Clinical Biochemistry of MSK System Flashcards
What are Biochemical markers of muscle damage?
- Creatine Kinase (CK) - the most widely used, sensitive
- Lactate Dehydrogenase (LDH), myoglobin, AST, Troponin, other enzymes
What are some causes of increased CK based on Upper Limit of Normal ULN
- >10 x Upper Limit of Normal (ULN): Often in polymyositis, rhabdomyolysis, Duchenne muscular dystrophy, myocardial infarction
- 5-10 x ULN: Post-surgery, trauma, severe exercise, grand mal convulsion, myositis, carriers of Duchenne muscular dystrophy
- < 5 x ULN: Physiological (related to muscle bulk e.g. weight lifters/athletes), hypothyroidism, drugs (e.g. statins – rare, 1 in 10,000)
What is Rhabdomyolysis?
- causes (5)
- Rapid destruction of striated muscle
- Resulting in release of myoglobin and other muscle proteins and intracellular ions into the circulation
Causes
- Severe exercise
- Injury (trauma, electrocution, crush injuries, surgery)
- Ischaemia
- Metabolic (severe hypokalaemia or hypophosphataemia, malignant hyperpyrexia, McArdle disease, phosphofructokinase deficiency etc.)
- Infections, toxins, drugs
What are the Metabolic causes of Rhabdomyolysis?
- severe hypokalaemia
- Hypophosphataemia
- Malignant hyperpyrexia,
- McArdle disease,
- Phosphofructokinase deficiency
What is seen in serology in Rhabdomyolysis cases? (7)
- urine dip?
- CK >10 x ULN
- Hyperkalaemia
- Hyperuricaemia (from purines, nephrotoxic)
- Hyperphosphataemia
- Hypocalcaemia
- Rise in [creatinine]>[urea]
- Metabolic acidosis (release of lactate and other acids)
- urine dip is positive for peroxidase activity of myoglobin
What is Renal failure in Rhabdomyolysis caused by?
- Hypovolaemia
- Metabolic acidosis (hypovol. release of organic acids)
- Aciduria (causes myoglobin to convert to ferrihaemate, nephrotoxic, and precipitates causing physical obstruction)
- Hyperuricaemia (purine → urate and intrarenal deposition)
- Dehydration increases urine concn. and tubular obstruction by myoglobin casts, uric acid casts products
How are the kidney’s protected in rhabdomyolysis?
- Identify those at risk e.g. older age, higher CK
- Fluid status/BP etc – proactive management of hypovolaemia
- Less common:
- Mannitol – osmotic diuretic
- Urine alkalinisation – pHu >8 with bicarb infusion
- Early haemofiltration
- Note compartment syndrome is another complication of rhabdomyolysis
What biochemical investigations are done for muscle disease?
- Routine biochemical studies
- plasma sodium, potassium, chloride,
- urea, bicarbonate, glucose, calcium, phosphate,
- simple endocrine function tests
- Plasma creatine kinase activity
- Other enzymes (ALT, AST)
- Highly specialised biochemical investigations (carnitine, fatty acids, etc.)
What non-biochemical investigations can be done for muscle disease?
- Histological Studies
- Immunocytochemical studies
- Genetic analyses
- EMG
What are the three groups of Metabolic Muscle Disease?
1- Disorders of Carbohydrate Metabolism
2- Defects of Respiratory Chain (e.g. mitochondrial)
3- Defects of fatty acid oxidation (FAOD)
- they are all to do with energy depletion or structural damage
What are the symptoms of metabolic muscle disease?
- Symptoms vary; most present early in life (infancy to adolescence) and can be mild (exercise intolerance) to fatal:
- Exercise intolerance,
- muscle pain (myalgia) after exercise, cramps,
- muscle damage, myoglobinuria,
- rhabdomyolysis (CK) leading to renal failure,
- proximal muscle weakness,
- hypotonia,
- other organs may be affected e.g. heart, lungs
What are the key features and causes of Respiratory Chain (Mitochondrial Enzyme deficiencies/myopathies) metabolic muscle disease?
Key features
- Multisystem disorders; very variable.
- Muscle weakness, exercise intolerance,
- MELAS: mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes
- hearing loss, seizures, ataxia,
- pigmentary retinopathy,
- cardiomyopathy
Causes
- Maternal inheritance
- MERRF
- Kearns SAYRE
What are the key features and causes of Carbohydrate metabolic muscle disease?
Key features
- Chronic, progressive weakness with atrophy,
- Cardiomegaly, hepatomegaly, macroglossia, respiratory dysfunction
Causes
- Glycogen storage diseases (GSD): e.g.
- McArdle disease (GSD V, myophosphorylase deficiency)
- Pompe (GSD II, a-glucosidase deficiency)
What are the key features of Defects of fatty acid oxidation metabolic muscle disease?
Key features
- Muscle weakness and pain, myoglobinuria, exercise intolerance.
- Symptoms usually present after a prolonged period of exercise.
What biochemical abnormalities would be seen in Metabolic muscle disease? (9)
- Elevated CK (intermittent)
- Elevated troponin
- Hypoglycaemia
- Abnormal LFTs (may be muscle damage)
- Myoglobinuria
- Increased plasma lactate
- Increased cholesterol & triglycerides
- Increased plasma urate
- Abnormal acylcarnitines
- may only be present during an attack
What Clinical investigations would you order in suspected Metabolic Muscle disease?
- Family history, Neurological, Cardiac
- *Gastrointestinal, Ophthalmology, Audiology (*mitochondrial)
-
CSF*
- Lactate
-
CSF*
-
Plasma
- Lactate
- Creatine kinase
- Amino Acids
- Acylcarnitines
- Free carnitine
-
Urine
- Amino acids
- Organic acids
What are bone turnover markers?
- A plethora, all have pitfalls including enzymes and crosslinks associated with collagen etc.
- Serum CTX and urinary NTX: osteolysis
- Serum bone ALP and PINP: osteogenesis
How is Uric Acid generated?
- important enzymes in treatment?
-
Xanthine oxidase converts Hypoxanthine to Xanthine which forms uric acid
- this can be inhibited by Allopurinol and Febuxostat
What is the clinical presentation of Osteomalacia?
- causes (4)
- Malaise, Bone pain, Proximal muscle weakness/myopathy
- Alk phosphatase raised, [Ca2+] low/N, [PO42-] low/N
- Looser zones in X-rays
What is the biochemical presentation of the following causes of Osteomalacia?
- Vit D Deficiency
- Low 1,25 D (renal failure, Vit D dependent Rickets type I = mutated 1alpha hydroxylase)
- Vit D dependent Rickets Type II (mutation in VDR)
- Low phosphate
