IHD – GROUP C

1. IHD – GROUP C

2. 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

3. 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

4. Symptoms of Rhabdomyolysis • Abnormal urine colour (dark red/cola) • Muscle tenderness • Weakness of the affected muscle • General weakness • Fever, tachycardia, seizures • Myalgia

5. 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

6. Potential predisposing factors cont. • Shaking chills • Heat intolerance/heat stroke • Alcoholism (with subsequent muscle tremors) • Low phosphate levels

7. Contents of Muscle Cells • ENZYMES: - Creatinine Kinase - Lactic Dehydrogenase - Glutamic Oxalacetic Transaminase - Aldolase • HEME PIGMENT MYOGLOBIN • ELECTROLYTES:Potassium, Phosphates • PURINES • URIC ACID

8. 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

9. 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

10. 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 • 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.

11. 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.

12. Test Principle Of CK Isoenzymes

13. 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’

14. 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

15. Large Increase: Myocardial infarction Shock Circulatory failure Muscle disorders (muscular dystrophy, polymyositis) Rhabdomyolysis Small Increase: Muscle injury Surgery Physical exercise Cramp Epileptic fit Hypothyroidism ELEVATED LEVELS OF CK

16. 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

17. 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

18. 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

19. 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+

20. COMMON CAUSES OF PERSISTENTNY ELEVATED TRANSAMINASE ACTIVITY

21. 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

22. Test Principle of LDH PYRUVATE to LACTATE • Most commonph 7.0 • Pyruvate + NADH → Lactate + NAD+ • Rate of disappearance of absorption of NADH at 340nm measured

23. ELEVATED LEVELS OF LDH Reasons include: • Myocardial Infarction • Hepatocellular damage • Haemolytic and megaloblastic anaemia • Skeletal muscle disease • Renal impairment

24. 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

25. Case study - Chemistry

26. 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

27. Significance of Dark Urine Most tell-tale sign of Rhabdomyolysis Result of the release of muscle contents into the plasma Not definitive of Myoglobinuria

28. 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

29. Treatment • Removal of causative agent with activated charcoal • Enhancing clearance of toxins • Restoring intravascular volume • Urinary alkalinization • Solute diuresis • Dialysis

30. 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

31. 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

32. Diuresis • Mannitol – potent osmotic diuretic • Increases urine output • Keeps kidney flushed • Prevents formation of casts in tubules • Frusemide can be added to maintain urine output

33. Dialysis • Emergency haemodialysis when kidneys don’t respond to other interventions • For the management of :  oliguria  acidosis • uremic encephalopathy • fluid overload

34. 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