-4 -Osama Khader Mousa Alabbadidiabetes mellitus which can be fatal. They are hyperosmolar coma and...
Transcript of -4 -Osama Khader Mousa Alabbadidiabetes mellitus which can be fatal. They are hyperosmolar coma and...
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-Amera Al- zoubi
-Osama Khader
- Mousa Alabbadi
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In the previous lecture we started talking about the acute complications of
diabetes mellitus which can be fatal. They are hyperosmolar coma and DKA
(diabetic ketoacidosis).
Now we will start about the chronic complications of DM, they are the ones
responsible for almost all the mortalities and morbidities. The main reason for
these complications is chronic hyperglycemia. These complications happen due
tovascular pathway:
- Macrovascular, which affects large blood vessels and mainly arteries. The
three major targets of macrovascular complications: MI (myocardial
infarction), stroke, lower limb ischemia.
-Microvascular, affects end organ blood vessels and arteries. It affects all cells,
but the most important targets are: the eye (retinopathy), the kidney
(nephropathy), and the nervous system (mostly peripheral nervous system).
There is some overlap between macrovascualr and microvascular
complications.
These complications vary from patient to patient, for some their kidneys are
more affected while others suffer from peripheral nervous system
complications. To delay these complications,you must have tight control over
your blood sugar.
The long-term complications may include infarcts, strokes and hemorrhage in
the brain. Atherosclerosis of macro and microvesicles. In the eye: cataracts,
retinopathy, and glaucoma. Peripheral vascular atherosclerosis, diabetic foot,
ischemia, amputations. Peripheral neuropathy, impotence, urinary bladder
dysfunction, GI tract dysfunction, chronic renal failure.
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The most common cause of death in diabetic patients is myocardial infarction
and after it comes renal failure. The most common cause of renal failure in
adults in Jordan and USA is diabetes.
Why do long term complications happen?
Pathogenesis of chronic complications:
1- Advanced glycation end products (AGEs):
The blood has hyperglycemia, so everything in the body becomes
glycosylated. These glycosylated end products will have receptors: receptors of
advanced glycated end products (RAGE). These glycated end products increase
all the injuriousagents including the oxidative end products like ROS and causes
damage to all tissues (blood vessels, interstitium, epithelial cells, and
macrophages). This is the main pathway of chronic complications of diabetes?
2) activation of the protein kinase which eventually results in advanced
glycated end products.
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3) polyol pathway, the sugar is reduced which produces ROS systems which
causes injury to tissues.
All these pathways lead to ROS production and oxidative stress and this causes
tissue injury. (biochemical toxicity )
SO, the underlying pathogenesis of long term complications of diabetes is due
At the morphological level:
-Amyloid deposition.
-destructed and Decreased number and size of islets (in type 1).
-In baby of diabetic mother, the number and size of islets increases, because in
utero hyperglycemia stimulates the pancreas islet cells for long periods of
time.
-Insulitis: autoantibodies against Langerhans cells.
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Vascular changes:
- Myocardial infarction is the most common cause of death in diabetics,
because their blood vessels are not normal. There is mass atherosclerosis. You
have to be careful because these patients might not have the classic symptoms
of myocardial infarction, why?
Because these diabetic patients have peripheral neuropathy, so they'd get
vague symptoms. That's why if a diabetic patient comes to ER with vague
symptoms you must rule out myocardial infarction (silent MI).
- Gangrene and ischemia of lower extremities(macrovascular complications).
Gangrene is of two types: wet gangrene (infected) and dry gangrene.
- Hyaline arteriosclerosis, thickened artery, happens in the kidney and all small
blood vessels, and it increases the risk of hypertension.
- Diabetic microangiopathy, affects every single organ in your body but the
main targets are the eye (retinopathy), the kidney (nephropathy), and
peripheral nervous system.
Nephropathy:
- Second to MI as a cause of mortality, and the main cause of renal failure in
adults is diabetes.
Kidney consists of: Glomeruli, tubules, interstitium and blood vessels*
- Glomeruli will have thickening of the basement membrane due to
glucolypolysis (diffuse or localized).
- Mesangium is the interstitium which contains interglomerular structures, this
mesangium becomes destructed and acquires sclerosis, it can either be diffuse
mesangial sclerosis or nodular glomerulosclerosis (Kimmelstiel-Wilson disease)
and this is a characteristic of diabetic glomeruli.
