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
Give 3 Structural Muscle disease Disorders
- Duchenne muscular dystrophy
- Myaesthenia Gravis
- Lambert-Eaton myaesthenic syndrome
What is Duchenne Muscular Dystrophy?
- presentation (physical and labs)
- X-linked - dystrophin gene
- Proximal weakness, Progressive
- Gower’s sign, hypertrophy, contractures
- Lab - very high CK, biopsy, genetic tests
What is Myasthenia Gravis?
- cause
- Weakness, easy tiring
- Especially cranial nerves
- diplopia and ptosis
- Due to antibodies AChR at the synapse
- Occurs in young women OR a/w thymoma
What is Lambert-Eaton myasthenic syndrome?
- cause
- Antibodies against the presynaptic voltage-gated calcium channels
- Rare paraneoplastic
How are DMARDs- methotrexate monitored?
- why is monitoring important
- PIIINP (type III procollagen peptide) is a marker of liver fibrosis and serial measurements can indicate need for a liver biopsy in those on long term methotrexate
How are Immunosuppressant –azathioprine monitored?
- why is monitoring important
- TPMT (thiopurine methyl transferase) metabolises azathioprine to 6-methylxanthine (inactive)
- Thiopurines are also metabolites of azathioprine that are myelotoxic. If levels low you use a lower dose.
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
What is CTX?
- monitoring importance?
- CTX (carboxy-terminal collagen crosslinks):
- Specific and sensitive indicator of bone resorption, low if anti-resorptive agents e.g. bisphosphonate are working
What is P1NP?
- monitoring importance?
- P1NP (procollagen type I terminal peptide):
- Bone formation marker,
- a fairly good marker of osteogenesis (higher being better).
How is biochemistry involved in Osteoporosis diagnosis and management?
- what other investigations are done?
Laboratory investigations
- FBC, ESR, Creatinine, U & E, LFT ,s, Ca, P, TFT, PTH, 25(OH)D
- Bone turnover markers (formation and resorption)
- If secondary causes suspected
- Gonadotrophins, testosterone, oestrogen
- SPE, U-BJ/light chains etc, Coeliac screen, urine calcium, tryptase (systemic mastocytosis)
- Radiology: DEXA, XR
What are the broad categories of secondary causes of Osteoporosis?
- Endocrine
- Malignancy
- Connective Tissue Disease
- Drugs
- Gastro-intestinal
What are Gastrointestinal causes of Osteoporosis?
(4)
- Gastrointestinal disease
- Chronic liver disease – PBC
- Chronic Renal Failure
- Post Organ Transplant
What Drugs cause Osteoporosis?
(4)
- Glucocorticoids
- Alcohol
- Heparin
- Anticonvulsants
What Connective Tissues diseases cause Osteoporosis?
(4)
- Osteogenesis imperfecta
- Marfan’s syndrome
- Ehlers Danlos syndrome
- Homocystinuria
What are Malignancy causes of Osteoporosis?
(4)
- Myeloma
- Mastocytosis
- Lymphoma
- Leukaemia
What are Endocrine causes of Osteoporosis?
(4)
- 1° and 2° Hypogonadism
- Thyrotoxicosis
- Hyperparathyroidism
- Cushing’s Syndrome
What is the clinical significance of Urate?
- what is it/ how does it behave
- pathologies?
- Urate is a by-product of purine metabolism but can precipitate out in soft tissues, kidneys (renal stones) and joints (gout inflammation caused by monosodium urate crystals)
- Solubility decreased by low pH, and lower temperatures and affected by the concentration of other ions
- Also some IMD (inherited metabolic diseases) of purine metabolism
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
What are other differentials for Osteomalacia?
- Other metabolic bone disease: Osteoporosis / PTH bone disease / Neoplastic
- Proximal muscle weakness: PMR, Muscular dystrophy
- Bone pain: Paget’s, Rheumatological, Leukaemia, Myeloma
- Unexplained fractures: Osteoporosis, Paget’s disease
- Psychological illness
What is Paget’s Disease?
- Focal disorder of bone remodelling, unknown cause
- Characterised by
- Accelerated bone turnover
- Initiated by increased osteoclast mediated resorption
- Abnormal bone remodelling – weakened, disorganised, enlarged
- Monostotic / polyostotic: pelvis, femur, tibia, skull, spine
- Malignant complications: Sarcoma <1%
What are the Features of Paget’s Disease?
- Bone pain
- Bone enlargement / deformity
- Degenerative joint disease
- Fractures
- Auditory complications
- Neurological complications
- Immobilisation hypercalcaemia
- High output cardiac failure (multifactorial)
What is the relation between Hypothyroidism and Muscle pathologies?
- Muscle conditions/symptoms with hypothyroidism are common (30-80%) – usually myalgia, weakness, cramps, fatigability and stiffness.
- Get delay in tendon reflexes, proximal muscle weakness and rarely hypertrophy (legs, tongue).
- CK 10-100*normal, no correlation to weakness. Rhabdomyolysis is rare.
- Replacing thyroid hormones should reverse the condition
- so if they present with hypercholesterolaemia always rule out hyperthyroidism as treating that would reverse the effects
- rare syndromic presentation
- Kocher-Debré-Sémélaigne syndrome; called Herculean appearance in children
