Endocrine System Pathology_ Ppt Lecture Series (5 in 1)

Pathology of Endocrine System

Prepared and presented by: Marc Imhotep Cray, M.D. Photos: The surgeon in this photo is transfusing donor islet cells into a diabetic patient. The islet cells may take residence in the pancreas and secrete insulin for the patient. Note the new islet cells in the right-hand photo. They are now functioning normally. This patient will never again need to inject insulin. From: Seeley’s Anatomy & Physiology 10th ed. New York, NY: McGraw-Hill 2010.

Learning Objectives 1. List types of pituitary adenomas and describe their morphology.

2. List the causes of hypopituitarism.

3. Classify thyroiditis and describe the pathogenesis, complications and morphology of Hashimoto’s thyroiditis in particular.

4. Define Graves’ disease and describe its pathogenesis and morphology and correlate with the clinical features.

Marc Imhotep Cray, MD

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Learning Objectives cont.

5. Describe different types of goiters and their pathology and clinical features.

6. Classify tumors of thyroid gland and describe the morphology and clinical features of thyroid adenoma and thyroid carcinoma 7. Describe causes, pathology, clinical features and complication of parathyroid hypo and hyperfunction.

8. Describe etiology, pathophysiology, clinical features and complications of adrenocortical hyperfunction and hypofunctions.

Marc Imhotep Cray, MD

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Learning Objectives cont.

9. Describe etiology, pathophysiology , clinical features and complications of adrenomedullary lesions 10. Define Diabetes mellitus (DM), classify it and describe its pathogenesis of the different types.

11. Describe the morphological changes of blood vessels in different organs in DM. 12. List and classify the long-term complications of DM. 13. Describe the primary cause, signs, symptoms and treatment of hypoglycemia and other acute complications of DM. Marc Imhotep Cray, MD

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Topics Outline This sequence will cover the following topics: Lect. 1 Overview and the pituitary gland (hyperpituitarism, hypopituitarism, mass effect as related to pituitary gland lesions, and posterior pituitary gland pathology) Lect. 2 Diseases of the thyroid gland (goiter, hyperthyroidism, hypothyroidism, thyroiditis, and thyroid neoplasms) Lect. 3 Diseases of the parathyroid glands (hyperparathyroidism and hypoparathyroidism) Lect. 4 Diseases of the adrenal glands (hyperadrenalism hypoadrenalism, hyperaldosteronism, and adrenal neoplasms) Lect. 5 Diabetes mellitus (T1DM & T2DM) and complications Marc Imhotep Cray, MD

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Function of Endocrine System and Overview of Endocrine Disease A working knowledge of the pathways that regulate normal hormone levels helps to interpret the symptoms, signs and diagnostic studies in patients being worked up for suspected endocrine disorders.

Marc Imhotep Cray, MD

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Function of Endocrine System  Main function of endocrine system is communication orchestrates metabolic equilibrium among organs of body  Although nervous and endocrine systems use some of same mediators and sometimes overlap functionally (=neuroendocrine integration) endocrine system is unique in its ability to communicate at a distance using soluble mediators= hormones  Ultimately, body’s chemical messenger systems(nervous & endocrine) interact with one another to maintain homeostasis

Marc Imhotep Cray, MD

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Function of Endocrine System (2)  Term hormone (from Greek, horman, “set in motion”) applies to chemicals secreted by “ductless” (i.e., endocrine) glands into circulation carries it to target organ= classic endocrine pathway  Many hormones, such as thyroid hormone, corticosteroids and pituitary hormones, fit this definition o Biological messages may also be transmitted by mechanisms other than classic endocrine pathway (see next 2 slides) Marc Imhotep Cray, MD

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Function of Endocrine System (3) Biological messages of endocrine system may also be transmitted by autocrine, paracrine, neuroendocrine & cytokine modes of communication

 Some hormones, such as catecholamines, are produced in multiple sites and act either locally or through circulation

 Other mediators function only in restricted circulation compartments:  e.g., hypothalamic hormones only act on pituitary and reach it via portal tributaries without entering systemic circulation

 Some hormones exert their effects in very tissues that make them (autocrine), e.g., MIF (Müllerian inhibitory factor) Marc Imhotep Cray, MD

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Mechanisms of chemically mediated cell-to-cell communication illustrated.

Strayer D, et al., eds. Rubin’s Pathology. Clinicopathologic Foundations of Medicine, 6th ed. Baltimore: Wolters Kluwer Health, 2012.

Learn more: Molecular and Cell Biology of Endocrine System Ppt.

Marc Imhotep Cray, MD

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Function of Endocrine System (5) NB: To qualify as a hormone, a chemical messenger must bind a receptor, whether on cell’s surface or inside (cytoplasm or nucleus)

 Hormones act either on final effector target or on other glands that in turn produce other hormones  For example, thyroid stimulating hormone (TSH) released by pituitary promotes thyroid hormone (TH) secretion by thyroid gland TH, then, directly affects many types of peripheral cells TH will in turn down-regulate activity of pituitary TSH (as well as hypothalamic TRH)= a process known as feedback inhibition Marc Imhotep Cray, MD

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Function of Endocrine System (6)  At the core of endocrine system are endocrine organs, include: pituitary, adrenals, thyroid, parathyroids, pancreas & gonads  Endocrine glands synthesize and secrete hormones into bloodstream hormones are carried to distant sites to exert their physiologic effects 

In this way endocrine glands are able to influence function of distant target organs and tissues

 Disorders of endocrine system are usually due to either overproduction or underproduction of a particular hormone, or mass lesions (mass effect) 

To aid understanding, these lectures will be presented in a similar scheme

Marc Imhotep Cray, MD

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Major Endocrine Organs

Marc Imhotep Cray, MD

Merali Z, Woodfine JD (eds.) Toronto Notes 2016, 33rd Ed. Toronto, Ontario, Canada, 2016.

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Overview of Endocrine Disease/Disorders  Endocrine system plays an important part in regulation of reproduction, growth and development, maintenance of internal environment, and energy production, utilization and storage  Disorders of endocrine system are therefore important b/c they can have far-reaching and devastating effects in some cases can be life-threatening (e.g. thyroid storm, myxedema coma, addisonian crisis, diabetic ketoacidosis, pituitary apoplexy etc.)

NB: Study of endocrine diseases requires integration of morphologic findings w biochemical measurements of levels of hormones, their regulators, and other metabolites.

Marc Imhotep Cray, MD

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Overview of Endocrine Disease (2)  Several processes can disturb normal activity of endocrine system, including (3): 1) impaired synthesis or release of hormones 2) abnormal interactions betw. hormones and their target tissues 3) abnormal responses of target organs

 Endocrine diseases can be classified as 1) diseases of underproduction or overproduction of hormones and their resulting biochemical and clinical consequences 2) diseases associated w development of mass lesions  These lesions might be nonfunctional, or assoc. w overproduction or underproduction of hormones Marc Imhotep Cray, MD

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Overview of Endocrine Disease (3) Tumors (benign & malignant), hyperplasia, or inflammatory lesions of endocrine organs can cause endocrine hypofunction and hyperfunction  Pathogenesis is frequently autoimmune and (or) genetic

 Since hypothalamus and pituitary gland control hormone secretion by many endocrine organs there is potential for lesions at this level to result in abnormal hormone secretion by downstream endocrine organs Marc Imhotep Cray, MD

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Overview of Endocrine Disease (4)  Identifying root cause of abnormal hormone production is critical for establishing correct diagnosis and managing treatment  Simultaneous measurement of conc. of pituitary hormones (e.g., TSH or ACTH) and downstream hormones (e.g., thyroid hormone or cortisol) often allows localization of endocrine abnormality  Assessing stimulation or inhibition of hormone release using various pharmacologic agents is also applied Marc Imhotep Cray, MD

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Overview of Endocrine Disease (5) Stimulation tests  Evaluate hypofunctioning disorders  Example—adrenocorticotropic hormone (ACTH)= Cosyntropin stimulation test is used in workup of hypocortisolism Causes of hypofunction • Autoimmune destruction (most common) Examples—Addison’s disease, Hashimoto’s thyroiditis, Grave’s disease • Infarction Example—Sheehan’s postpartum necrosis, WaterhouseFriderichsen syndrome • Decreased hormone stimulation Example—decreased thyroidstimulating hormone in hypopituitarism • Enzyme deficiency, infection, neoplasia, congenital disorder Marc Imhotep Cray, MD

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Overview of Endocrine Disease (6)  Suppression tests  Evaluate hyperfunctioning disorders Examples o dexamethasone suppression test evaluates hypercortisolism o saline infusion test evaluations of hyperaldosteronism o glucose tolerance test evaluations GH excess

 Most hyperfunctioning disorders cannot be suppressed • Notable exceptions prolactinoma and pituitary Cushing's syndrome (= Cushing's Disease)  Causes of hyperfunction • Adenoma (most common), acute inflammation, Marc Imhotep Cray, MD hyperplasia, cancer

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Overview of Endocrine Disease (7) Also remember, it is important to understand hypothalamic-pituitary axis so you can distinguish 1° from 2° disorders  primary diseases are diseases that originate within gland in question 

e.g., primary hyperthyroidism is due to a defect in thyroid gland), and

 secondary diseases represent change in one organ as a result of disease in another organ 

e.g., secondary hyperthyroidism may be due to a TSH-secreting pituitary adenoma

Marc Imhotep Cray, MD

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Overview of Endocrine Disease (8) Negative feedback loops  Normally, control an increase or decrease in hormone production  Example—↑ calcium, ↓ PTH; ↓ calcium, ↑ PTH

Hormone synthesis and release are governed at multiple levels typically involves regulation by a pituitary hormone which itself is regulated by a hypothalamic hormone (=releasing factor)  This general pathway structure is commonly referred to as a hypothalamic-pituitary-(organ) axis  e.g., HPO axis, where O refers to ovary, HPA axis, where A refers to adrenal gland etc. o NB: These various axes represent examples of nervous system-endocrine system integration (or “neuroendocrine systems”)

Marc Imhotep Cray, MD

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Overview of Endocrine Disease (9)  As indicated above, important to understand hypothalamic–pituitary axis so you can distinguish primary from secondary disorders  In primary endocrine disturbances, gland itself is malfunctioning (e.g., from tumor, inflammation, enzyme deficiency), but pituitary and hypothalamus are functioning normally and exhibit appropriate response to gland's action o For example, thyroid-stimulating hormone (TSH) is low in Graves disease b/c thyroid is overproducing thyroid hormone (TH) in response to presence of thyroid-stimulating antibody appropriate response is for pituitary to secrete less TSH b/c of feedback inhibition Marc Imhotep Cray, MD

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Overview of Endocrine Disease (10) ď ą In a secondary endocrine disturbance, gland is perfectly normal, but pituitary or hypothalamus is malfunctioning  For example, if pituitary secretes low or normal levels of TSH in pts w low thyroid hormone levels, then pituitary is malfunctioning b/c it should be secreting higher levels of TSH in response to inadequate levels of TH

Marc Imhotep Cray, MD

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Neuroendocrine System (Neuroendocrinology) Neuroendocrine cells receive neuronal input (NTs released by nerve cells or neurosecretory cells) and release message molecules (hormones) into blood  In this way they bring about an integration betw. nervous system and endocrine system known as neuroendocrine integration o Example of a neuroendocrine cell is a cell of adrenal medulla which releases Epi & NE (=neuroendocrine hormones) into bld

A major center of neuroendocrine integration is hypothalamus and pituitary gland hypothalamic neurosecretory cells release factors (=neuroendocrine hormones) in blood  Some of these hormones released at hypothalamic median eminence, control secretion of anterior pituitary hormones, while others (oxytocin & vasopressin) are released directly into blood Marc Imhotep Cray, MD

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Hypothalamic-pituitary axis feedback loops are neuroendocrine integration systems  In most cases, a hypothalamic– pituitary–target gland axis is regulated by negative feedback, whereby  tropic hormone of anterior pituitary gland has negative feedback effects on hypothalamus and  target gland hormone has negative feedback effects on both hypothalamus and anterior pituitary o By way of these mechanisms levels of target gland hormone are maintained within normal physiological range

Marc Imhotep Cray, MD

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Hormones of hypothalamic-pituitary axis Major neuroendocrine systems (Hormonal Feedback Regulatory Systems) Individual Axes: Anterior Pituitary Gland Hypothalamic-Pituitary–GH Axis Hypothalamic-Pituitary–Prolactin Axis Hypothalamic-Pituitary–Thyroid Axis Hypothalamic-Pituitary–Adrenal Axis Hypothalamic-Pituitary–Gonadal Axis Posterior Pituitary Gland Antidiuretic Hormone (ADH) & Oxytocin McInnis M., Mehta S. Step-up to USMLE Step 1 2015 Ed. Wolters 26 Kluwer, 2015.

“the negative feedback principle”

 A negative feedback mechanism is an example of a negative effect  Negative feedback occurs when a product downstream of an axis inhibits production of a reactant by which it is regulated  for example, thyroid hormone inhibition of

Solid lines = positive effect Dashed lines = negative effect

 It is essential to understand “the negative feedback principle” of hypothalamic /pituitary/ target organ axis

thyroid-stimulating hormone (TSH) Marc Imhotep Cray, MD

Pazdernik TL, Kerecsen L. Rapid Review Pharmacology, 3rd Ed. Mosby, 2010

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Example, thyroid hormone feedback loop ď ąA small reduction of TH triggers a rapid increase of TRH and TSH secretion, resulting in thyroid gland stimulation and increased thyroid hormone production ď ąWhen thyroid hormone reaches a normal level, it feeds back to suppress TRH and TSH, and a new steady state is attained Brown TA, Brown D. USMLE Step 1 Secrets, 3rd Ed. Saunders, 2013 Marc Imhotep Cray, MD

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Example of no feedback loop in Endemic Goiter Iodine deficiency no TH synthesis no feedback >>↑TSH>>follicular hyperplasia

Widmaier EP, Raff H & Strang KT. Vander’s Human Physiology : The Mechanisms of Body Function, Marc Imhotep Cray, MD 11th ed. New York, NY: McGraw-Hill, 2008.

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The Pituitary Gland Topics discussed Outline: Anatomy: Gross and Microscopic and Hypothalamic–Pituitary Axis Anterior Pituitary Tumors Pituitary Adenomas: General Features Functioning Adenomas and Hyperpituatarism Hypopituitarism Posterior Pituitary Syndromes Marc Imhotep Cray, MD

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Pituitary Gland Anatomy  Pituitary gland (hypophysis) a small gland that weighs 0.5-1.0 g and measures 1.3 × 0.9 × 0.5 cm  It sits at base of brain in a bony cavity called sella turcica, within sphenoid bone

Anatomically, it is composed of two lobes  Anterior lobe, or adenohypophysis arises from ectoderm, makes up 80% of gland is populated by epithelial cells  Posterior lobe, or neurohypophysis originates from neuroectoderm as a prolongation of hypothalamus Marc Imhotep Cray, MD

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Pituitary gland anatomy illustration  Anterior pituitary is formed from an out-pouching of pharyngeal roof and is called Rathke's pouch  Posterior pituitary gland arises from an extension of hypothalamic neurons  NB: pituitary gland sits in a protective bony enclosure called sella turcica (Turkish chair/saddle) Marc Imhotep Cray, MD

Strayer D, et al., eds. Rubin’s Pathology. Clinicopathologic Foundations of Medicine, 6th ed. Baltimore: Wolters Kluwer Health, 2012.

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Normal pituitary gland, gross

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

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Normal pituitary, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

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Normal pituitary, microscopic (2)

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

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Pituitary Gland (6) Histologic sections of anterior pituitary reveals cells that contain eosinophilic cytoplasm (acidophil), basophilic cytoplasm (basophil), or poorly staining cytoplasm (chromophobe) cells  Note also presence of a fine reticulin network between cells  Basophils: FSH, LH, ACTH, TSH (B-FLAT)  Acidophils: GH, PRL

Marc Imhotep Cray, MD

Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease, 9th ed. Philadelphia: Saunders-Elsevier, 2015.