Vessels of the kidney get atherosclerosis and arteriosclerosis.-
Diabetic patients are more prone to develop UTIs. Urinary tract infections are
divided into upper and lower infections; the upper UTIs are more dangerous
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because they're a major cause of sepsis. You must check the patient's kidneys
and ask for a urine analysis before surgery.
- Pyelonephritis (acute and chronic) and necrotizing papillitis (necrosis of the
renal papillary) are a characteristic of diabetes.
Ocular changes:
- Retinopathy: the most important of ocular changes. Retina becomes
microangiopathic. There are two types of diabetic retinopathy;
Kidney tubules stained with PAS stain which highlights
the basement membrane. Here the basement
membrane appears thickened (dark purple).
A glomerulus, the functional part of the
kidney.
Nodules on external surface indicate
atherosclerosis.
Basement membrane of glomerulus
which is thickened.
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1) non-proliferative diabetic retinopathy, it is not very dangerous, has early
changes, patients get hemorrhage, exudates, edema, aneurysms, venous
dilatation.
2) proliferative diabetic retinopathy, neovascularization from
lipoglucotoxicity and new vessels form, may cause bleeding, retinal
detachment and blindness. More dangerous than non-proliferative
retinopathy. Most common cause of blindness in adults is diabetic retinopathy.
*Question sample: which one of the following is considered a proliferative
complication of diabetic retinopathy? Answer: neovascularization.
- Cataract: clouding of the lens in the eye happens with old age, diabetics get
early cataracts.
- Glaucoma: increased intraocular pressure, one of the main reasons which
causes red eye.
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Diabetic neuropathy:
-There is peripheral and central neuropathy, the peripheral is more common.
Its mechanism is mainly microangiopathy.
- peripheral symmetrical sensory (more common than motor) diabetic
neuropathy (gloves and stocking neuropathy).
-Autonomous nervous system also gets affected, main manifestation:
impotency in men, urinary bladder dysfunction and GI tract (diarrhea or
constipation).
Management:
-Major cause of mortality and morbidity is chronic hyperglycemia, so there
must be tight glycemic control.
Type1: insulin replacement therapy.
-Type2: diet, exercise, medications (there's a big pool of drugs, some affect
kidney tubules, some act on pancreas, and some to increase peripheral
sensitivity to insulin) ultimately insulin therapy will be needed.
HbA1c (hemoglobin c) must be monitored and kept below 7%-
-Lipid profiles must be regulated; HDL and LDL level must be controlled. In
diabetic patients, LDL must be below 100, the risk of MI almost disappears.
HDL must be as high as possible, HDL increases through exercise.
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Pancreatic neuroendocrine tumors:
The major killer in pancreatic tumors (exocrine) is pancreatic ductal like
adenocarcinoma.
Endocrine pancreatic tumors are rare compared to exocrine tumors; they
make up 2% of all pancreatic tumors.
Almost all pancreatic neuroendocrine tumors have a possibility of
malignancyexcept insulinomas.
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They are part of the Multiple Endocrine Neoplasia syndrome type 1 (MEN1 3
P's: Pituitary, Parathyroid, and Pancreas).
Mutations happen in tumor suppressor genes: MEN1, PTEN or mutation in
inactivating genes like ATRX.
Insulinomas:
Most common pancreatic Neuroendocrine tumor.
How to diagnose? Hypoglycemic symptoms, you must check and confirm its
hypoglycemia through serum blood sugar, then you give the patient sugar and
the symptoms are relieved. This is called Whipple triad. Patients with this
have insulinoma.
Now you must find out the source of the insulinoma and find out where it's
located. Because it can be somewhere other than pancreas.
Has 10% malignancy potential (invasion and metastasis).
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Pinkish material might be sclerosis, fibrosis, which might be type 4 collagen or
it might be amyloid. To differentiate between them you use congo red stain.
Amyloid becomes apple green with the stain.
Gastrinoma
-Secrete gastrin, have multiple ulcers in duodenum and stomach. It's an
intractable ulcer(do not respond to any drugs).
