Acute and Chronic Complications of Diabetes Dr. Amel Arnaout.
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Transcript of Acute and Chronic Complications of Diabetes Dr. Amel Arnaout.
Acute and Chronic Complications of Diabetes
Dr. Amel Arnaout
Objectives1. Explain the pathophysiology of diabetic ketoacidosis.
2. Describe the major symptoms, signs and laboratory findings in
diabetic ketoacidosis.
3. Discuss the principles of management for DKA.
4. Describe the pathogenesis of microvascular disease in diabetes.
5. Discuss the mechanisms and clinical effects of macrovascular
disease in diabetes mellitus.
6. Describe the mechanisms & clinical effects of microvascular
disease in diabetes mellitus.
7. Recognize hypoglycemia as an important complication of
diabetes mellitus.
Lecture OutlineAcute Complications
1. Diabetes Ketoacidosis2. Hyperosmotic State3. Hypoglycemia
Chronic Complications1. Microvascular2. Macrovascular
Diabetic ketoacidosis
Diagnostic criteriaHyperglycemia
Glucose >11.1 mmol/l; usually > 15 mmol/l
Metabolic acidosis (increased anion gap)pH < 7.35decreased bicarbonate <15 (best estimation
with venous)
Positive serum ketonesUrine ketones: may be absent in early stages
PrecipitantsInsulin deficiency
new diagnosis OmissionInadequate dosePump failure
Excess counter-regulatory hormones
GHCatecholaminesGlucagonCortisol (stress, infection, MI)
Four “I’s”Insulin DeficiencyIschemiaInfectionIntra-abdominal
process
(30 – 45%)
PathophysiologyInsulin deficiency
↓Decreased peripheral glucose
utilization↓
Increased glucose production↓
Increased ketogenesis
Increased lipolysis in adipocytes↓
Increasead free fatty acids for ketone production
↓Increased glycerol for gluconeogenesis
Excess counter-regulatory hormones
↑↑ insulin resistance
↑↑ ketone production
Increased lipolysis results in the production of acetylCoA from fatty acids which
Acetyl-CoA acts as the substrate for hepatic synthesis of ketone bodies
ACETOACETATE
BETA-HYDROXYBUTYRATE
ACETONE
Wallace T , Matthews D QJM 2004;97:773-780
QJM vol. 97 no. 12 © Association of Physicians 2004; all rights reserved.
Type 1Diabetes
Consequences of DKAHyperglycemiaosmotic diuresis
dehydrationloss of K+, Na+,
HCO3- in urine
hyperosmolar statefree water drawn
into blood hyponatremia, cerebral dehydration decreased level of consciousness
Acidosiscompensatory
respiratory alkalosis
K+ shift but total body K is
low
Calculations for Diagnosis
serum osmolality2 (Na + K) + glucose + BUN
serum Na+for each 10mM ↑in glucose>10, Na+ ↓ by 3
E.g. Glucose 40mmol and Na 130, Na really 139
anion gapNa – (Cl + HCO3)
compensation for metabolic acidosisfor each 1 mmol drop in HCO3, PCO2 should
↓by 1mmHg
Goals of Treatment1. Replace volume loss
2. Stop ketone production
3. Replace K+ loss
4. Lower serum glucose
5. Correct acidosis
Treatment
DKA
CDA Guidelines 2013-Management of Hyperglycemia Emergencies
Hyperosmolar Hyperglycemic State(HHS)
Hyperosmolar non-ketotic state1. Severe hyperglycemia
2. Dehydration
3. Serum hyperosmolality
4. *Lack of significant ketosisit takes less insulin to prevent ketosis than it
does to stop hyperglycemiaif there is some insulin around ketosis will not
occur
Precipitants
1. Stressor - ↑insulin resistance
2. Relative insulin deficiency
3. ↑glucose production, ↓utilization