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Hypothalamic–Pituitary Axis  Endocrine function responds to feedback control  Hypothalamus, pituitary stalk and pituitary gland constitute an anatomically and functionally integrated “neuroendocrine system”  Neuron groups in hypothalamus secrete a number of factors that stimulate anterior pituitary secretion of hypothalamic factors, in turn, are antagonized by hormones secreted by peripheral target organs, thereby completing a feedback loop  In addition, specific hypothalamic inhibitory hormones have been identified o For example, dopamine inhibits pituitary secretion of prolactin Marc Imhotep Cray, MD

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Hypothalamic-pituitary axis cont. Hypothalamus regulates secretion of hormones from adenohypophysis (anterior pituitary gland) by releasing  stimulatory factors (corticotropin-releasing hormone, CRH; growth hormone-releasing hormone, GHRH; gonadotropinreleasing hormone, GnRH; thyrotropin-releasing hormone TRH, and  inhibitory factors (growth hormone inhibitory hormone, GHIH or somatostatin; prolactin inhibitory factor, PIF or dopamine)  these in turn modulate release of six hormones from anterior pituitary (next slide) Marc Imhotep Cray, MD

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Anterior pituitary (6 major hormones) ď ą Anterior pituitary synthesizes and releases six hormones: 1. Growth hormone (GH): regulated by growth hormone-releasing hormone (GHRH) 2. Prolactin (PRL): inhibited by dopamine from hypothalamus, stimulated by thyrotrophin-releasing hormone (TRH) 3. Adrenocorticotrophic hormone (ACTH): regulated by corticotrophinreleasing hormone (CRH) 4. Thyroid-stimulating hormone (TSH): regulated by TRH 5. Follicle-stimulating hormone (FSH): regulated by gonadotrophinreleasing hormone (GnRH) 6. luteinizing hormone (LH): regulated by GnRH

FLAT PiG: FSH, LH, ACTH, TSH, PRL, GH Marc Imhotep Cray, MD

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hypothalamic-hypophysial portal system

Hall JE. Guyton and Hall Textbook of Medical Physiology, 13e. Philadelphia: Elsevier , 2016.

Marc Imhotep Cray, MD

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Hypothalamic-pituitary axis illustrated ď ąProduction of pituitary hormones is controlled by positively and negatively acting factors from hypothalamus ďƒ carried to anterior pituitary by a portal vascular system

Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease, 9th ed. Philadelphia: Saunders-Elsevier, 2015.

Marc Imhotep Cray, MD

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Pituitary Gland (7) Posterior pituitary contains pituicytes modified glial cells w no secretory function, axon terminals and unmyelinated nerve fibers containing ADH and oxytocin  Both are synthesized in neurons of hypothalamus and transported along axons to neurohypophysis (=stored and released here) o ADH promotes water resorption from distal renal tubules o oxytocin stimulates contraction of pregnant uterus at term and also of cells around lactiferous ducts in breasts

Marc Imhotep Cray, MD

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Pituitary Gland (8) Clinical Manifestations of Pituitary Disease  Manifestations of pituitary disorders are related to either excess or deficiency of pituitary hormones, or to mass effects  Hyperpituitarism: Arising from excess secretion of trophic hormones o Causes include pituitary adenoma, hyperplasia & carcinomas of anterior pituitary, secretion of hormones by nonpituitary tumors, & certain hypothalamic disorders o Symptoms (Sx) of hyperpituitarism are discussed later in context of individual tumors  Hypopituitarism: Arising from deficiency of trophic hormones o Caused by destructive processes, including ischemic injury, surgery or radiation, inflammatory reactions, and nonfunctional (silent) pituitary adenomas Marc Imhotep Cray, MD

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Pituitary Gland (9)  Local mass effects: Among earliest changes referable to mass effect are radiographic abnormalities of sella turcica, including sellar expansion, bony erosion, and disruption of diaphragma sella o b/c of close proximity of optic nerves & chiasm to sella expanding pituitary lesions often compress decussating fibers in optic chiasm gives rise to visual field abnormalities, classically, defects in both lateral (temporal) visual fields called bitemporal hemianopsia (See next slide) • may also invade cavernous sinus compromising cranial nerves III, IV, and VI o Like any expanding intracranial mass pituitary adenomas can produce signs (Sn) and symptoms (Sx) of elevated intracranial pressure, including headache, vomiting, ocular palsies, altered level of consciousness, back pain Marc Imhotep Cray,and MD papilledema

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Effects of Pituitary Tumors on Visual Apparatus  Graphic shows compression of optic chiasm causing defects in both lateral (temporal) visual fields= bitemporal hemianopsia  In addition, a variety of other visual field abnormalities may be caused by asymmetric growth of many tumors To learn more study: Endocrinology Tutorial 3_Anterior Pituitary Endocrine Pathology Case 2 SDL Tutorial Marc Imhotep Cray, MD

Young WF. The Netter Collection of Medical Illustrations Vol 2- The Endocrine System 2nd Edn. Philadelphia: Saunders, 2011.

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Anterior Pituitary Tumors  Most common cause of anterior pituitary disorders are pituitary tumors most are benign adenomas  Some produce hormones and result in endocrine abnormalities  Others are nonfunctional, but produce mass effects o Non-functioning (or silent) adenomas progressively enlarge until they break out of sella turcica in an upwards direction, compressing optic chiasm

 Following, we will first discuss general features of pituitary adenomas, then specific tumors Marc Imhotep Cray, MD

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Pituitary Adenomas: General Features  Most common cause of hyperpituitarism is a hormone producing adenoma arising in anterior lobe  Other, less common, causes include hyperplasia and carcinomas of anterior pituitary; secretion of hormones by some extrapituitary tumors; hypothalamic disorders  Main features of pituitary adenomas are:  Classified on basis of hormone(s) produced by neoplastic cells detected by immunohistochemical stains of tissue sections (see slide 50)

Marc Imhotep Cray, MD

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Pituitary Adenomas: General Features (2) Main features cont.  Pituitary adenomas can be functional (hormone producing) or nonfunctioning (not producing hormone) , or silent (i.e., demonstration of hormone production at tissue level only, without clinical manifestations of hormone excess) o Both functional and nonfunctioning pituitary adenomas usually are composed of a single cell type and produce at most a single predominant hormone but there are exceptions • Some pituitary adenomas secrete two different hormones (GH and PRL most common combination) Marc Imhotep Cray, MD

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Pituitary Adenomas: General Features (3)  Main features cont.  Pituitary adenomas are designated as microadenomas if less than 1 cm in diameter and macroadenomas if they exceed 1 cm

 Nonfunctioning adenomas more likely to come to clinical attention at a later stage are, therefore, more likely to be macroadenomas o b/c of larger size, nonfunctioning adenomas may encroach upon and destroy adjacent anterior pituitary parenchyma leading to hypopituitarism Marc Imhotep Cray, MD

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Classification of Pituitary Adenomas

Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease, 9th ed. Philadelphia: Saunders-Elsevier, 2015.

Note: PRL producing adenomas (prolactinoma) are most common hormone secreting tumors in both adults and children. Gonadotroph adenomas are more common in elderly.

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CT scan (a) of a large pituitary adenoma (A) expanding upwards to compress optic chiasma (arrows)

Stevens A, Lowe J, Scott I. Core Pathology, 3rd Ed. St. Marc Imhotep Cray, MD Louis: Mosby-Elsevier, 2009.

Large pituitary adenoma was an incidental finding at autopsy. As would be suggested by size of tumor, this pituitary adenoma did not secrete any hormones.

Kemp WL, Burns DK, Brown TG, Pathology: The Big Picture.

New York:McGraw-Hill,2008.

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Important point regarding pituitary adenomas: Stalk effect  Secretion of all of AP hormones, except prolactin, is stimulated by delivery of releasing hormones including TRH, GnRH, and CRH, from hypothalamus via hypophyseal portal system  Secretion of PRL, however, is tonically inhibited by delivery of dopamine via same portal system  A mass pressing on stalk will prevent dopamine from reaching pituitary gland thus causing increased levels of prolactin without actually producing prolactin o However, level of PRL in “stalk effect” less than that produced by a PRL secreting adenoma  This stalk effect will, simultaneously, cause inhibition of secretion of other AP hormones Marc Imhotep Cray, MD

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Pituitary Adenomas: Pathogenesis Several genetic abnormalities associated w pituitary adenomas have been identified:  G-protein mutations are one of most common genomic alterations causing pituitary adenomas o G-proteins play a critical role in signal transduction transmitting signals from cell surface receptors e.g. growth hormone-releasing hormone (GHRH) receptor to intracellular effectors (e.g., adenyl cyclase) which then generate second messengers (e.g., cAMP)

o G-proteins are heterotrimeric proteins, composed of a specific αsubunit that binds guanine nucleotides and interacts w both cell surface receptors and intracellular effectors • β- and γ-subunits are noncovalently bound to α-subunit Marc Imhotep Cray, MD

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G-protein signaling in endocrine neoplasia  Mutations that lead to G-protein hyperactivity are seen in a variety of endocrine neoplasms, including pituitary, thyroid, and parathyroid adenomas  G proteins play a critical role in signal transduction, transmitting signals from cell surface receptors (GHRH, TSH or PTH receptor) to intracellular effectors (e.g., adenyl cyclase) which generate second messengers (cAMP) For Hormone-Receptor Interactions and Signal Transduction Mechanisms see Molecular and Cell Biology of Endocrine System : Ppt. Marc Imhotep Cray, MD

Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease, 9th ed. Philadelphia: Saunders-Elsevier, 2015.

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Pituitary Adenomas: Pathogenesis (3)  Gs is a stimulatory G protein that has a pivotal role in signal transduction in several endocrine organs, including pituitary o α-subunit of Gs (Gsα) is encoded by GNAS gene o In basal state, Gs exists in an inactive state, w guanosine diphosphate (GDP) bound to guanine nucleotide-binding site of Gsα

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On interaction w ligand-bound cell surface receptor, GDP dissociates, and guanosine triphosphate (GTP) binds to Gsα, activating G protein activation of Gsα results in generation of cAMP= a potent mitogenic stimulus in several endocrine cells (e.g., pituitary somatotrophs and corticotrophs, thyroid follicular cells, parathyroid cells) promoting cellular proliferation and hormone synthesis and secretion

Marc Imhotep Cray, MD

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Pituitary Adenomas: Pathogenesis (4) Normally, Gsα activation is transient b/c of an intrinsic GTPase activity in α-subunit hydrolyzes GTP into GDP  Approx. 40% of somatotroph cell adenomas bear GNAS mutations that nullify GTPase activity of Gsα leading to continual activation of Gsα persistent generation of cAMP unchecked cellular proliferation  GNAS mutations also occur in minority of corticotroph adenomas Contrastly,  GNAS mutations are absent in thyrotroph, lactotroph, & gonadotroph adenomas b/c these arise from cells whose hypothalamic release hormones do not signal via cAMP-dependent pathways Marc Imhotep Cray, MD

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Pituitary adenoma, gross and microscopic Two distinctive morphologic features cellular monomorphism and absence of a reticulin network.

Massive, nonfunctioning adenoma that has grown far beyond confines of sella turcica and has distorted overlying brain.

Monomorphism of these cells contrasts with admixture of cells seen in normal anterior pituitary gland. Note also absence of reticulin network.

Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease, 9th ed. Philadelphia: Saunders-Elsevier, 2015.

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Functioning Adenomas & Hyperpituatarism  Adenomas arising from different pituitary cells produce hormones characteristic of that cell type and cause clinical syndromes that reflect activity of hormones

 Lactotroph Adenomas   

Prolactin-secreting lactotroph adenomas are most frequent type of hyperfunctioning pituitary adenoma accounting for 30% of all clinical cases Hyperprolactinemia causes amenorrhea, galactorrhea, loss of libido, and infertility b/c manifestations of hyperprolactinemia (e.g., amenorrhea) are obvious in premenopausal women prolactinomas are diagnosed at an earlier stage in women of reproductive age than in others w these tumors

Marc Imhotep Cray, MD

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Functioning Adenomas & Hyperpituatarism (2)  Lactotroph Adenomas cont.  Compared to premenopausal women effects of hyperprolactinemia are subtle in men and older women thus, tumor may reach a large size before coming to clinical attention= mass effect  Hyperprolactinemia also is a feature of other conditions, including pregnancy, high-dose estrogen therapy, renal failure, hypothyroidism, hypothalamic lesions, and dopamineinhibiting drugs (e.g., antipsychotic agents) Marc Imhotep Cray, MD

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Functioning Adenomas & Hyperpituatarism (3)  Somatotroph Adenomas  Growth hormone–secreting somatotroph adenomas are second most common type of functioning pituitary adenoma, and cause gigantism in children or acromegaly in adults  b/c clinical manifestations of excess GH may be subtle somatotroph cell adenomas may be quite large by time they come to clinical attention

Marc Imhotep Cray, MD

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Physiologic actions of Growth hormone (GH) (somatotropin or STH)

Marc Imhotep Cray, MD

Brown TA, Brown D. USMLE Step 1 Secrets, 3rd Ed. Saunders, 2013.

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Functioning Adenomas & Hyperpituatarism (4) ď ą Somatotroph Adenomas cont.

Persistent GH excess stimulates hepatic secretion of insulin-like growth factor 1 (IGF1, somatomedin C), which acts in conjunction w GH to induce overgrowth of bones and muscle  If a GH-secreting adenoma develops before epiphyses close, as is case in prepubertal children, result in gigantism o Characterized by a generalized increase in body size, w disproportionately long arms and legs Marc Imhotep Cray, MD

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Functioning Adenomas & Hyperpituatarism (5)  Somatotroph Adenomas cont.  If elevated levels of GH and IGF1 persist or develop after closure of epiphyses, affected individuals develop acromegaly o growth is most conspicuous in soft tissues, skin, viscera, and bones of face, hands, and feet o Enlargement of jaw results in its protrusion (prognathism), broadening of lower face, and separation of teeth o hands and feet are enlarged, and fingers are broad and sausage-like Marc Imhotep Cray, MD

Strayer D, et al., eds. Rubin’s Pathology. Clinicopathologic Foundations of Medicine, 6th ed. Baltimore: Wolters Kluwer Health, 2012.

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Functioning Adenomas & Hyperpituatarism (6) Somatotroph Adenomas cont.  Persistent GH excess also is assoc. w metabolic abnormalities most important is diabetes mellitus o DM arises b/c of GH-induced peripheral insulin resistance “blunts” body’s response to elevated glucose levels=GH is diabetogenic • Failure to suppress GH production in response to an oral load of glucose most specific tests to Dx acromegaly • IGF1 provides most sensitive lab test for the Dx of acromegaly

 Other manifestations of GH excess include gonadal dysfunction, generalized muscle weakness, hypertension, arthritis, congestive heart failure, increased risk for GI cancers Marc Imhotep Cray, MD

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Question A 38-year-old man presents complaining of gradually enlarging hands and feet over past several years. In comparison with a photo from 15 years ago, his facial features have become obviously coarsened. Laboratory evaluation shows mildly elevated plasma glucose, and MRI of brain reveals an enlarged mass in sella turcica.

Given suspected diagnosis, specialized testing is performed in which GH levels are measured following administration of an oral glucose load; no measurable decrease is seen.

What is the diagnosis?

Note: One good way to diagnose this disorder is to look at an old picture of pt. and compare it w patient’s current appearance. Because physical changes take place over decades, family members and friends often do not recognize them.

Marc Imhotep Cray, MD

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A. A 26-year-old attractive woman prior to acromegaly changes.

B. Facial changes 20 years later in the same woman.

Note the coarse facial features with large nose, lips, and chin.

Protrusion of lower jaw is visible.

