0 | P a g e

ظظظ/

-4

-Amera Al- zoubi

-Osama Khader

- Mousa Alabbadi

1 | P a g e

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.

2 | P a g e

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.

3 | P a g e

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.

4 | P a g e

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

5 | P a g e

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.

6 | P a g e

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.

7 | P a g e

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.

8 | P a g e

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.

9 | P a g e

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).

10 | P a g e

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.

11 | P a g e

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.

12 | P a g e

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.

13 | P a g e

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.

14 | P a g e

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.

15 | P a g e

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.