Flashcards in Module 5: Endocrine: DM and Acromegaly Deck (39):
Starting off with endocrine pathology is DM, which is the most common endocrine disorder. First, explain the levels of C-peptide in your body in relation to insulin
Normal levels: exogenous
Elevated levels: insulinoma (pancreas is secreting insulin which breaks down to C-peptide)
Now there are two types of DM, firs being type I DM. What is the etiology for type I?
Viruses: Coxsackie B4, Rubella, Mumps (molecular mimicry -- damage to the beta cells)
Autoimmune: HLA DR3 and DR4 --- immune response
--note that since this would be an autoimmune condition it can co-exist with other autoimmune conditions like Lupus, RA, Grave's, Hashimoto's
What is the presentation for patients with DM type I?
Less than 40 y.o
Skinny (lack insulin -- catabolic state)
Vomiting (ketones irritate Area Postrema)
Kaussmal's Breathing (hyperventilation in response to the metabolic acidosis results in respiratory alkalosis)
What is the histology for type I DM?
Autoimmune damage to the pancreas by T cells
Complete destruction of the islets of Langerhan's by lymphocytes
--Increased CD8 lymphocyte
Is insulin needed in type I DM?
Need insulin for life
What are the acute complications for type I DM?
1. Insulin overdose leading to hypoglycemia (most common): confusion, sweating, coma and seizures
2. Diabetic Ketoacidosis:
---trigger is infection (pneumonia, UTI, etc) the body's response to stress is increased cortisol but cortisol is gluconeogenic so your antagonizing insulin but favoring gluconeogenesis which worsens the hyperglycemia
--severe hyperglycemia leads to osmotic diuresis and gross dehydration
---ketone bodies (made by the liver and muscle cells) = acetoacidic, B-hydroxybutyrate
3. Mucomycosis is the fungal infection that loves glucose so therefore associated with DKA
Now for type II DM, what is the etiology?
1.Obese: Increases production of insulin antagonists such as fatty acids and TNF by adipose tissue, esp in central obesity.
2. Over 40 y.o
3. Associated with PCOS
4. More genetic predisposition than type I
5. Primary Beta cell defect (genetic) + peripheral insulin resistance (obesity) --- hyperglycemia --- beta cell exhaustion -- type II DM
6. NO HLA associated
What is the histology for patients with Type II DM?
--amylin associated amyloid (AA)
-extra-cellular, hyaline, amorphous
(other endocrine disorder thaw is localized amyloid is medullary carcinoma of the thyroid)
At what point in time do patients with DM type II need insulin?
When the pancreas becomes burned out then the production of insulin will stop
--at this point patients at risk for developing DM
What are symptoms associated with type II DM?
Can be asymptomatic:
--incidentally picked up on blood tests
Polyphagia (only one you dont see in DI)
Polyuria: increased urination
Polydypsia: increased thirst
What are the acute complications for type II DM?
1. Hyperosmolar, non-ketotic coma (aka dehydration + hyperglycemia)
--glucose in the urine --- water and Na follows ---- dehydration and hyponatremia (leads to cerebral edema -- comatose)
Elderly ppl who forget to drink who have DM
For both type I and type II DM, what investigations can be done?
1. 2 samples of fasting BG greater than 126mg/dl (hyperglycemia)(better for screening)
2. Random Blood Glucose greater than 200mg/dl but with symptoms (polyphagia, polydipsia and polyuria)
3. HbA1c greater than 6.5% is diagnostic but more useful for evaluation of long term glycemic control. (over the past 120 days)
4. 2 hour plasma glucose greater than 200mg/dl during OGTT (overnight fast + 75mg glucose) -- this tests the residual capacity of pancreas challenging the pancreas to produce insulin.
Now for both type I and type II DM what would be the most common causes of death?
Silent MIs (most common) -- silent due to the neuropathy
Renal Failure (2nd most common)
Now lets talk about the chronic complications of both types of DM. First lets talk about the Macroangiopathy complications. What is the major complications?