Marc Imhotep Cray, MD

Usatine RP etal. (Eds.) The Color Atlas of Family Medicine. New York: McGraw-Hill, 2013

66

Features of acromegaly /gigantism  A 22-year-old man w gigantism due to excess GH is shown to left of his identical twin  increased height and prognathism (A) and enlarged hand (B) and foot (C) of affected twin are apparent  Their clinical features began to diverge at age of approx.

13 years 67

Functioning Adenomas & Hyperpituatarism(10)  Corticotroph Adenomas  Excess production of ACTH by functioning corticotroph adenomas leads to adrenal hypersecretion of cortisol and development of hypercortisolism (also known as Cushing syndrome) o Cushing syndrome (discussed later w diseases of adrenal gland) may be caused by other conditions as well o When hypercortisolism is caused by excessive production of ACTH by pituitary, it is called Cushing disease  after neurosurgeon Harvey Cushing who first described disorder Marc Imhotep Cray, MD

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Functioning Adenomas & Hyperpituatarism(11) Corticotroph Adenomas cont.  Most corticotroph adenomas are microadenomas at time of diagnosis o Stain positively w periodic acid–Schiff (PAS) stains due to accumulation of glycosylated ACTH protein o ACTH can also be specifically detected by immunohistochemistry methods

Marc Imhotep Cray, MD

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Functioning Adenomas & Hyperpituatarism(12)  Corticotroph Adenomas cont.  Large, clinically aggressive corticotroph cell adenomas may develop after surgical removal of adrenal glands for Tx of Cushing syndrome o In most cases this condition, known as Nelson syndrome, results from loss of inhibitory effect of adrenal corticosteroids on a preexisting corticotroph microadenoma o b/c adrenals are absent, hypercortisolism does not develop instead, pts present w mass effects of pituitary tumor Note: Pts w Cushing syndrome often have hyperpigmented skin b/c of ↑ production of melanocyte stimulating hormone (MSH) derived from same precursor as ACTH (=pro-opiomelanocortin), so its synthesis accompanies thatImhotep of ACTH Marc Cray, MD(see slide 195)

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Hypopituitarism In hypopituitarism secretion of one or more pituitary hormones is lacking has many causes and various clinical presentations  

Most often, only one or a few of pituitary hormones are deficient Occasionally, total failure of pituitary function, or panhypopituitarism (pituitary cachexia), occurs

 Effects of hypopituitarism depend on 1) extent of loss 2) specific hormones involved and 3) age of patient

 Symptoms usually relate to deficient function of thyroid, adrenal glands and reproductive system  Growth retardation and delayed puberty may occur in children Marc Imhotep Cray, MD

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Hypopituitarism (2) Causes Pituitary Tumors:  More than half of all cases of hypopituitarism in adults are caused by pituitary tumors, usually adenomas (discussed above)  Tumor itself may be functional but symptoms of hypopituitarism result from compression of adjacent tissue by tumor mass

Marc Imhotep Cray, MD

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Hypopituitarism (3) Causes Sheehan Syndrome:  Panhypopituitarism may be caused by ischemic necrosis of gland, commonly due to severe hypotension caused by intrapartum or postpartum hemorrhage/necrosis 

enlargement of pituitary reduces its blood flow, rendering it particularly vulnerable  Clinical manifestations due at first to loss of gonadotropins, then to subsequent loss of TSH and ACTH  Agalactia (lactation failure), amenorrhea, hypothyroidism and adrenocortical insufficiency are important consequences o w modern obstetric care, Sheehan syndrome is rare

Marc Imhotep Cray, MD

Note: Occurrence of similar process wo preceding pregnancy, as well as, its occurrence in males is termed Simmond’s disease (=Pituitary cachexia)

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Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012.

See Endocrinology Tutorial 1_Postpartum Necrosis

Young WF. The Netter Collection of Medical Illustrations Vol 2The Endocrine System 2nd Edn. Philadelphia: Saunders, 2011.

Hypopituitarism, Mild=FSH and LH are usually affected first

Buja LM, Krueger GR. Netter’s Illustrated Human Pathology, 2nd Ed. Philadelphia: Saunders-Elsevier, 2014.

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Hypopituitarism, Moderate=TSH and ACTH affected

Buja LM, Krueger GR. Netter’s Illustrated Human Pathology, 2nd Ed. Philadelphia: Saunders-Elsevier, 2014.

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Hypopituitarism: Severe=Frank TSH and ACTH deficiency

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Philadelphia: Saunders-Elsevier, 2014.

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Hypopituitarism, Pituitary Cachexia=AP & PP deficiency

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Philadelphia: Saunders-Elsevier, 2014.

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Question A 53-year-old woman is diagnosed with hypopituitarism.

Which of the following hormones is most likely to be affected first?

A. Follicle stimulating hormone (FSH) and luteinizing hormone (LH) B. Thyroid stimulating hormone (TSH) C. Adrenocorticotropic hormone (ACTH) D. Prolactin E. Growth hormone Marc Imhotep Cray, MD

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Question A 25-year-old woman is diagnosed with hypopituitarism.

Which of the following hormones is essential to replace first when managing her condition?

A. Thyroid hormone B. Estrogen C. Growth hormone D. Luteinizing hormone E. Follicle stimulating hormone

Marc Imhotep Cray, MD

80

Other Causes of Hypopituitarism  Pituitary Apoplexy: acute hemorrhage or impaired bld supply to pituitary can occur in nml pituitary  but at least half cases assoc. w endocrinologically inactive adenomas 

On occasion, pituitary apoplexy  leads to hypopituitarism

 Iatrogenic Hypopituitarism: radiation damage to hypothalamic– pituitary axis during therapy or prophylactic irradiation may cause neuroendocrine abnormalities, including hypopituitarism  Similarly, neurosurgical procedures may damage pituitary  Trauma: traumatic brain injury is assoc. w significant risk to pituitary gland w potential development of diabetes insipidus , hypopituitarism & other endocrinopathies Marc Imhotep Cray, MD

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Other Causes of Hypopituitarism cont.  Infiltrative Diseases: bacterial and viral infections may lead to inflammation can damage gland  Hypothalamic–pituitary axis involvement in Langerhans cell histiocytosis (formerly Hand-Schüller-Christian syndrome) results in endocrine abnormalities including diabetes insipidus and panhypopituitarism 

 Empty Sella Syndrome: primarily a radiologic term that describes an enlarged sella containing a thin, flattened pituitary at base secondary to a congenitally defective or absent diaphragma sella permits transmission of CSF pressure into sella 

can cause pituitary dysfunction and endocrine abnormalities

 Genetic Abnormalities of Pituitary Development Marc Imhotep Cray, MD

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Empty Sella Syndrome CT Scan

A computed tomography (CT) scan of cranium in an axial section demonstrates an empty sella turcica (arrows).

BS=brainstem; E=eye; TL=temporal lobe.

Marc Imhotep Cray, MD

Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012.

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Posterior pituitary (neurohypophysis)

Posterior pituitary bright spot. Sagittal T1-MRI image showing hyperintensity (arrow) in the posterior aspect of the sella turcica.

Young WF. The Cray, NetterMD Collection of Medical Illustrations Vol 2- The Endocrine System, 2nd Edn. Saunders, 2011 Marc Imhotep

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Hormones of Posterior Pituitary Oxytocin  Used in obstetrics to stimulate uterine contraction and induce labor  Oxytocin also causes milk ejection

Vasopressin (antidiuretic hormone, ADH) is structurally related to oxytocin  Has both antidiuretic and vasopressor effects  In kidney, it binds to V2 receptor to increase water permeability and reabsorption in collecting tubules Thus, major use of vasopressin is to treat diabetes insipidus  Other effects of vasopressin are mediated by V1 receptor, which is found in liver, vascular smooth muscle (where it causes constriction), and other tissues Marc Imhotep Cray, MD

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Summary of posterior pituitary hormones & their effects Hormone

Synthesized by

Stimulated by

Inhibited by

Antidiuretic hormone (ADH)

Supraoptic vasopressinergic neurons

Raised osmolarity; Lower low blood volume osmolarity

Kidney

Increases permeability of collecting duct to reabsorb water

Oxytocin

Paraventricular oxytocinergic neurons

Stretch receptors in the nipple and cervix, estrogen

Uterus and mammary glands

Smooth muscle contraction leading to birth or milk ejection

Stress

Target

Organ Effect

ď ą Diseases of posterior pituitary often come to clinical attention b/c of decreased (Diabetes insipidus ) or increased (Syndrome of inappropriate antidiuretic hormone secretion ) secretion of ADH Marc Imhotep Cray, MD

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Diabetes insipidus (DI)  Deficient hormone release by neurohypophysis results in inadequate ADH availability DI  failure of resorption of free water in renal collecting tubules hence ↑ dilute urine w higher serum osmolality and hypernatremia

 Dx can be made by water deprivation test o However, still need to distinguish central vs nephrogenic

 Diabetes insipidus characterized by uncontrolled water diuresis/polyuria, and polydipsia (excessive thirst)  Although pts. consume large amounts of water daily, they may experience life-threatening dehydration Marc Imhotep Cray, MD

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Diabetes insipidus (2)  DI can be caused by deficient ADH production (central) or resistance to ADH in kidneys (nephrogenic)  DDx injection of exogenous ADH can distinguish betw. central vs nephrogenic DI o ADH increases urine osmolality in pts w central DI, whereas, o pts w nephrogenic DI have no significant change in urine osmolality after ADH administration

 ADH is synthesized in paraventricular and supraoptic nuclei of hypothalamus and stored and released from neurohypophysis Marc Imhotep Cray, MD

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Diabetes insipidus (3)  DI caused by variety of processes head trauma, infection, neoplasm are most common   

many cases develop without recognizable underlying disease Note: Damage to PP produces only transient central DI, whereas damage to hypothalamic nuclei [paraventricular & (or) supraoptic] will cause permanent central DI

 Craniopharyngioma is a tumors that compresses & destroys neurohypophysis resulting in DI 

Benign childhood tumor (betw ages of 5 & 10 yrs.) from remnants of Rathke pouch  Often cystic and calcified not a true pituitary tumor but can have mass effects that cause pituitary hypofunction  Radiographic detection often possible b/c of calcification Marc Imhotep Cray, MD

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Diabetes insipidus (3)  Craniopharyngioma symptoms include:  headaches  visual field defects, and  hypopituitarism may be evidenced by growth retardation  ultimately, compression of pituitary stalk leads to hyperprolactinemia due to loss of dopaminergic inhibition  Typically, craniopharyngiomas have three components: solid, comprised of actual tumor cells; cystic, filled w liquid; and a calcified component 

Any suprasellar mass w these three components is highly suggestive of craniopharyngioma

Marc Imhotep Cray, MD

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Craniopharyngioma  One fourth of cases of central DI are assoc. w brain tumors, notably craniopharyngioma • As stated above, tumor arises above sella turcica from remnants of Rathke pouch & invades & compresses adjacent tissues Marc Imhotep Cray, MD

Coronal section of brain shows a large, cystic tumor mass replacing midline structures in region of hypothalamus.

Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012.

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DI Illustrated  ADH level is ↓ in central diabetes insipidus ; nml or ↑ in nephrogenic DI o Nephrogenic DI can be caused by mutation in V2-receptor o Nephrogenic DI can be caused by drugs eg., lithium, demeclocycline

Management  Desmopressin acetate (ADH analog) along w hydration Tx for central DI  HCTZ or amiloride along w hydration, dietary salt restriction, & avoidance of offending agent Tx for Nephrogenic DI Marc Imhotep Cray, MD

Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012.

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Syndrome of inappropriate antidiuretic hormone secretion (SIADH) SIADH is characterized by:  Excessive free water retention  Euvolemic hyponatremia w continued urinary Na + excretion  Urine osmolality > serum osmolality

Body responds to water retention w ↓ aldosterone and ↑ANP & BNP ↑urinary Na+ excretion normalization of extracellular fluid volume  euvolemic hyponatremia

 Very low serum Na+ levels lead to cerebral edema, seizures  Must correct Na+ slowly to prevent osmotic demyelination syndrome (formerly known as central pontine myelinolysis) Marc Imhotep Cray, MD

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Question A 32-year-old man with a recent diagnosis of mania is treated with lithium. Three weeks later he returns complaining of feeling thirsty and going to pass urine up to 8 times a day. Which of the following investigations is most likely to confirm the diagnosis?

A. Urine volume measurement B. Plasma sodium concentration C. Urine osmolality D. Plasma osmolality E. Water deprivation test

Marc Imhotep Cray, MD

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SIADH cont.  SIADH causes include:  Ectopic ADH (eg, small cell lung cancer)=most common cause  CNS disorders/head trauma  Pulmonary disease  Drugs (eg, cyclophosphamide)  Treatment: fluid restriction, salt tablets, IV hypertonic saline, diuretics, conivaptan, tolvaptan ADH antagonists=block action of ADH at V2-receptor or demeclocycline NB: Increased urine osmolality during water deprivation test indicates psychogenic polydipsia.

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The Thyroid Gland Discussion topics outline: Anatomy Function Nontoxic Goiter Toxic Multinodular Goiter Hypothyroidism Primary (Idiopathic) Hypothyroidism Goitrous Hypothyroidism Congenital Hypothyroidism Hyperthyroidism Graves Disease Thyroid Storm Marc Imhotep Cray, MD

Thyroiditis Acute Thyroiditis Chronic Autoimmune Thyroiditis Subacute Thyroiditis Follicular Adenoma of Thyroid Thyroid Cancer Papillary Thyroid Carcinoma Follicular Thyroid Carcinoma Medullary Thyroid Carcinoma Anaplastic (Undifferentiated) Thyroid Carcinoma 96

Anatomy of Thyroid Gland  Thyroid is one of largest endocrine organs  It forms early in fetal life can be recognized as early as 24 days of development  Primitive thyroid descends to its eventual location in lower anterior neck by elongation of its tubular attachment to tongue=thyroglossal duct which then atrophies around seventh week of life

 Adult thyroid has two lobes connected by an isthmus is situated below thyroid cartilage anterior to trachea  

Each lobe is about 4 cm in greatest dimension Entire gland weighs 25 to 35 g

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Thyroid Gland Structure

Widmaier EP, Raff H & Strang KT. Vander’s Human Physiology : The Mechanisms of Body Function, 11th ed. New York: McGraw-Hill, 2008.

Mulroney SE & Myers AK. Netter's Essential Physiology 2nd Ed. Philadelphia: Elsevier, 2016.

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Normal thyroid in situ, gross

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

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Normal thyroid, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

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Function of Thyroid hormone  Thyroid hormone affects almost all organs  

 

It stimulates basal metabolic rate (BMR) and metabolism of carbohydrates, lipids and proteins It increases body heat and hepatic glucose production by increasing gluconeogenesis and glycogenolysis It promotes synthesis of many structural proteins, enzymes and other hormones Glucose use, fatty acid synthesis in liver, and adipose tissue lipolysis are all increased

 In general, thyroid hormone upregulates body’s overall metabolic activities, both anabolic and catabolic Marc Imhotep Cray, MD

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Homeostasis in hypothalamus-pituitary-thyroid axis and mechanism of action of thyroid hormones:  Secretion of T3 and T4 is controlled by trophic factors secreted by both hypothalamus and anterior pituitary gland  Decreased levels of T3 and T4 stimulate release of TRH from hypothalamus and TSH from anterior pituitary, causing T3 and T4 levels to rise  Elevated T3 and T4 levels, in turn, suppress secretion of both TRH and TSH (negative-feedback loop)  TSH binds to TSH receptor on thyroid follicular epithelium, which causes activation of G proteins, release of cAMP, and cAMP mediated synthesis and release of THs (i.e., T3 and T4)  In periphery, T3 and T4 interact w thyroid hormone receptor (TR) and form a complex that translocates to nucleus and binds to so-called “thyroid response elements” (TREs) on target genes, thereby initiating transcription Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease, 9th ed. Philadelphia: Saunders-Elsevier, 2015.

