Alterations of Hormonal Regulation
P727-728
1) Inappropriate amounts of hormone delivered to target cell (hypo/hypersecretion) due to:
a. Inadequate hormone synthesis (problems with hormone precursors)
b. Failure of feedback systems (negative or positive feedback isn’t recognized)
c. Hormone inactive (circulating inhibitors, inadequate hormone floating around,
hormone degraded too quickly/too slowly)
d. Dysfunctional delivery stem (inadequate blood supply or carrier proteins so hormone
never makes it to appropriate receptor, ectopic production of hormones (hormones
produced by nonendocrine tissues))
2) Inappropriate response by target cell
a. Cell surface receptor associated disorders (decrease in number of receptors, impaired
receptor function)
b. Intracellular disorders (defects in postreceptor signaling, inadequate synthesis of
second messenger, intracellular enzymes or proteins are altered, protein synthesis
goes wrong)
Alterations of Hypothalamic-Pituitary System
P728
 It’s hard to study problems in this system due to its sensitive location in the brain.
 The most common disease is usually the result of an interruption in the infundibular stem
(connects hypothalamus to pituitary) caused by trauma or tumor.
 When the hypothalamus is disrupted, it causes a variety of problems because hormones can
no longer travel to the pituitary to activate release. Some problems include:
o Diabetes insipidus: lack of ADH (hormones that regulates plasma osmolality by
stimulating water reabsorption in kidneys)
o Cessation of menses/sperm production: lack of GnRH
o Hyperprolactinemia: lack of usual inhibitory controls
o Low levels of ACTH: lack of coritcotropin-releasing hormone (CRH)
o Low levels of GH: absence of regulatory hormones that monitor GH
Diseases of Posterior Pituitary
P728-731
 Most diseases related to abnormal secretion of ADH. Excess amount = water retention &
hypoosmolar state, deficiency = serum hyperosmolarity
o NOTE: important b/c ADH has profound effects on the modulation of body fluids &
electrolytes and also cognitive/emotional responses to stress
 Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
o What is it?
 Characterized by high amounts of ADH when there is no normal physiologic
stimuli for its release
o How does it complicate?
 Can cause complications in the following:
 malignancies: tumors that secrete ADH include lymphomas, sarcomas
& small cell carcinoma of lung, stomach, pancreas, bladder, prostate
 pulmonary disorders: pneumonia, asthma, cystic fibrosis, respiratory
failure
 CNS disorders: encephalitis, meningitis, intracranial hemorrhage,
tumors and trauma
 surgical procedures: postoperative surgery causes fluid volume shifts
that result in high ADH secretion, can last 5-7 days after surgery,

especially sensitive in pituitary surgeries (may be related to
amount/type of intravenous fluids given and the use of analgesics)
 the use of certain medications: hypoglycemic medications,
antidepressants, antipsychotics, narcotics, anesthetics,
chemotherapeutic agents
o What’s the pathologic mechanism?
 Most common cause is ectopically produced ADH (hormones produced by
nonendocrine tissues, such as tumors).
 Cardinal feature is enhanced renal water retention by the action of ADH on
collecting ducts in kidney. This results in an expansion of extracellular fluid
volume that leads to low serum Na+, hypoosmolarity, and urine that is too
concentrated.
o What are the symptoms?
 Usually the result of hypotonic (dilutional) hyponatremia (low serum Na+)
 Thirst, impaired taste, anorexia, dyspnea on exertion, fatigue and dulled
sensorium with a Na+ drop from 140 to 130 mEq/L
 Vomiting and abdominal cramps from 130-120
 Confusion, lethargy, muscle twitching and convulsions at 115
 Any lower than 115 can cause severe neurologic damage
o What’s the treatment?
 Once you rule thyroid and adrenal function as normal (because they are
crucial for free water clearance by the kidneys), you correct the underlying
causal problem
 You then administer a hypertonic saline with fluid restriction to 600/800 ml a
day (if you give too much fluid too quickly you can cause neurologic damage)
Diabetes Insipidus
o What is it?
 An insufficiency of ADH
o How does it complicate?