Atherosclerosis in large to medium arteries
Risk Factors: hyperlipidemia, smoking and HTN
--Atherosclerosis --- rupture of atherosclerotic plaque --- superimposed thrombus ---- narrowing of lumen -- ischemia and infarction
--circle of willis = stroke
---coronary blood vessels = transmural MI (painless due to autonomic neuropathy) = most common cause of death
--Peripheral vascular disease: intermittent claudication followed by pain at rest --ulcers and gangrene
--Renal Artery Stenosis: HTN due to JG cells secreting renin in response to hypoperfusion
Moving onto Microangiopathy complications of diabetes the first is neuropathy. What is the etiology for this?
Affects the capillaries, arterioles and small blood vessels
Etiology: glucose -- sorbital via aldose reductase -- sorbital accumulation
Neuropathy is first because nerves dont require insulin for sugar uptake
What is the first type of neuropathy seen in patients with DM type I and type II?
Distal Symmetric Peripheral Neuropathy: glove and stocking distribution
---mostly sensory but can affect motor nerves (muscle weakness and atrophy)
What are the other neuropathy signs seen in patients with type I and II DM?
--loss of just radial nerve = wrist and foot drop
--sexual dysfunction: impotence
---diabetic gastroparesis: loss of stomach stretch receptors and decreased motility = early satiety, bloating and constipation
--neurogenic bladder due to loss of PNS -- stasis --UTI -- ascending infection to kidney --- acute pyelonephritis
--silent MI because no peripheral pain sensation
--wrist and foot drop = loss of radial nerve
Explain the diabetic foot in regards to Neuropathy in type I and II DM?
Diabetic foot: ischemia + neruopathy + infection
--recurrent infections that can't heal properly due to available glucose for bacteria.
--also seen in patients with Cushing's Disease b/c cortisol antagonizes insulin --- hyperglycemia --- type 2 diabetes
The next microangiopathy chronic complication is Retinopathy in type I and II DM. What is the etiology for this?
Etiology: Glycosylation of proteins --- advanced glycosylation end products (AGE)
--loss of pericytes earliest structural change (Don't see nuclei surrounding vasculature): maintain the structural framework
There is pre-proliferative and proliferative retinopathy. What is seen in pre-proliferative retinopathy?
Microaneurysm's due to loss of pericytes
--rupture of microaneurysms --- dot and blot retinal hemorrhages, hard exudates, and cotton wool spots (Due to ischemia -- retinal infarct)
--cotton wool spots are also seen in HTN retinopathy
What is seen in proliferative retinopathy?
Neovascularization (due to VEGF) without pericytes -- hemorrhage -- retinal detachment and blindness
--point in which you would consider doing laser surgery in a patient
What are other retinal chronic complications in type I and type II DM patients?
Cataracts: due to sorbitol accumulation
-nerves and lens dont need glucose for uptake
--glucose taken up into lens without insulin -- reduced sorbitol via aldose reductase -- attracts H20 --- cloudy lens/cataracts
The last microangiopathy complication in type I and type II DM is nephropathy. Which involves what?
Athersclerosis of renal artery
--papillary necrosis due to ischemia of renal papillae -- coagulative necrosis and atrophy of kidney --- increased susceptibility for infections (Recurrent acute pyelonephritis)
--autonomic neuropathy also increased susceptibility to infections due to loss of PNS and ability to empty bladder
--atrophy tubules --- fibrosis --- chronic renal failure
What casts are found in nephropathy of type I and type II DM?
Granular (muddy brown): tubular necrosis
WBC casts: pyleonephritis
Waxy: kidney failure
What is the pathogenesis for nephropathy in type I and type II DM?
Renal artery stenosis --- increased renin --- long standing benign HTN --- hyaline arteriosclerosis in both Afferent and Efferent arterioles
--begins with efferent though
What is the first structural changes in nephropathy in type I and type II DM
First structural change in the glomerulus: mesangial expansion then thickening of GBM --- Kimmelstein Wilson Nodular deposits and diffuse glomerulosclerosis --- nephrotic macroalbuminuria
--overt nephropathy: macroalbuminuria = greater than 3.5g/day
--KW nodules made of lipids and fibrin and mesangial cells
--damage to BM -- lose nephrin in the urine
What are the first functional and biochemical changes in nephropathy of type I and type II DM?
