10/15- Chronic Complications of Diabetes 1 & 2 Flashcards
1
Q
What are some serious complications of diabetes?
A
- Diabetic retinopathy: leading cause of blindness in working-age adults
- Diabetic nephropathy: leading cause of end-stage renal disease
- Stroke: 2-4x increase in CV mortality and stroke
- CV disease: 80% of diabetic pts die from CV events
- Diabetic neuropathy: leading cause of nontraumatic lower extremity ampuations
2
Q
What causes diabetic retinopathy?
A
Cellular abnormalities resulting from hyperglycemia:
- Increased polyol accumulation, decreased myo-inositol
- Formation of AGEs
- Increased oxidant stress
- Increased protein kinase C – β activity
3
Q
Describe the “Polyol pathway”
A
The reactions deplete NADPH, leading to decreased glutathione synthesis and increased oxygen free radicals
4
Q
Describe the formation of AGEs?
A
- Increased glucose production causing glycosylation of hemoglobin (?)
- Forms reversible Schiff base at first, but over extended amount of time, may get irreversible product
- Used in HbA1c measurements
5
Q
How common is eye disease in diabetics?
A
- Prevalent in ½ of all diabetic patients
- Incidence initially greater in older patients
- Incidence “flattens out” after 25y at ~ 80%
6
Q
Describe the stages of eye disease in diabetics
A
Background:
- Microaneurysms
- “Dot-blot” hemorrhages
- Hard exudates
Pre-proliferative
- Soft exudates
- IRMA
- Large hemorrhages
Proliferative:
- Neovascularization -> pre-retinal/vitreous hemorrhage
- Vitreous fibrosis -> retinal detachment
7
Q
Describe the pathophysiology of retinopathy
A
- Increased epithelial cells and decreased pericytes
8
Q
What is seen here?
A
Normal retina
9
Q
What is seen here?
A
Fairly advanced background retinopathy
- Micro-aneurysms: little red dots
- Micro-hemorrhages
- White spots are lipid deposits from old hemorrhages
10
Q
What is seen here?
A
Even more advanced background retinopathy
- Micro aneurysms
- Exudates WITH additional complication
- Proliferation of vessels with leaked blood
- Fairly acute hemorrhage resulting from blood vessel proliferation
- This is an emergency
11
Q
What is seen here?
A
Neovascularization sitting right over the macula
- Rupture of this would lead to complete blindness
- Needs emergent laser therapy
12
Q
What is seen here?
A
- Multiple hemorrhages have caused fibrosis
- Retina gets stuck to vitreous and vitreous pulls retina off the back of the eye
13
Q
How can you treat diabetic retinopathy?
A
Pan-retinal laser photocoagulation
- Series of controlled burns
- Problem is that hypoxia in the center of the eye and drive of VEGF and vessel proliferation; laser ablation drives blood from periphery to center
14
Q
What is seen here?
A
Eye post-laser photocoagulation
- Laser burns in periphery
- Better appearance centrally
15
Q
What is seen here?
A
Rubeosis Iridis
- Abnormal blood vessels that may be seen in naked eye
16
Q
What are the effects of glycemic control in diabetic retinopathy?
A
Intensive treatment reduced the treatment of:
- First appearance of any retinopathy by 30%
- Severe NPDR, proliferative retinopathy and laser Rx by 50%
- “Clinically meaningful retinopathy” by 30-80%
17
Q
Is kidney disease more common in type I or type II diabetes
A
Type 1 > 2
- Very high morbidity and mortality
18
Q
T/F: Distinct susceptibility genes play a role in kidney disease in diabetics
A
True
- Na/H pump overexpression
- Ethnic differences
- Seen in sibling-pair analysis
19
Q
What is the pathogenesis of kidney disease in diabetes?
- Timeline
A
- Initial hyperfiltration
- Increase in glomerular pressure, GFR, and kidney size
- Glomerulosclerosis and proliferation of mesangium
- Onset of proteinuria, azotemia
- Increased creatinine and eventual end stage renal failure
Timeline from start to symptomatic kidney disease is ~ 15 yrs
20
Q
What test may reflect initial changes of kidney disease in diabetes before they become symptomatic?
A
Micro-albuminemia
- Any amount of protein in the urine means that you’ve stared down the slippery slope of diabetic nephropathy
21
Q
What are the end histological features of diabetic nephropathy?
A
- Thickening of basement membrane
- Mesangial proliferation
- Glomerulosclerosis
- Tubular atrophy
- Interstitial fibrosis and cellular infiltration
22
Q
What is seen here?
A
Left: normal glomerulus
Right: diabetic nephropathy
23
Q
What is seen here?
A
Diabetic nephropathy with ESRD
- Glomerulosclerosis
- Vessels sclerotic
- Urinary space almost gone
24
Q
What treatments may improve survival after treatment of ESRD in diabetes?
A
- Living-related transplant (best)
- Cadaver transplant (Although diabetes will end up destroying new kidneys as well)
- Hemodialysis
25
Describe albuminuria levels
- Normal
- Microalbuminuria
- (Macro)abluminuria
- Normal: under 30 mg/24 hr
- Microalbuminuria: 30-300 mg/24 hr
- (Macro)albuminuria: \> 300 mg/24 hr
26
Macro-albuminuria is associated with what?
