Module 7

Microangiopathy
 Objective

• To enumerate the micro-vascular complications of diabetes mellitus and

discuss their pathogenesis.
• To detect and manage various types of diabetic retinopathies.
• To detect and mange diabetic nephropathy.
• To detect and manage various types of diabetic neuropathies.
 Introduction to chronic complications of
diabetes mellitus
• Diabetes mellitus is a chronic, debilitating disease, which is associated with a range
of severe complications. Diabetes mellitus as a disease has earned its importance
by its widespread complications. Chronic complications produce changes in small
or large vessels of the body.
Microangiopathy
capillaries are
Micro-vascular affected
complications
Two types
Macroangiopathy
bigger vessels are
Macro-vascular affected
complications
 Risk factor to develop micro- and macro-
angiopathies
Hyperglycemia is the principle Magnitude and pattern of Complications may be present at

Time
principle risk factor

risk factor to develop micro- and complications are changing with detection of diabetes.
macro-angiopathiesin a diabetic time. During pre-insulin era, life Routine/annual health check-up
individuals. Both the lesions expectancy was very short due programs pick up significant of
result in organ acute metabolic complications, diabetic subjects with chronic
dysfunctions. Early detection of like ketoacidosis. However, with complications.
these angiopathies and the discovery of insulin and
meticulous management to subsequently other drugs, lives Many studies namely DCCT (in
prevent complications is the of diabetic patients have been T1DM), and UKPDS and
major challenge of diabetic care. prolonged, exposing the patients ADVANCE (in T2DM), have
to chronic complications, some shown that the morbidity as well
of which may lead to premature as mortality risks associated with
death or considerable morbidity diabetes can be reduced by
treating to its targets
 Risk factor to develop microangiopathies
Microangiopathies of DM strongly related to both Genetic susceptibility to

Status of glycemic control

( blood glucose or HbA1c):
Duration of diabetes

Other factors
generally increase with micro and certain complications may
duration of diabetes. macroangiopathies of be present.
• In type1 DM they are rarely seen diabetes. Age may be related to some
before 5-7 years. Microangiopathies
occurs usually after 10 years or Numerous studies have complications.
more. proved that good control of Hypertension and
• T2DM people often have a long blood glucose reduces the dyslipidemia are the two
undiagnosed period and therefore rate of development of
significant proportions may have very important modifiable
one or more microangiopathies at complications. factors in the development
diagnosis of diabetes. their
prevalence increases with duration But some diabetics do not of both micro and
of diabetes seem to be affected by macroangiopathies in a
complications regardless of diabetic person.
their duration or metabolic
control.

All these factors should be taken into account during prevention and treatment of complications
 Mechanism of microangiopathy
Increased glycation leading to 1. Capillary basement

Overall effects
to Hyperglycemia

of Hyperglycemia
Changes due

accumulation of basement membrane

collagen and membrane leakiness. membrane thickening
Stimulation of intracellular polyol 2. Protein leakage
pathway (with production of sorbitol)
leading to basement membrane and 3. Micro thrombus formation
capillary endothelial cell damage.
4. Tissue ischemia
Accumulation of a number of other
chemical substances, e.g. Advanced
Glycocylation End products (AGEs),
free radicals etc

Micro-vascular complications/ Diabetic micro-angiopathy: proposed mechanisms ( by Hyperglycamia)

 Organ affected by microangiopathy

Kidneys- Eyes- Peripheral nerves-

• leads to nephropathy • leads to retinopathy • leads to neuropathy

All together TRIPATHY

 Diabetic retinopathy (DR)
It is a specific form of micro-angiopathy of retina with one or more of the following lesions:

Microaneurysm

New
vessel
formation
Haemorrhage

Exudate

Early changes may be asymptomatic, but later may even lead to blindness.
Diabetic retinopathy is the leading cause of blindness.
Some degree of retinopathy is evident after 30 years in 87-98% T1DM and after 15 years in 60 - 85% of T2DM
 Diagnosis and classification of DR
It is done on the basis of findings of

Fundoscopy Stereoscopic Fluorescein

color fundus angiography
photography
 Diagnosis and classification of DR
It is done on the basis of findings of

