Unexplained Rhabdomyolysis: A Step Too Far

1. Unexplained Rhabdomyolysis: A Step Too Far? Sarah Hatch Senior Clinical Biochemist Royal Liverpool Hospital

2. The Patient 25 year old female student Non-smoker, no alcohol Originally from Zimbabwe (2002) No recent travel (3 years)

3. Presentation A&E Assessment: Loss of appetite Persistent nausea Vomiting 10x daily Weakness and lethargy Lower back pain Mild fever Previously well

4. Initial Examination Temperature 36.7 oC Heart rate 95 beats/min Respiratory rate 14 breaths/min Blood pressure 114/78 mmHg Glasgow coma scale 15/15 Sterno-subcostel pain Radiating to the back Related to standing and walking

5. Previous Medical History Heavy fall down stairs two weeks earlier No loss of consciousness Mild bruising and lower back pain Attended A&E Analgesia Co-codamol 30 mg codeine phosphate 500 mg paracetamol x2 QDS Celecoxib NSAID, COX-2 inhibitor 200 mg OD

6. Biochemistry

7. Acute Renal Failure ? Pre-renal: Secondary to hypovolaemia Persistent vomiting Co-codamol Hepatorenal syndrome ? Intrinsic: Secondary to NSAIDs Celecoxib Sepsis Mild febrile illness Sickle cell anaemia Glomerulonephritis Rhabdomyolysis Injury 2/52 ago, no significant bruising

8. Urinalysis Patient stated no haematuria Output 30 - 50 mL/hour Darkly coloured pH 6.0 Strongly positive for protein (3+) > 3 g/L Strongly positive for blood (3+) Colorimetric detection of peroxidase activity Equally sensitive to haemoglobin and myoglobin Detects red cells

9. Renal ultrasound: echobright kidneys consistent with diffuse parenchymal disease, no obstruction

10. “Add-On” Investigation Acute renal failure secondary to rhabdomyolysis

11. Creatine Kinase 82 kDa dimeric enzyme 2500 U/g protein in skeletal muscle 97 - 99% CK-3 (MM) 1 - 3 % CK-2 (MB) < 1% CK-1 (BB) Non-cardiac source

12. Damage to skeletal muscle may take various forms. Crush injuries damage muscle cells directly, as well as impairing the blood supply; other causes may damage muscle cells by interfering with their metabolism. The muscle tissue rapidly fills with fluid from the bloodstream, as well as sodium and chloride. The swelling itself may lead to destruction of muscle cells, but those cells that survive react by pumping sodium out of the cells in exchange for calcium (through the sodium-calcium exchanger). The accumulation of calcium in the sarcoplasmic reticulum leads to continuous muscle contraction and depletion of ATP (the main source of energy); calcium also stimulates phospholipase A2, and the production of free radicals. In addition, neutrophil granulocytes (the most abundant white blood cells) enter the muscle tissue, perpetuating an inflammatory reaction and releasing further free radicals. A phospholipase is an enzyme that converts phospholipids into fatty acids and other lipophilic substances. Phospholipase A2 - cleaves the SN-2 acyl chain Damage to skeletal muscle may take various forms. Crush injuries damage muscle cells directly, as well as impairing the blood supply; other causes may damage muscle cells by interfering with their metabolism. The muscle tissue rapidly fills with fluid from the bloodstream, as well as sodium and chloride. The swelling itself may lead to destruction of muscle cells, but those cells that survive react by pumping sodium out of the cells in exchange for calcium (through the sodium-calcium exchanger). The accumulation of calcium in the sarcoplasmic reticulum leads to continuous muscle contraction and depletion of ATP (the main source of energy); calcium also stimulates phospholipase A2, and the production of free radicals. In addition, neutrophil granulocytes (the most abundant white blood cells) enter the muscle tissue, perpetuating an inflammatory reaction and releasing further free radicals. A phospholipase is an enzyme that converts phospholipids into fatty acids and other lipophilic substances. Phospholipase A2 - cleaves the SN-2 acyl chain

