Lecture 22

Question 1

Describe the etiology, clinical manifestations, and the pathophysiology for diabetes insipidus.

Definition of Diabetes Insipidus: insufficient secretion of ADH

Answer 1

Etiology:

Neurogenic: lesion of the hypothalamus (most common), stroke, head injury. - decreases synthesis, transport, or release of hormone

Nephrogenic: end stage of renal failure. distal tubule loses its response to ADH

Psychogenic: drinking extremely large volumes of H2O

Clinical Manifestations:

1. Polydipsia
2. Polyuria
3. Nocturia
4. Urine specific gravity 1.000 - 1.005
5. Circulatory collapse, loss of BP

Pathophysiology:

1. inability to reabsorb large volumes of pure water in collecting ducts
2. increased blood osmolality, cells crenate
3. large urine volumes 4-12 L/Day
4. Severe thirst, person craves cold drinks
5. Hypovolemic shock

Question 2

Describe the etiology, clinical manifestations, and the pathophysiology for diabetes mellitus type 1.

Diabetes Mellitus Type 1: chronic hyperglycemia and other disturbance of CHO, Fat, and Protein metabolism

• juvenile onset (ages 8-20)
• 80-90% of beta cells missing before clinical manifestations appear

Insulin dependent!

Answer 2

Etiology:

1. cell mediated autoimmune destruction of pancreatic B cells (Type IV hypersensitivity reaction) –> loss of insulin and amylin
2. genetic predisposition/environmental interaction
3. Triggered by an exogenous factor or an infection

• un utero rubella viral infection
• mumps
• coxsackie
• cytomegalo virus
• nitrosamines
• milk products

4. Non-immune Type I DM - severe pancreatitis

Pathophysiology :

A. Hyperglycemia –> impaired fasting glucose (IFG) > 126 mg/dL
Oral glucose tolerance test (OCTT) > 200 mg/dL

Blood glucose exceeds 180 mg/dL

B. 80-90% of B cells are lost

C. Osmotic imbalance in the nephron loop, distal convoluted tubule, and collecting duct

D. Renal osmotic diureses

E. Weight loss due to lack of lipogenesis and storage. (Insulin promotes protein synthesis, lipogenesis, and formation of trigylcerides)

F. Failure of high plasma glucose suppression of glucagon!

G. Increased glucagon secretion continues to stimulate glucose production by the liver (normally insulin suppresses glucagon secretion)

H. Glycosylation occurs with Hb and glycolation binds with tissue proteins

I. HbA glycosylated

Clinical Manifestations:

1. polyuria (frequent urination of large amounts of water due to renal osmotic diuresis)
2. polydypsia (frequent drinking of large amounts of water due to intracellular dehydration and crenation.)
3. polyphagia ( increased hunger due to CHO starvation of cells and depletion of fat and proteins stores)
4. weight loss and chronic fatigue

Question 3

Describe the etiology, clinical manifestations, and the pathophysiology for DM II.

DM II: adult onset, after the age of 30, heavy genetic and behavioral component

• often accompanied by obesity
• most victims have symptoms 7 years before being diagnosed and most are hyper-insulinemic at the time of diagnosis, which eventually deteriorates with pancreatic fatigue to hypo-insulin secretion

Insulin resistant!

Answer 3

Etiology:

1. obesity
2. dyslipidemia (elevated blood triglycerides and cholesterol)
3. prehypertension (systolic > 135 and diastolic > 80)
4. fasting glucose > 100
5. gestational diabetes
6. hypoglycemia when teenagers or in early 20s
7. years of hyperninsulemia

a. insulin stimulated lipogenesis and adipose cell mitosis
b. increased adipose cells secrete more leptin
c. leptin decreases liver, mm., and adipose cells responsiveness to insulin
d. decreased responsiveness to insulin causes hyperglycemia
e. prolonged exposure of B cells to hyperglycemia causes apoptosis of the B cells
f. apoptosis of B cells cause decreased insulin secretion
g. target cells of insulin don’t upregulate response to decreased insulin