4. ↓renal excretion of glucose (2˚ to renal disease, aging kidneys)unable to undergo osmotic diuresis : can’t get rid of
glucose through urine, therefore very hyperglycemic
NO KETOSIS
Goals of Treatment -HHS
Summary
METABOLICPRECIPITATING CAUSE OF DKA/HHS
OTHER COMPLICATIONS OF DKA/HHS
• ECFV contraction• Potassium deficit• Metabolic acidosis
caused by ketosis• Hyperosmolality
(water deficit leading to increased corrected sodium concentration plus hyperglycemia)
• New diagnosis of diabetes
• Insulin omission• Infection• Myocardial
infarction• (ECG changes may
reflect hyperkalemia ; A small increase in troponin may occur without overt ischemia )
• Thyrotoxicosis • Drugs
(e.g.antibiotics, steroids)
• Abdominal disease
• Hyper/hypokalemia• ECFV overexpansion• Cerebral edema• Hypoglycemia• Pulmonary emboli• Aspiration• Hypocalcemia (if
phosphate used)• Stroke• Acute renal failure• Deep vein
thrombosis
Hypoglycemia
Hypoglycemia
HYPOGLYCEMIA is defined by:
1.The development of autonomic or neuroglycopenic symptoms
2.Low plasma glucose level (<4.0 mmol/L for patients treated with insulin or an insulin secretagogue)
3.Symptoms responding to the administration of carbohydrate
Hypoglycemia
NON-DIABETIC
Insulin excess insulinoma, postprandial hypoglycemia
Non- insulin mediated Adrenal insufficiency Severe liver disease Malignancy
May be factitious Exogenous insulinOral agents
DIABETIC
Excess InsulinMiscalculation of doseMixed-up insulin
Inadequate oral intakeOverestimate appetiteIllness (nausea/vomiting)gastroparesis
ExerciseIncreased insulin
sensitivityIncreased glucose
utilization
Response to HypoglycemiaADRENERGIC
diaphoresis, tremulous, palpitations etc.
NEUROGLYCOPENICconfused, loss of consciousness,
seizure
HYPOGLYCEMIA UNAWARENESSLack of adrenergic signalsUnaware of hypoglycemia until ↓
LOCRisk of severe reactions that are
unpredictableLoss of drivers license
Risk factors for severe hypoglycemia
Canadian Diabetes Association Guidelines 2013: Hypoglycemia
Prior episode of severe hypoglycemiaCurrent low A1C (<6.0%)Hypoglycemia unawarenessLong duration of insulin therapyAutonomic neuropathyLow economic statusFood insecurityLow health literacyCognitive impairmentAdolescencePreschool-age children unable to detect and/or
treat mild hypoglycemia on their own
Treatment Mild – Moderate Hypoglycemia
15 g glucose in the form of glucose tablets
15 mL (3 teaspoons) or 3 packets of table sugar dissolved in water
175 mL (3/4 cup) of juice or regular soft drink
6 LifeSavers (1 = 2.5 g carbohydrate)
15 mL (1 tablespoon) of honey
Canadian Diabetes Association Guidelines 2013: Hypoglycemia
Diabetes Complications
MACROVASCULAR MICROVASCULAR
Stroke
Heart disease and hypertension
Foot problems
Renal disease
Neuropathy
Foot problems
Diabetes: Chronic Complications
Peripheral vascular disease
Diabetic eye disease(retinopathy and cataracts)
Mechanisms for chronic complications
MICROVASCULAR• Clearly related to blood glucose, but also genetics• Glucose control lowers risk
MACROVASCULAR• Not as clearly related to blood glucose• Other risks
Hypertension Lipids Hyperinsulinemia/insulin resistance Hypercoagulable state etc. Smoking
• Glucose control may lower risk but blood pressure and lipid control also important
Does lowering blood sugar reduce or prevent
complications?