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Function of Thyroid hormone (3) Thyroid gland is responsible for regulating normal growth and development by maintaining a level of metabolism in body tissues that is optimal for normal function  TH is central to normal brain development

Thyroid synthesizes, stores, and releases 2 major*, metabolically active hormones: triiodothyronine (T3) and thyroxine (T4)  T3= active form of TH, is 4 times more potent than T4 (prohormone) but its serum concentration is lower *Thyroid gland secretes 3 hormones essential for regulation of metabolism: Follicular cells T3, T4 Parafollicular cells Calcitonin (contrebalance to PTH from parathyroids) Marc Imhotep Cray, MD

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Function of Thyroid hormone (4) Approximately 80% of gland’s total daily production of T3 results from conversion of T4 to T3 through deiodination of T4  T3 & T4 exist in either free (active) or protein-bound (inactive) forms  More than 99% of circulating T4 is bound to plasma proteins, so only a small fraction exists in free form o As a result, T4 is metabolized very slowly & has a long half-life (7 days) o T3 is less bound to plasma proteins and thus undergoes faster metabolism and has a shorter half-life (1.5 days)

Marc Imhotep Cray, MD

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Summary of physiological effects of TH  Principal effects of TH are:  stimulation of metabolismraised BMR  promotion of normal growth and maturation, particularly  of CNS and skeleton  sensitization to effects of catecholamines

Marc Imhotep Cray, MD

          

Other effects: ↑Body temperature ↑Cardiac rate and contractility ↑Peripheral vasodilatation ↑Red cell mass ↑Circulatory volume ↑Respiratory drive ↑Peripheral nerves (reflexes) ↑Hepatic metabolic enzymes ↑Bone turnover Skin and soft tissue effects 105

Nontoxic Goiter  Goiter, or thyroid enlargement, may be nodular or diffuse It is classified by its functionality  Nontoxic goiter (from Latin, guttur, “throat”), also called simple, colloid, multinodular goiter or nodular hyperplasia, is thyroid enlargement without functional, inflammatory or neoplastic alterations  Patients are euthyroid and without any thyroiditis  Far more likely to be women than men (8:1)  Diffuse goiter is common in adolescence and during pregnancy, whereas multinodular type usually occurs in people older than 50 years Marc Imhotep Cray, MD

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Nontoxic goiter A. In a middle-aged woman w nontoxic goiter, thyroid has enlarged to produce a conspicuous neck mass B. Coronal section of enlarged thyroid gland shows numerous irregular nodules, some w cystic degeneration & old hemorrhage C. Microscopic view of one of macroscopic nodules shows marked variation in size of follicles Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012.

107

Toxic nodular goiter (TNG)  TNG (or Plummer syndrome) = when a hyperfunctioning nodule develops within a longstanding nontoxic goiter results in hyperthyroidism without ophthalmologic effects seen in Grave's disease  most common in women age 40- 60  a cause of hyperthyroidism due to excess production of TH from functionally autonomous thyroid nodules do not require stimulation from TSH (as in Grave's disease)

 second most common cause of hyperthyroidism (after Graves' disease) in developed world Marc Imhotep Cray, MD

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Thyroid, multinodular goiter, gross and scintigraphic scan (“Hot nodules�)

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

Marc Imhotep Cray, MD

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Hypothyroidism ď ą Hypothyroidism refers to clinical manifestations of thyroid hormone deficiencyďƒ can be consequence of three general processes: 1. Defective thyroid hormone synthesis, w compensatory goitrogenesis (goitrous hypothyroidism) 2. Inadequate thyroid function, usually due to thyroiditis, surgical resection of gland or therapeutic administration of radioiodine 3. Inadequate secretion of TSH by pituitary or TRH by hypothalamus Marc Imhotep Cray, MD

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Hypothyroidism cont. Symptoms develop insidiously & reflect ↓ circulating TH  90% of all problems involving thyroid are due to dysfunction of thyroid itself, such as primary hypothyroidism

Pts. presents w Sx of “slowing down” including: weight gain, fatigue, sluggishness, cold intolerance, constipation, muscle aches and goiter may or may not be present  Pts. w end-stage hypothyroidism = myxedema coma may experience hypothermia, confusion, stupor or coma, carbon dioxide retention, hyponatremia, and ileus NB: Sick euthyroidism= During systemic illness circulating levels of all thyroid hormones tend to be low. These need to be rechecked once patient has recovered.

As pt. recovers from underlying disease, thyroid function usually returns to normal.

111

Dominant clinical manifestations of hypothyroidism

Marc Imhotep Cray, MD

Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012.

112

Hypothyroidism Most common cause of primary hypothyroidism is Hashimoto thyroiditis (=chronic thyroiditis)  autoimmune disorder in which unsuppressed T lymphocytes produce excessive amounts of antibodies that destroy thyroid cells

Certain drugs, such as amiodarone (antiarrhythmic), lithium (bipolar disorder ), nitroprusside, iodides, and sulfonylureas, can also induce hypothyroidism Hypothyroidism is more prevalent in females and persons older than 60 years Marc Imhotep Cray, MD

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Hashimoto thyroiditis, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

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Hashimoto thyroiditis, gross

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

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Hypothyroidism  Laboratory findings include increased TSH and low free T4 levels  Pts. w primary hypothyroidism have decreased T3 and T4 levels and elevated TSH  Pts. w pituitary (secondary) hypothyroidism and hypothalamic (tertiary) hypothyroidism have decreased T3, T4, and TSH  Anemia = typically normocytic or macrocytic

Marc Imhotep Cray, MD

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Primary (Idiopathic) hypothyroidism is most often autoimmune (2)  Primary hypothyroidism occurs in fifth & sixth decades  like most thyroid disorders, is more common in women than in men  Three fourths of pts have circulating antibodies to thyroid antigens suggesting these cases represent end stage of autoimmune thyroiditis  Nongoitrous hypothyroidism may also result from antibodies that block TSH or TSH receptor without activating thyroid

Marc Imhotep Cray, MD

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Goitrous hypothyroidism reflects inadequate secretion of thyroid hormone (3)  Thyroid enlargement (goiter) may occur in hypothyroidism  Etiology includes iodine deficiency (most common), antithyroid agents (drugs or dietary goitrogens), long-term iodide intake and a number of hereditary defects in TH synthesis  Evolution of pathology of goitrous hypothyroidism is similar to that described above for nontoxic goiter

Marc Imhotep Cray, MD

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Goitrous Hypothyroidism & Endemic goiter Epidemiology  One form of hypothyroidism that exists around world is caused by iodine deficiency  Worldwide, goiter is most common endocrine disorder w rates of 4% to 15% in areas of adequate iodine intake & more than 90% where there is iodine deficiency  Endemic goiter is defined as goiter that affects more than 5% of population  Most goiters are not associated w thyroid dysfunction o FM-to-M ratio of goiter is lower than goitrous hypothyroidism

Marc Imhotep Cray, MD

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Worldwide iodine nutrition

Marc Imhotep Cray, MD

See: WHO and the International Council for the Control of Iodine Deficiency Disorders (http://indorgs.virginia.edu/iccidd/mi/cidds.html)

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Endemic goiter ď ą Massive goiter in an Ethiopian woman who lives in an endemic area for goiters ď ą Many adults have large goiters in Ethiopia where there is little iodine in their diets Usatine RP etal. (Eds.) The Color Atlas of Family Medicine. New York: McGraw-Hill, 2013.

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Goitrous Hypothyroidism: Pathophysiology  With inadequate iodine consumption synthesis of TH is compromised leading to a decrease in plasma levels of T3 & T4

Goiter at an advanced stage

 This, in turn, releases negative feedback on hypothalamus and pituitary TRH levels become chronically elevated in portal circ. of anterior pituitary plasma TSH conc. is also elevated due to increased TRH  Resulting overstimulation of thyroid can produce goiters that can achieve astounding sizes if untreated

Widmaier EP, Raff H & Strang KT. Vander’s Human Physiology : The Mechanisms of Body Function, 11th ed. New York, NY: McGraw-Hill, 2008.

Note: This form of hypothyroidism is reversible if iodine is added to diet.

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Thyroid, goiter, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

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Myxedema Can be described as hypothyroidism of adult Causes  Hashimoto thyroiditis  Idiopathic causes  Iodine deficiency o A problem in geographic areas with poor nutrition o Deficiency in pregnant women can lead to cretinism in child (remember, TH is vital to CNS development)  Paradoxically, high doses of iodine lead to a ↓ in TH production  Over-irradiation of thyroid using iodine-131 for treatment of hyperthyroidism Marc Imhotep Cray, MD

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Myxedema coma Myxedema coma is a state of decompensated hypothyroidism It is a medical emergency with a high mortality rate  Patient may have lab values identical to a "normal" hypothyroid state but a stressful event (infection, myocardial infarction or stroke) precipitates myxedema coma state, usually in elderly

 Primary symptoms of myxedema coma are  Altered mental status, low body temperature, hypoglycemia, low blood pressure, hyponatremia, hypercapnia, hypoxia, bradycardia , and hypoventilation

Treatment Levothyroxine IV Marc Imhotep Cray, MD

Note: Myxedema, although included in name, is not necessarily seen in myxedema coma.

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Congenital Hypothyroidism (Cretinism)  Cretinism (infantile hypothyroidism) severe fetal hypothyroidism due to maternal hypothyroidism  

may be endemic, sporadic or familial twice as frequent in girls as boys

 In nonendemic regions, 90% of cases result from developmental defects of thyroid (dysgenesis/agenesis) 

remainder have a variety of inherited metabolic defects including mutations in genes for TRH and its receptor, TSH and its receptor, sodium-iodide symporter, thyroglobulin and thyroid oxidase

 By 6 months clinical syndrome is well developed  Mental retardation, stunted growth (owing to defective osseous maturation) and characteristic facies are evident  Serum T4 and T3 are low, and TSH levels high (unless problem relates to a lack of TSH secretion itself) Marc Imhotep Cray, MD

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Sx and Sn of infantile hypothyroidism

Clinical findings: the 6 P’s Pot-bellied, Pale, Puffy-faced child with Protruding umbilicus, Protuberant tongue, and Poor brain development Marc Imhotep Cray, MD

Cray MI. Hormones and Their Actions Illustrated Notes.pdf. 2017 update.

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Hyperthyroidism Hyperthyroidism is condition that occurs due to excessive production of thyroid hormone by thyroid gland Thyrotoxicosis is condition that occurs due to excessive thyroid hormone of any causeďƒ therefore includes hyperthyroidism ďƒ˜ Some use the terms interchangeably

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Hyperthyroidism (2) Hyperthyroidism occurs more often in FM than in M Hyperthyroidism ↑ metabolism in all body tissues Most common cause of hyperthyroidism is Graves disease an autoimmune disorder in which an Abn. thyroid immunoglobulin binds to TSH receptor (mimic TSH) causes uncontrolled TH production 

Autoantibodies are called long acting thyroid stimulators (LATS)

 In older patients, most common cause of hyperthyroidism is multinodular toxic goiter Drugs such as amiodarone, iodides, and lithium can also cause hyperthyroidism, as well as hypothyroidism Marc Imhotep Cray, MD

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Graves disease, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

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Graves disease, microscopic (2)

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Hyperthyroidism (5)  Symptoms of hyperthyroidism include goiter, exophthalmos, nervousness, heat intolerance, palpitations, weight loss, insomnia, and new or worsening cardiac findings (atrial fibrillation, angina) Untreated hyperthyroidism can progress to thyroid storm, a possibly fatal state with acute onset of high fever, exaggerated thyrotoxicosis symptoms, cardiovascular collapse, and shock  Laboratory findings include high serum levels of free T4, undetectable TSH levels, or both, radioactive iodine uptake is increased and radioiodine scans show a diffuse uptake Marc Imhotep Cray, MD

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Graves disease

A young woman w hyperthyroidism displays a mass in neck & exophthalmos.

Major clinical manifestations of Graves disease.

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Graves disease pathophysiology Triad of Clinical Findings 1. Hyperthyroidism: due to diffuse hyperplasia of thyroid 2. Infiltrative ophthalmopathy → results in exophthalmos 3. Localized, infiltrative dermopathy (pretibial myxedema) in some patients Pathophysiology  Pretibial myxedema is a nonpitting edema caused by accumulation of interstitial glycosaminoglycans (GAGs) within dermis. Paradoxically, pretibial myxedema can also be seen in severe hypothyroidism.  Exophthalmos-systemic or local-production of antibodies that stimulate orbital fibroblasts to proliferate and produce collagen and glycosaminoglycans. Increase osmotic muscle swelling, muscle inflammation, and adipocyte count>> exophthalmos Marc Imhotep Cray, MD

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Thyroid storm  Uncommon but serious complication that occurs when hyperthyroidism is incompletely treated/untreated and then significantly worsens in setting of acute stress such as infection, trauma, surgery  Presents w agitation, delirium, substantial elevation in BMR & extreme fever, diarrhea, coma, and tachyarrhythmia (cause of death) NB: Treatment of thyroid storm is  Treat with 4 P’s: same as that for hyperthyroidism, β-blockers (e.g., Propranolol), except that drugs are given in higher Propylthiouracil, doses & more frequently corticosteroids (e.g., Prednisolone), IV administration of medication is Potassium iodide (Lugol iodine) most efficacious Marc Imhotep Cray, MD

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Immune mechanisms of Graves disease and Hashimoto thyroiditis (schematic next slide)  CD4 T cells stimulate antibody production by autoreactive B cells 

Anti-thyroid-stimulating hormone receptor antibodies stimulate TH synthesis in Graves disease

 Antibodies induce thyrocyte cell death in Hashimoto thyroiditis by complement-dependent cytotoxicity & antibody-dependent cell-mediated cytotoxicity (ADDC) o Thyrocyte death also results from attack by CD8 (cytotoxic) T cells

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Immune mechanisms of Graves disease & Hashimoto thyroiditis

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Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012.

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Thyroid Disorders Labs Capsule  Hypothyroidism results in low levels of T4 and high TSH  Hyperthyroidism is assoc. w high levels of T4 and low TSH  Low TSH and normal T4 suggest subclinical hyperthyroidism should be monitored be physician if clinical signs develop, patient may benefit from Tx  risks and benefits must be evaluated  High TSH and high T4 can be due to either thyroid hormone resistance or a TSH secreting tumor Marc Imhotep Cray, MD

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Thyroiditis ď ą Thyroiditides are a heterogeneous group of inflammatory disorders of thyroid gland, including those caused byďƒ autoimmune mechanisms, and infectious agents 1. Acute Thyroiditis usually reflects thyroid involvement in acute systemic infections o Responsible infectious agent reaches thyroid by hematogenous spread o most common causative organisms are Streptococcus, Staphylococcus and Pneumococcus o Patients present w fever, chills, malaise and a painful, swollen neck

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Thyroiditis (2) 2. Hashimoto thyroiditis is an autoimmune disease characterized by progressive destruction of thyroid parenchyma, Hürthle cell metaplasia, and massive mononuclear (lymphoplasmacytic) infiltrates, with or without extensive fibrosis   

Chronic Autoimmune Thyroiditis (=Hashimoto Thyroiditis) is most common cause of goitrous hypothyroidism in U. S. Transient phase of hyperthyroidism not uncommon 8% develop papillary thyroid cancer

Etiopathogenesis  Marc Imhotep Cray, MD

As explained above, multiple autoimmune mechanisms account for thyroid injury, including cytotoxicity mediated by CD8+ T cells, cytokines (IFN-γ), and anti-thyroid antibodies

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Thyroiditis (3) 3. Subacute granulomatous (de Quervain) thyroiditis is a selflimited disease secondary to a viral infection (e.g. mumps, coxsackie virus, adenovirus), and is characterized by pain and presence of a granulomatous inflammation in thyroid 4. Subacute lymphocytic thyroiditis is a self-limited disease often occurs after a pregnancy (postpartum thyroiditis), typically is painless, and is characterized by lymphocytic inflammation in thyroid  no fibrosis or Hürthle cell metaplasia on microscopy as in Hashimoto’s Marc Imhotep Cray, MD

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Thyroiditis (4) 5. Riedel thyroiditis is very rare and characterized by progressive and extensive fibrosis of thyroid gland  fibrosis may extend from thyroid gland to involve contiguous structures of neck leading to recurrent laryngeal nerve paralysis and tracheal compromise  It is easily mistaken for a malignant process  gland is hard, fixed, and often described as “stony”  Circulating anti-thyroid antibodies can be detected

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Follicular Adenoma of Thyroid  Follicular adenoma is a benign neoplasm showing follicular differentiation  most common thyroid tumor typically presents in euthyroid persons as a “cold” nodule (i.e., a tumor that does not take up radiolabeled iodine)  It is a solitary encapsulated neoplasm cells are arranged in follicles resembling normal thyroid gland or mimicking stages in the gland’s embryonic development  Multiple adenomas may occur

NB: In up to 90% of cases, palpable, solitary follicular lesions are actually dominant nodule in a multinodular goiter, and follicular adenomas are correspondingly infrequent Marc Imhotep Cray, MD

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Follicular adenoma A. Colloid adenoma. cut surface of an encapsulated mass reveals hemorrhage, fibrosis and cystic change B. Embryonal adenoma. tumor features a trabecular pattern w poorly formed follicles that contain little if any colloid C.