Clinical Manifestations:

1. polyuria
2. polydypsia
3. polyphagia
4. weight loss and chronic fatigue
5. visual changes

Pathophysiology:

1. Cellular resistance to insulin, down regulation of receptors
2. Endogenous insulin is often sub-physiological but present
   - beta cells decrease sensitivity to glucose –> decrease insulin secretion,
3. decreased weight and number of B cells
4. abnormal glucagon secretion in the face of elevated glucose levels. decreased sensitivity to glucose levels
5. believed onset is 7 years before diagnosis
6. insulin resistance - suboptimal response of insulin sensitive tissues (liver and adipose tissues)

• down regulation of receptors
• decrease activation of post receptor kinases
• alteration of GLUT transporter

7. Apoptosis of B cells of pancreas - chronic and uncontrolled hyperglycemia and hyperlipidemia
8. Obesity - contributes to insulin resistance
   - increased leptin and resisten, associated with decreased insulin sensitivity
   - increased serum triglycerides, interferes with intracellular insulin signaling
   - inflammatory cytokines - from abdominal adipose cells, affect post receptor insulin response
   - decreased insulin receptor density - due to increased hyperinsulemia

Question 4

Describe the etiology, clinical manifestations, and the pathophysiology for hyperthyroidism. (also known as thyrotoxicosis)

Answer 4

Etiology:

1. Graves disease (most common cause)

• autoimmune disease: antibody irreversibly bind to TSH receptor (on the thyroid) causing continuous stimulation
  (Type II hypersensitivity response)
  –> ophalopathy: protruding eyes leading to optic nerve detachment
  –> goiter: with increased levels of T3/4

2. Toxic Multinodular Goiter
   - caused by overstimulation of the thyroid by TSH, when the demand for more T3 is reduced, some cells remain large and autonomous
3. Thyroid Cancer
   - autonomous cancer cell that doesn’t respond to negative feedback
4. Increased TSH secretion
   - defective TRH or TSH production

Clinical Manifestations:

1. Hyperthermia in the absence of infections (heat intolerance)
2. Tachycardia
3. Tachy-dysrhythmias
4. High output heart failure
   - due to increased B adrenergic receptors and oversecretion of NE and Epi due to hyper metabolism

Patho:

1. increased iodine uptake and increase metabolic rates
2. hyperactive sympathetic nervous system
3. infiltration changes of orbital and ocular mm. changes causing protrusion of the eyeball. can lead to blindness.

Question 5

Describe the etiology, clinical manifestations, and the pathophysiology for hypothyroidism.

Answer 5

Etiology:

1. defective hormone or defective synthesis enzymes
2. iodine deficiency in diet
3. iatrogenic - surgical removal of thyroid after hyperthyroidism
4. Hashimoto’s disease: destruction of thyroid due to Tc and NK cell (Type IV hypersensitivity response)
5. insufficient stimulation of TRH and TSH in the hypothalamus and the Ant. Pit due to lower T3/4 levels (damage to the hypo and ant. pit)
6. post partum thyroiditis

Pathophysiology:

1. goiter
2. cretinism (dwarfism in children from damage to the ant. pit)
3. myxedema - production of interstitial protein increasing interstitial osmotic pressure shifting water out of capillaries and into interstitial compartment
4. low metabolism - often overweight
5. cold intolerance
6. anemia
7. myxedema coma - life threatening!

