Endocrine Dysfunction PDF

CHAPTER 12 Endocrine System 777 Endocrine Activity in Adipose Tissue In addition to its metabolic functions of synthesizing fatty acids and storing triglycerides, adipose tissue is a source of adipokines (i.e., chemical compounds produced by adipocytes that are secreted into the blood and act on dis...

CHAPTER 12 Endocrine System 777 Endocrine Activity in Adipose Tissue In addition to its metabolic functions of synthesizing fatty acids and storing triglycerides, adipose tissue is a source of adipokines (i.e., chemical compounds produced by adipocytes that are secreted into the blood and act on distant target cells, such as in the hypothalamus, liver, and skeletal muscle). Thus, adipocytes are cells capable of endocrine signaling. Two adipokines have particular metabolic importance: leptin and adiponectin. Leptin is involved in appetite suppression and heat generation, and it is proinflammatory. In contrast, adiponectin enhances glucose uptake and metabolism, and it is antiinflammatory. See subsequent sections on Diseases Affecting Multiple Species of Domestic Animals, Obesity, and Diseases of Horses and Diseases of Pigs, Metabolic Syndrome. Dysfunction/Responses to Injury Figure 12.14 Pancreatic Islet, Normal Dog. The islet is surrounded by the exocrine pancreas. Hematoxylin and eosin (H&E) stain. (Courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.) adipocytes, and skeletal myocytes) and to enhance glucose oxidation, glycogenesis, lipogenesis, and formation of ATP and nucleic acids. Glucagon, secreted in response to decreased blood glucose concentration, works in opposition to insulin and promotes glycogenolysis, gluconeogenesis, and lipolysis. Islet α cells, like the other non-β cell types (e.g., somatostatin-secreting δ cells and pancreatic polypeptide-secreting PP cells), are not restricted to pancreatic islets and can be found in other, mainly gastrointestinal, sites. Pineal Gland The pineal gland, situated between the cerebral hemispheres just dorsal and caudal to the thalamus, is seldom associated with disease in domestic mammals. The pineal gland is derived from the ependymal lining of the third ventricle in the developing diencephalon and is first observed at 30 to 40 days of gestation in the bovine fetus. Its importance in adult animals lies in its ability to relay information about photoperiod length to the hypothalamic-pituitary axis and thereby regulate circadian rhythm and seasonal reproduction. Pinealocytes secrete several neurotransmitters in addition to the hormone melatonin, a polypeptide derivative of tryptophan, in response to decreasing daylight hours. Melatonin binds receptors in the pituitary pars tuberalis and blocks the action of gonadotrophin-releasing hormone on the adenohypophysis. Lengthening of the photoperiod suppresses melatonin secretion, which explains increased reproductive activity in the spring, especially in seasonal breeders. Consequently, horses and small ruminants tend to have particularly prominent pineal glands compared with the other domestic species. Chemoreceptor Organs Chemoreceptor organs, such as the carotid bodies (near the bifurcation of the carotid arteries) and the aortic body (adjacent to the ascending aorta at the base of the heart), are clusters of glomus cells supported by glia-like cells. The glomus cells have numerous vesicles that contain various neurotransmitters (e.g., dopamine, catecholamines) used to relay their response to hypoxia to the nervous system. Lesions are not commonly encountered in the carotid or aortic bodies of domestic mammals, but the aortic body in particular is an occasional source of neuroendocrine neoplasia, known as chemodectoma (see Diseases Affecting Multiple Species of Domestic Animals, Disorders of the Chemoreceptor Organs), particularly in brachycephalic dogs. Mechanisms of Endocrine Diseases Endocrine organs are subject to all categories of injury, including degeneration and necrosis, vascular disturbances, inflammation from immune-mediated or infectious causes, and disturbances of growth (e.g., atrophy, hyperplasia, or neoplasia). Nevertheless, growth disturbances account for a disproportionate number of diagnoses. Disturbances of growth (whether atrophic or proliferative) in an endocrine organ can alter its function and have striking effects on distant and diverse target organs. These target organ injuries often account for the clinical presentation and major lesions. For example, cutaneous lesions can reflect hypothyroidism or