Endocrine Pathologies – April 3rd, 2007

Adrenal Gland
-paired; sit above the KI
-cortex – outside
-sustained stress response = glucocorticoids (steroids)
-mineralocorticoids = aldosterone (increases Na retention; hypovolemia triggers
aldosterone to release Na to increase water retention and therefore increase blood
volume)
-sex steroids (estrogens and androgens)
-overexertion / adrenal fatigues and TCM KI deficiency  correlated with CVA pain
-medulla – inside
-catecholamines (epinephrine)  SNS, stress / acute response
-cortisol  adaptive purpose, inhibit formation of bone and collagen, suppresses pituitary
gland hormones (know functions for exam!)

Cushing’s Syndrome
-excess glucocorticoids
-exogenous  most common (drugs)
-endogenous  primary (adrenals showing hyperplasia), secondary (pituitary tumour),
tertiary (hypothalamus tumour), LU small cell carcinoma (ectopic production)
-manifestations: buffalo hump, moon face, violaceous striae on abdomen
-ACTH hypersecretion at pituitary is m/c cause of endogenous Cushing’s = Cushing’s
disease
-striae  pink then silver, caused by breakdown of skin / collagen (it’s happening too fast
b/c cortisol not allowing skin to heal and therefore decrease collagen)
-stretched skin
-glucose increased in bloodstream, development of DM, hyperglycemia  increase urine
excretion by KIs, glucose follows water  osmotic diaphoresis
-changes in metabolism of lipids, proteins and fats
-store fat for later on  buffalo hump
-suppression of immune sys, skews reaction, get T inflammatory state leading to
manifestations of autoimmune disorders
-corticosteroid drugs
-person stops taking drugs abruptly can lead to adrenal failure b/c adrenals have not
been working
-topical and inhaled don’t have as much impact

Primary Cushing’s Syndrome – Adenocortical

-usually unilateral neoplasm (Adenoma or carcinoma)
-increased cortisol production, has negative feedback to pituitary
-causes suppression of ACTH
-which causes atrophy of adjacent and contralateral adrenal cortex (b/c lack of use d/t
overuse of other adrenal gland)
-lab tests: increase cortisol, decrease ACTH
Secondary Cushing’s DISEASE – Hypothalamic/Pituitary
-ATCH-producing adenoma; no mass effects
-bilateral nodular adrenocortical hyperplasia/hypertrophy d/t increase ACTH
-lab tests: increased cortisol AND ACTH

Ectopic Cushing’s Syndrome

-often d/t small cell carcinoma of lung secretion ACTH
-gross morphology: hypertrophy and hyperplasia
-labs: increased cortisol AND ACTH
-to ddx Ectopic and Cushing’s disease: look into LU (X-ray  masses, nodules, LU CA)
and brain (CT  enlarged pituitary, sella tursica enlarged)

Hyperaldosteronism
-renin-angiotensin-aldosterone system
-Primary:
-Angiotehnsion II – vasoconstriction and activate aldosterone, exchanges Na for KI
-hypokalemia  arrhythmia, tetany, weakness in general, CHF, hypertrophy of HT
-aldo secreted @ adrenals abnormally  increased BP and edema
-bilateral nodular hyperplasia
-familial (ACTH-induced): genetic disposition
-Conn’s Syndrome  neoplasma in cortex, producing aldosterone
-in adults, adenoma, not malignant, non-metastatic, unilateral, single, solitary,
no invasive mass effects, well-encapsulated  just a functional problem
-no atrophy of opposite gland, there’s still enough ACTH b/c there’s no
feedback with aldosterone (feedback pathways are different)
-bilateral  mostly children, congenital, nodular hyperplasia
-secondary: aldosterone secreted b/c of other cuase
-d/t hemorrhage, KI failure, nephrotic syndrome, body is just compensating

