Download ihd – group c

IHD – GROUP C
Rhabdomyolysis
• Breakdown of muscle fibres  release of
muscle fibre contents into the blood
circulation
• Some of these breakdown products are toxic
to the kidney kidney damage
Rhabdomyolysis
• Myoglobin is released when muscle fibres
breakdown and is filtered by the kidneys
occluding structures of the kidney causing
damage
• Breakdown products of myoglobin are
potentially toxic to the kidney
• Blood flow to the kidney may decrease due
to necrotic tissue
Symptoms of Rhabdomyolysis
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Abnormal urine colour (dark red/cola)
Muscle tenderness
Weakness of the affected muscle
General weakness
Fever, tachycardia, seizures
Myalgia
Potential predisposing factors for
Rhabdomyolysis
• Usually caused by any condition which
causes damage to the skeletal muscle
• Severe exertion eg marathon running
• Ischaemia/necrosis of tissues
• Use/overdose of drugs eg amphetamines
• Trauma
Potential predisposing factors
cont.
• Shaking chills
• Heat intolerance/heat stroke
• Alcoholism (with subsequent muscle
tremors)
• Low phosphate levels
Contents of Muscle Cells
• ENZYMES:
- Creatinine Kinase
- Lactic Dehydrogenase
- Glutamic Oxalacetic Transaminase
- Aldolase
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HEME PIGMENT MYOGLOBIN
ELECTROLYTES: Potassium, Phosphates
PURINES
URIC ACID
Serology
In Rhabdomyolysis shows:
• Hyperkalemia, Hyperphosphatemia
• Early Hypocalcemia + Late Hypercalcemia
• Marked Hyperuricemia
• Elevated BUN and Creatinine
• Elevated Muscle enzymes: Aldolase, Lactate
Dehydrogenase, Hydroxybutyric Acid Aminotransferase,
Creatinine Kinase, Glutamic Oxalacetic Transaminase
Urinalysis
In Rhabdomyolysis, Urinalysis shows:
• Hemoglobin without formed red blood cells
• Elevated Creatinine Phosphokinase >16,000
consistent with renal failure
• Myoglobinuria (75% of patients)
• Proteinuria (40% of patients)
• Elevated AST and ALT
• Elevated Bilirubin
• Normal Alkaline Phosphatase
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CK in Rhabdomyolysis
Most significant clinical marker
Three isoenzymes of CK ( a dimer composed of 2
subunits: brain(B) and muscle (M)
1. BB: 100% brain
2. MB: 20-30% cardiac + 5% muscle
3. MM: 98% muscle
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CK-MM is raised in rhabdomyolysis along with
total
elevation of CK
• Pattern of CK elevation:
Begins 2-12 hours after injury
Peaks in 1-3 days
Declines within 3-5 days.
Test Principle Of Creatinine Kinase
OLIVER & ROSALKI METHOD
An enzyme coupled system, using reverse reaction
The production of NADH is continuously monitored at 340 nm.
CK
Creatine phosphate + ADP  Creatine + ATP
HK
ATP + Glucose  Glucose – 6 P + ADP
G6PDH
Glucose – 6 P + NADP -- Gluconate – 6 – P + NADPH + H+
Equimolar quantities of NADPH and creatine are formed at the same
rate. The photometrically measured rate of formation of NADPH is
proportional to the CK activity.
Test Principle Of CK Isoenzymes
METHOD
USAGE
COMMENTS
Electrophoresis
Frequently
Separates 3 isoenzymes MB,
MM and BB
Immunoinhobition
Rare
Used to detect CK-BB and
macro-CK
Mass assay MB Very Common
Fast and specific for CK-MB
Drugs and hemolysis don’t
interfere
NOW TO EXPLAIN…
• Antibody attached to solid phase which binds B subunit of
CK-MB
• CK-MM in solution cannot bind and is then washed away
• Labelled antibody binds M subunit of CK-MB i.e.