-Zollinger- Ellison syndrome: it's a gastrinoma with increased gastric acid and
severe peptic ulceration (can have multiple ulcers).
The ulcers can be severe, multifocal, and in unusual locations.-
-More than 50% of gastrinomas are malignant and have a chance of
metastasis. They're more dangerous than insulinomas.
Can be a part of MEN-1 syndrome.-
Adrenal cortex gland:
Has cortex and medulla. Cortex has 3 layers: zona glomerulosa (aldosterone),
zona fasciculata (cortisol), zona reticularis (androgens). Medulla produces
Epinephrine and norepinephrine. They are under the hypothalamic-pituitary-
axis control system.
Adrenal gland can have either hyperfunction, hypofunction or tumors.
Hyperfunction is called hyepradrenalism, if there's increased cortisol
Cushing syndrome.
If there's increased aldosterone hyperaldosteronism.
If there's increased androgens adrenogenital syndrome.
Sometimes there's overlap in the hyperfunction of the adrenal cortex, for
example you can get Cushing syndrome with a little bit of hypersecretion of
androgens or with aldosterone.
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Cushing syndrome:
Cushing syndrome features: hyperglycemia -secondary diabetes- (because
steroids are anti-insulin), moonface, central obesity, striae in the abdomen,
weakened bone, osteoporosis, nuchal hump (consists of fat).
*remember: people with acromegaly also have secondary diabetes.
Four major causes for Cushing:
1) ACTH producing adenoma of the pituitary (Cushing disease) high ACTH
level affects both right and left glands this causes bilateral adrenal cortical
hyperplasia
2) Primary adrenal cause; a tumor in the adrenal gland itself like adrenal
cortical adenoma, or bilateral hyperplasia? here the pituitary is normal so
ACTH is suppressed because of high cortisol secretion.
3) paraneoplastic Cushing syndrome especially small cell carcinoma of the
lung which's a grade 4 neuroendocrine carcinoma, it produces ACTH like
material but pituitary here is normal, or it secretes cortisol directly.
4) most common cause is steroid medications, it is iatrogenic (man-induced).
If patient comes with Cushing syndrome features first thing you ask is if the
patient is taking drugs, to rule out the most common cause. Then you start
looking for the other causes.
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Cushing disease and Cushing syndrome: Cushing disease means that the
hyperplasia in the adrenal glands is due to a ACTH secreting tumor in the
pituitary.
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This is hyperplasia and not a
tumor
The color of the adenoma is yellow because it majorly consists of fat (steroids?)
This adenoma has increased cortisol secretion and decreased ACTH, and it appears as
a unilateral mass in the adrenal gland.
It might be an exam question so focus on it.
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Hyperaldosteronism:
- chronic excess of aldosterone secretion. Can be primary or secondary:
- Primary hyperaldosteronism means that the problem is in the adrenal
cortex itself. Happens because of autonomous aldosterone secretion from
gland, which causes suppression of the renin-angiotensin system, so the renin
activity in the serum will be low.
Most common cause of primary hyperaldosteronism: Bilateral idiopathic
hyperaldosteronism. Other causes include neoplasms like Conn syndrome
(adenoma that produces aldosterone) or carcinomas. Hyperaldosteronism can
be familial gene mutations in CYP11B2 (aldosterone synthase gene mutations).
- Hyperaldosteronism causes hypertension, hypokalemia (low K) and
hypernatremia (high Na).
Secondary hyperaldosteronism:
Increased aldosterone releases due to activation of renin-angiotensin system.
It is associated with:
- decreased renal perfusion (arteriolar nephrosclerosis, renal artery stenosis)
-Hypovolemia and edema (because of congestive heart failure, cirrhosis,
nephrotic syndrome)
-can occur in association with pregnancy
Clinically:
Patient appears with hypertension. The most common cause of secondary
hypertension is hyperaldosteronism.
Left ventricular hypertrophy also appears because the heart pumps blood
against decreased peripheral resistance. Patients also might have strokes and
myocardial infarction.
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Hypokalemia (decreased K) in 50% of cases, which may lead to weakness,
parasthesia, visual disturbances and sometimes tetany. Even though normal
blood potassium levels do not rule out hyperaldosteronism.
Treatment: is through surgery for adenomas, and anti-aldosterone agents
like spironolactone for other causes.