Clinical Biochemistry; Musculoskeletal System Flashcards
1
Q
Muscle Disease
- Skeletal muscle can be affected by several diseases e.g. …, inflammation, metabolic … (genetic/acquired), non-metabolic … etc.
- Biochemical Markers of muscle damage:
- Creatine Kinase (CK) - the … … used, s…
- Lactate … (LDH), myoglobin, AST, Troponin, other enzymes
A
- Skeletal muscle can be affected by several diseases e.g. trauma, inflammation, metabolic myopathies (genetic/acquired), non-metabolic myopathies etc.
- Biochemical Markers of muscle damage:
- Creatine Kinase (CK) - the most widely used, sensitive
- Lactate Dehydrogenase (LDH), myoglobin, AST, Troponin, other enzymes
2
Q
What is the main biochemical marker of muscle damage?
A
- Creatine Kinase (CK) - the most widely used, sensitive
- Others include: Lactate Dehydrogenase (LDH), myoglobin, AST, Troponin, other enzymes
3
Q
Why is Creatine Kinase (CK) the main biomarker of muscle damaged?
A
the most widely used, sensitive
4
Q
Some causes of skeletal muscle disease (taken from Marshall Clin Chem)
A
5
Q
Physical inj./ external agents - Causes of skeletal muscle diseases (7)
A
- Crush syndrome
- Ischaemic damage
- Snake venoms
- Statins
- Steroids
- Fibrates
- Chloroquine
6
Q
Inflam/Infection - Causes of skeletal muscle disease
A
- Poly-, dermato-myositis, viral/bacterial, inclusion body myositis
7
Q
Metabolic - Causes of Skeletal Muscle diseases
- Assoc. with endocrine diseases: hypo/hyper…, hyper…, acro…
- Genetic: ,,, metab. dis.( e.g. phosphorylase def.), fatty acid … dis. (acyl- CoA dehydrogenase def.), … chain dis. (mitochondrial dis.)
- Other: C…, ethanol, nutritional
A
- Assoc. with endocrine diseases: hypo/hyperthyroidism, hyperadrenalism, acromegaly
- Genetic: carbohydrate metab. dis.( e.g. phosphorylase def.), fatty acid oxidation dis. (acyl- CoA dehydrogenase def.), respiratory chain dis. (mitochondrial dis.)
- Other: CKD, ethanol, nutritional
8
Q
Non-metabolic (genetic) - Causes of Skeletal Muscle Diseases
- Muscular …
- D…
- Becker … dystrophies
- Periodic … (hyper & hypokalaemic)
A
- Muscular dystrophies
- Duchenne
- Becker myotonic dystrophies
- Periodic paralyses (hyper & hypokalaemic)
9
Q
Other causes of skeletal muscle diseases include myopathy associated with … disease
A
myopathy associated with malignant disease
10
Q
Terminology in muscle disease
A
11
Q
Terminology in muscle disease
A
dystrophy - progressive abnormality
12
Q
dystrophy - … abnormality
A
dystrophy - progressive abnormality
13
Q
Causes of increased CK
- >… x Upper Limit of Normal (ULN) : Often in polymyositis, rhabdomyolysis, Duchenne muscular dystrophy, myocardial infarction
- …-… x ULN: Post-surgery, trauma, severe exercise, grand mal convulsion, myositis, carriers of Duchenne muscular dystrophy
- < … x ULN: Physiological (related to muscle bulk e.g. weight lifters/athletes), hypothyroidism, drugs (e.g. statins – rare, 1 in 10,000)
A
- >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)
14
Q
Causes of increased CK
- >10 x Upper Limit of Normal (ULN) : Often in polymyositis, rhabdomyolysis, … muscular dystrophy, … infarction
- 5-10 x ULN: Post-…, trauma, severe …, grand … convulsion, myositis, carriers of … muscular dystrophy
- < 5 x ULN: Physiological (related to muscle bulk e.g. weight lifters/athletes), …thyroidism, drugs (e.g. … – rare, 1 in 10,000)
A
- >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)
15
Q
Causes of increased CK
- >10 x Upper Limit of Normal (ULN) : Often in poly…, …myolysis, Duchenne muscular dystrophy, myocardial infarction
- 5-10 x ULN: Post-surgery, t…, severe exercise, g… m… convulsion, myositis, carriers of Duchenne muscular dystrophy
- < 5 x ULN: Physiological (related to … … e.g. weight lifters/athletes), hypothyroidism, drugs (e.g. statins – rare, 1 in 10,000)
A
- >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)
16
Q
Causes of increased CK
- >.. x Upper Limit of Normal (ULN) : Often in polymyositis, rhabdomyolysis, Duchenne muscular dystrophy, myocardial infarction
- 5-… x ULN: Post-surgery, trauma, severe exercise, grand mal …, myositis, carriers of …
- < 5 x ULN: … (related to muscle bulk e.g. weight lifters/athletes), hypothyroidism, drugs (e.g. statins – rare, 1 in 10,000)
A
- >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)
17
Q
What is Rhabdomyolysis?