Addison’s Disease = Primary Hypoadrenalism

-acute or chronic
-uncommon
-destruction of adrenal cortex  parenchyma of cortex is broken down
-75-90% autoimmune
-infections: m/c TB
-elderly and HIV  any immunocompromised ppl
-decrease cortisol, therefore increase ACTH, therefore increase melanin
-metastatic neoplasms  invades tissue and takes over
-manifestations:
-increased ACTH  increased melanin, increased skin pigmentation
-decreased glucocorticoids  hypoglycemia, inability to respond to stressors 
acute stress and can have acute adrenal failure
-decreased mineralocorticoids  decrease BP therefore heart failure, shock

Addison’s Disease = Secondary Hypoadrenalism

-from pituitary gland
-decrease ACTH, atrophy of adrenals
-looks like iatrogenic Cushing’s
-can be d/t tumour eg: pituitary adenoma and mass effects push on cells so they can’t
make ACTH

Autoimmune Addison’s Disease

-autoAb vs steroidal enzymes
-lymphocytic destruction of cortex
-minimal cortical cells within atrophied connective tissue

Acute Adrenocortical Insufficiency

-inability of adrenal cortex to produce sufficient glucocorticoids in response to stress
-chronic adrenocortical insufficiency and stress
-volume depletion, cardiac failure, shock, death
-adrenal hemorrhage  Waterhouse Fredrichson Syndrome (infection and sepsis)

Adrenal Fatigue
-please see graph
-in alarm phase: temp and acute response
-in resistance phase: chronic long term stress
-exhaustion: subclinical Addison’s b/c not actual destruction of cells

MSS – maladaptive stress syndrome

-may ppl are on stage 2
-stage 3 is very burnt out

Adrenal Medulla
-distinct tissue from adrenal cortex
-more neurological function than endocrinological
-chromaffin cells
-secrete catecholamines: SNS to deal with acute stress
-tumour here increases catecholamine and always in this state

Pheochromocytoma
-functioning neoplasm of chromaffin cells
-“rule of 10s”
-10% familial (90% sporatic)
-10% extra-adrenal: “paragangliomas”  in ganglia
-10% bilateral (90% unilateral)
-10% malignant (90% non-malignant)
-may be small and circumscribed to large and hemorrhagic
-vascular and capsular invasion may occur in both benign and malignant lesions
-increase catecholamine  HTN d/t increase heart contractions, increase CO, increase
vasoconstriction
-ddx: hypoaldosteronism  d/t water retention
Endocrine Pancreas
-produce hormone
-Islets of Langerhans
-alpha cells (5-20%)  glucagons response to decrease blood sugar 
gluconeogenesis
-beta cells (70%)  insulin response to increase blood sugar, therefore store glucose
as glycogen and fat
-delta cells (5-10%)
-pancreatic polypeptide cells (1-2%)

Diabetes Mellitus
-deficiency in secretion or response to insulin
-impaired use of glucose  hyperglycemia
-seventh leading cause to death in USA
-type I (5-10%)  insulin deficiency
-type II (80%)  insulin resistance
-other causes (10%)

Type IA – Autoimmune
-genetic predisposition + environmental trigger
-selective AI destruction of beta cells
-association with other organ-specific AI disease, especially Grave’s and Hasimoto’s
-Northern European, 40% twin concordance rate
-genetic mutation marks molecules on beta-cell membrane as antigenic
-see CD4 T cell infiltration  development of autoAb in intracellular antigens
-environmental triggers
-viruses (coxsackievirus B, mumps, measles, rubella)
-“molecular mimicry” (children given cow’s milk) vs “bystander effect” (immune
complexes are formed)
-reduced number and size of islets and beta-cell degranulation  decreased insulin
synthesis and secretion  decrease uptake of glucose, decreased storage of glycogen,
increased glycogenolysis  hyperglycemia and glycosuria  osmotic diuresis 
polyuria and hyperosmolarity  thirst  polydipsia
-negative energy balance  weight loss and polyphagia
-oxidation of free fatty acids  ketone bodies  ketonemia, ketonuria, dehydration (also
increase ketone excretion in urine)
-increased blood lipid levels d/t fat tissue mobilization

