosteronism as a result of excessive aldosterone; shared molecular mechanisms and ontogeny are at play in and (3) adrenogenital or virilizing syndromes caused by an these cortisol-secreting lesions. excess of androgens. The clinical features of these syndromes Primary cortical hyperplasia (i.e., ACTH-independent overlap somewhat because of the overlapping functions of hyperplasia) is much less common than ACTH-dependent some of the adrenal steroids. adrenal cortical hyperplasia. In bilateral macronodular adrenal hyperplasia (BMAH), the nodules are usually greater than 10 mm in diameter. Familial forms associated with germline Hypercortisolism (Cushing Syndrome) mutations in the armadillo repeat containing 5 (ARMC5) Pathogenesis gene, a putative tumor suppressor gene, have been reported; This disorder is caused by conditions that produce elevated of note, up to 50% of apparently sporadic BMAH cases harbor glucocorticoid levels. Cushing syndrome can be broadly germline ARMC5 mutations with somatic loss of the second divided into exogenous and endogenous causes. The vast allele in the hyperplastic nodules. In true sporadic cases of majority of cases of Cushing syndrome are the result of the BMAH, nodular hyperplasia is not entirely “autonomous.” administration of exogenous glucocorticoids (iatrogenic Specifically, cortisol production is regulated by hormones Cushing syndrome). The endogenous causes can, in turn, other than ACTH because of ectopic overexpression of the be divided into those that are ACTH dependent and those corresponding G-protein–coupled hormone receptors in the that are ACTH independent (Table 24.8). hyperplastic adrenocortical cells. Implicated hormones other ACTH-secreting pituitary adenomas account for 60% than ACTH include gastric inhibitory peptide (GIP), LH, to 70% of cases of endogenous hypercortisolism. The and ADH (vasopressin). The mechanism by which these pituitary form of this syndrome is referred to as Cushing receptors are overexpressed is not known, but epigenetic disease. The disorder affects women about four times more changes may be involved. A subset of BMAH arises in frequently than men and occurs most frequently in young the setting of McCune-Albright syndrome (Chapter 26), a adults. In the vast majority of cases, it is caused by an multisystemic disease characterized by germline mutations ACTH-producing pituitary microadenoma. In some cases there that activate GNAS, which encodes a stimulatory Gsα. This is an underlying macroadenoma, and rarely there is corti- Gsα mutation causes hyperplasia by increasing intracellular cotroph cell hyperplasia without a discrete adenoma. Corti- levels of cAMP, which you will recall is an important second cotroph cell hyperplasia may be primary or arise secondarily messenger in many endocrine cell types. from excessive stimulation of ACTH release by a hypotha- ACTH-independent bilateral hyperplasia can also be lamic corticotrophin-releasing hormone (CRH)-producing micronodular (