 Causes polyuria (frequent urination) and polydipsia (frequent drinking)
o What’s the pathologic mechanism?
 In the DI cases below, the kidney is unable to increase permeability to water.
This means there are large amounts of diluted urine, which leads to an
increase in plasma osmolality. This induces the thirst mechanism (polydipsia)
and person must drink large amounts of H20 to keep hydrated.
 Neurogenic DI: insufficient amounts of ADH
 Caused by brain tumors, aneurysms, thrombosis, infections,
immunologic disorders, complication of closed-head trauma, genetic
mutations has been IDed as a cause, in rare cases it is hereditary
causing structural changes in pituitary
 Nephorgenic DI: inadequate response to ADH b/c collecting ducts in kidney
don’t response to ADH stimulation
 Genetic (variation in aquaporin-2, which is a water transport channel in
the renal tubule)
 Acquired (related to drug use or disorders that damage the renal
tubules or inhibit second messengers in tubules)
 Psychogenic (primary):

Chronic ingestion of large quantities of fluid that wash out the renal
concentration gradient, resulting in partial resistance to ADH
o What are the symptoms?
 Polyuria, nocturia, continuous thirst, and polydipsia
 Iodiopathic Nerogenic DI is abrupt, ppl with trauma may develop in a 3phases:
 Diuresis occurs (results of acute damage to hypothalamic centers
involving ADH secretion)
 Antidiuresis (necrosis of denervated tissue of posterior pituitary)
 Polyuria/polydipsia (permanent loss of ability to secrete adequate
amounts of ADH)
 Nephrogenic DI is usually more gradual
o What’s the treatment?
 First must distinguish between other polyuric states (diabetes mellitus,
diuresis, etc.) and may required ADH replacement
Diseases of the Anterior Pituitary
P731-736
 Hypopituitarism
o What is it?
 Can be the absence of selective pituitary trophic hormones or a complete
failure of hormonal functions of the anterior pituitary
o How does it complicate?
 Lack of ACTH (coristol): loss of functional maintenance of adrenal gland &
decreased aldosterone
 Lack of TSH – thyroid deficiency
 Lack of ADH: diabetes insipidus
 Lack of FSH & LH: gonadal failure, loss of 2nd degree sexual characteristics
 Lack of GH: dwarfism
o What’s the pathologic mechanism?
 Results from inadequate supply of hypothalamic releasing hormones, damage
to the pituitary stalk or an inability of the gland to produce hormones
 Pituitary gland is highly vascular and the blood supply to it (by way of the
hypophyseal system) is already partially deoxygenated, so it is vulnerable to
ischemia and infarction.
 Most common cause is infarction (as seen in Sheehan syndrome), head trauma
(blood supply altered, necrosis can occur, swelling, edema, compression on
gland) and infections
o What are the symptoms?
 Vary greatly depending on what the affected hormones are
o What’s the treatment?
 Rule out any other factors
 MRI/CT may show enlargement of gland or any abnormal lesions/tumors
 Most treatment involves replacing the deficient hormones (“replacement
therapy”)
 Hyperpituitarim: Primary Adenoma
o What is it?
 Usually benign, slow-growing tumors, don’t cause much trouble but some can
change hormone secretion or invade surrounding structures

 Incidence of primary adenomas is 22%
o How does it complicate?
 With enough pressure, it causes thyroid & adrenal hypofunction due to lack of
TSH and ACTH
 Hyposecretion of GH is asymptomatic in adults
 Gonadotropic hyposecretion results in menstrual ireegularity, decreased
libido and receding 2nd degree sexual characters
 Hypersecretion of GH in childhood causes giantism, in adult causes acromegaly
o What’s the pathologic mechanism?
 If tumor expands, can cause neurologic and secretory defects
 Example: impinge on the optic chiasm, invade cavernous sinus and cause
thrombosis, impair function to cranial nerves, could even cause dysfunction in
the hypothalamus (causing issues with wakefulness, thirst, appetite and temp)
o What are the symptoms?
 Pt may complain of headaches, fatigue and visual changes
 If the tumor is large enough, it may affect neurologic function
o What’s the treatment?