hyperadrenocorticism; hyperinsulinemia can manifest as seizures. The clinical signs of endocrine disease reflect hypofunction or hyperfunction. Hypofunction of endocrine tissue usually indicates insufficient production or release of hormone(s); hyperfunction is usually the result of excessive hormone production. Endocrine dysfunction can also result from (1) inability of target cells to respond to hormones, (2) systemic disease or metabolic disturbances, or (3) administration of exogenous hormones. Hypofunction of an Endocrine Gland Primary Hypofunction. Hypofunction is considered primary if the hormonal deficiency is the result of a biochemical defect in synthesis (e.g., dyshormonogenetic goiter; see Diseases Affecting Multiple Species of Domestic Animals, Disorders of the Thyroid Gland, Follicular Hyperplasia and Goiter, Congenital Dyshormonogenetic Goiter) or the result of either failure of glandular development (e.g., from aplasia or hypoplasia) or destruction of the secretory cells of the gland. An example of primary hypofunction caused by anomalous development is canine panhypopituitarism that results from failure of oropharyngeal ectoderm to differentiate into the adenohypophysis (see Diseases of Dogs). Most endocrine organs are susceptible to immune-mediated injury in which autoreactive T lymphocytes and autoantibodies selectively destroy endocrine cells. Unlike immune-mediated diseases, infectious diseases seldom selectively attack a particular endocrine organ; however, endocrine glands, especially the adrenal glands, are vulnerable to inflammation and necrosis in systemic infections and to metastatic neoplasia. Secondary Hypofunction. Hypofunction is considered secondary if the cause arises outside the hypofunctioning gland. Often, this outcome involves injury of the pituitary gland with resultant trophic hormone deficiency. In other words, primary hypofunction of the pituitary gland causes secondary hypofunction of those endocrine glands that depend on its trophic hormones. In addition to the 778 SECTION II Pathology of Organ Systems Table 12.1 n Primary Hyperfunction of Endocrine Glands Neoplasia Hormone Lesion/Sign Somatotroph adenoma (pituitary gland) Thyroid follicular cell adenoma C-cell adenoma/ carcinoma (thyroid gland) Adrenocortical adenoma/carcinoma Pheochromocytoma (adrenal medulla) Parathyroid chief cell adenoma Pancreatic β-cell adenoma/carcinoma Growth hormone T4, T3 Acromegaly Calcitonin Cortisol Norepinephrine Parathyroid hormone Insulin ↑Basal metabolic rate Osteosclerosis Alopecia, polyuria/ polydipsia Hypertension Hypercalcemia Hypoglycemia m Figure 12.15 Secondary Adrenocortical Hypofunction; Brain with Neoplasm and Left (Longitudinal Section) and Right (Cross Section) Adrenal Glands, Dog. The neoplasm (n), centered around the third ventricle, has invaded and destroyed the pituitary gland, hypothalamus, and most of the thalamus. Destruction of the adenohypophysis caused a lack of adrenocorticotrophic hormone (ACTH) and other trophic hormones, resulting in bilateral adrenocortical atrophy (arrowheads), especially in the ACTH-dependent zonae fasciculata and reticularis, and (consequently) a relatively more prominent adrenal medulla (m). (Courtesy Dr. C. Capen, College of Veterinary Medicine, The Ohio State University.) previously mentioned causes of (primary) pituitary hypofunction, nonfunctional (hormonally inactive) pituitary adenomas or even nearby neoplasms of nonpituitary origin can become large enough to destroy the adenohypophysis. Because neither the pituitary neoplasm nor the residual adenohypophyseal cells would then produce sufficient trophic hormones, atrophy with secondary hypofunction develops in target tissues, such as the adrenal cortex (Fig. 12.15), thyroid follicles, or gonads. Hyperfunction of an Endocrine Gland Primary Hyperfunction. In primary hyperfunction, the cells of the affected endocrine gland autonomously (i.e., without dependence on trophic hormone stimulation) synthesize and secrete excess hormone. This outcome is usually the result of a functional (i.e., hormone-producing) neoplasm. Examples and consequences of primary endocrine gland hyperfunction caused by neoplasms are listed in Table 12.1. Although primary neoplasia is the major cause of primary hyperfunction of an endocrine gland, hyperfunction is not the inevitable result of endocrine neoplasia. Nonfunctional endocrine neoplasms (and even once-functional neoplasms that lose their capacity to produce or secrete bioactive hormone) can, as they increase in