Question 6

Describe the etiology, clinical manifestations, and the pathophysiology for hypersecretion of ADH. (also known as syndrome of inappropriate ADHD production [SIADH])

Answer 6

Etiology:

1. Ectopic source (most common cause)
   - adenocarcinoma of the lung
   - pancreatic cancer
   - duodenal cancer
   - stomach cancer
   - bladder and prostate cancer
2. Pulmonary disorders
   - asthma
   - cystic fibrosis
   - pneumonia
   - mechanical ventilation
3. transient pituitary surgery (stored hormone is released unregulated)
4. Barbiturates, psychosis, anti-suppressants, NSAIDS (ibuprofen), anesthetics

Clinical Manifestations:

1. hypo-osmotic plasma (water intoxication), cell swelling
2. Hyponatremia: Na serum level is weight gain, impaired sensorium
   - -> if less than 115, confusion/lethargy/mm.twitching
   - -> if less than 110, severe and irreversible neurological damage
3. improves with H2O restriction
4. Na intake = Na output
5. causes cell swelling and possible neurological damage (fatigue, lethargy, confusion, convulsion)

Pathophysiology:

a. increased absorption of pure H2O in distal tubules and collecting ducts
b. decrease blood osmolality (hypotonic)
c. hyponatremia

Question 7

Describe the etiology, clinical manifestations, and the pathophysiology for hyperinsulinemia.

Answer 7

Etiology:

1. Obesity

Clinical Manifestations:

1. decreased insulin receptor density = hyperglycemia

Pathophysiology:

1. insulin stimulates lipogenesis and adipose cell mitosis
2. increased adipose cells secrete more leptin
3. Leptin decreases liver, mm., and adipose cell’s responsiveness to insulin
4. decreased responsiveness to insulin causes hyperglycemia
5. prolonged exposure of hyperglycemia to B pancreatic cells causes apoptosis of the B cells
6. Apoptosis of the B cells causes a decrease in insulin
7. Target cells don’t upregulate receptors in response to decreased insulin

Question 8

Describe the etiology, clinical manifestations, and the pathophysiology for infarction of the anterior pituitary.

Also known as hypopituitarism!

Answer 8

Etiology:

1. infarction of the hypothalamus (sickle cell anemia or diabetes mellitus)
2. Anorexia Nervosa
3. Vasospasm postpartum - reflex or circulatory collapse

Note: Anterior Pituitary is susceptible b/c it is dependent on portal blood which is already somewhat O2 depleted because it is venous blood.

Traumatic brain injury –> disruption of blood flow –> ischemia

Clinical Manifestations:

1. Hypothyroidism - cold intolerance, myxedema, decreased metabolism, dry skin
2. Hyposecretion of cortisol - potentially deadly, loss of hair, n/v, anorexia, weakness, fatigue, decreased renal function
3. Diabetes Insipidus
4. Loss of FSH and LH - amenorrhea (abnormal menstruation), gonadal atrophy and failure
5. Decrease or loss of GH - most common cause in trauma or injury to the hypothalamus

• can be due to a recessive mutation in the synthesis pathway or due to the secretory pathway
• leads to dwarfism in preadolescence
• in post adolescence it leads to social withdrawal, loss of motivation, GH decreases with age

Pathophysiology:

1. Panohypopituitarism - loss of all the ant. pit hormones (FSH, LH, GH, ACTH, TSH, ADH)

• TSH is rarely seen in isolation but with other Ant Pit hormone deficiencies
• ACTH dysfunction is LIFE THREATENING (usually only occurs during generalized pituitary dysfunction)
• decreased TSH = decreases in T3/4 = hypothyroidism (thyroid atrophy)
• decreased ACTH = absence of cortisol secretion, adrenal cortex atrophy

Question 9

Describe the etiology, clinical manifestations, and the pathophysiology for Adenoma of the anterior pituitary

For this one, Hyperpituitarism

Answer 9

Etiology:

1. adenoma of the pituitary
2. adenomatous tissue secretes hormone of the cell type from which the tumor originated (doesn’t respond to negative feedback)
3. other pituitary hormones are subject to hyposecretion because of increased pressure from the growth of the tumor

*** most adenomas are of the cells that secrete GH or prolactin resulting in hyper secretion of these and in hyposecretion of all the other hormones due to increased pressure in the sella turcica.