 Physical/lab exams including hormone assays and radiographic exam of skull
(CT or MRI)
 Depending on tumor size/type, pt may be treated with meds to suppress
tumor growth, tumor removal or radiation therapy
Hypersecretion of GH: Acromegaly
o What is it?
 Rare, slowly progressive disease, 70 persons per million
 A tumor (adenoma) secretes excessive levels of GH, causing acromegaly in
adults and giantism in children
o How does it complicate?
 Can decrease life expectancy if untreated
 Causes thickening of the articular cartilage with fibrosis, narrowing of joint
spaces, formation of osteophytes (leading to arthritis)
 GH impairs carbohydrate tolerance and increases metabolic rate
 Excess glucose is in body (b/c GH inhibits glucose uptake) and creates insulin
resistance so many times people with this disease develop type 2 diabetes
mellitus
 Complications include: cardiac hypertrophy, hypertension, atherosclerosis,
type 2 diabetes mellitus, many cancers are associated with acromegaly too
o What’s the pathologic mechanism?
 GH baseline secretion pattern is lost
 Main cause is a primary autonomous GH-secreting pituitary adenoma
o What are the symptoms?
 Enlarged tongues, interstitial edema, increase in size/function of sebaceous &
sweat glands, course skin/body hair (more noticeable when trying to insert
intravenous needle), large joint arthropathy with swelling, decreased range of
motion, enlargement of facial bones, elongated ribs
 Hypertension & left heart failure are seen, if tumor grows CNS problems can
occur
o What’s the treatment?
 Surgical removal of the GH secreting adenoma, maybe radiation, some drugs
reduce the amount of GH secretion/tumor size

Hypersecretion of Prolactin: Prolactinoma
o What is it?
 A tumor that secretes prolactin
 The most common pituitary tumor encountered in clinical medicine
o What’s the pathologic mechanism?
 Sustained increases in serum prolactin, this suppresses GnRH pulses at the
hypothalamus, impairing pulsatile pituitary gonadotropin release and blunts
the gonadal responsiveness to gonadotropins
o What are the symptoms?
 In women: amnorrhea (absence of period in reproductive aged woman),
nonpuerperal milk production (producing milk when not pregnant), excessive
body hair, and osteopenia caused by estrogen deficiency
 In men: erectile dysfunction, impaired libido, oligospermia (low concentration
of sperm), dimished ejaculate volume and hypogonadism (little/no sexual
hormones being produced)
o What’s the treatment?
 Exclude medications that may cause problem, screen with a serum TSH,
medications can help reduce size of tumor, surgery (remove tumor) and
radiotherapy
Diseases of the Thyroid
P736-742
 Hyperthyroidism/Thyrotoxicosis
o What is it?
 Any cause of increased levels of circulating TH
o What’s the pathologic mechanism?
 Primary hyperthyroidism: excess TH is made/secreted by thyroid
 Secondary hyperthyroidism: very rare, caused by TSH-secreting pituitary
adenomas (if a tumor in pituitary affects TSH secretion, naturally it will affect
TH secretion by thyroid)
o What are the symptoms?
 Increased metabolic rate with heat intolerance, increased tissue sensitivity to
simulation, enlargement of thyroid gland, weakness in respiratory muscles,
overactivity of eye muscles, menstrual cycle alterations (look at Table 21-2 on
P738 for details)
o What’s the treatment?
 Antithyroid drug therapy, radioactive iodine therapy and surgery
o What diseases are associated with this disorder?