size, destroy surrounding glandular tissue and result in hypofunction. Secondary Hyperfunction. In secondary hyperfunction, excessive hormone production is a response to a signal (e.g., a trophic hormone) from outside the hyperfunctioning gland. For example, a functional neoplasm of adenohypophyseal (anterior pituitary gland) corticotrophs, with prolonged and excessive secretion of ACTH, would cause diffuse adrenocortical hyperplasia of the zonae fasciculata and reticularis (Fig. 12.16; E-Fig. 12.10) with resulting increased synthesis and secretion of cortisol. Theoretically, secondary hyperplasia and hyperfunction of an endocrine gland should subside when the stimulus of excessive trophic hormone is removed; however, chronic and severe hyperplasia is not always reversible. Endocrine cell proliferation can also be nodular or even clonal rather than diffuse. With long-term trophic hormone stimulation, there seems to be a continuum between focal or nodular hyperplasia and neoplasia. Secondary hyperfunction can also develop in endocrine glands or cells that are not under the control of pituitary trophic hormones. In renal secondary hyperparathyroidism and nutritional secondary hyperparathyroidism (see Diseases Affecting Multiple Species of Domestic Animals, Disorders of the Parathyroid Glands, Chief Cell Proliferation and Hyperparathyroidism), the parathyroid glands respond to decreased blood calcium concentrations with hyperplasia and increased production and secretion of PTH. Hypersecretion of Hormones or Hormone-Like Factors by Nonendocrine Neoplasms Some nonendocrine neoplasms secrete biologically active humoral substances. Most of these hormone-like chemicals produced by neoplastic cells are peptides because nonpeptide hormones (steroids, iodothyronines, or catecholamines) have more complex synthetic pathways. Pseudohyperparathyroidism or humoral hypercalcemia of malignancy (HHM) is a paraneoplastic syndrome caused by the autonomous hypersecretion of PTH-related peptide (PTHrP) by cancer cells. A well-characterized example is the canine apocrine carcinoma of the anal sac glands (see Diseases of Dogs). PTHrP acts as an agonist of the PTH receptor in target cells (e.g., in bone and kidney), leading to persistent hypercalcemia. Serum PTH concentration is decreased in response to the hypercalcemia, and PTH is not detectable in the neoplastic tissue. Endocrine Dysfunction Caused by Failure of Target Cell Response Endocrine dysfunction can be the result of failure of the target organ or tissue to respond to a hormone because of defective cell surface receptors or second messenger systems. For example, downregulation of insulin receptors on target cells (especially adipocytes, hepatocytes, or myocytes) can result in insulin resistance in obese animals. Iatrogenic Syndromes of Hormone Excess The administration of exogenous hormones has far-reaching effects on diverse populations of target cells and can result in clinically CHAPTER 12 Endocrine System E-Figure 12.10 Corticotroph Adenoma, Adenohypophysis, Dog. The ­corticotroph adenoma consists of a sheet of monotonous chromophobic cells with abundant pale amphophilic cytoplasm. Note the lack of acidophils. Hematoxylin and eosin (H&E) stain. (Courtesy Dr. M.A. Miller, College of Veterinary Medicine, Purdue University.) 778.e1 CHAPTER 12 Endocrine System 779 c m a A B zg Figure 12.17 Iatrogenic Hyperadrenocorticism, Left and Right Adrenal Glands, Dog. Hyperadrenocorticism, caused by long-term administration of exogenous glucocorticosteroids, has resulted in trophic atrophy of the adrenocorticotrophic hormone (ACTH)-dependent zonae fasciculata and reticularis of the adrenal cortex (c). Consequentially, the adrenal medulla (m) makes up a relatively greater proportion of the cross-sectional area. (Courtesy Dr. C. Capen, College of Veterinary Medicine, The Ohio State University.) important functional disturbances. The long-term administration of glucocorticoids, used to treat a variety of conditions, can reproduce most of the abnormalities of spontaneous adrenocortical hyperfunction. Nevertheless, although naturally occurring adrenocortical hyperfunction is usually the result of a disrupted hypothalamicpituitary-adrenocortical axis with hyperplasia or neoplasia of endocrine cells, iatrogenic glucocorticoid excess tends to cause profound atrophy of the adrenal cortex (especially in the ACTH-dependent zonae fasciculata and reticularis) via negative feedback through an intact hypothalamic-pituitary-adrenocortical axis (Fig. 