Hyperfiltration: compensation (First functional change)
Microalbuminuria: first biochemical change
What is secondary hyperaldosteronism, in regards to nephropathy in type I and II DM?
Due to edema --- decreased intravascular volume --- hypoperfusion or organs --- increased renin and increased aldosterone (which absorbs Na and water but cant hold water due to lack of albumin) -- still decrease intravascular volume
Now moving onto Acromegaly, what is the etiology for this?
Etiology: Excess growth hormone after fusion of the epiphysis (part of MEN-1 syndrome due to MEN 1 gene mutation)
--more common in middle aged women
The first MEN 1 mutation is Parathyroid Adenoma/Hyperplasia what is the mechanism?
--primary hyperparathyroidism --- increased PTH --- increased calcium and decreased phosphate
Explain the three P's of MEN 1 mutations
Parathyroid Adenoma--- makes PTH leads to hypercalcemia
Pituitary adenoma (anterior) --- makes growth hormones in the case of acromegaly but most common is prolactinoma
In the case of Acromegaly what is the effect of an Anterior Pituitary adenoma?
GH adenoma ---- produces GH --- liver Releases Insulin like growth factor 1 (IGF-1)
--also called somatomedin (this is responsible for anabolic effects therefore reason for chipmunk faces and frontal bossing)
--GH is catabolic --- antagonist to insulin --- gluconeogensis and hyperglycemia -- type 2 diabetes and may lead to simultaneous secretion of prolactin (decreased LH and FSH --- decreased libido in men and anovulation in females)
Anterior Pituitary Adenoma, can also lead to pan-hypopituitarism, how?
Decreased ACTH: bilateral adrenal atrophy (secondary adrenal insufficiency)
--secondary adrenal insufficiency: decreased cortisol, normal aldosterone, no hyperpigmentation
--differential primary adrenal insufficiency (Addison's): decreased cortisol, decreased aldosterone and increased ACTH and hyperpigmentation
Decreased TSH: secondary hypothyroidism -- decreased T4
Decreased FSH and LH: females (Amenorrhea, galactorrhea, infertility) and males (gynecomastia, galactorhea, decreased libido, infertility)
The last of the Three P's is pancreatic tumor, what can this lead to?
--insulinoma: makes insulin
---gastrinoma: makes gastrin (Zollinger Ellison Gatrinoma)
--Vipoma: makes VIP
What stomach tumor would you see in a patient with acromegaly?
Carcinoid type II tumor because gastrin stimulates neuroendocrine cells and histamine stimulates partial cells to make acid and therefore creates Duodenal Ulcers
What is the presentation for a patient with acromegaly?
Prognathism and Wide spaced teeth
Enlarged hands (sausage finger, spade like hands)
Frontal bossing and Chipmunk face
Macroglossia (affects speech)
Sweat Gland Hypertrophy ( body odor and oily skin)
Large, ring, cap and shoe size
Bitemporal hemianopsia (Compression of optic nerve)
HTN (due to upregulation of alpha receptors -- allows permissive action of catecholamines -- vasoconstriction)
Atherosclerosis (due to HTN and type 2 DM)
In regards to Acromegaly, which test is used for screening and which one for dx?
Screening: IGF-1 (very sensitive, not specific and stable throughout the day); GH not used because its pulsatile
Dx: Hyperdynamic testing (OGTT + serial GH levels)
--normal patients: decreased GH due to the presence of glucose
--acromegaly: presence of glucose does not inhibit GH (Remains high)
GH is gluconeogenic so it counter acts the effects of insulin
What are the complications in acromegaly?
Death from congestive heart failure (most common cause of death)(from HTN and cardiomegaly)
Hyperprolactinemia: co-secretion of prolactin with GH producing tumor
Obstructive Sleep Apnea
Neoplastic polyps in colon