 Graves Disease: autoimmune disease, causes 50-80% of cases, occurs more
commonly in women
 Characterized by:
o Hyperthyroidism (increased metabolism)
o Diffuse thyroid enlargement (goiter)
o Ophthalmopathy (exophthalmus or protruding eyes)
o Dermopathy (hardening and erythematous, or reddening, of the
skin)
o Myxedema (severe hypothyroidism characterized by firm
inelastic edema, dry skin and hair, and loss of mental & physical
vigor)

o Pretibial myxedema (subcutaneous swelling on legs,
erythematous skin)
 Nodular Thyroid Disease: similar manifestation as Graves (minus eye
protrusion and myxedema)
 Symptoms slowly develop, malignancy is 9% so MRI recommended
 Some cells of the thyroid are hyperactive and some don’t act at all so
there is an imbalance in TH production, and a swelling/shrinking of the
gland itself
 Once thyrotoxicosis results, pt is either “toxic multinodular goiter”
(both nodules) or “toxic adenoma” (one nodule)
 Thyrotoxic Crisis: “thyroid storm”
 Rare, dangerous worsening of hyperthyroidism due to excessive stress
(infection, pulmonary/cardio disorders, trauma, burns, seizures,
surgery, emotional)
 Death can ensure within 48 hours w/out treatment
Hypothyroidism
o What is it?
 Most common disorder of thyroid
 Caused by a deficient production of TH by thyroid gland
 Primary: defective hormone synthesis results from autoimmune thyroiditis
(inflamm disease where WBC and healthy cells attack thyroid cells), endemic
iodine deficiency (regionally associated iron deficiency) or iatrogenic loss of
thyroid tissue after surgical/radioactive treatment
 Secondary: much lesson common, includes conditions that cause pituitary or
hypothalamic failure with failure to simulate normal thyroid function (so there
are inadequate amounts of TSH or TH being produced), usually due to
adenomas that are compressing tissues
o What’s the pathologic mechanism?
 Loss of functional thyroid tissue leads to decreased production of TH
 Without the negative feedback of TH on the pituitary, there is increased
secretion of TSH that can lead to goiter
o What are the symptoms?
 Decreased energy metabolism (love BMR), decreased heat production, cold
intolerance, lethargy, tiredness and slightly lowered basal body temp
 The excessive level of TSH can cause goiter
 Myxedema: sign of severe/long standing hypothyroidism, results in thick,
slurred speech and hoarseness , also results in edema around eyes, hands and
feet
 Myxedema coma: diminished level of consciousness associated with severe
hypothyroidism
o What’s the treatment?
 Hormone replacement therapy
o What are the different kinds?
 Primary Hypothyroidism
 defective hormone synthesis results from autoimmune thyroiditis
(inflamm disease where WBC and healthy cells attack thyroid cells),
endemic iodine deficiency (regionally associated iron deficiency) or
iatrogenic loss of thyroid tissue after surgical/radioactive treatment


Congential Hypothyroidism
 Rare form of primary hypothyroidism
 Occurs in infants as a result of absent thyroid tissue and hereditary
defects in TH synthesis
 More common in females
Thyroid Carcinoma
 Most common endocrine malignancy but is rare
 Iodine deficiency and exposure to ionizing radiation during
childhood/puberty are risk factors
 Low mortality, well differentiated tumor
Diseases of the Parathyroid
P742-745
 Hyperparathyroidism
o What is it?
 A greater than normal secretion of PTH (parathyroid hormone)
o What’s the pathologic mechanism?
 Primary: excess secretion of PTH by one or more of the parathyroid glands,
one of the most common endocrine disorders
 Most cases caused by parathyroid adenomas, 15% caused by
parathyroid hyperplasia, 1% caused by parathyroid carcinoma
 Origin of problem not known but may be 1 of 2 things: 1) clonal
proliferation of parathyroid cells with a higher threshold for Ca+
feedback or 2) generalized growth of parathyroid tissue
 Secondary: an increase in PTH secondary to a chronic disease (example: renal
failure cases decrease in serum Ca+ levels
 Causes are renal failure, decreased intestinal absorption of vitamin
D/Ca+, dietary deficiency for vitamin D/Ca+ and drugs affecting
absorption/metabolism of vitamin D/Ca+
 Tertiary: hyperplasia of gland & loss of sensitivity to circulating Ca+ levels,
may be due to renal failure
o What are the symptoms?
 Excessive osteoclastic activity, resulting in bone resorption, bones become
deformed and susceptible to fractures, predisposition to Ca+ stones
 Condition can also be called osteitis fibrosa cystica b/c areas of bone are
replaced by cavities that fill with fibrous tissue
o What’s the treatment?
 Exclude all other causes of hypercalcemia, surgical removal of some or all
glands may be necessary
 Hypoparathyroidsim
o What is it?