SOLID-AB1-BM-AB2-LABEL
• Remainder labelled antibody washed away, only CK-MB
detected
NB. Label used is usually an enzyme ‘Alkaline Phosphatase’
ELEVATED LEVELS OF CK-ISOENZYMES
CK-MM  muscle disorder or injury, MI
CK-MB  MI, certain other muscle disorders
(Muscular dystrophy, polymyositis)
CK-BB  Not usually detected in plasma
ELEVATED LEVELS OF CK
Large Increase:
• Myocardial infarction
• Shock
• Circulatory failure
• Muscle disorders
(muscular dystrophy,
polymyositis)
• Rhabdomyolysis
Small Increase:
• Muscle injury
• Surgery
• Physical exercise
• Cramp
• Epileptic fit
• Hypothyroidism
Role of enzymes to evaluate liver
function
• Usually, enzymes reside in the liver cells. In
liver damage, these enzymes spill into the
blood stream
• ALT
• AST
• LDH
ALT – Alanine aminotransferasae
• Normal range: 5-40 units per litre of serum
• Found mainly in the liver
• Released in the serum when there is liver
damage
• Fairly specific indicator of liver condition
but not liver disease
AST – Aspartate
aminotransferase
• Normal range: 10-45 units per litre of serum
• Found in liver, heart muscle, kidney, brain
• Released into serum when any of these
organs are damaged
• NOT a specific indicator of liver damage
Test Principle of AST & ALT
• Similar to CK principle
AST
AST
L-Aspartate + α-Ketogluterate <_____> Oxaloacetate + L-Glutamate
maleate deH
Oxaloacetate + NADH <___________> Maleate + NAD+ + H+
ALT
AST
L-Alanine + α-Ketogluterate <_____> Pyruvate + L-Glutamate
lactate deH
Pyruvate + NADH <___________> Lactate + NAD+ + H+
COMMON CAUSES OF PERSISTENTNY ELEVATED
TRANSAMINASE ACTIVITY
HEPATIC CAUSES:
INFORMATIVE TESTS:
Ethanol Abuse
Chronic viral hepatitis
HBV and HCV serologic, molecular studies
Medication
Steatosis (Fatty change)
Non-alcoholic steatohepatitis (NASH)
Hemochromatosis
Autoimmune Hepatitis
Wilson's Disease
Alpha-1-antitrypsin (AAT) deficiency
Serum iron, ferritin, transferrin saturation;
molecular testing for HFE gene mutations
Autoantibody testing
Serum ceruloplasmin; urine copper
Serum protein electrophoresis; AAT
quantitation
NONHEPATIC CAUSES:
Inherited or acquired muscle diseases
Celiac disease
Creatine kinase
Anti-gliadin, anti-endomysial antibodies
Lactic Dehydrogenase - LDH
• Normal range: 110-230 units per litre
• An isoenzyme (protein) that is involved in the
body’s metabolic process (Lactic acid  pyruvic
acid)
• Detect tissue damage and aids in the diagnosis of
liver disease
• Non specific indicator of disease
• Found in heart, liver, kidney, skeletal muscle,
brain, blood cells and lungs
Test Principle of LDH
PYRUVATE to LACTATE
• Most common
• Pyruvate + NADH → Lactate + NAD+
• Rate of disappearance of absorption of
NADH at 340nm measured
ph 7.0
ELEVATED LEVELS OF LDH
Reasons include:
1. Myocardial Infarction
2. Hepatocellular damage
3. Haemolytic and megaloblastic anaemia
4. Skeletal muscle disease
5. Renal impairment
Case Study
• Mr RM takes the following medications on
a regular basis
• Pravastatin 40mg nocte
• Gemfibrozil 600mg BD
• Captopril 25mg BD
• Symptoms: muscle weakness, muscle pain,
brown urine developed over past week
Case study - Chemistry
CK
R1
D1
D2
D3
D4
D5 D6
0-25u/L
38000 36000 3400 300 120 1000
0
00 00 0
CK- 0-7ng/ml 183.6 160.2
MB
ALT 0-50
307
302
AST 0-45
949
526
LDH 0-230
1490
905
187
Potential problems in drug
therapy
• Statins known to cause rhabdomyolyis
• Combination of Pravastatin and
Gemfibrozil increases the risk of
rhabdomyolysis
• Captopril can cause hyperkalaemia and
renal impairment as a side effect
Significance of Dark Urine
• Most tell-tale sign of Rhabdomyolysis
• Result of the release of muscle contents
into the plasma
• Not definitive of Myoglobinuria
Liver Enzymes
• Aspartate aminotransferase (AST) is the most
sensitive marker of the impact of statins and other
dyslipidemic agents.
• Alanine aminotransferase (ALT) is less sensitive to
statin impact. Elevation is lesser than CK and AST
• LFTs are recommended 12 weeks following initiation
of Statin therapy and any dose increase. Liver enzyme
changes generally occur in the first 3 months of
treatment
• If ALT and AST is persistently 3 x higher than ULN
 cease Statin therapy
• Bilirubin is elevated in Rhabdomyolysis
• Alkaline Phosphatase is normal
Treatment
• Removal of causative agent with activated
charcoal
• Enhancing clearance of toxins
• Restoring intravascular volume
• Urinary alkalinization
• Solute diuresis
• Dialysis
Fluid replacement
• Administering large quantities of fluid to
maintain adequate hydration and urinary
output
• Restoring intravascular volume
• Flushing out tubular debris
• Normal saline 1.5L per hour until urinary
output of 300ml/hr
Urinary alkalinization
• Alkalinize urine to pH >6.5 to prevent
dissociation of myoglobin into nephrotoxic
metabolite
• Add sodium bicarbonate to infusion
• BUT: large amount required – metabolic
alkalosis risk
• Not routinely recommended
Diuresis
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Mannitol – potent osmotic diuretic
Increases urine output
Keeps kidney flushed
Prevents formation of casts in tubules
Frusemide can be added to maintain urine
output
Dialysis
• Emergency haemodialysis when kidneys
don’t respond to other interventions
• For the management of :
 oliguria
 acidosis
 uremic encephalopathy
 fluid overload
Future management
• Monitor patient’s serum electrolytes
• Check patient’s lipid levels and
biochemistry
• Cease Gemfibrozil and Pravastatin
• Consider fish oil for elevated TGs
• Consider bile acid binding resin such as
cholestyramine for elevated total cholesterol