Fetal adenoma. A regular pattern of small follicles is noted

D. HĂźrthle cell adenoma. Tumor is composed of cells w small, regular nuclei and abundant eosinophilic cytoplasm

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Thyroid Cancer To be studied along with Endocrine Pathology Case 1_SDL Tutorial.

 Malignant thyroid tumors cause 0.4% of all cancer deaths in US  Approximately 10,000 new cases are diagnosed each year  Mortality from thyroid cancer exceeds that from malignant tumors of all other endocrine organs  Most cases of thyroid carcinoma occur between third and seventh decades, but children can also be affected  Tumors occur in women 2.5 times more often than in men Marc Imhotep Cray, MD

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Thyroid Cancer (2) Investigations  Fine-needle biopsy (FNB) of thyroid nodules makes a diagnosis in most cases  Prognosis is a function of morphology of tumor range from a very indolent clinical course to a rapidly fatal disease  Radioscintigraphy of gland may help in assessing thyroid tumors  

hyperfunctioning (“hot”) nodules are usually benign “Cold” or nonfunctioning nodules, more frequently malignant, but may also be benign (i.e., adenoma)

Clinical Correlation: FINE-NEEDLE ASPIRATION OF THYROID NODULES  Fifteen percent of people have a detectable nodule in thyroid, either by palpation, or by ultrasound imaging  Fine-needle aspiration (FNA) is a minimally invasive method to biopsy Marcnodules Imhotep Cray, MDscreen for rare cases of carcinoma and

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Thyroid Ca (4) Etiopathogenesis  Most important environmental factor is external radiation 1. External radiation single most important environmental factor assoc. w increased risk of developing thyroid carcinoma esp. many years of exposure to of high dose 2. Iodine excess and TSH In regions where endemic goiter is widespread, addition of iodine to diet has resulted in increase in incidence of papillary cancer

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Thyroid Ca (5) Etiopathogenesis 3. Genetic basis familial clustering of thyroid cancer has been observed especially in medullary carcinoma  Molecular studies reveal thyroid Ca is a multistep process: i. Papillary thyroid carcinoma: mutation in RET gene (overexpression) located on chromosome 10q is seen in about 20% cases of papillary thyroid carcinoma ii. Follicular thyroid carcinoma: About 50% cases of follicular thyroid carcinoma have mutation in RAS family of oncogenes includes H-RAS, N-RAS and K-RAS Marc Imhotep Cray, MD

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Thyroid Ca (6) Etiopathogenesis 3. Genetic basis familial clustering cont. iii. Medullary thyroid carcinoma: Medullary thyroid carcinoma arises from parafollicular C-cells in thyroidďƒ point mutation in RET-proto-oncogene is seen in both familial (MEN2) as a well as sporadic cases of medullary thyroid carcinoma iv. Anaplastic thyroid carcinoma: This tumor either arises from further dedifferentiation of differentiated papillary or follicular thyroid Ca, or by inactivating point mutation in p53 tumor suppressor gene or by mutation in gene coding for β-catenin pathway Marc Imhotep Cray, MD

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Thyroid Cancer (7)  Major subtypes of thyroid cancer and their relative frequencies are as follows:    

Papillary carcinoma (more than 85% of cases) Follicular carcinoma (5% to 15% of cases) Medullary carcinoma (5% of cases) Anaplastic (undifferentiated) carcinoma (<5% of cases)

Remember genetic markers: Papillary thyroid carcinoma—RET gene Follicular thyroid carcinoma—RAS family of oncogenes Medullary thyroid carcinoma—-RET-proto-oncogene Anaplastic thyroid carcinoma—p53 tumor suppressor gene Marc Imhotep Cray, MD

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Papillary adenocarcinoma Epidemiology  Most common endocrine cancer  Papillary carcinoma most common thyroid cancer (>75%)  More common in women than men (3:1) o Usually occur in second and third decades

 Main risk factor: assoc. w radiation exposure Gross and microscopic findings  Usually multifocal  Papillary leafs intermixed w follicles  Psammoma bodies (35–45% of cases) o Dystrophically calcified cancer cells

 Empty-appearing nuclei o Called Orphan Annie nuclei

 Lymphatic invasion Metastasize to cervical nodes, lung Diagnose with FNA Marc Imhotep Cray, MD

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Papillary carcinoma cont. Treatment  Subtotal thyroidectomy w sampling of cervical nodes  Followed in a few weeks by radiotherapy w 131I  Suppressive therapy w thyroid hormone o Tumor is TSH dependent Five-year survival rate > 95%

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Papillary carcinoma of thyroid A. Cut surface of a surgically resected thyroid displays a circumscribed pale tan mass w foci of cystic change B. Branching papillae are lined by neoplastic columnar epithelium w clear nuclei ď&#x201A;§ A psammoma body is evident (arrow)

Marc Imhotep Cray, MD

Rubin R , Strayer DS Eds. Rubinâ&#x20AC;&#x2122;s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012.

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Follicular carcinoma  Epidemiology  Most common thyroid cancer presenting as a solitary cold nodule  Female dominant cancer

 Gross and microscopic findings  Invasion of capsule (distinguishing from follicular adenoma)  Neoplastic follicles invade blood vessels  Lymph node metastasis is uncommon

 Metastasize to lung and bone (hematogenous)  Treatment similar to papillary cancer  Five-year survival rate >80% w treatment Marc Imhotep Cray, MD

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Capsular invasion in follicular carcinoma ď&#x201A;§ Evaluating integrity of capsule is critical in distinguishing follicular adenomas from follicular carcinomas: (A) In adenomas, a fibrous capsule, usually thin but occasionally more prominent, surrounds neoplastic follicles and no capsular invasion is seen; compressed normal thyroid parenchyma usually is present external to capsule (top) (B) By contrast, follicular carcinomas demonstrate capsular invasion that may be minimal, as in this case, or widespread, with extension into local structures of neck Marc Imhotep Cray, MD

Rubin R , Strayer DS Eds. Rubinâ&#x20AC;&#x2122;s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012.

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Medullary carcinoma Epidemiology  Types o Sporadic (80% of cases) o Familial (20% of cases)

 Familial type o Associated w autosomal dominant MEN IIa/IIb o MEN IIa syndrome • Medullary carcinoma, hyperparathyroidism (HPTH), pheochromocytoma

o MEN IIb (III) syndrome • Medullary carcinoma, mucosal neuromas (lips/tongue), pheochromocytoma

 Familial type has a better prognosis than sporadic type  Ectopic hormones o ACTH, which can produce Cushing syndrome  Male: female ratio is equal Marc Imhotep Cray, MD

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Medullary carcinoma cont. Pathogenesis  Tumors derive from parafollicular C cells  C cells synthesize calcitonin o Tumor marker o May produce hypocalcemia o Converted into amyloid can be stained w Congo-red for histologic ID

 C-cell hyperplasia is a precursor lesion o Calcitonin levels increase w infusion of pentagastrin Diagnosis  FNA  Serum calcitonin Treatment  Total thyroidectomy  Genetic screening for familial cases o Detection of mutation of RET proto-oncogene o Thyroidectomy is performed if family member is a gene carrier Marc Imhotep Cray, MD

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Medullary thyroid carcinoma. A. Coronal section of a total thyroid resection shows bilateral involvement by a firm, pale tumor.

B. The tumor features nests of polygonal cells embedded in a collagenous framework.

The connective tissue septa contain eosinophilic amyloid. C. A section stained with Congo red and viewed under polarized light demonstrates the pale green birefringence of amyloid.

Marc Imhotep Cray, MD

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Anaplastic thyroid cancer  Epidemiology  Most often occurs in elderly women  Risk factors o Multinodular goiter, history of follicular cancer  Rapidly aggressive and uniformly fatal  Treatment o Palliative surgery often compresses trachea o Irradiation or chemotherapy  Five-year survival rate is 5% Marc Imhotep Cray, MD

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Anaplastic carcinoma of thyroid A. tumor in transverse section partially surrounds the trachea and extends into the adjacent soft tissue B. tumor is composed of bizarre spindle and giant cells with polyploid nuclei and numerous mitoses

Rubin R , Strayer DS Eds. Rubinâ&#x20AC;&#x2122;s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012.

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Thyroid Carcinoma Treatment  1° treatment for thyroid carcinoma is total thyroidectomy w lymph node dissection depending on tumor stage  Radioactive iodine is administered postoperatively to ablate thyroid remnant

 Thyroglobulin (Tg) can then be used as a tumor marker Tg is undetectable in absence of functioning thyroid tissue Rising Tg following 131I ablation indicates recurrence Marc Imhotep Cray, MD

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Investigations to assess thyroid nodule  When presented w a thyroid nodule, your job is to exclude presence of a malignant thyroid lesion

Investigation

Result

Thyroid function tests Thyroglobulin Radioactive iodine scan Ultrasound scan FNA cytology

T3, T4 & TSH (nml or Abn) Post Ca Tx monitoring (raising=recurrence) inactive “cold” or active “hot” nodule Is nodule solid or cystic in consistency Benign or malignant (if carcinoma, what type based on histology) Chest CT If malignant lesion R/O tracheal compression or retrosternal extension NB: A short clinical history and an asymmetrically enlarged, hard thyroid nodule with adjacent cervical lymphadenopathy are all suggestive of cancer.

See:Imhotep Endocrine Pathology Marc Cray, MD

Case 1 SDL Tutorial (Thyroid nodule)

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Investigating a thyroid nodule (2)  About 5% of all thyroid nodules are malignant, regardless of size  Be suspicious of cancer in any of following scenarios: o cold nodule on a nuclear scan o male patient o history of childhood irradiation, o nodule described as “stony hard” o recent or rapid enlargement, and o ↑calcitonin level (medullary thyroid cancer usually in pts w MEN type II)  Next slide shows algorithm for investigation of a thyroid nodule

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Steps in investigating a thyroid nodule Thyroid nodule

Check TSH

High

Check free T4 and T3 (investigate for Hashimotoâ&#x20AC;&#x2122;s nodule)

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Normal

FNA

Low

Nuclear medicine uptake scan (investigate for hot/cold) 164

Parathyroid Gland Disorders and Disorders of Calcium Homeostasis Topics discussed Outline: Anatomy of Parathyroid Gland Physiology of Parathyroid Gland Hypoparathyroidism Hyperparathyroidism Calcium-relate Diseases & Disorders

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Anatomy of Parathyroid Gland Embryologically, parathyroids derived from third and fourth pharyngeal pouches and present on posterior aspect of thyroid gland as superior and inferior pairs  Occasionally an ectopic parathyroid is located substernally in thymus

Normal parathyroid gland comprised of variable numbers of adipocytes, mixed w small nests of chief cells that secrete PTH  Clear cells are chief cells whose cytoplasm is packed w glycogen  Oxyphil cells appear after puberty, are larger than chief cells and have deeply eosinophilic cytoplasm, owing to numerous mitochondria they have no secretory granules and do not secrete PTH (function is obscure)

Parathyroid has rich vascular supply PTH is release into bloodstream inversely to ionized Ca+2 and Mg+2 levels in blood Marc Imhotep Cray, MD

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Parathyroid gland, normal

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Physiology of Parathyroid Gland  Parathyroid glands are key regulators of calcium homeostasis  Activity of parathyroid glands is controlled by level of free (ionized) calcium in blood  Normally, ↓levels of free calcium stimulate synthesis & secretion of PTH PTH has following effects on its target tissues= kidneys and bones:    

↑renal tubular reabsorption of calcium ↑urinary phosphate excretion, thereby lowering serum phosphate levels (since phosphate binds to ionized calcium) ↑ conversion of vitamin D to its active dihydroxy form in kidneys which in turn augments GI calcium absorption Enhanced osteoclastic activity (i.e., bone resorption, thus releasing ionized calcium) mediated indirectly by promoting differentiation of osteoclast 168 progenitor cells into mature osteoclasts

Hypoparathyroidism  Hypoparathyroidism results from decreased secretion of PTH or end-organ insensitivity to it (pseudohypoparathyroidism) owing to congenital or acquired conditions 

Characterized by hypocalcemia & hyperphosphatemia

Etiology (common causes):  

Thyroid* and other head & neck surgery Infiltration and destruction of parathyroid glands e.g., Wilson disease, hemachromatosis, and radiation  Congenital absence of parathyroid glands (as seen in DiGeorge syndrome)  PTH production may be suppressed in hypomagnesemia (magnesium important for PTH homeostasis) *Note: Hypoparathyroidism is most often due to surgical removal of parathyroids at time of thyroidectomy.

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Hypoparathyroidism (2) Clinical manifestations Symptoms (related to hypocalcemia)  Seizures  Chvostek’s sign (facial twitching when  Constipation zygomatic arch is tapped)  Muscle cramps  Trousseau’s sign (forearm spasms induced by inflating BP cuff on upper arm)  Hyperreflexia  Tetany  Abdominal pain  Lethargy  Cardiac dysrhythmia  Neuropsychiatric  depression  paranoia  psychoses Marc Imhotep Cray, MD

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Pseudohypoparathyroidism: Caused by target organ insensitivity to PTH Molecular Pathogenesis of Pseudohypoparathyroidism:  Hypocalcemia in this group of hereditary conditions reflects mutation of GNAS1 gene on long arm of chromosome 20 resulting in decreased activity of Gs (G protein that couples hormone receptors to stimulation of adenyl cyclase)  Consequently, renal tubular cell production of cAMP in response to PTH is impaired leading to inadequate resorption of calcium from glomerular filtrate  These patients have a characteristic phenotype (Albright hereditary osteodystrophy) including short stature, obesity, mental retardation, subcutaneous calcification and congenital anomalies of bone, particularly abnormally short metacarpals and metatarsals Marc Imhotep Cray, MD

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Rubin R , Strayer DS Eds. Rubinâ&#x20AC;&#x2122;s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012.

Pseudohypoparathyroidism. A radiograph of the hand reveals characteristic shortness of fourth and fifth metacarpal bones.

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Reference scale graphic.