Disc: 1. margins sharp, 2. color: yellowish orange

to creamy pink, 3. shape: round or oval, 4. Cup 1. Blood vessels will have normal shape and size,
to disc ratio: < .5. 2. No blockages or leaks in the vessels.
Vessels: 1. AV ratio, 2. AV crossing: no
indentation, 3. No arterial light reflex
Fundus background: 1. No exudates or
hemorrhages, 2. color : red to purplish
Macula: 1. macula is located 2.5 disc distance
temporal to disc, 2. no vessels are noted around
Macula, 3. it may be slightly pigmented
 Classification of Diabetic retinopathy (DR)
Classification of Diabetic retinopathy is on the basis of the lesions that are documented in eye examination.
Lesions in an advance or severe class of DR may or may not have the lesion(s) of preceding class.
For example PDR = Lesion(s) of PDR (+Lesion(s) of NPDR)

Class of DR Description/ Lesions

1. Microaneurysm
Early Non-proliferative diabetic retinopaty (NPDR) 2. Dot & blot haemorrhage
3. Hard exudates
1. Cotton wool spots/soft exudates
Moderate to severe NPDR 2. Venous beads & loops
3. Intra-Retinal Microvascular Abnormalities (IRMA)
1. Neovascularization of Disc - NVD
2. Neovascularization of elswere - NVE
Proliferative diabetic retinopaty (PDR)
3. Vitreous haemorrhage
4. Tractional retinal detachment
Maculopathy Oedema, exudate or haemorrhage in and around the macula
Lesions in different class of DR
Lesions in different class of DR
Lesions in different class of DR
Lesions in different class of DR
 Evaluation of DR
Evaluation schedule/indication Evaluation process
1. Visual acuity, cataract etc.
Routine examination
2. Direct ophthalmoscopy
If media is hazyand when peripheral
1. Indirect ophthalmoscopy
lesions are anticipated
For document of haemorrhage,
1. Fundus drawing
exudate, oedema and new vessels.
To evaluate:
 Ischemic retinal leakage, 1. Colour fundus photography
 Neovascularization and & Fluorescein angiogram
 Unexplained reduction of vision
Treatment strategies of Diabetic Retinopathy
Treatment modality Description
Good metabolic control reduces incidence of diabetic retinopathy and delays its progression
Metabolic control: significantly. Control of hypertension: It is very important because uncontrolled hypertension
cause rapid progression of diabetic retinopathy

Patient with proliferative diabetic retinopathy are treated by panretinal photocoagulation

Panretinal
with argon laser. In this procedure a series of 1200 to 1600 laser burns of 500 micrometers of
photocoagulation
diameter are applied in the mid-peripheral retina, avoiding macular region. This procedure
(PRP):
reduces the rate of progression to blindness by about 50%

It is done in cases with advanced proliferative diabetic retinopathy. It can often restore useful
Vitrectomy:
vision of eyes that would otherwise be blind.
Drugs, such as, aldose reductase inhibitors are being tried to reduce the progress of diabetic
Pharmacotherapy
retinopathy with variable success.
 Other changes in eye of diabetics
1. Cataract: Premature cataract Snow-flake cataract

Similar to senile cataract; but

changes are accelerated and occurs
prematurely. Very rarely, diabetes
specific ‘snow-flake cataract’ occurs
in young subjects

2. Glaucoma : Secondary glaucoma Rubeosisiridis

Secondary (angle-closure)
glaucoma develops due to blockage
of aqueous flow by new vessels on
anterior surface of iris
(rubeosisiridis).
 Decision making path of Diabetic Retinopathy
Management( 5 steps)
in T2DM at diagnosis and then once a year.
Eye Evaluation in diabetic person
Step 1 in T1DM at diagnosis and after 5 years or earlier.
( Schedule) (when no retinopathy is documented).
Dilated eye examination for
Step 2 Direct Ophthalmoscopy
retinopathy
Documentation & classification of Indirect Ophthalmoscopy,angiogram, fundus
Step 3
retinopathy photo etc.
a. Establish and maintain
 HbA1c <7% ,
Step 4 Care strategies
 Maintain BP<140/80 mm of Hg
b. Look for other micro-angiopathies
Establish joint care if the retinopathy is beyond
Step 5 Referral to ophthalmologist
early NPDR
 Diabetic nephropathy (DN)