12.17). Likewise, long-term administration of exogenous thyroid hormones results in negative feedback on the hypothalamus and on adenohypophyseal thyrotrophs with diminished TSH secretion and thyroid follicular atrophy (see Fig. 12.8, B). Exogenous sex hormones can also result in endocrine imbalances. For example, the administration of synthetic progestins, such as medroxyprogesterone acetate (also known as megestrol acetate), can induce mammary hypertrophy and hyperplasia in both male and female cats and dogs (see Chapter 18, Female Reproductive System and Mammae). Because hyperplastic mammary epithelial cells can be an extrapituitary source of GH, some progestin-treated dogs also develop acromegaly (E-Fig. 12.11). Portals of Entry/Pathways of Spread zf C Figure 12.16 Secondary Adrenocortical Hyperfunction (PituitaryDependent Hyperadrenocorticism); Brain, Pituitary Gland, and Adrenal Glands, Dog. A, A functional corticotroph (adrenocorticotrophic hormone [ACTH]-secreting) adenoma (a) in the pituitary gland caused diffuse and bilateral adrenocortical hyperplasia (arrows) leading to excessive secretion of cortisol (hyperadrenocorticism) by the zonae fasciculata and reticularis. B, Adenohypophysis. The corticotroph adenoma consists of packets of hypertrophied basophils with densely granulated cytoplasm. Note the lack of acidophils. Hematoxylin and eosin (H&E) stain. C, Adrenal cortex. Diffuse adrenocortical hyperplasia. Cells in the zona fasciculata (zf) are enlarged with abundant lipid-vacuolated cytoplasm. Zona glomerulosa (zg, top) is unaffected. H&E stain. (A courtesy Dr. C. Capen, College of Veterinary Medicine, The Ohio State University. B and C courtesy Dr. M.A. Miller, College of Veterinary Medicine, Purdue University.) Endocrine tissue is well vascularized, so the most common route of entry of a potentially injurious agent—be it microorganisms, leukocytes, trophic hormones, or an exogenous endocrine disruptor—is hematogenous. In addition, inflammation or other disease processes in adjacent tissues can extend to endocrine organs. The pituitary gland, with its neurohypophyseal connection to the hypothalamus and third ventricle of the brain and its adenohypophyseal origin from the craniopharyngeal duct, is particularly susceptible to extension of inflammation or neoplasia from the brain or from the pharynx. Defense Mechanisms/Barrier Systems Because of their ample blood supply, endocrine tissues are subjected to the benefits and potential harm of inflammation and innate and/ or adaptive immune responses. The pituitary gland gains some protection from pharyngeal microbiota by its bony encasement in the sella turcica but, at the same time, is more susceptible than the brain to hematogenous insults because of its lack of a blood-brain barrier. In general, because endocrine cells need ready access to the bloodstream to secrete their hormones, they are vulnerable to injury CHAPTER 12 Endocrine System E-Figure 12.11 Iatrogenic Acromegaly, Beagle (Center) Compared with Unaffected Littermates (Left and Right). Note the coarseness of the facial features and the markedly thick folds of the skin of the face. These characteristic changes are the result of the protein anabolic effects of somatotropin (produced by hyperplastic mammary ductular epithelial cells), which have been stimulated by the administration of exogenous medroxyprogesterone acetate. (Courtesy Dr. P. Concannon, College of Veterinary Medicine, Cornell University.) 779.e1 780 SECTION II Pathology of Organ Systems by chemical or infectious agents that arrive hematogenously. Most endocrine glands are protected from the external environment by their deep-seated location and from neighboring tissues or body cavities by a thin capsule of fibrous tissue. Diseases Affecting Multiple Species of Domestic Animalse Disorders of the Adenohypophysis Adenohypophyseal proliferation (hyperplasia or pituitary adenoma) is the most common postmortem lesion in canine pituitary glands. Secondary neoplasia, inflammation, or degeneration and necrosis unassociated with a pituitary tumor are rare. This predominance of proliferations among adenohypophyseal lesions seems to be true for the other domestic species as well. The increasing use of transsphenoidal hypophysectomy in the diagnosis and treatment of pituitary tumors in dogs and cats has changed adenohypophyseal pathology from a strictly postmortem endeavor to an important surgical biopsy practice. A Proliferative Disorders of the Adenohypophysis Hyperplasia and neoplasia are important