 Abnormally low PTH levels
o What’s the pathologic mechanism?
 Can be caused by injury to the parathyroid glands during thyroid surgery, may
also be genetic
 What happens: a lack of circulating PTH causes a depressed serum Ca+ level
and an increased serum phosphate level. This is because the kidneys are not
being stimulated by PTH to excrete phosphate and absorb Ca+
o What are the symptoms?
Since this condition results in hypocalcemia, the threshold for nerve and
muscle excitation is lowered (b/c there’s less Ca+) so even the slightest
stimulus can cause movements: muscle spams, tonic-clonic, tremors,
convulsions or tetany
 Trousseau sign: an effect that can be seen where a binding of a cuff around the
upper arm produces contraction of the fingers & inability to open hand
 Chvostek sign: an effect that can be seen by the contraction of the facial
muscle by tapping the facial nerves @ the angle of the jaw
o What’s the treatment?
 Eliminate secondary causes if possible, administration of Ca+, and maintain
level by giving pharmacologic doses of an active form of vitamin D and oral
Ca+

Diseases of the Endocrine Pancreas
P745-765
 NOTE: Diabetes Mellitus is not one disease. It is a group of disorders that have glucose
intolerance in common (meaning, there is an excess of glucose in the body and subsequently
in the urine)
 Type I Diabetes Mellitus (IDDM)
o What is it?
 Mostly found in those under 20
 Autoimmune mediated loss of beta cells in the pancreatic islets
o What’s pathologic mechanism?
 Destruction of beta cells leads to deficiency in insulin, resulting in high glucose
levels
 Pt can also develop ketosis (accelerated fat breakdown causes
production of organic acids, which lowers pH of blood resulting in
death)
 Autoimmune (type 1A): environmental-genetic factors are thought to trigger
cell-mediated destruction of pancreatic beta cells
 Genetics: strong association with HLA (human leukocyte antigens)
 Environment: exposure to antigenic triggers (like a virus)
 Nonimmune (type 1B): less common, occurs mostly in ppl of Asian/African
descent, occurs secondary to other diseases (such as pancreatitis)
o What are the symptoms?
 Originally thought to be abrupt onset but now realizing it has a long preclinical
period with gradual destruction of beta cells
 One sign would be glucose in the urine or wide fluctuations in blood glucose
levels
 Protein& fat breakdown occur due to lack of insulin so pt may undergo weight
loss
 Excessive thirst (polydipsia), large amounts of diluted urine (polyuria) and
excessive appetite (polyphagia)
o What is the treatment?
 Insulin injection, diet (55% carbs, <30% fats, 15% proteins), exercise
(diminishes insulin requirements), transplant (still experimenting)
 Type II Diabetes Mellitus (NIDDM)
o What is it?
High glucose levels due to insulin resistance (target cells just don’t respond to
insulin being produced) and decreased production of insulin by beta cells
 Most common type, most often found in people over 40, overweight, most
popular in Black women
o What’s the pathologic mechanism?
 Genetic: genes that are associated with type 2 diabetes include those that code
for beta cell mass, beta cell function, proinsulin/insulin molecular structure,
insulin receptors (there are too few), synthesis of glucose, glucagon synthesis
and cellular response to insulin stimulation
 Insulin resistance can form, contributes to obesity
 Beta cell dysfunction develops, there is a decrease in weight/number of
beta cells
 Alpha cell sensitivity to glucagon secretion results in increased
glucagon secretion. These high levels of glucagon result in
hyperglycemia
 A deficit in amylin, which inhibits glucagon secretion
 Decreased levels of ghrelin (a peptide produced in stomach/pancreatic
islets) associated with insulin resistance and increased fasting insulin
levels
 Environmental: obesity, smoking, diet
o What are the symptoms?
 Often non specific (fatigue, recurrent infections, visual changes, pruritus (red,
itchy skin)), usually overweight, dyslipidemic (high amount of lipids in blood),
hyperinsulinemic (excessive insulin in blood), and hypertensive, may show
signs such as polyuria & polydipsia
o What is the treatment?