DN is a specific form of micro-angiopathy of kidney with hallmarks of:

1. Persistent loss of albumin in urine and
2. Progressive renal insufficiency with or without
3. Hypertension
Diabetic nephropathy is the leading cause of end-stage renal failure(ESRD) in
the world. Approximately 30% of T1DM will eventually develop diabetic
nephropathy. Nephropathy is less common in T2DM (15-20%) than T1DM, but
due to the greater number of T2DM, the majority of patients with ESRD are
T2DM.
 Diagnosis of Diabetic nephropathy (DN)
A diabetic person is diagnosed to have DN upon documenting hall marks of DN. Persistent loss of
albumin in urine and progressive renal insufficiency with or without hypertension are the hall mark of
DN. DN is has a progressive natural history. In early stage it is asymptomatic, which progresses to end
stage renal failure (ESRD) passing through some intermediate stages.

Hallmark Diabetic Nephropathy

A diabetic person with persistent albumin Urinary albumin: > 200 mcg/min or > 3000
1.
loss in urine and mg/day
a. declining Glumerular Filtration Rate (GFR)
2. Progressive renal insufficiency
b. declining Creatinine Clearance Rate (CCR )
3. Hypertension (may or may not be)
Ideally diagnosis of DN depends on documentation of diabetic specific changes in kidney
biopsy material.
 Tests use for DN diagnosis

Test Result/value Remark

< 20 mcg/min or < 30 mg/day =Normal
Urinary Albumin Excretion
1. (UAE)
20 to < 200 mcg/min or 30 to < 300 mg/day = Microalbuminuria
> 200 mcg/min or > 3000 mg/day = Overt proteinuria
EstimetedGlumerular  100 - 130 ml/min/1.73 sq. M for adult male
2. Filtration Rate (eGFR)  90 - 120 ml/min/1.73 sq. Mfor adult female
Cockcroft-Gault formula= (140- Age)xWeigt(in Kg)x contant* /Serum
EstimetedCreatinineClearan Indirect estimation
3 ceRate (eCCR )
Creatinine (in micromol/L). *contant= 1.23 for men & 1.04 for women.
GFR
Normal value: 97 to 137 mL/min for male and 88 to 128 mL/min for female
Albumin-Creatinine Ration
4 (ACR)
Normal value: <30 microgram/mg ( It mathes with Microalbuminuria) Prefered method
Glumerular size increased, basement membrane thicken, mesangial Reserve for specifc
5 Kidney Biopsy
proliferation, glumerular sclerosis (Kimmelstiel-Wilson lesion) etc. cases.
 Staging of diabetic nephropathy
It is an essential step in management. There are two commonly use system of staging of diabetic
nephropathy
a. GFR based staging and
b. combining GFR , UAE Rate, BP and Histological changes together ( adopted from Mogensen).

Stages of DN / CKD by GFR

Stage Description GFR (ml/minute)
1 Renal damage + Normal/raised GFR > 90
2 Renal damage + mild decreased GFR 60 to 89
3 Moderately decreased GFR 30 to 59
4 Severely decreased GFR 15 to 29
5 Kidney failure < 15 or on dialysis
 Staging of diabetic nephropathy
It is an essential step in management. There are two commonly use system of staging of diabetic
nephropathy
a. GFR based staging and
b. combining GFR , UAE Rate, BP and Histological changes together ( adopted from Mogensen).