Increased risk for:
- Renal failiure
- CV disease
27
How does glycemic control affect nephropathy?
In type I pts, intensive treatment reduced development of:
- MIcroalbuminuria (by 40%)
- Macroalbuminuria (by 50%)
Treat HTN with ACEI...
28
What is the most common chronic complication of diabetes?
Affected nervous system
29
What nervous systems are affected in diabetic retinopathy?
Systems affected:
- Sensory
- Motor
- Cranial
- Autonomic
30
How are nervous system complications classified in diabetic neuropathy?
Classification:
- Symmetric, distal polyneuropathy
- Mononeuropathy (simplex or multiple)
- Radiculopathy
- Autonomic neuropathy
31
Describe the pathophysiology of diabetic neuropathy?
- **Distal**, multiple neuropathies usually **metabolic** (polyol pathway)
- **Proximal**, mononeuropathies usually **vascular**
32
The DCC study focused on what pt cohort?
Type I diabetes
33
Fun fact: within 5 yrs of diagnosis, about half of the patients with type II diabetes had developed some kind of neuropathy
):
34
Classification of diabetic neuropathies: symmetric
- Distal, primarily sensory polyneuropathy
* Mainly large fibers affected
* Mixed\*
* Mainly small fibers affected\*
- Autonomic neuropathy
- Chronically evolving proximal motor neuropathy\* (recovery likely)
* \*Often painful*
35
Classification of diabetic neuropathies: asymmetric
- Acute or subacute proximal motor neuropathy\* (painful)
- Cranial mononeuropathy\*
- Truncal neuropathy\* (painful)
- Entrapment neuropathy in the limbs
* \*Recovery (partial or complete) is likely*
36
What is seen here?
Overactivity of extensors
- Sign of diabetic neuropathy (at least 3-4 yrs)
- At this point, typically have lost sensation as well
37
What test can be done as a (cheap) alternative to nerve conduction test?
Monofilament test
- Press into foot until it just bends
38
What is seen here?
Distal/peripheral symmetric polyneuropathy in hands
- Interossei and lumbricals lost
- Sensation lost as well
39
What is seen here?
Charcot's foot
40
What is seen here?
Splintered tarsal bones and splintered head of metatarsal; Charcot's foot
- Result of very severe symmetric polyneuropathy
- Due to loss of sensation and bone nutrition
41
What is seen here?
- What is causing this? Onset?
Mononeuropathy: wrist drop
- "Mononeuritis simplex"
- Due to radial neuropathy
- Large nerves damaged due to block of BV supplying that nerve
- Acute onset; not much you can do after it happens
42
What is seen here?
Diabetic amyotrophy (or myoatrophy); mononeuritis
- "Mononeuritis multiplex"
- Tremendous wasting of both hamstrings and quadriceps
- Also a large vessel problem (affecting both groups of muscles)
- This would be preceded by tremendous pain (infarction of the muscle)
- At big risk for falls
43
What are some diabetic autonomic neuropathy syndromes?
- **Cardiovascular**:
* Orthostatic hypotension
* Tachycardia
* Sudden death
- **Gastroparesis**
* Vomiting; typically food that was ingested a day before
- **Erectile dysfunction** (have to asked; very rarely volunteered)
* ED is very closely related to CV risks
- **Cystopathy**
* Ask about dribbling or prostatic sort of symptoms in men; sense of incomplete voiding
- **Sudomotor disorders**
* Sweating
**- Hypoglycemia unawareness**
44
How common is ED in diabetes?
- Diabetes results in ED in **50%-75%** of men
- In men with diabetes, the incidence of ED is:
* 9% from age 20 to 29 years
* 95% by age 70
- ED may be the **presenting** symptom of diabetes
- \> 50% of men develop ED within 10 years of diagnosis, and it may precede the other complications of diabetes
45
What are the 4 phases to the arterial pulse and volume change with Valsalva maneuver?
First 3 are sympathetic responses and 4th is parasympathetic
Bedside test will tell you about phase 2 (S) and 4 (PS)
- Normal response in heart rate is sinus arrhythmia
* Deep breathing causes **wide variations** in heart rate
* Bradycardia upon resumption of breathing after Valsalva(?)- PS part of response?
- In diabetic autonomic neuropathy, pt already has **baseline tachycardia**
* **No change** with Valsalva maneuver/deep breathing
46
What are strategies to reduce microvascular complications?
_Prevention_ (proven by intervention trials):
- Hyperglycemia
- HTN
_Treatments_ (proven by intervention trials):
- ACE inhibition for nephropathy
- Laser photcoagulation for retinopathy
47
What is diabetic dermopathy?
- Slightly depressed brownish lesions
- They are **tiny infarcts** in dermis
- May feel slightly painful or itchy
- Sign of long-standing and poorly controlled diabetes
48
What is seen here?
- What commonly accompanies it?