 Restore the blood glucose level to normal, correct any related metabolic
disorders, dietary restrictions, exercise , medications
Mature onset diabetes of youth (MODY)
o Originally classified as type 2 but obesity and gene mutations that are found in type 2
are not found in MODY. Diagnosis/treatment same as type 2. Usually diagnosed
before age 25
Gestational diabetes mellitus (GDM)
o Any degree of glucose intolerance with onset/first recognition during pregnancy
(usually 3rd trimester), obsess women at greater risk, increases the chance of
developing NIDDM later



Acute Complications of Diabetes Mellitus
P654-758
 Hypoglycemia:
o What is it?
 a lowered plasma glucose level (“insulin shock” or “insulin reaction”)
o What’s the pathologic mechanism?
 Causes may be exogenous, endogenous or functional
 Symptoms results from either activation of the sympathetic nervous system
(adrenergic symptoms) or from an abrupt cessation of glucose delivery to the
brain (neuroglycopenic symptoms)
o What are the symptoms?
Tachycardia (heart rate that exceeds normal rhythm), diaphoresis (excessive
sweating), tremors, pallor, hunger, headache, irritability & confusion leading
to seizure or coma
o What’s the treatment?
 Raise glucose levels
Diabetic ketoacidosis (DKA):
o What is it/How does it work?
 Serious complication that occurs with absolute deficiency of insulin
 There is an increase release of fatty acids, accelerated gluconeogenesis &
ketogenesis due to insulin deficiency
o What are the symptoms?
 Polyuria, dehydration, glycosuria, electrolyte disturbances, Kussmaul
respirations (hyperventilation in an attempt to compensate for acidosis),
postural dizziness, ketonuria, anorexia, nausea, abdominal pain, thirst &
acetone odor on breath
o What’s the treatment?
 Continuous administration of low-dose insulin to decrease glucose levels,
restore fluids/electrolytes
Hyperosmolar hyperglycemic nonketotic syndrome (HHNKS)
o What is it/how does it work?
 Life threatening, precipitated by infections, meds, nonadherence to diabetic
treatment or coexisting disease
 Differs in DKA in the degree of insulin deficiency (which is more profound in
DKA) and the degree of fluid deficiency (which is more marked in HHNKS).
HHNKS also have lower free fatty acids, no ketosis and glucose levels are
higher because of volume depletion
o What are the symptoms?
 Absent/small ketones in urine & serum, glycosuria/polyuria from extreme
glucose elevation, extreme dehydration, as it progresses loss of consciousness
may occur
o What’s the treatment?
 Rehydration & electrolyte replacement are vital
Somogyi Effect
o What is it/how does it work?
 Combination of hypoglycemia followed by rebound hyperglycemia, more
common with type I and children
 Overtreatment of insulin stimulates hypoglycemia = initiates the release of
epinephrine, ACTH, glucagon and HGH = stimulates lipolysis, gluconeogenesis
& glycogenolysis = rebound hyperglycemia and ketosis
o What are the symptoms?
 Fluctuating glucose levels, subtle symptoms of hypoglycemia, maybe
nightmares/early morning headaches, ketonuria can occur
o What’s the treatment?
 Decreasing insulin dosage or changing the time of administration
Dawn Phenomenon
o What is it?
 An early morning rise in blood glucose concentration with no hypoglycemia in
the night





Seems to be related to nocturnal elevations in GH (a counter-regulatory
hormone that causes hyperglycemia by decreasing peripheral (other than
liver) glucose uptake
o What’s the treatment?