Type 2 – Insulin Resistance

-black, Hispanic, aboriginal NA, Asian
-60-80% twin concordance rate
-central obesity
-peripheral resistance  get initial compensatory insulin increase  decreased
sensitivity of beta cells to glucose with eventual loss of beta cells  hyperglycemia
-excessive production of amylin (secreted with insulin)  deposition of amyloid in islets
 toxic to beta cells, and inhibit reception of glucose
-adipose tissue  “adipokines” (messenger molecules) which increase insulin resistance
-leptins (an adipokine)  act on CNS to increase satiety and reduce food intake
-in ABSENCE causes obesity and insulin resistance
-increase in blood with increase adiposity
-lays adipose down in diabetics maybe d/t brain not responding
-often asxs, dx by routine lab tests

Advanced Glycoslyation End Products (AGEs)

-irreversible, non-enzymatic attachment of glucose metabolites to proteins
-effects of AGEs:
-cross-linking of collagen in blood vessel walls (damage)
-increased permeability of endothelium
-modification of circulating plasma proteins  thrombosis
-immune cell activation  fibroblastic and smooth muscle cell proliferation
-glycosylated hemoblogin (HbA1C)  can use to test how well diabetes is controlled

Sorbital formation
-hyperglycemia of cells not requiring insulin (nerves, lens of eye, KI, blood vessel)
-glucose  sorbitol (aldose reductase) and fructose  get accumulation  intracellular
osmolarity shifts, causing influx of water (mechanical damage in neuropathy)
-NADPH used as a co-factor for aldose reductase
-needed for glutathione (powerful AO  therefore get oxidative damage if NADPH
decreased)

Activation of Protein Kinase C

-intracellular hyperglycemia  second messenger cascade  PKC activation
-elements that predispose to blood vessel damage:
-proangiogenic  neovascularization
-increased endothelin-1 and decrease endothelial nitric oxide synthase 
vasoconstriction
-profibrogenic  thickening of basement membrane
-procoagulant
-proinflammatory

Atherosclerosis
-MI m/c cause of death in diabetics
-early onset, accelerated, women = men
-multifactorial (AGEx, immune activation and fibroblasts, vasonconstriction, thrombosis,
elevated blood lipids)

Microangiopathy
-thickening of basement membranes of capillaries with type IV collagen
-increased permeability of capillaries
-damage to endothelial cells  vessel weakness  microaneurysms

Diabetic Nephropathy
-second leading cause of death in DM
-glomerular lesions: capillary BM thickens  glomerulosclerosis  nephrotic syndrome
+ tubular ischemia (in KI)
-renal vascular lesions: d/t atherosclerosis
-pyelonephritis: ischemia + susceptibility to infections (ascend UB quickly)

Diabetic Ocular Disease

-fourth leading cause of death in DM
-retinopathy:
-nonproliferative: microangiopathy in retina  exudates, microhemorrhages,
aneurysms, macular edema
-proliferative: atherosclerosis + activation of PKCs  neovascularization and fibrosis
 disruption of retinal membrane  retinal detachment
-cataracts: sorbital production increases water in lens of eye therefore cataract
-glaucoma

Diabetic Neuropathy
-uptake of glucose by nerve cells  conversion to sorbitol / fructose  influx of water
 Cell damage  motor and sensory peripheral neuropathy
-microangiopathy of afferent blood vessels  generalized neuronal degeneration

Infection
-common in skin, lung, urinary tract
-impaired immune function + poor blood supply + increased risk of injury  increase
risk of infection (Gangrene, candida, sepsis)
-check px’s feet

Functional Hypoglycemia
-breakdown of normal blood glucose maintenance
-possible causes: hyperinsulinism, MSS, hypothyroidism, liver disease
-inability of body to respond to changes in blood glucose  work on diet and lifestyle!

Dysinsulinism and Syndrome X

-dysinsulinism = stage between functional hypoglycemia and type 2 DM
-see reactive hypoglycemia  hyperinsulinism
-increased cortisol  MSS  insulin resistance
-syndrome X = insulin resistance + dyslipidemia + obesity
-sedentary lifestyle, consumption of refined CHO, deficient fiber, obesity, MSS-2