**Necrobiosis Lipoidica Diabeticorum**
- Will see pretty advanced retinopathy with this
- Sign of terribly controlled diabetes with both micro and macrovascular complications
49
What are the macrovascular complications of diabetes?
Diabetes increases the risk of occlusive vascular disease several fold
- **Angina, exercise intolerance** --\> **CAD**
* If autonomic neuropathy, “silent”
* (50% of pts who come into ER with heart attack deny any chest pain, but have had progressive SOB)
- **Claudication** --\> **PVD**
- **TIAs, strokes** --\> **CVA**
- **Renal artery sclerosis** --\> **renal failure**
* First sign of diabetes clinically is micro-albuminemia (?)
50
How does diabetes affect Cardiovascular risk?
Diabetic has:
- **2-3x** higher risk of **CAD**
- **4x** higher risk of **dying** during **acute MI**
- **2x** higher risk of **post-MI death**
- Persons with Impaired Fasting Glucose are also at increased risk of all these implications
Relative to other diabetic complications:
- 80% of all mortality
- Present in 50% of newly diagnosed diabetics
51
HbA1C is predictive of what in Type 2 Diabetes?
HbA1C predicts **CHD** in Type 2 Diabetes
- Other things may be more important:
52
What factors are implicated in macrovascular disease (contributing/mechanistic factors)?
- Hyperglycemia
- Dyslipidemia
- Hypertension
- Insulin resistance
- Obesity/sedentary lifestyle
- Altered coagulation, platelet function, and fibrinolysis
- Nephropathy
- Cigarette smoking (seems to be multiplicative rather than just additive)
53
Describe the pathophysiology of macrovascular lesions in diabetics
- "AGE" of endothelial proteins
- HTN
- Accelerated atherosclerosis
- Dyslipidemia
54
What are some strategies for reducing macrovascular complications?
_Prevention proven by **intervention trials**_
- Dyslipidemia
- Hypertension
- Antiplatelet therapies
_Prevention suggested by **epidemiologic** analysis_
- Disorders of thrombolysis
- Endothelial disorders
55
What is the most easily measured (but not only) aspect of pathophysiology of diabetes and atherosclerosis?
Hyperlipidemia
- Also, dysplipidemia diminishes the risk
56
What are 4 key features of diabetic dyslipidemia?
- **Increased fraction of small, dense LDL-cholesterol** (without increase in total quantity of LDL-C)
- **Decreased HDL-cholesterol**
- **Hypertriglyceridemia**
- **Postprandial lipemia**
57
What are the different types of dyslipidemia?
- Blood tests?
- Symptoms?
**1. High chylomicrons**
- High TGs
- Eruptive xanthomas
**2. High cholesterol** (homo/heterozygous)
- Normal TGs, but high cholesterol, high LDL
- Tendinous xanthomas (large lumps on large tendons)
**3. High interdensity lipoproteins**
- Palmar xanthoma (yellow streaks across palm)
**4. High VLDL**
- Blood appears milky
- Eruptive xanthomas
- Often in 2' disease (diabetes, hyperthyroidism)
**5. High chylomicrons and high VLDL**
- Genetic or acquired
Diabetics get **type 1, 4, or 5** dyslipidemia with **eruptive xanthomas**
58
Describe normal lipoprotein metabolism
_When fasting_, insulin drops
- Hormone sensitive lipase converts TGs to free fatty acids and sent to liver where they are converted into VLDL
- Some converted into IDL and tehn LDL
_When you eat_, insulin rises and inhibits HSL
- Preserves TGs within adipocytes
- Activates lipoprotein lipase (stores circulating TGs in adipose)
59
Describe lipoprotein metabolism in diabetics
No insulin
- Can't restrain lipases
- \> Excess fatty acids, more TG formation, more VLDL
- Insulin prevents/supresses transcription of cholesteryl ester trnasfer protein
- CETP normally takes transfers TGs from VLDL to HDL; without insulin, this is not suppressed and excess transfer actually makes HDL abnormal
60
How should dyslipidemia be managed in pts with diabetes?
- ATP-III diet for Metabolic Syndrome
- Hyper-TG/low HDL-C
* Niacin (may not reduce CV risk; controversial)
* Fibrates
- LDL-C:
* Statins
- Combinations: statins + fibrates (beware rhabdomyolysis)
61
Body type/obesity may also be a risk factor for macrovascular complications. How so?
- Apple-shaped (andrenoid?) (more weight carried above waist) is higher risk vs. pear-shaped (gynecoid?); marker of **visceral obesity and dyslipidemia**
62
What is the biggest predictive factor for risk of diabetes?
Visceral fat distribution
63
How to manage AMI in Diabetes?
- Medical Management
* β-blockers
* ASA
* ACE inhibitors
- Angioplasty vs. bypass (BARI)
* Outcomes are much better with **bypass** than balloon angioplasty or stents (although elusion may get it close) for diabetics!
* Rate of restenosis is really high in diabetics (atherosclerosis, high coagulability...)
- Glucose control (DIGAMI)
* Continuous intravenous insulin infusion
* Followed by intensive glucose control