 Altering the time/dose of insulin manages problem
 Treatment may cause Somogyi effect & vice versa

Chronic Complications of Diabetes Mellitus
P758-765
 Complications that arise from diabetes mellitus include
1. Microvascular: leading cause of blindness, end stage renal failure and various
neuropathies, the thickening of capillary basement membrane, endothelial cell
hyperplasis, thrombosis lead to decrease in tissue perfusion. Hyperglycemia is a
prerequisite for these changes. Includes three categories:
a. Retinopathy: retinal ischemia resulting from blood vessel changes and RBC
aggregation
i. Prevelance/severity related to person and duration of the diabetes
ii. Strongly related to vascular complications (nephropathy, cardio
vascular complications and stroke)
iii. Begins with venous abnormalities, microaneurysms, interretinal
hemorrhages, and edema. Progresses to cotton-wood patches (infarcts
of the nerve fiber) and shunt formation between retinal vessels. End
stage leads to retinal detachment.
b. Nephropathy
i. Beginning stage is asymptomatic and develops after 10 years in type 1
or 5-8 years in type 2.
ii. Believed that thickening of the glomerular basement membrane (in the
kidney) results in glomerulosclerosis (hardening of glomerulus). As
kidney starts to fail, hypoglycemia may occur b/c ppl can’t metabolize
insulin (along with other renal functions). Situation accelerates
retinopathy & cardiovascular disease.
iii. Microalbuminuria is first manifestation of renal dysfunction, then
proteinuria, person can become nauseous, lethargic, and anemic, death
is common
c. Neuropathy
i. High blood glucose interferes with the ability of the nerves to transmit
signals. It also weakens the walls of the small blood vessels (capillaries)
that supply the nerves with oxygen and nutrients
ii. The most common cause of neuropathy in Western world and most
common complication of diabetes
iii. Subclinical stage there is EMG evidence of peripheral nerve
dysfunctions (such as slowed motor/sensory nerve condition). In
clinical stage, neurologic deficits are clinically detectable.
iv. Diabetic neuropathy is a form of “dying back” neuropathy in which
distal portions of neurons are eventually more severely affected.
Begins with axon damage that involves sensory nerves
v. Distal symmetric polyneuropathy: most common form and involves
both large & small nerve fibers, includes sensory, autonomic and motor
nerves

2. Macrovascular: premature atherosclerosis of diabetes creates lots of vascular
problems, in addition to the deposition of lipids in vascular lesions
a. Coronary Artery Disease
i. Highest in and leading cause of death in type II
ii. Increased platelet adhesion & decreased fibrinolysis promote thrombus
formation and vascular occlusion, leading to myocardial infarction
(death of heart muscle as a result of coronary artery occlusion)
iii. There is also a high incidence of cardiomyopathy (myocardial
dysfunction in the absence of coronary artery disease & hypertension)
b. Stroke
i. Twice as common in ppl with diabetes as in the nondiabetic population
ii. Hypertension, hyperglycemia and dyslipidemia (abnormal amount of
lipids in blood) are risk factors
c. Peripheral Artery Disease
i. Many ppl with type II show signs of this
ii. The atherosclerotic process in diabetic persons is more common,
appears at younger age, advances more rapidly and increases the risk
of cardiac death
iii. Because of occlusions of small arteries/arterioles, most of gangrenous
changes are in feet and toes and amputation is common
3. Infection: increased morbidity/mortality from infectious agents have been
documented in diabetic ppl. This may be due to:
a. Impaired vision (retinal changes) and impaired touch (neuropathy changes)
diminishes the prevention of breaks in the skin by decreasing early warning
systems
b. Microvascular/macrovascular complications cause decreased O supply to
tissues
c. Pathogens can multiply rapidly once they’ve gained access
d. Decreased blood supply resulting from vascular changes decreases the supply
of WBC to affected area
e. Function of WBC is impaired by ischemia and hyperglycemia
f. Inflammatory responses to invasion are diminished
g. Sensory neuropathy leads to loss of protective sensation with injury &
repeated trauma that leads to open wounds/soft tissue infection
Most complications are associated with metabolic alterations, primarily hyperglycemia. 5
metabolic events are associated with tissue-damaging effects of chronic hyperglycemia:
o Shunting of glucose to the polyol pathway: glucose is sent to this pathway and over
time an accumulation fructose and sorbital (which glucose is converted into) leads to
cell injury
 leads to swelling of eye with visual changes & cataracts
 disrupts nerve impulses, damages Schwann cells, interferes with ion pumps
 RBCs become swollen and stiff, interfering with profusion
o Protein kinase C: an enzyme that is inappropriately activated by hyperglycemia
 Creates insulin resistance, production of extracellular matrix/cytokines,
vascular cell proliferation, enhanced contractility and permeability
o Nonenzymatic glycosylation: reversible attachment of glucose to proteins, lipids and
nucleic acids w/out the action of enzymes
 This can cross-link and trap proteins, with thickens the basement membrane
or increases permeability in blood vessels and nerves
 Can bind to cell receptors and induce release of cytokines or growth factors
 Induction of lipid oxidation, oxidative stress and inflammation
o Oxidative stress: caused by an imbalance between the production of reactive oxygen
and a biological system's ability to readily detoxify the reactive intermediates or
easily repair the resulting damage
o Hexosamine pathway: excess intracellular glucose is shunted to this pathway
 Causes glycosylation of enzymes/proteins which interferes with signal
transduction pathways
Disorders of the Adrenal Cortex
P765-772
 Hyperfunction
o Cushing’s Syndrome: increased levels of circulating cortisol
 What it is? What’s the pathologic mechanism?