UAE
Stage BP GFR Histology
(mcg/min)
1: Hyperfiltration < 20 Normal Increased by 20 - 50% Increased Glumerular size
2.Normoalbuminuria < 20 Normal Increased Basemen Membrane (BM) thickening
Normal/ele Still high, but start BM thickening with
3: Microalbuminuria 20 - <200
vated declining mesengialproliferation
4: Overt prtienuria > 200 Elevated Reduced Pronounced &progressive abnormalities.
 Renal Function evaluation in DM
Structured evaluation strategies for prevention and early detection of complication in diabetes care
protocol has brighten the dream of complication life for people with diabetes.
Renal function evaluation is one of the most prioritized issue in diabetic management.
Tests Schedule
Full clinical check-up, specially blood pressure,
1. during each visit
pedal oedema etc
2. UAE Two of three samples of UAE abnormal in 3-6 months
If UAE abnormal or at least once in every year (Otherwise screening and
Blood urea, creatinine, protein, electrolytes,
3. follow-up with only urine albumin will miss> 20% of progressive renal
eGFR, CCr and ACR estimation.
disease).
Monitoring of other urinary complications e.g. If bladder dysfunction (autonomic bladder) etc or at least once in every 6/ 12
4.
UTI months
Monitoring by sonography-kidney size,
5. If DN present at least once in every 6 months of advise of neprologist.
progressive increase in echogenicity of cortex.
Indicated in nephropathy
 in absence of retinopathy,
6. Renal biopsy
 heavy proteinuria,
 rapid unexplained deterioration of renal function etc
 Treatment of DN
Good metabolic control reduces incidence of diabetic
1. Metabolic control
nephropathy and delays its progression significantly.

Uncontrolled hypertension causes rapid progression of Target of BP is <140/80 mm of Hg.

Control of diabetic nephropathy and Nephropathy itself makes Intensive and combination regimens are often neded.
2.
hypertension hypertension refractory to antihypertensive drugs. thus ACE inhibitors and ARBs are drugs of first choice to reduce or revert
necessitates intensive and combination regimens. nephropathy, (these two drugs must not be combined).

Dietary protein Protein intake up to 0.8 gm/kg/day of ideal body weight may
3. Protein restriction is not required in early nephropathy.
restriction be appropriate in advanced kidney disease.

Fluid and
4.
electrolyte balance

Iron supplementation often fails to correct anaemia in renal

Treatment of
5. failure. Iron along with erythropoietin provide optimum
anaemia
response.

Renal replacement therapy includes dialysis and renal transplantation.

Should start earlier (CCr 15 ml/ min unlike 10 ml/min in non-
 Dialysis comprises haemodialysis and peritoneal dialysis
Renal replacement diabetic) because most patients with ESRD have severe
6. (intermittent or continuous ambulatory peritoneal dialysis).
therapy: organ involvement and fluid overload are often difficult to
 Renal transplantation comprises only kidney transplantation and
treat.
dual transplantation of pancreas with kidney.
 Decision making path of Diabetic
Nephropathy Management( 5 steps)
in T2DM at diagnosis and then once a year.
Kidney Evaluation in diabetic
Step 1 in T1DM at diagnosis and after 5 years or earlier.
person ( Schedule) (when no nephropathytinopathy is documented).
Step 2 Screening tests Urinary albumin and serum creatinine
Documentation &
a. eGFR, CCr and ACR estimation.
Step 3 classification/staging of
b. Ultra sonogram, biopsy (if indicated)
nephropathy
a. Establish and maintain
 HbA1c <7% ,
Step 4 Care strategies
 Maintain BP<140/80 mm of Hg
b. Look for other micro-angiopathies
Establish joint care if the nephropathy at list at CKD
Step 5 Referral to nephrologist
stage 4
 Diabetic neuropathy
Diabetic neuropathy is descriptive term that denotes demonstrable (either clinical or sub-clinical)
evidence of peripheral or autonomic neuropathy in a diabetic individual.
Diabetic polyneuropathy is the most common neuropathy. Approximately 50% of patients with diabetes
eventually develops neuropathy

1. Chronic/insudious sensory 1.Gastroparesis

neuropathy
Somatic

Autonomic
neuropathy

neuropathy 2. Diabetic diarrhoea

2. Acute painful neuropathy 3. Impotence ( in male)
and Diabetic amyotrophy
4. Gustatory Sweating
3. Diffuse motor neuropathy
5. Neurogenic Bladder
4. Focal neuropathies
6. Impaired Cardiovascular
reflexes
 Diabetic neuropathy (Somatic )

Progressive development of Usually unilateral amyotrophy

2. Acute painful
neuropathy and
diabetic amyotrophy
sensory neuropathy
1. Chronic/insidious

unpleasant sensations Severe muscle wasting may

Pain and hyperaesthesia in lead to severe weight loss
legs and feet No sensory loss
Associated muscle wasting These often begin during
and autonomic dysfunctions hyperglycemia; may improve
are common on strict control of blood
glucose
 Diabetic neuropathy (Somatic)