Landmark trialsDiabetes control and complications Trial (DCCT)
Type 1 diabetes (n=1441)
Intensive insulin management (<7% HbA1C) on prevention or progression of microvascular complications
NEJM 1993;329:977-986
Outcomes54-76% reduction
in retinopathy
39-54% reduction in nephropathy
60% reduction in neuropathy
UK Prevention of diabetes study (UKPDS)Type 2 diabetes (n=3867)
Intensive glycemic control (<7% HbA1C)) versus conventional treatment
Outcomes: macrovascular microvascular reduction
www.dtu.ox.ac.uk/ukpds
Risk Reduction in UKPDS with Intensive glucose control
12% for any diabetes related endpointp=0.029
25% for microvascular endpoints p=<0.01
16% for myocardial infarctionp=0.052
24% for cataract extractionp=0.046
21% for retinopathy at twelve yearsp=0.015
33% for albuminuria at twelve years p=<0.01
How does hyperglycemia cause complications?
Mechanisms1. Glucose Metabolic effectsEg. Polyol pathway, glycation of proteins
2. Growth factors/cytokinesEg. Transforming growth factor β, IGF-1, VEGF etc
3. Hemodynamic effectsEg. Nitric oxide, endothelium changes
4. Intracellular effectsEg. Protein kinases
From JAMA 2002;288:2582
Copyright restrictions may apply.
Sheetz, M. J. et al. JAMA 2002;288:2579-2588.
Aldose Reductase Pathway Theory
Glycosylation of protein Non-enzymatic glycosylation
Interaction of glucose with amino groups on proteins ( eg HbA1c) - reversible
Advanced glycosylationlonger-term exposure; correlates with level
of glycemiairreversible changes forms advanced
glycosylation end products (AGE)form cross-links, interact with receptors,
modify cell functions, accumulate, attract macrophages
Copyright restrictions may apply.
Sheetz, M. J. et al. JAMA 2002;288:2579-2588.
Advanced Glycation Endproduct (AGE) Pathway Theory
Increased levels of AGE occurs with:agingsmokingdiabetesrenal disease (AGE accumulate as GFR declines)
AGE crosslinked proteins:Recognized by macrophages that phagocytoze the
crosslinked AGE Induce leaky endotheliumPotent chemotaxic agentPromote growth factor release to make new blood
vessels.Quench nitric oxide
Glycosylation of protein
Reactive Oxygen Intermediate Pathway Theory
Hyperglycemia may increase oxidative stress through both enzymatic and nonenzymatic processes
Increased oxidant stress: reduces nitric oxide levelsdamages cellular proteinspromotes leukocyte adhesion
to the endothelium while inhibiting its barrier function.
Protein Kinase C (PKC)
Alters transcription of genes for:
fibronectintype IV collagencontractile
proteins ECM proteins in
endothelial cells and neurons
Diabetic NephropathyMost common cause of renal failure in North
America
Progressive increase in proteinuria in people with longstanding diabetes followed by declining function that leads to ESRD.
If diagnosed early, progression to end stage renal disease can be stopped
May occur at presentation in type 2 diabetes, not before 5 yrs in type 1 diabetes
Risk Factors
Long duration of diabetes
Poor glycemic control
Hypertension
Male gender
Obesity
Smoking
Structural Changes in glomerulus•Increased ECM•Basement membrane thickening•Mesangial expansion•Fibrosis
Changes lead to leaky filtration membrane• increased filtration of protein• damage to renal tubules and loss of nephrons
Five Stages of Kidney Disease
Stage 1:
•Hyperfiltration -↑ GFR occurs. Kidneys increase in size
Stage 2: •Glomeruli begin to show damage•Microalbuminurea occurs. (Earliest clinical sign of nephropathy)
Stage 3: •eGFR 30-60 ml/min •Albumin excretion > 300 mg/day•Blood pressure rises.
Five Stages of Kidney Disease (con’t.)
Stage 4: •GFR decreases to less than 30 ml/min•large amounts of protein pass into the urine•high blood pressure almost always occurs. •Levels of creatinine and urea-nitrogen in the blood rise further.
Stage 5: •End stage renal disease (ESRD). GFR is less than 15 ml/min.•Average length of time to progress from Stage 1 to Stage 4 kidney disease is 17 years for a person with type 1 diabetes. •The average length of time to progress to Stage 5, kidney failure, is 23 years.