13. The swollen and inflamed muscle may directly compress structures in the same fascial compartment, causing compartment syndrome. The swelling may also further compromise blood supply into the area. Finally, destroyed muscle cells release potassium, phosphate, myoglobin (a heme and therefore iron-containing protein), creatine kinase (an enzyme) and uric acid (a breakdown product of purines from DNA) into the blood. Activation of the coagulation system may precipitate diffuse intravascular coagulation. High potassium levels (hyperkalemia) may lead to potentially fatal disruptions in heart rhythm. Phosphate precipitates with calcium from the circulation, leading to hypocalcemia (low calcium levels). Compartment syndrome is an acute medical problem following injury or surgery in which increased pressure (usually caused by inflammation) within a confined space (fascial compartment) in the body impairs blood supply,without prompt treatment, leading to nerve damage and muscle death The swollen and inflamed muscle may directly compress structures in the same fascial compartment, causing compartment syndrome. The swelling may also further compromise blood supply into the area. Finally, destroyed muscle cells release potassium, phosphate, myoglobin (a heme and therefore iron-containing protein), creatine kinase (an enzyme) and uric acid (a breakdown product of purines from DNA) into the blood. Activation of the coagulation system may precipitate diffuse intravascular coagulation. High potassium levels (hyperkalemia) may lead to potentially fatal disruptions in heart rhythm. Phosphate precipitates with calcium from the circulation, leading to hypocalcemia (low calcium levels). Compartment syndrome is an acute medical problem following injury or surgery in which increased pressure (usually caused by inflammation) within a confined space (fascial compartment) in the body impairs blood supply,without prompt treatment, leading to nerve damage and muscle death

14. Myoglobin 17.8 kDa haem protein Renal clearance Freely filtered Endocytosis and proteolysis in proximal tubule 0.01 - 5.0 % filtered load in urine Rhabdomyolysis Reabsorption saturated Red-brown discoloured urine Renal damage Obstructive casts formed in acidic conditions Haem toxic to renal tubules Acute tubular necrosis and renal failure The pathophysiology of myoglobinuric ARF has been extensively studied in an animal model of glycerol-induced ARF. The main mechanisms involved are renal vasoconstriction, intraluminal cast formation and direct heme protein-induced cytotoxicity. Renal vasoconstriction is favored by muscle necrosis, which leads to hypovolemia and the activation of cytokines. This increases capillary permeability and the binding of heme protein to nitric oxide: the endothelium relaxing factor. Casts are produced after the filtration of myoglobin through the glomerular basement membrane, which causes water reabsorption and a rise in myoglobin concentration. Following this, in the presence of acidic urine, myoglobin precipitation takes place and causes obstructive cast formation. Dehydration and renal vasoconstriction favor this process, through increased tubule reabsorption of sodium and water, which consequently increases myoglobin concentration in the tubules.The pathophysiology of myoglobinuric ARF has been extensively studied in an animal model of glycerol-induced ARF. The main mechanisms involved are renal vasoconstriction, intraluminal cast formation and direct heme protein-induced cytotoxicity. Renal vasoconstriction is favored by muscle necrosis, which leads to hypovolemia and the activation of cytokines. This increases capillary permeability and the binding of heme protein to nitric oxide: the endothelium relaxing factor. Casts are produced after the filtration of myoglobin through the glomerular basement membrane, which causes water reabsorption and a rise in myoglobin concentration. Following this, in the presence of acidic urine, myoglobin precipitation takes place and causes obstructive cast formation. Dehydration and renal vasoconstriction favor this process, through increased tubule reabsorption of sodium and water, which consequently increases myoglobin concentration in the tubules.

15. Clinical Sequelae Of Rhabdomyolysis Acute renal failure Renal vasoconstriction, acute tubular necrosis Rapid deterioration, slow recovery Falling creatine kinase suggests single acute muscle insult

16. Hyperkalaemia Release of cellular potassium Impaired renal excretion Dialysis withheld

18. Principles Of Management Fluid resuscitation Catherisation Oral and 1.4 % intravenous sodium bicarbonate Maintain urine > pH 7 to prevent tubular precipitation of myoglobin Renal replacement therapy Dialysis Haemofiltration

19. Causes Of Rhabdomyolysis: Differential Diagnosis Physical Direct muscle damage Impaired blood supply Prolonged immobilisation Seizures Electric shock Burns Ischemia or necrosis Extreme exertion Inflammatory Infections Polymyositis Dermatomyositis

20. Final Diagnosis: Inconclusive Minor bruising on buttocks Autoimmune disease negative ANCA and anti-GBM Sickle cell disease negative Haemoglobin electrophoresis Not medication

21. Awaiting Neurological Referral Investigation for underlying metabolic myopathy Glycogen storage disease Type V (McArdles, glycogen phosphorylase) Fatty acid oxidation defect Carnitine-palmitoyl transferase deficiency Mitochondrial defect No background history Exercise intolerance Muscle cramps Discoloured urine

22. Outcome Further investigations Muscle biopsy Electromyography Acyl carnitines Enzyme analysis Possible long-term renal impairment 12 weeks post admission: Creatinine = 58, Urea = 4.3, CK = 124

24. Biochemical Response Relatively slow improvement in plasma glucose. Became hypokalaemic despite K+ supplements. Rehydration slowly decreased Na+, urea, creatinine… Bicarbonate low indicating persistence of underlying acidosis.Relatively slow improvement in plasma glucose. Became hypokalaemic despite K+ supplements. Rehydration slowly decreased Na+, urea, creatinine… Bicarbonate low indicating persistence of underlying acidosis.