lesions of the adenohypophysis. Physiologic hyperplasia is the result of stimulation through the hypothalamic-pituitary-target organ axis and tends to affect the trophic hormone-producing cells of interest throughout the adenohypophysis. In contrast, pathologic proliferation tends to be focal or multifocal. Nodular proliferations of cells in the pars distalis or pars intermedia that are multiple and smaller than 2 mm in diameter are typical of hyperplasia. Hyperplastic nodules do not disrupt the reticulin scaffolding of the adenohypophysis, but they can be recognized histologically because the nodule is composed mainly of one cell type (e.g., corticotrophs) (Fig. 12.18, A and E-Fig. 12.12), instead of the normal mixture of corticotrophs, somatotrophs, and other trophic hormone-producing cells. Immunohistochemistry can be used to identify the trophic hormone produced. Hyperplastic nodules are seldom large enough to be evident on clinical diagnostic imaging or gross examination; nevertheless, they can secrete excessive bioactive trophic hormones and thus be responsible for hyperplasia or even secondary hyperfunction of the targeted endocrine organ, depending on which trophic hormone is produced. Adenohypophyseal neoplasms are usually solitary and almost always classified as adenomas rather than carcinomas. It is plausible that hyperplastic nodules of adenohypophyseal cells could become clonal or that multiple nodules could coalesce to form an adenoma. Importantly, smaller adenohypophyseal lesions (whether hyperplastic or neoplastic [microadenomas]) are likely to be functional—that is, to produce and release trophic hormones into the peripheral blood—whereas large macroadenomas (see Fig. 12.18, B) may exert their effect mainly through destruction of adjacent pituitary parenchyma, often resulting in insufficient (rather than excessive) trophic hormone(s) or through compression of surrounding tissue, such as optic nerves or overlying hypothalamus. In addition to classifying nonphysiologic pituitary proliferations as hyperplastic nodules, microadenomas, or macroadenomas, it is useful to determine the type of trophic hormone produced by the proliferating cells. In veterinary medicine, this goal is generally accomplished by a combination of biochemical analysis of serum, clinical signs, and/ or immunohistochemistry on surgical biopsy or autopsy (syn: necropsy; see E-Appendix 12.1) specimens of affected pituitary gland. ePostmortem examination of the endocrine system is discussed in E-Appendix 12.1. Disorders that are known or thought to have a genetic basis are listed in E-Tables 12.1 and 1.2. a B Figure 12.18 Adenohypophyseal Hyperplasia and Neoplasia, Pituitary Gland. A, Corticotroph hyperplasia, dog. A hyperplastic nodule (lower twothirds), about 1 mm in diameter, consists of corticotrophs with basophilic granular cytoplasm that are hypertrophied, but retain the normal acinar pattern. Adjacent normal adenohypophyseal tissue (upper one-third) is a mixture of acidophils and (smaller) basophils or chromophobes. Note a few acidophils scattered through the hyperplastic nodule (arrow). Hematoxylin and eosin (H&E) stain. B, Pituitary macroadenoma, dog. The large adenoma (a) compresses the brain and optic chiasm (arrow). The adenohypophysis, neurohypophysis, and hypothalamus have been destroyed by the neoplasm. (A courtesy Dr. M.A. Miller, College of Veterinary Medicine, Purdue University. B courtesy Dr. C. Capen, College of Veterinary Medicine, The Ohio State University.) Immunohistochemical expression of trophic hormone in the cytoplasm of adenohypophyseal cells does not necessarily correlate with increased plasma concentrations of bioactive hormone. In poorly differentiated pituitary neoplasms that do not express detectable immunoreactive hormone, polymerase chain reaction (PCR) testing for mRNA of trophic hormones can be used to determine the cell of origin. Pituitary Carcinomas. Pituitary carcinomas are exceedingly rare, but that is at least partly because of stringent classification criteria. By convention, to be classified as malignant, a pituitary neoplasm must metastasize, not merely invade, either within the central nervous system or systemically. Adenomas of the Pars Distalis. Adenomas can arise from any of the trophic hormone-producing cells of the pars distalis. Depending on the cell lineage, the neoplastic cells may produce more than one type of trophic hormone. Of the domestic animal species, pars distalis adenomas are most commonly diagnosed in dogs and cats.