Screening for nephropathyTimed urine
24 hour urine for creatinine clearance, microalbumin, total protein
Gold Standard but cumbersome and not always performed correctly
Random urine albumin/creatinine ratioTest of choiceRequired to be persistently elevatedAt least 2 or 3 urine samples over time
Preventing Development or Progression of Diabetic Nephropathy
Glycemic control
Blood pressureACE inhibitors/ angiotensin receptor blockersEffects of ACEi/ARB reduce risk independent of
effect on BP
Protein restrictionOnly in advanced disease with significant
proteinuria
Diabetic Nephropathy
Test When Normal Range
Blood Pressure1
Each office visit <130/80 mm/Hg
Urinary Albumin1
Type 2: Annually beginning at diagnosis Type 1: Annually, 5-years post-diagnosis
<2.0 mg/mmol (ACR) <30 mg /day (24UFA)
CDA Guidelines 2013
Diabetic RetinopathyThe most common cause of new cases of legal
blindness in people of working age.
Associated with significant morbidity (i.e. falls, hip fractures and 4-fold increase in mortality).
Linked to duration and severity of hyperglycemia
Stagesbackground (non-proliferative)pre-proliferativeproliferative
Background (non-proliferative)Microaneurysms and hemorrhages
↑capillary permeabilityRetinal edema leads to hard exudates (composed of
lipoproteins)
Pre-proliferativeDilated, irregular veinsIntraretinal microvascular changes
small loops of fine vessels danger of burstingHemorrhagic infarct seen as large blot hemorrhageUp to 50% develop proliferative retinopathy
Proliferative Retinal ischemia stimulates proliferation
stimulates vessel growth in retina new vessel do not have the same support and easily
bleeds into surrounding areas Retinal detachment and blindness
Diabetic Retinopathy
Diabetic Neuropathies
1. Polyneuropathy (peripheral, symmetric)May be sensory
and/or motorMay involve small
fibers, large fibers or both
May be chronic (common) or acute (rare)
Longest fibres affected first – “glove and stocking”
Diabetic Neuropathy
2. Mononeuropathyaffects single nerve; less
commoninfarct of nerve (vascular
problem) reversible
3. Entrapment neuropathies (e.g. carpal tunnel syndrome)
4. Autonomic neuropathy
CardiovascularResting sinus tachycardia (fixed heart
rate) Exercise intolerance, “denervated
heart” Orthostatic hypotension
Gastrointestinal Autonomic gastropathy and delayed
gastric emptying Diabetic diarrhea (is uncommon,
usually intermittent)
Genitourinary Erectile impotence Bladder dysfunction (e.g. urinary
retention)
Hammer toesHallux valgusSubluxed MTPRocker bottoms
Diabetic Neuropathies
Pathological Abnormalities Axonal loss Paranodal and Segmental demyelination
Functional Abnormalities: Reduced nerve conduction velocity
(sensory and motor)
Effects on nerves related to fibre length Most distal portions of nerves affected earliest
(distal polyneuropathy)
Macrovascular diseasediabetes ↑ risk of heart disease,
cerebrovascular disease must look at all risk factors
lipidsblood pressuresmokingfamily historyetc
Coronary artery diseaseleading cause of death in Type 2 DMhigh incidence in Type 1 DMoccurs at younger agefrequency of coronary events doubleddeath rate per event doubledcoronary bypass surgery very difficult
(extensive narrowing and occlusions of coronary arteries)
Vascular diseases
Increased frequency of severe peripheral vascular disease with multiple lesions, especially in lower part of body
Ischemic ulcers and amputations in lower extremities occur more frequent than in non-diabetic individuals
“Stroke” (CVA) is more frequent than in non-diabetic individuals
UlcersVascular and neuropathic complications
put people at riskcommon place: balls of feetsubluxation of joints press on joints
deformity skin breakdown can’t feel trauma to the feetcan’t heal properly due to poor vascular
supplydue to neuropathy and peripheral
vascular disease