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DiGeorge Syndrome  Etiology 

Caused by microdeletion on chr 22q11 results in failure of development of third and fourth pharyngeal pouches

 Pathology & Pathophysiology  Thyroid & parathyroid tissue hypoplasia o Thymic hypoplasia results in T-cell deficiency o Parathyroid hypoplasia results in hypocalcemia

 Clinical Manifestations    

recurrent viral, fungal, and protozoal infections tetany (owing to hypocalcemia) congenital cardiovascular defects facial abnormalities including cleft palate

 Treatment 

Fetal thymus transplanted to restore T-cell immunity

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Hypoparathyroidism (3)  Laboratory  Decreased serum PTH  Hypocalcemia  Hyperphosphatemia  Normal 25-hydroxyvitamin D level  Decreased 1,25- dihydroxyvitamin D levels

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Hypoparathyroidism (3)  Diagnosis  Increased urine calcium to creatinine ratio and hypophosphaturia (hyperphosphatemia)  ECG: prolonged Q-T interval  due to hypocalcemia  Treatment  Supplementation w Ca+2 & 1,25-dihydroxyvitamin D  Caution w IV calcium admin. can result in vasodilation, cardiac arrhythmias, decreased BP & bradycardia Marc Imhotep Cray, MD

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Hyperparathyroidism Definition High levels of PTH usually due to excessive release  Types of HPT  Primary Hyperparathyroidism  Secondary Hyperparathyroidism  Tertiary Hyperparathyroidism

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Primary Hyperparathyroidism  Parathyroid adenoma is most common cause 

85% of all hyperparathyroid cases

 Hyperplasia of parathyroid glands (10-15% of cases)  Parathyroid carcinoma (rare, 1%) Clinical Findings  Hypercalcemia, hypercalciuria (renal stones), polyuria (thrones), hypophosphatemia  Labs ↑ PTH,↑ ALP, ↑cAMP in urine  Sn & Sx Most often asymptomatic may present w weakness and constipation (“groans”), abdominal/flank pain (kidney stones, acute pancreatitis), depression (“psychiatric overtones”), osteitis fibrosa cystica cystic bone spaces filled w fibrous tissue “Stones, thrones, bones, groans, and psychiatric overtones”

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Parathyroid adenoma, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

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Parathyroid, adenoma, scintigraphic scan

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

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Parathyroid hyperplasia, gross

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

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Secondary Hyperparathyroidism  Feedback response to hypocalcemia stimulates parathyroid glands leading to hyperplasia & excessive PTH production o Causes of hypocalcemia: • Renal failure is most common cause • Vitamin D deficiency • Malabsorption of intestinal calcium

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Rubin R , Strayer DS Eds. Rubinâ&#x20AC;&#x2122;s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012.

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Tertiary Hyperparathyroidism  Constant stimulation of parathyroids in secondary hyperparathyroidism  causes autonomous secretion of PTH by gland o End result is hypercalcemia b/c feedback response is functional

 Tx: Correction of hypercalcemia assoc. w tertiary HPT requires surgical resection of most of four parathyroid glands Marc Imhotep Cray, MD

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Summary of Ca++ Regulation by PTH and Vitamin D

Miksad RA, Meyer GK & DeLaMora PA. Last Minute Internal Medicine. New York: McGraw-Hill, 2008.

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Calcium-relate Diseases & Disorders Osteoporosis, Paget disease, & osteomalacia disorders of bone

 Osteoporosis is characterized by progressive loss of

bone mass and skeletal fragility  Patients w osteoporosis have an increased risk of fractures, which can cause significant morbidity  Osteoporosis occurs in older men and women but is most pronounced in postmenopausal women

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Changes in bone morphology in osteoporosis  Trabecular (spongy) and cortical bone lose mass and interconnections despite normal bone mineralization and lab values (serum Ca2+ and PO43−)  Most commonly due to ↑bone resorption related to↓ estrogen levels and old age  Can be secondary to drugs (eg, steroids, alcohol, anticonvulsants, anticoagulants, thyroid replacement therapy) or  Other medical conditions (eg, hyperparathyroidism, hyperthyroidism, multiple myeloma, malabsorption syndromes) Whalen K. Lippincott Illustrated Reviews: Pharmacology 6th Ed. Wolters Kluwer, 2015 Marc Imhotep Cray, MD

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Osteoporosis Can lead to vertebral compression fractures small arrows (large arrows show normal-for-age vertebral body height for comparison)acute back pain, loss of height, kyphosis

Diagnosed by a bone mineral density scan (dual energy x-ray absorptiometry [DEXA]) w a T-score of ≤ −2.5 or by a fragility fracture of hip or vertebra  Screening recommended in women > 65 years old

Le T, Bhushan V. First Aid for the USMLE Step 1 2017. New York: McGraw-Hill Education, 2017.

Prophylaxis: regular weight-bearing exercise and adequate Ca2+ and vitamin D intake Tx: bisphosphonates, teriparatide, SERMs, calcitonin 187

Calcium-relate Diseases & Disorders (4) Paget disease is a disorder of bone remodeling that results in disorganized bone formation and enlarged or misshapen bones  Unlike osteoporosis, Paget disease is usually limited to one or a few bones  Patients may experience bone pain, bone deformities, or fractures

Osteomalacia is softening of bones that is most often attributed to vitamin D deficiency  Osteomalacia in children is referred to as rickets Marc Imhotep Cray, MD

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Adrenocortical Dysfunction Topics discussed outline: Anatomy of Adrenal Gland Physiologic, Biochemical & Immunologic Effects of Cortisol ACTH (corticotropin) Congenital adrenal hyperplasia (CAH) Waterhouse-Friderichsen syndrome Cushing Syndrome Adrenocortical insufficiency: 1°, 2° , 3° and Adrenal crisis Hyperaldosteronism Adrenomedullary pathology: Pheochromocytoma and Neuroblastoma Marc Imhotep Cray, MD

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Hormones of adrenal gland (cortex) Principal hormone is glucocorticoid cortisol secreted from largest zone, fasciculata; mineralocorticoid aldosterone is secreted by glomerulosa, and of androgens and estrogens are secreted by zona reticularis Hypothalamic–pituitary system, through corticotropin releasing factor (CRF) and ACTH (corticotropin), controls cortisol and, to a lesser extent, aldosterone secretion  synthesis and secretion of aldosterone is regulated mainly by the renin– angiotensin system (ATII) , and by variation in plasma K + levels

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Hormones of adrenal gland cont.  Adrenal cortex (derived from mesoderm) & Adrenal medulla (derived from neural crest)  Adrenal cortex, think GFR:  Glomerulosa (Na+)  Fasciculata (glucocorticoids)  Reticularis (androgens) Mnemonic To remember hormones produced by each layer “the deeper you go, the sweeter it gets”: • Mineralocorticoid (salt hormone) o aldosterone • Glucocorticoid (sugar hormone) o hydrocortisone • Androgen (sex hormone) McInnis M., Mehta S. Step-up to USMLE Step 1 2015 Edition. Wolters191 Kluwer, 2015 o dehydroepiandrosterone

Adrenal gland

Reisner HM. Pathology: A Modern Case Study. New York: McGraw-Hill Education,2015.

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Normal adrenal gland, gross

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

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Normal adrenal gland, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

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Comparison of atrophic, normal, and hyperplastic adrenal glands

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

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Cortisol  Cortisol is a steroid hormone, in glucocorticoid class of hormones  When used as a medication, known as hydrocortisone  Produced in humans by zona fasciculata of adrenal cortex within adrenal gland  Released in response to stress and low blood-glucose concs.  Functions to  to increase blood sugar through gluconeogenesis,  to suppress immune system, and  to aid in metabolism of fat, protein, and carbohydrates  It also decreases bone formation Marc Imhotep Cray, MD

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Physiologic, Biochemical & Immunologic Effects of Cortisol “Cortisol is a BIG FIB” ↑Blood pressure:  Upregulates α1-receptors on arterioles↑sensitivity to NE and Epi  At high concs., can bind to mineralocorticoid receptors

↑Insulin resistance (diabetogenic) ↑Gluconeogenesis, lipolysis, and proteolysis ↓Fibroblast activity (causes striae) ↓Inflammatory and Immune responses:

Brown TA, Brown D. USMLE Step 1 Secrets, 3rd Ed. Saunders, 2013.

 Inhibits production of leukotrienes and prostaglandins  Inhibits WBC adhesion neutrophilia (neutrophil demargination) N.B Exogenous corticosteroids can cause  Blocks histamine release from mast cells  Reduces eosinophils reactivation of TB and candidiasis (blocks IL-2  Blocks IL-2 production production), as IL-2 stimulates growth of helper,

↓Bone formation (osteoblast activity)

cytotoxic, and regulatory T cells, and NK cells.

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ACTH (corticotropin)  ACTH is a single polypeptide of 39-amino acid 

Amino acids 1 to 24 is required for full biological activity

 Amino terminal sequence (1–13) of ACTH is identical to alphamelanocyte-stimulating hormone (α-MSH) 

Thus, excess secretion of ACTH from pituitary in 1° adrenocortical insufficiency, causes hyperpigmentation due to its α-MSH activity o

In 2°and 3° forms of adrenal insufficiency, skin darkening does not occur, as ACTH is not overproduced

 A Synthetic corticotropin-derivative is used clinically to assess adrenocortical status  

Synthetic human ACTH(1-24) is called Cosyntropin In adrenocortical insufficiency (Addison’s disease), adrenocortical response to cosyntropin administration of is reduced

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ACTH Synthesis [A pro-opiomelanocortin(POMC)-derived melanocortins]

Marc Imhotep Cray, MD

Melanocortins POMC-derived melanocortin peptides include Îą-MSH ď&#x192; generated as a proteolytic cleavage product from ACTH , which is in turn is a cleavage product of proopiomelanocortin (POMC)

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Clinical Vignette A 16-year-old girl is brought to your office complaining of delayed menarche. She denies sexual activity and pregnancy test was negative. Physical examination reveals the absence of breasts, hair on her upper lip, chin, and axillary region, and hypertension.

When laboratory results reveal decreased cortisol and aldosterone levels, you suspect that this girl may have a rare autosomal recessive enzyme deficiency.

What is the diagnosis?

What is the enzyme deficiency?

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Congenital adrenal hyperplasia (CAH) Etiology: Autosomal recessive deficiency in enzymes involved in biosynthesis of cortical steroids Pathology & Pathophysiology: Bilateral nodular hyperplasia of adrenal gland w lipid-depleted cortical cells  21-Hydroxylase deficiency (95% cases): Interferes w aldosterone and cortisol production results in shunting of precursor molecules to form sex hormones  11β-Hydroxylase deficiency: Interferes w aldosterone and cortisol production results in shunting of precursor molecules to form sex hormones  17α-Hydroxylase deficiency: Interferes w cortisol and sex hormone production results in shunting of precursor molecules to form aldosterone Marc Imhotep Cray, MD

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CAH cont.  Clinical Manifestations  21-Hydroxylase deficiency: Masculinization; hypotension; hyperkalemia; hyponatremia (salt wasting can lead to hypovolemia)  11β-Hydroxylase deficiency: Masculinization; hypertension (weak mineralocorticoid precursor activity); no salt wasting  17α-Hydroxylase deficiency: Hypertension; hypokalemia; no sexual maturation

 Treatment Replacement of deficiency hormones; symptomatic treatment See: Schematic and companion table (Adrenal steroids and congenital adrenal hyperplasias). In: First Aid for the USMLE Step 1 2017; pg. 317.

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Pathophysiology of CAH In CAH, 21α-hydroxylase is deficient, such that production of aldosterone and cortisol decrease owing to metabolic block leads to an overproduction of steroid precursors (such as 17-hydroxyprogesterone)these precursors are shunted into pathway of sex hormone biosynthesis leading to excessive accumulation of adrenal androgens causes in utero masculinization of external genitalia in developing females

Brown TA, Brown D. USMLE Step 1 Secrets, 3rd Ed. Saunders, 2013.

Learn more and test your understanding: Steroidogenesis and Application to CAH Diagnosis.PDF Marc Imhotep Cray, MD

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Congenital adrenal hyperplasia

Rubin R , Strayer DS Eds. Rubinâ&#x20AC;&#x2122;s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012.

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Congenital adrenal hyperplasia

Gynecomastia. M/5 yrs.

Precocious puberty. M/11 months.

Cooke RA. Color Atlas of Anatomical Pathology. Edinburgh: Churchill Livingstone-Elsevier, 2004.

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Question  What adrenal disease should be suspected in a young patient with bacterial meningitis due to Neisseria meningitidis who also becomes acutely hypotensive?  Sn & Sx:  septicemia, hypotension  disseminated intravascular coagulation (DIC)  adrenal hemorrhage, and  petechial rash Marc Imhotep Cray, MD

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edn. Saunders, 2014

Waterhouse-Friderichsen syndrome Ques. What adrenal disease should be suspected in a young patient with bacterial meningitis due to Neisseria meningitidis who also becomes acutely hypotensive?

Ans. Waterhouse-Friderichsen syndrome typically causes bilateral adrenal hemorrhage, which can be rapidly fatal acute adrenal cortical insufficiency syndrome Responsible bacterium is Neisseria meningitidis Sn & Sx:  septicemia, hypotension  disseminated intravascular coagulation (DIC)  adrenal hemorrhage, and  petechial rash Marc Imhotep Cray, MD

Waterhouse-Friderichsen syndrome, gross

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

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Waterhouse-Friderichsen syndrome, CT

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

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Cushing Syndrome Cushing syndrome is a group of clinical symptoms that result from prolonged exposure to excess glucocorticoids May be caused by exogenous factors, such as long-term corticosteroid use, or  May be of endogenous origin due to either  excess ACTH secretion (ACTH dependent) = Cushing Disease or  autonomous cortisol hypersecretion (ACTH independent)  adrenocortical adenomas, carcinomas, ectopic ACTH & CRH syndromes are responsible for endogenous syndrome Marc Imhotep Cray, MD

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Etiology Cushing Syndrome Increase cortisol due 3 major causes: 1. Exogenous corticosteroids result in ↓ ACTH, bilateral adrenal atrophy (most common cause) 2. Primary adrenal adenoma, hyperplasia, or carcinoma result in ↓ACTH, atrophy of uninvolved adrenal gland 3. ACTH-secreting pituitary adenoma (Cushing disease) or paraneoplastic ACTH secretion (eg, small cell lung cancer, bronchial carcinoids) result in ↑ACTH, bilateral adrenal hyperplasia Note: Cushing disease is responsible for majority of endogenous cases of Cushing syndrome.

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Schematic representation of various forms of Cushing syndrome

Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease, 9th ed. Philadelphia: Saunders-Elsevier, 2015.

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Adrenal adenoma, gross

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

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 Clinical manifestations affect multiple organ systems and depend on degree and duration of hypercortisolism  Most common sign is progressive obesity seen in face, neck, trunk, and abdomen  Facial fat accumulation produces a moon-face appearance, enlarged dorsocervical fat pad produces a buffalo hump  Other Sx include: o weight gain o weakness o muscle wasting (reduced arm muscle mass) o osteoporosis o cardiovascular (hypertension) o hyperglycemia (insulin resistance) o amenorrhea o immunosuppression

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Buja LM, Krueger GR. Netter’s Illustrated Human Pathology, 2nd Ed. Philadelphia: Saunders-Elsevier, 2014.

Clinical findings in Cushing Syndrome

Diagnosis of Cushing Syndrome  Screening tests include:  increase free cortisol on 24-hr urinalysis  increase midnight salivary cortisol, and no suppression w overnight low-dose dexamethasone test

 Measure serum ACTH  

If decrease suspect adrenal tumor or exogenous glucocorticoids If increase distinguish between Cushing disease and ectopic ACTH secretion w a high-dose (8 mg) dexamethasone suppression test and CRH stimulation test o Ectopic secretion will not decrease w dexamethasone b/c source is resistant to negative feedback o Ectopic secretion will not increase w CRH b/c pituitary ACTH is suppressed

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Cushing syndrome Diagnostic Algorithm

↑24-hr urine free cortisol,↑ late night salivary cortisol, and/or inadequate suppression on 1 mg overnight dexamethasone test

Measure ACTH Suppressed

Elevated

ACTH-independent Cushing syndrome

ACTH-dependent Cushing syndrome

Exogenous glucocorticoids or adrenal tumor (consider adrenal CT to confirm)

High-dose (8mg) dexamethasone suppression test

No suppression Ectopic ACTH secretion

Redrawn after: Le T, Bhushan, et al. First Aid for the USMLE Step 1 2017. McGraw-Hill Education, 2017.

