Clinical Biochemistry of MSK System

Question 1

What are Biochemical markers of muscle damage?

Answer 1

• Creatine Kinase (CK) - the most widely used, sensitive
• Lactate Dehydrogenase (LDH), myoglobin, AST, Troponin, other enzymes

Question 2

What are some causes of increased CK based on Upper Limit of Normal ULN

Answer 2

• >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)

Question 3

What is Rhabdomyolysis?

• causes (5)

Answer 3

• 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

Question 4

What are the Metabolic causes of Rhabdomyolysis?

Answer 4

• severe hypokalaemia
• Hypophosphataemia
• Malignant hyperpyrexia,
• McArdle disease,
• Phosphofructokinase deficiency

Question 5

What is seen in serology in Rhabdomyolysis cases? (7)

• urine dip?

Answer 5

• 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

Question 6

What is Renal failure in Rhabdomyolysis caused by?

Answer 6

• 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

Question 7

How are the kidney’s protected in rhabdomyolysis?

Answer 7

• 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

Question 8

What biochemical investigations are done for muscle disease?

Answer 8

• 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.)

Question 9

What non-biochemical investigations can be done for muscle disease?

Answer 9

• Histological Studies
• Immunocytochemical studies
• Genetic analyses
• EMG

Question 10

What are the three groups of Metabolic Muscle Disease?

Answer 10

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

Question 11

What are the symptoms of metabolic muscle disease?

Answer 11

• 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

Question 12

What are the key features and causes of Respiratory Chain (Mitochondrial Enzyme deficiencies/myopathies) metabolic muscle disease?

Answer 12

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

Question 13

What are the key features and causes of Carbohydrate metabolic muscle disease?

Answer 13

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)

Question 14

What are the key features of Defects of fatty acid oxidation metabolic muscle disease?

Answer 14

Key features

• Muscle weakness and pain, myoglobinuria, exercise intolerance.
• Symptoms usually present after a prolonged period of exercise.

Question 15

What biochemical abnormalities would be seen in Metabolic muscle disease? (9)

Answer 15

• 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

Question 16

What Clinical investigations would you order in suspected Metabolic Muscle disease?

Answer 16

• Family history, Neurological, Cardiac
• *Gastrointestinal, Ophthalmology, Audiology (*mitochondrial)
  
  • CSF*
    
    • Lactate
• Plasma
  
  • Lactate
  • Creatine kinase
  • Amino Acids
  • Acylcarnitines
  • Free carnitine
• Urine
  
  • Amino acids
  • Organic acids

Question 17

Give 3 Structural Muscle disease Disorders

Answer 17

• Duchenne muscular dystrophy
• Myaesthenia Gravis
• Lambert-Eaton myaesthenic syndrome

Question 18

What is Duchenne Muscular Dystrophy?

• presentation (physical and labs)

Answer 18

• X-linked - dystrophin gene
• Proximal weakness, Progressive
• Gower’s sign, hypertrophy, contractures
• Lab - very high CK, biopsy, genetic tests

Question 19

What is Myasthenia Gravis?

• cause

Answer 19

• Weakness, easy tiring
• Especially cranial nerves
  
  • diplopia and ptosis
• Due to antibodies AChR at the synapse
• Occurs in young women OR a/w thymoma

Question 20

What is Lambert-Eaton myasthenic syndrome?

• cause

Answer 20

• Antibodies against the presynaptic voltage-gated calcium channels
• Rare paraneoplastic

Question 21

How are DMARDs- methotrexate monitored?

• why is monitoring important

Answer 21

• 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

Question 22

How are Immunosuppressant –azathioprine monitored?

• why is monitoring important

Answer 22

• 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.

Question 23

What are bone turnover markers?

Answer 23

• 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

Question 24

What is CTX?

• monitoring importance?

Answer 24

• CTX (carboxy-terminal collagen crosslinks):
• Specific and sensitive indicator of bone resorption, low if anti-resorptive agents e.g. bisphosphonate are working

Question 25

What is P1NP? - monitoring importance?

Answer 25

* P1NP (procollagen type I terminal peptide): * Bone formation marker, * a fairly good marker of osteogenesis (higher being better).

Question 26

How is biochemistry involved in Osteoporosis diagnosis and management? - what other investigations are done?

Answer 26

_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

Question 27

What are the broad categories of secondary causes of Osteoporosis?

Answer 27

- Endocrine - Malignancy - Connective Tissue Disease - Drugs - Gastro-intestinal

Question 28

What are Gastrointestinal causes of Osteoporosis? (4)

Answer 28

* Gastrointestinal disease * Chronic liver disease – PBC * Chronic Renal Failure * Post Organ Transplant

Question 29

What Drugs cause Osteoporosis? | (4)

Answer 29

* Glucocorticoids * Alcohol * Heparin * Anticonvulsants

Question 30

What Connective Tissues diseases cause Osteoporosis? (4)

Answer 30

* Osteogenesis imperfecta * Marfan’s syndrome * Ehlers Danlos syndrome * Homocystinuria

Question 31

What are Malignancy causes of Osteoporosis? (4)

Answer 31

* Myeloma * Mastocytosis * Lymphoma * Leukaemia

Question 32

What are Endocrine causes of Osteoporosis? (4)

Answer 32

* 1° and 2° Hypogonadism * Thyrotoxicosis * Hyperparathyroidism * Cushing’s Syndrome

Question 33

What is the clinical significance of Urate? - what is it/ how does it behave - pathologies?

Answer 33

* 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

Question 34

How is Uric Acid generated? - important enzymes in treatment?

Answer 34

* *Xanthine oxidase* converts Hypoxanthine to Xanthine which forms uric acid * this can be inhibited by **Allopurinol** and **Febuxostat**

Question 35

What is the clinical presentation of Osteomalacia? - causes (4)

Answer 35

* Malaise, Bone pain, Proximal muscle weakness/myopathy * Alk phosphatase raised, [Ca2+] low/N, [PO42-] low/N * Looser zones in X-rays

Question 36

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

Answer 36

Question 37

What are other differentials for Osteomalacia?

Answer 37

* 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

Question 38

What is Paget's Disease?

Answer 38

* 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%

Question 39

What are the Features of Paget's Disease?

Answer 39

* Bone pain * Bone enlargement / deformity * Degenerative joint disease * Fractures * Auditory complications * Neurological complications * Immobilisation hypercalcaemia * High output cardiac failure (multifactorial)

Question 40

What is the relation between Hypothyroidism and Muscle pathologies?

Answer 40

* 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