Severe, generalized muscle Occur due to pressure damage

3. Diffuse motor
neuropathy

4. Focal
neuropathies
wasting and weakness or vascular damage.
No pain or sensory loss Examples Pressure damage –
Recovery is poor median nerve, common
peroneal nerve
Examples Vascular damage – III,
IV VI, VII nerve palsies, phrenic
and thoracic nerve palsies
 Diabetic neuropathy (Autonomic)
1. Gastroparesis
Delayed emptying or retention of gastric contents may lead to nausea, vomiting, abdominal discomfort.
2. Diabetic diarrhoea
Delayed emptying or retention of gastric contents may lead to nausea, vomiting, abdominal discomfort.
3. Impotence (in male)
Diabetes is responsible for about 15% cases of total number of impotence. It may be combination of
neuropathy and vasculopathy.
4. Gustatory sweating
Profuse sweating of face during eating
5. Neurogenic bladder
Gradual loss of ability to void urine is the clinical hallmark. Diagnostic confirmation is done
bycystometric abnormality and residual volume. Chronic retention may lead to repeated infection and
renal failure.
6. Impaired cardiovascular reflexes
Orthostatic hypotension and persistent tachycardia result from autonomic neuropathy affecting
cardiovascular reflexes.
 Evaluation of neuropathyh
[Clinical evaluation]
Upto 50% of diabetic Symptoms & signs

symptomatic
asymptomatic

polyneuropathies are Through neurological

asymptomatic examination

Plus exclusion of
a. Lumber root disease
b. Peripheral vascular disease
c. Non diabetic neuropathy (~ 10%)
 Evaluation of neuropathyh
[Autonomic nerve function test]

Resting Postural Slowing of

3
1

2
tachycardia drop of heart rate <
> 100 systolic 10/min
beats/min pressure > 20 during deep
mmHg breating
(ECG)
 Evaluation of neuropathyh
[Special test]
Nerve action Motor & sensory EMG of intrinsic

3
1

2
potential nerve foot muscles
amplitude conduction may reveal
measurement study reflects partial
represents total fictional status degeneration –
of active nerve of large sign of early
fibres. myelinated diabetic
fibres. neuropathy.
 Evaluation of neuropathyh
[Special test]
Electro Vibration Thermoreceptive
4

6
5
diagnostic study threshold study and pain
of motor and by threshold
sensory nerves biothesiometer measurement by
function contact thermos.
Ulner, median,
peroneal, sural N
 Treatment of Painful Diabetic Peripheral
Neuropathy
Metabolic control:
Optimum glycemic control.
For burning pain:
antidepressants e.g. duloxetine, tricyclic anti-depressants etc. or anticonvulsants e.g.
gabapentin, pregabalin, or topical capsaicin etc. are used.
For lancinating pain:
anticonvulsants e.g. carbamazepine, phenytoin or valproate are used.
For painful cramps:
quinine sulfate.
Aldose reductase inhibitors may be used.
Other contributing factors e.g. alcohol. cord lesions, vitamin deficiency, renal failure etc.
should be addressed.
 Treatment of Autonomic Neuropathy
Metabolic control:
Good metabolic control may halt its progression.
For gastroparesis:
erythromycin, metoclopramide, domperidone.
For diarrhoea:
antibiotics, loperamide.
For impotence:
PDES inhibitors.
For neurogenic bladder:
intermittent catheterization, surgery, drug (rarely).
For orthostatic hypotension:
midodrine, mineralocorticoids, elastic stockings, fluid and salt intake, positional adjustments etc.
Supportive measures e.g. physiotherapy.
 Decision making path of Diabetic
Neuropathy Management( 5 steps)
 in T2DM at diagnosis and then once a year.
Detailed neurological
 in T1DM at diagnosis and after 5 years or
Step 1 examination in diabetic person
earlier.
( Schedule)
(when no neuropathy is documented)
Clinical examinations Monofilament, pin-prick,
Step 2 Screening tests
vibration, postural hypotension etc.
Step 3 Evidence of neuropathy with classification
a. Establish and maintain
Step 4 Care strategies  HbA1c <7% , of Hg
b. Look for other micro-angiopathies
Establish joint care if the if the neuropathy is
Step 5 Referral to neurologist
difficult to manage
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