 Common complication of Cushing disease (caused by excessive anterior
pituitary secretion of ACTH)
 ACTH secreting pituitary tumors are 85% of cases, more common in
woman. Remaining cases are ACTH secreting carcnoid tumors or small
cell carcinoma of the lung
 What are the symptoms?
 Weight gain in trunk, face & cervical area “moon face, buffalo hump on
the back), develop stretch marks, diabetes mellitus can develop, protein
and muscle wasting occurs, poor wound healing and subject to fungal
infections
 ½ develop mood changes from irritability to psychiatric disturbance
 What’s the treatment?
 Includes radiation therapy, medication and surgery
o Virilization/Feminization:
 What is it? What’s the pathologic mechanism
 increased secretion of adrenal androgens & estrogens
 casued by adrenal tumors (adenomas or carcinomas), Cushing’s
Syndrome or defects in steroid synthesis
 What are the symptoms?
 Depends on hormone secreted, gender of the person and the age it
begins at
 Men develop feminine characteristics, females develop male
characteristics
 What’s the treatment?
 Surgical excision
o Hyperaldosteronism: excessive secretion of aldosterone
 What is it? What’s the mechanism?
 Decrease in body’s potassium concentration & excessive retention of
Na+ and H2O. If K+ depletion is great enough neruons can’t depolarize
& paralysis results. The increased H2) volume in the blood causes high
BP and edema.
 What types are there?
 Primary: caused by an abnormality of the cortex (most often a tumor)
 Secondary: caused by an extra-adrenal stimulus that stimulates
aldosterone secretion
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What are the symptoms?
 Hypokalemia (lower than normal level of K+ in blood), hypertension
and metabolic alkalosis (pH of tissue is elevated beyond the normal
range)
What’s the treatment?
 Glucocorticoid & electrolyte replacement, remove tumor if possible
Hypofunction
o Low levels of cortisol secretion develops b/c of an inadequate simulation of adrenal
glands by ACTH or a primary inability of the adrenals to produce/secrete the
adrenocortical hormones
o Addison disease (primary adrenal insufficiency)
 relatively rare, 30-60 years of age, more common in women
 There is an elevated ACTH level with inadequate corticosteroid
synthesis/output
 Caused by autoimmune destruction of cortex
o Secondary hypocoritsolism
 Characterized by low/absent ACTH levels, which cause inadequate adrenal
stimulation & adrenal atrophy
o What are symptoms?
 Fatigue, diarrhea, nausea, anorexia, hypotension, hyperpigmentation
o What is treatment?
 Lifetime of glucocorticoid replacement therapy, diet strictly monitored
Disorders of the Adrenal Medulla
P772
 Hyperfunction:
o What is it? Pathologic Mechanism?
 Caused by tumors derived from chromaffin cells of medulla
(pheochromocytomas)
 Tumors secrete catecholamines on continual/episodic basis (most secrete
norepinephrine), eventually will wear out the body and weakness will result
o What are the symptoms?
 Chronic “flight or fight” response activated, leading to hypertension, high BP,
increased metabolic rate, nervousness, sweating
o What’s the treatment?
 Surgical excision of tumor