*** cells most sensitive to pressure are GH, LH, and FSH (post. pituitary hormones are seldomly affected)

4. local invasion of the tumor often leads to visual disturbances due to pressure on the optic chiasma

clinical manifestations:

1. Nonspecific symptoms: HA, neck pain, seizures
2. Specific Symptoms: visual disturbances (optic nerve pressure)
3. irregular menstruation, receding secondary sex characteristics
4. hyposecretion of all other ant pit hormones

• ACTH is life threatening and TSH if pressure becomes great enough
• dwarfism due to decreased GH

Question 10

Describe the etiology, clinical manifestations, and the pathophysiology for hypersecretion of growth hormone.

Answer 10

Etiology:

adenoma of the cells secreting GH

Clinical Manifestations:

1. enlarged tongues, changes in speech
2. enlarged phalanges, frontal bones, and jaw
3. thick tough skin

Pathophysiology:

1. Increase GH = overproduction of IGF 1
   - -> growth of cartilage and long bones
2. Juvenile = giantism
3. Adult = acromegaly

• continued growth of c.t.
• increased growth of cytoplamsic matrix
• continued growth of flat bones/phalanges
• inhibition of peripheral glucose uptake –> hyperinsulinism –> DM II

pancreas is unable to secrete enough insulin due to offset elevated GH effects

4. Atherosclerosis, HTN
   seldom do these people live past their 40s

Question 11

Describe the etiology, clinical manifestations, and the pathophysiology for hypersecretion of prolactin.

Answer 11

Etiology: adenoma of the Ant. Pit

Prolactin secreting cells are under inhibitory control of the hypothalamus through the effects of dopamine secreting neurons

Therefore, drug that diminish the secretion of dopamine in turn stimulate the cells that secrete prolactin and increase their release

Clinical manifestation:

1. amenorrhea
2. abnormal milk production
3. hirsutism (abnormal hair growth)

Patho:

1. impairs the pulsatile release of GnRH, blunts the response of the gonads
2. causes milk synthesis in estrogen and progesterone primed breasts

Question 12

Describe the etiology, clinical manifestations, and the pathophysiology for hyperaparathyroidism.

Note: parathyroid hormone stimulates activation of Vit D

in renal failure vit D is not activated:

• -> plasma Ca levels fall
• -> plasma PO4 levels increase

Answer 12

Etiology:
Primary - adenomas, clonal proliferation of cells with set point higher than normal and a failure of negative feed back system
Secondary - renal failure, increased PTH with decreased blood Ca, intestinal malabsoprtion (lack of vit D), renal inability to produce vit D, hypocalcemia stimulates PTH secretion

symptoms -

primary = those associated with hypercalcemia –> loss of neuromuscular excitability = fatigue, weakness, lethargy, anorexia, nausea

secondary = osteoporosis

Clinical Manifestations:

1. calcium oxalate kidney stones
2. lethargy
3. mm. weakness
4. constipation
5. very alkaline urine, PO4 excretion

Patho:

1. excessive stimulation of osteoclasts
2. osteoporosis due to pathological bone fractures, kyphosis
3. hypercalcemia

Question 13

Describe the etiology, clinical manifestations, and the pathophysiology for hypoparathyroidism.

Answer 13

Etiology:

1. damage to the parathyroid glands as a result of thyroidectomy surgery
   (most common cause)

may also be due to hypomagnesia

Clinical Manifestation:

1. mm. spasms
2. hyperreflexia
3. tonic and clonic convulsions
4. laryngeal spasms
5. death by asphyxiation (severely deficient supply of O2 to the body)
6. Chvostek and Trousseau signs
   - Chvostek = tetany of the facial nerve
   - Trousseau = spasms in mm. of the hand and forearm when a pressure cuff is inflated and lack of blood flow is in the area