Adequate suppression Cushing disease

CT of chest/abdomen/pelvis

CRH stimulation test

↑ ACTH and cortisol Cushing disease

MRI of the pituitary

No ↑in ACTH and cortisol Ectopic ACTH secretion

CT of chest/abdomen/pelvis

Adrenocortical insufficiency 1. Primary adrenocortical insufficiency most commonly caused by autoimmune destruction of adrenal cortex can be chronic (=Addison disease) or causes acute adrenal crisis (Addisonian crisis) Characterized by following Sn & Sx:  ↓ adrenal glucocorticoid, androgen, and mineralocorticoid  ↑ ACTH (Low cortisol stimulate ACTH secretion by negative feedback)  Hypoglycemia (caused by cortisol deficiency)  Weight loss, weakness, nausea, and vomiting  Hyperpigmentation (low cortisol stimulate ACTH secretion) ACTH contains MSH fragment  ↓ pubic & axillary hair in FM (caused by deficiency of adrenal androgens)  ECF volume contraction (hyponatremic), hypotension, hyperkalemia, and Marc Imhotep Cray, MD metabolic acidosis (caused by aldosterone deficiency)

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Addison’s disease (1° adrenal insufficiency) Symptoms, caused by reduced production of  glucocorticoids  mineralocorticoids, and  sex hormones

Biochemical abnormalities (eg, hyponatremia, hyperkalemia) usually exist Dx ACTH stimulation test (cosyntropin) can be used to diagnose Addison's disease 

failure of serum cortisol levels to increase after administration makes a Dx of primary adrenocortical insufficiency more likely

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1o Adrenal Insufficiency (Addison’s disease) Caused by  autoimmune-mediated destruction of adrenal cortex  Mycobacterial infection (TB)  adrenal metastases  use of certain drugs

Marc Imhotep Cray, MD

Buja LM, Krueger GR. Netter’s Illustrated Human Pathology, 2nd Ed. Philadelphia: Saunders-Elsevier, 2014.

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Pathophysiology of adrenal cortex (2) 2. Secondary adrenocortical insufficiency    

Caused by primary deficiency of ACTH does not exhibit hyperpigmentation (b/c there is a deficiency of ACTH) does not exhibit volume contraction, hyperkalemia, or metabolic acidosis (b/c aldosterone levels are normal) Symptoms are otherwise similar to those of Addison disease

3. Tertiary adrenal insufficiency  

Seen in patients w chronic exogenous steroid use, precipitated by abrupt withdrawal adrenal crisis Aldosterone synthesis unaffected

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Acute Adrenal Insufficiency (3)  life-threatening acute adrenal crisis, also occurs in cases of undiagnosed adrenal insufficiency & untreated stress; mimics septic shock, presents w  severe anorexia (lack or loss of appetite for food)  dehydration, and  hypotension cardiovascular collapse>>death  Treatment: IV fluids and high-dose IV glucocorticoids immediately after taking a blood sample for random cortisol  Chronic disease is managed w a glucocorticoid (hydrocortisone) plus a mineralocorticoid (fludrocortisone) w dosage tailored to avoid Cushing syndrome or inadequate therapy  Pts should be monitored for fludrocortisone (mineralocorticoid) adverse effects Marc Imhotep Cray,(eg, MD electrolyte changes, hypertension, edema, and hyperglycemia)

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Abrupt corticosteroid withdrawal & adrenal crisis  Use of high-dose steroids for more than a week begins to produce suppression of pt's adrenal glands b/c exogenous glucocorticoids suppress CRH and pituitary ACTH 

With prolonged suppression, adrenal glands atrophy can take months to recover full function after D/C of exogenous glucocorticoid



During this recovery time, patient is vulnerable to acute adrenal insufficiency (adrenal crisis)  during times of stress, such as illness, due to both adrenal atrophy and suppression of CRH and ACTH release

NB: Adrenal crisis is a medical emergency and potentially lifethreatening situation requiring immediate emergency treatment.

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Pathophysiology of acute adrenal crisis  As stated, occur in pts w undiagnosed ACTH deficiency, in patients receiving corticosteroids and who are not given increased steroid dosage during periods of stress Precipitants include: o Infection o Trauma o Surgery, and o Dehydration o GI infections  particularly challenging b/c of assoc. inability to ingest or absorb oral hydrocortisone replacement  can lead to adrenal crisis despite other treatments  If unrecognized and untreated, coma, severe hypotension, or shock unresponsive to vasopressors may rapidly lead to death Marc Imhotep Cray, MD

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Pathophysiology of acute adrenal crisis (2)  Pts. w acute adrenal crisis have Sx of fever, weakness, apathy, & confusion  Anorexia, nausea/vomiting may lead to volume depletion & dehydration  Abdominal pain may mimic that of an acute abdominal process  Evidence suggests Sx of acute glucocorticoid deficiency are mediated by significantly elevated plasma levels of cytokines particularly IL-6 and, to a lesser extent, IL-1 and TNF  Hyponatremia, hyperkalemia, lymphocytosis, eosinophilia, and hypoglycemia occur frequently

Marc Imhotep Cray, MD

Question A 37-year-old kidney transplant recipient presents to her primary care physician for follow-up. Among other immunosuppressant drugs, she has been taking daily prednisone for the past 2 months since her transplant. With only a few doses of prednisone left, she gets snowed into her house and cannot refill her prescription (but she has enough of the other medications to last a few more weeks).

If she runs out of prednisone and cannot get it refilled, what is she most at risk for developing?

(A)Cardiovascular collapse (B) Osteoporosis (C) Increased risk of infection (D)Insomnia (E) Nausea/vomiting Marc Imhotep Cray, MD

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The correct answer is A: Cardiovascular collapse (acute adrenal crisis) Chronic use of glucocorticoids (such as prednisone) will lead to adrenal atrophy b/c exogenous steroid suppresses hypothalamic-pituitary-adrenal (HPA) axis. If exogenous steroid is abruptly withdrawn, atrophied adrenal gland is unable to compensate by producing endogenous steroids quickly enough. Sudden loss of adrenal steroids is termed â&#x20AC;&#x153;adrenal crisisâ&#x20AC;? and can result in cardiovascular collapse and death.

Incorrect answers (B) Osteoporosis is a possible result of continued chronic glucocorticoid therapy, not abrupt cessation.

(C) Increased risk of infection is a result of continued chronic glucocorticoid therapy, not abrupt cessation.

(D) Insomnia is a possible side effect from short-term oral or parenteral glucocorticoid therapy.

(E) Nausea/vomiting are possible side effects from short-term oral or parenteral glucocorticoid therapy.

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Hyperaldosteronism Increased secretion of aldosterone from adrenal gland  Clinical features include hypertension (2°), hypokalemia, metabolic alkalosis 

No edema due to aldosterone escape mechanism

Primary hyperaldosteronism 

Seen w adrenal cortex adenoma (Conn syndrome) 33% or idiopathic bilateral adrenal hyperplasia (66%) ↑aldosterone, ↓renin

Secondary hyperaldosteronism 

Marc Imhotep Cray, MD

Seen in pts. w renovascular HTN/renal artery stenosis, juxtaglomerular cell tumor, edema (eg, cirrhosis, heart failure, nephrotic syndrome)  due to independent activation of renin-angiotensinaldosterone system) ↑aldosterone, ↑renin

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Clinical Vignette A 29-year-old man presents to the emergency department complaining of a crushing headache and heart palpitations. He tells you that he has had similar episodes in the past. Physical examination reveals a pulse of 140 and a BP of 200/110. A 24-hour urine collection reveals increased vanillylmandelic acid (VMA) and metanephrine levels and blood tests demonstrate increased plasma catecholamine levels. You immediately prescribe phenoxybenzamine for the patient and tell him that it is likely that he will need surgery to definitively treat his condition.

What is the diagnosis?

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Pheochromocytoma (usually benign) See Endocrinology Tutorial 2 MEN Syndromes

 Most common tumor of adrenal medulla in adults  Derived from chromaffin cells (arise from neural crest)

 Etiology Most (90%) cases occur sporadically  Other cases are assoc. w MEN IIa, MEN IIb, neurofibromatosis, or von Hippel-Lindau disease

 Pathology  Gross: Variable changes in adrenal medulla range from small, circumscribed lesions to large, hemorrhagic lesions w lobular pattern  Microscopic: Tumor composed of nests of polygonal chromaffin cells containing catecholamine-rich granules giant, pleomorphic cells are sometimes seen Marc Imhotep Cray, MD

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Pheochromocytoma cont.  Clinical Manifestations release of Epi & NE from tumors results in intermittent attacks of hypertension, headache, palpitations, and diaphoresis  Lab findings: ↑ 24-hour urinary catecholamine and VMA, metanephrine levels, ↑ plasma metanephrine levels  Treatment Initial treatment w α-adrenergic blocking agents (phenoxybenzamine) followed by surgical resection of mass Note:  Pheochromocytomas are assoc. w rule of 10s: 10% malignant, 10% bilateral, 10% familial, 10% extra-adrenal, & 10% occur in children  can occur outside adrenal called paragangliomas Marc Imhotep Cray, MD

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Pheochromocytoma. (a) adrenal contains a well-circumscribed, spherical, brown tumor w small foci of hemorrhage. (b) Histology shows a typical neuroendocrine tumor with cells resembling those of normal adrenal medulla.

Stevens A, Lowe J, Scott I. Core Pathology, 3rd Ed. St. Louis: Mosby-Elsevier, 2009.

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Neuroblastoma (malignant)  Most common tumor of adrenal medulla in children (usually < 4 years old)  

Originates from neural crest cells Occurs anywhere along sympathetic chain

 Most common presentation is abdominal distension and a firm, irregular mass that can cross midline (vs Wilms tumor[nephroblastoma], which is smooth and unilateral)   

Less likely to develop hypertension than w pheochromocytoma Can also present w opsoclonus-myoclonus syndrome (“dancing eyesdancing feet”). ↑HVA and VMA (catecholamine metabolites) in urine

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Neuroblastoma (2)

Neuroblastoma (arrows)

Homer-Wright rosettes characteristic of neuroblastoma Circular grouping of dark tumor cells surrounding pale neurofibrils

Le T, Bhushan V. First Aid for the USMLE Step 1 2017. New York: McGraw-Hill Education, 2017.

ď&#x201A;§ Associated with overexpression of N-myc oncogene ď&#x201A;§ Classified as an APUD (amine precursor uptake decarboxylase) tumor Marc Imhotep Cray, MD

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Diabetes Mellitus (DM) Discussion topics outline: Blood glucose regulation & endocrine pancreas cell types Preproinsulin, proinsulin, Insulin and C-peptide Lack of lnsulin Diabetes Mellitus: Etiologic Classification Type I DM pathogenesis & clinical features Type II DM pathogenesis & clinical features MODY â&#x20AC;&#x153;type one-and-a halfâ&#x20AC;?

Other Specific Causes of DM Acute Manifestations and Diagnosis Chronic Complications and Consequences Intended to be studied along with: Diabetes mellitus Type 1 SDL Tutorial Diabetes mellitus Type 2 SDL Tutorial Marc Imhotep Cray, MD

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Blood glucose regulation Insulin is an important hormone in glucose metabolism made by pancreatic β cells and is cleaved from a precursor molecule called proinsulin  Glucagon is another hormone (of arguably lesser importance) in glucose metabolism  Glucagon is made in α cells and is an antagonist to insulin therefore important in recovering from hypoglycemia

 Insulin is an anabolic hormone that promotes energy storage while, glucagon is catabolic (i.e., it breaks down molecules) Marc Imhotep Cray, MD

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Blood glucose regulation

Marc Imhotep Cray, MD

Merali Z, Woodfine JD (eds.) Toronto Notes 2016, 33rd Ed. Toronto, Ontario, Canada, 2016.

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Endocrine pancreas cell types  Islets of Langerhans are collections of α, β, and δ endocrine cells Islets arise from pancreatic buds  α = glucagon (peripheral)  β = insulin (central)  δ = somatostatin (interspersed)  Preproinsulin (synthesized in RER)  cleavage of “presignal ”to proinsulin (stored in secretory granules)  cleavage of proinsulin  exocytosis of insulin and C- peptide equally  Insulin and C-peptide increased in insulinoma and sulfonylurea use, whereas  Exogenous insulin lacks C-peptide o Thus, C-peptide quantitation enables differentiation of exogenous hyperinsulinemia from endogenous hyperinsulinemia Marc Imhotep Cray, MD

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Structure of insulin (A) & formation of human insulin from preproinsulin (B)

Marc Imhotep Cray, MD

McInnis M., Mehta S. Step-up to USMLE Step 1 2015 Edition. Wolters Kluwer, 2015

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Lack of lnsulin Without insulin glucose is not transported across cell membranes leads to a cascade of metabolic events  Body reacts by inducing gluconeogenesis (liver converts glycogen to glucose)

To produce energy skeletal muscle converts its structural proteins to amino acids which are carried to liver where they are converted to glucose  Resultant excess glucose, still not being used by cells, leads to hyperglycemia

Insulin deficiency increases fat catabolism: free fatty acids are broken down into keto acids to increase energy sources Marc Imhotep Cray, MD

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Lack of lnsulin (2)  Kidneys eliminate keto acids produces ketonuria and ketonemia  Keto acids also reduce blood pH can result in ketoacidosis, coma, and death  Diabetes is caused by a relative or absolute lack of insulin w hyperglycemia being hallmark medical finding  Once thought of as 1 disease, diabetes is now believed to be a chronic heterogeneous group of disorders that result from pathologic processes that depend on diabetes type Marc Imhotep Cray, MD

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Diabetes Mellitus: Etiologic Classification Most common & important disease assoc. w endocrine pancreas DM is a multisystem disease w both biochemical and structural consequences  It is a chronic disease of carbohydrate, fat & protein metabolism resulting from inadequate action of hormone insulin

Two main types of DM identified, on clinical grounds  Type I (insulin- dependent diabetes mellitus – IDDM), and  Type II (non-insulin dependent diabetes –NIDDM) --------- Type III DM refers to specific types of diabetes caused by rare genetic defects in islet insulin-secreting cell function and genetic defects in insulin action (MODY)  Type IV disease (Gestational DM) refers to diabetes related to pregnancy Marc Imhotep Cray, MD

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Pre-Diabetes (Impaired Glucose Tolerance/ Impaired Fasting Glucose)     

1-5% per yr. of pre-diabetes go on to develop T2DM 50-80% revert to normal glucose tolerance weight loss may improve glucose tolerance ↑ risk of developing macrovascular complications (IGT >IFG) lifestyle modifications ↓ progression to DM by 58%

 IGT is defined as: two-hour glucose levels of 140 to 199 mg per dL on 75-g oral glucose tolerance test. A patient is said to be under condition of IGT when he/she has an intermediately raised glucose level after 2 hours, but less than level that would qualify for T2DM.  IFG is a type of prediabetes, in which blood sugar level during fasting is consistently higher than what are considered normal levels; however, level is not high enough to be diagnosed as DM

NB: It is likely that pre-diabetes and metabolic syndrome (next 2 slides) denote same disorder, defining it by different sets of biological markers.

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Metabolic syndrome Metabolic syndrome is a clustering of at least three of five of following medical conditions:     

abdominal (central) obesity elevated blood pressure elevated fasting plasma glucose high serum triglycerides low high-density lipoprotein (HDL) levels

Syndrome is thought to be caused by an underlying disorder of energy utilization and storage

Metabolic syndrome is assoc. w ↑ risk of developing CVD and T2DM Some studies have shown prevalence in USA to be an estimated 34% of adult population  prevalence ↑ w age NB: Insulin resistance, metabolic syndrome, and pre-diabetes are closely toMDone another and have overlapping aspects Marcrelated Imhotep Cray,

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Metabolic syndrome cont. Metabolic syndrome quintuples (X5) risk of T2DM T2DM is considered a complication of metabolic syndrome In people w IGT or IFG presence of metabolic syndrome doubles risk of developing T2DM  As stated above, prediabetes and metabolic syndrome probably denote same disorder, defining it by different sets of biological markers

 Presence of metabolic syndrome is assoc. w higher prevalence of CVD than found in pts w T2DM or IGT without syndrome Hypoadiponectinemia , known to increase insulin resistance , is considered a risk factor for developing metabolic syndrome Marc Imhotep Cray, MD

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Diabetes Mellitus cont. In simplest terms, DM is inability to properly manage glucose metabolism (glucose intolerance) b/c of either  inability to produce and secrete insulin as a result of autoimmune destruction of pancreatic β-cells (T1DM) or  inability of peripheral tissues to respond to circulating insulin as a result of diminished or impaired insulin receptor signaling (T2DM)

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Type 1 Diabetes Mellitus In T1DM, insulin-producing β cells of pancreas are destroyed by either intrinsic genetic factors or extrinsic factors such as viruses or chemical toxins  In one theory that involves an autoimmune-mediated mechanism predisposed pts. react abnormally to environmental triggers by producing antibodies that are directed against β cells insulin secretion is impaired early in disease and eventually stops absolutely  In serum, autoantibodies to insulin appear early followed by antibodies to beta cell antigen glutamic acid decarboxylase (GAD-65) and islet cell antigen (ICA-512) Marc Imhotep Cray, MD

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Type 1 Diabetes Mellitus (2)  Type 1 DM usually develops abruptly during childhood or adolescence and usually presents w polydipsia, polyuria, polyphagia and weight loss  C-peptide levels are low or undetectable  Ketoacidosis is more likely to occur in type 1 DM than in type 2 DM  Signs and Symptoms of DKA: Kussmaul respirations, fruity breath, abdominal pain, N/V, polyuria, polydipsia, dehydration and fatigue Marc Imhotep Cray, MD

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Type 1 Diabetes Mellitus (3)  Patients require lifelong Tx w exogenous insulin to control bld glucose levels and prevent short-term and long-term macrovascular and microvascular complications, such as  nephropathy  neuropathy  retinopathy, and  cardiovascular disease NB: Oral hypoglycemic agents are ineffective in pts w type 1 DM b/c functioning β cells are required for these agents to work.

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Pathogenetic stages in development of (T1DM)  Disease develops from an initial genetic susceptibility to defective recognition of beta cell epitopes and ends with essentially complete beta cell destruction in most patients.  An environmental event is believed to trigger immune attack, and persons with certain genetic markers (human leukocyte antigen [HLA]-DR3 and -DR4) are particularly susceptible to autoimmune disease.  Pts w islet cell antibodies and normal blood glucose levels are considered to have a state of “pre-type 1 diabetes.”  Rate of decline in beta cell mass (blue line) determines the length of time between onset of beta cell destruction and eventual hyperglycemia (red line, fasting blood glucose) owing to loss of greater than 90% of functioning beta cells.

BCM, beta cell mass.

Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012.

Insulitis, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

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Diabetic Ketoacidosis  In pts w T2DM, significant deviations from normal dietary intake, unusual physical activity, infection, or any other forms of stress may worsen metabolic imbalance leading to diabetic ketoacidosis  Plasma glucose usually is in range of 500 to 700 mg/dL as a result of absolute insulin deficiency and unopposed effects of counterregulatory hormones (epinephrine, glucagon)

Marked hyperglycemia causes an osmotic diuresis and dehydration characteristic of ketoacidotic state

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DKA (2)  Second major effect is activation of ketogenic machinery insulin deficiency leads to activation of hormone-sensitive lipase w resultant excessive breakdown of adipose stores, giving rise to ↑ FFAs oxidized by liver to produce ketones  Ketogenesis is an adaptive phenomenon in times of starvation, generating ketones as a source of energy for consumption by vital organs (e.g., brain)

 Rate ketones are formed may exceed rate they can be used by peripheral tissues leading to ketonemia and ketonuria  If urinary excretion of ketones is compromised by dehydration accumulating ketones ↓ blood Ph resulting in metabolic acidosis Marc Imhotep Cray, MD

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Sx and Sn of uncontrolled hyperglycemia in T1DM

Rubin R , Strayer DS Eds. Rubinâ&#x20AC;&#x2122;s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012.

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Type 2 Diabetes Mellitus Central defects in type 2 DM are decreased insulin secretion and insulin resistance  Before diabetes is diagnosed, patients, often obese have hyperinsulinemia caused by excess dietary carbohydrates NB: Obesity is a major risk factor for development of T2DM 

incidence of T2DM ↑ w obesity & consumption of glucose (in all nutritional forms)

T2DM is much more common than T1DM accounting for 95% of cases Marc Imhotep Cray, MD

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Type 2 Diabetes Mellitus (2) Pancreas malfunctions and fails to supply high insulin demands  Also, impaired secretion is complicated by insulin resistance:  insulin resistance means insulin cannot decrease plasma glucose levels through suppression of hepatic glucose production and stimulation of glucose use in skeletal muscle and adipose tissue  Resistance develops in several possible ways, eg, o chronic hyperinsulinemia causes insulin receptor downregulation leads to defects in insulin binding and post-receptor insulin signaling pathways

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Pathogenesis of obesity-related T2DM  Expanded visceral fat mass in upper body obesity elaborates several factors that contribute to tissue insulin resistance include ↑ in circulating free (nonesterified) fatty acids (FFAs) and cytokines that inhibit insulin action, as well as a↓ in factors that enhance insulin signaling, such as adiponectin  These changes result in a block to insulin action in liver and skeletal muscle at level of insulin receptor and at postreceptor signaling sites resulting in a failure of insulin to suppress hepatic glucose production and to promote glucose uptake into muscle  Resulting hyperglycemia is normally countered by ↑ insulin secretion by pancreatic beta cells  In persons w T2DM, combination of resistance to insulin action and a genetically determined impairment of beta cell response to hyperglycemia results in hyperglycemia, and T2DM ensues

Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012.

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Glucose regulation and metabolic activity during development of T2DM  Insulin resistance alone rarely causes T2DM since increased insulin secretion (hyperinsulinism) by beta cells will compensate for insulin resistance and thereby prevent blood glucose levels from rising  It is only when beta cells start showing evidence of dysfunction that blood glucose levels start to increase

NGT, normal glucose tolerance ;IGT, impaired glucose tolerance; IFG, impaired fasting glucose Rubin R , Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012.

Insulin response in T2DM Insulin resistance and hyperinsulinemia of T2DM (“metabolic syndrome”) are very harmful to body contribute to ↑ incidence of HTN, CVD, obesity, and hyperlipidemia in pts w T2DM

Typical patterns of insulin production in response to glucose challenge in normal (blue) and type 2 diabetic (red) patients.

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Type 2 Diabetes Mellitus (4)  Unlike type 1 DM, T2DM  has a more gradual onset  may not present w classic symptoms, and  usually occurs in overweight pts older than 35 years  Oral hypoglycemic agents  decrease plasma glucose levels  improve insulin resistance, and  reduce long-term complications  Note: Many pts require insulin therapy as well Marc Imhotep Cray, MD

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Hyperosmolar Non-ketotic Coma  T2DM also may manifest w polyuria and polydipsia  

In some cases, medical attention is sought b/c of unexplained weakness or weight loss Most frequently, however, diagnosis is made after routine blood or urine testing in asymptomatic individuals

 In decompensated state, pts w T2DM may develop hyperosmolar nonketotic coma  Syndrome is engendered by severe dehydration resulting from sustained osmotic diuresis and urinary fluid loss due to chronic hyperglycemia Marc Imhotep Cray, MD

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HNC (2)  Typically, affected older adult diabetic disabled by stroke or infection  unable to maintain adequate water intake  Absence of ketoacidosis and its symptoms (nausea, vomiting, respiratory difficulties) delays recognition of seriousness of situation until onset of severe dehydration and coma

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Comparison of type 1 and type 2 DM T1DM

T2DM

Childhood and adolescence onset

Late middle-age/elderly onset

Thin Ketoacidosis (DKA) common

Obese Ketoacidosis rare Hyperosmolar hyperglycemic nonketotic syndrome (HHNS) Relative deficiency and end-organ resistance No islet-cell antibodies No autoimmune mechanism Polygenic inheritance

Severe insulin deficiency Islet-cell antibodies Autoimmune mechanism Genetic predisposition associated with HLA-DR genotype

Redrawn after: Stevens A, Lowe J, Scott I. Core Pathology, 3rd Ed. St. Louis: Mosby-Elsevier, 2009.

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Type III=Mature onset diabetes of the young (MODY) MODY also called “type one-and-a half,” stems from genetic defects in beta-islet cells, but no loss of β cells  clinical presentation is different than type 1 & 2DM o o o o

Ketoacidosis can be presenting manifestation There are no circulating autoantibodies, presents later in patient’s life than type 1 diabetes presents earlier in patient’s life than type 2 diabetes

 Treatment is insulin therapy

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Other Specific Causes of DM Secondary DM occurs as a 2o phenomenon in pancreatic & other endocrine diseases and pregnancy Diseases of exocrine pancreas:  Pancreatitis, pancreatectomy, neoplasia, cystic fibrosis, hemochromatosis (“bronze diabetes”)

Endocrinopathies:  Acromegaly, Cushing’s syndrome, glucagonoma, pheochromocytoma, hyperthyroidism

Drug-induced:  Glucocorticoids, thyroid hormone, β-adrenergic agonists, thiazides, phenytoin, clozapine

Infections:  Congenital rubella, CMV, coxsackie

Genetic syndromes associated w DM:  Down’s syndrome, Klinefelter’s syndrome, Turner’s syndrome

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Type IV=Gestational Diabetes Pregnancy may be associated w transient DM (gestational diabetes) overt nongestational diabetes sometimes develops later Diabetes mellitus is characteristically associated w increased fetal birth weight and increased fetal mortality, notably from neonatal respiratory distress syndrome (hyaline membrane disease) When a mother has hyperglycemia, her infant may be born w hyperplasia of pancreatic islets and hypoglycemia Marc Imhotep Cray, MD

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DM Acute Manifestations and Diagnosis Acute Manifestations Polydipsia, polyuria, polyphagia, weight loss, DKA (type 1), Hyperosmolar hyperglycemic state (HHS) (type 2) Rarely, can be caused by unopposed secretion of GH and epinephrine  Also seen in pts on glucocorticoid therapy (steroid diabetes) Diagnosis TEST HbA1c

DIAGNOSTIC CUTOFF ≥ 6.5%

FPG

≥ 126 mg/dL

2-hour OGTT

≥ 200 mg/dL

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DM Chronic Complications  Morbidity assoc. w long-standing diabetes of any type results from chronic complications of hyperglycemia resulting damage induced in both large- and medium-sized muscular arteries (diabetic macrovascular disease) and small-vessels (diabetic microvascular disease) 

Macrovascular disease causes accelerated atherosclerosis among diabetics resulting in increased myocardial infarction, stroke, and lower-extremity ischemia o NB: MI is most common cause of death in diabetics



Microvascular disease effects are most profound in retina, kidneys, and peripheral nerves resulting in diabetic retinopathy, nephropathy, and neuropathy, respectively

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DM Chronic Complications

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Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease, 9th ed.

Philadelphia: Saunders-Elsevier, 2015.

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DM Chronic Complications cont.  NB: Complications of DM are far less common and less severe in people who have well-controlled blood sugar levels hence need for tight control of hyperglycemia  Wider health problems accelerate deleterious effects of diabetes  These include o smoking o elevated cholesterol levels o obesity o high blood pressure o lack of regular exercise Marc Imhotep Cray, MD

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Consequences of DM Complications As a result of aforementioned complications, diabetics of both types have a predisposition to develop  ischemic heart disease  cerebrovascular disease  gangrene of lower limbs  chronic renal disease  reduced visual acuity leading to blindness  peripheral neuropathy Marc Imhotep Cray, MD

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DM Chronic Complications cont. Nonenzymatic glycation:  Small vessel disease= microvascular (diffuse thickening of basement membrane) retinopathy (hemorrhage, exudates, microaneurysms, vessel proliferation), glaucoma, neuropathy, nephropathy (nodular glomerulosclerosis, aka KimmelstielWilson nodules) progressive proteinuria [initially microalbuminuria/ACE inhibitors are renoprotective] and arteriolosclerosis hypertension  both nephropathy & arteriolosclerosis lead to chronic renal failure (CRF) NB: The following terms are similar, yet distinct, in both spelling and meaning, and can be easily confused: arteriosclerosis, arteriolosclerosis, and atherosclerosis.

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Hyaline arteriolosclerosis, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

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Nodular glomerulosclerosis, microscopic

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Atherosclerosis, gross

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DM Chronic Complications cont.  Large vessel atherosclerosis= macrovascular o o o o

CAD (Again, MI most common cause of death in DM) peripheral vascular occlusive disease gangrene limb loss cerebrovascular disease stroke

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Atherosclerosis, gross

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

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Peripheral vascular disease, grafts, CT image

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DM Chronic Complications cont. Osmotic damage (sorbitol accumulation in organs w aldose reductase and decrease or absent sorbitol dehydrogenase):  Neuropathy (motor, sensory [classic glove and stocking distribution], and autonomic degeneration)  Cataracts

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Diabetic neuropathy, microscopic

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Cataract, gross

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Diabetic retinopathy, funduscopy Normal retina, funduscopy

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

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Acute Complications of DM        

Diabetic ketoacidosis Hyperglycemia hyperosmolar state Hypoglycemia Diabetic coma Erectile Dysfunction Respiratory infections Periodontal disease Skin infections

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Hypoglycemia Hypoglycemia (low blood sugar) is when blood sugar decreases to below normal levels  May result in a variety of symptoms including clumsiness, trouble talking, confusion, loss of consciousness, seizures, or death  A feeling of hunger, sweating, shakiness, and weakness may also be present o Symptoms typically come on quickly

Cause Most common cause of hypoglycemia is medications used to treat DM, such as insulin and sulfonylureas 

Risk is greater in diabetics who have eaten less than usual, exercised more than usual, or have drunk alcohol

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Hypoglycemia cont.  Hypoglycemic symptoms and manifestations can be divided into those produced by counterregulatory hormones (epinephrine and glucagon) triggered by falling glucose, and neuroglycopenic effects produced by the reduced brain sugar:  Shakiness, anxiety, nervousness  Palpitations, tachycardia  Sweating, feeling of warmth (sympathetic muscarinic rather than adrenergic)  Pallor, coldness, clamminess  Dilated pupils (mydriasis)  Hunger, stomach rumble  Nausea, vomiting, abdominal discomfort  Headache Marc Imhotep Cray, MD

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Acute Hypoglycemia Antidote Use of sugar packets, candy, or pure glucose products can help w hypoglycemia  Unconscious pts must be injected w glucagon or IV glucose or dextrose

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edn. Saunders,285 2014

THE END

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Further study tools and resources: Inside Endocrine System BMS Cloud Folder:  Endocrine System Pathology Outline  Molecular and Cell Biology of Endocrine System Ppt.  Endocrine Pathology Case 1 SDL Tutorial  Endocrine Pathology Case 2 SDL Tutorial  Endocrinology Tutorial 1 Postpartum Necrosis  Endocrinology Tutorial 2 MEN Syndromes  Endocrinology Tutorial 3 Anterior Pituitary  Diabetes mellitus Type 1 SDL Tutorial  Diabetes mellitus Type 2 SDL Tutorial  Endocrine Pathology Clinical Vignettes  Hormones and Their Actions_Illustrated Notes  Endocrine Pathology Rapid Review Notes Also see Medical Pathology Cloud Folder Marc Imhotep Cray, MD

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