A
Rhabdomyolysis is rapid destruction of striated muscle resulting in release of myoglobin and other muscle proteins and intracellular ions into the circulation
18
Q
Rhabdomyolysis is rapid … of … muscle resulting in release of … and other muscle proteins and intracellular ions into the circulation
A
Rhabdomyolysis is rapid destruction of striated muscle resulting in release of myoglobin and other muscle proteins and intracellular ions into the circulation
19
Q
Skeletal muscle consists …% of body weight.
A
Skeletal muscle consists 40% of body weight.
20
Q
Skeletal muscle consists …% of body weight. Therefore loss of integrity of cell membranes (reversible or irreversible) has a huge potential for loss of … (into muscle cells), potassium, phosphate, enzymes, proteins, and purines (into ECF).
A
Skeletal muscle consists 40% of body weight. Therefore loss of integrity of cell membranes (reversible or irreversible) has a huge potential for loss of water (into muscle cells), potassium, phosphate, enzymes, proteins, and purines (into ECF).
21
Q
Causes of rhabdomyolysis
- Severe …
- … (trauma, electrocution, crush injuries, surgery)
- I…
- … (severe hypokalaemia or hypophosphataemia, malignant hyperpyrexia, McArdle disease, phosphofructokinase deficiency etc.)
- Infections, T…, drugs
A
- Severe exercise
- Injury (trauma, electrocution, crush injuries, surgery)
- Ischaemia
- Metabolic (severe hypokalaemia or hypophosphataemia, malignant hyperpyrexia, McArdle disease, phosphofructokinase deficiency etc.)
- Infections, toxins, drugs
22
Q
Causes of rhabdomyolysis
- … exercise
- Injury (trauma, E…, C… injuries, surgery)
- Ischaemia
- Metabolic (severe ….kalaemia or hypophosphataemia, malignant hyperpyrexia, McArdle disease, phosphofructokinase deficiency etc.)
- Infections, toxins, D..
A
- Severe exercise
- Injury (trauma, electrocution, crush injuries, surgery)
- Ischaemia
- Metabolic (severe hypokalaemia or hypophosphataemia, malignant hyperpyrexia, McArdle disease, phosphofructokinase deficiency etc.)
- Infections, toxins, drugs
23
Q
Rhabdomyolysis
- Serum:
- CK >… x ULN
- …kalaemia
- …uricaemia (from purines, nephrotoxic)
- …phosphataemia
- …calcaemia
- Rise in [creatinine]>[…]
- Metabolic acidosis (release of lactate and other acids)
- Urine dip positive for peroxidase activity of myoglobulin
A
-
Serum:
- 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 positive for peroxidase activity of myoglobulin
24
Q
Rhabdomyolysis
- Serum:
- … >10 x ULN
- Hyperkalaemia
- Hyperuricaemia (from P…, nephrotoxic)
- Hyperphosphataemia
- Hypocalcaemia
- Rise in […]>[urea]
- … acidosis (release of lactate and other acids)
- Urine dip positive for peroxidase activity of myoglobulin
A
- Serum:
- 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 positive for peroxidase activity of myoglobulin
25
_Rhabdomyolysis_
* Serum:
* CK \>10 x ULN
* Hyperkalaemia
* Hyper... (from purines, nephrotoxic)
* Hyperphosphataemia
* Hypo...
* ... in [creatinine]\>[urea]
* Metabolic acidosis (release of lactate and other acids)
* Urine dip ... for peroxidase activity of myoglobulin
* Serum:
* 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 **positive** for peroxidase activity of myoglobulin
26
_Rhabdomyolysis_
* Serum:
* CK \>... x ULN
* Hyperkalaemia
* Hyperuricaemia (from purines, nephrotoxic)
* Hyperphosphataemia
* Hypocalcaemia
* Rise in [creatinine]\>[urea]
* Metabolic acidosis (release of ... and other acids)
* Urine dip positive for ... activity of ...
* Serum:
* 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 positive for **peroxidase** activity of **myoglobulin**
27
_Renal failure in rhabdomyolysis_
* Myoglobin is NOT directly ... but renal failure in rhabdomyolysis caused by:
* Hypovolaemia
* Metabolic ... (hypovol., release of organic acids)
* ...uria (causes myoglobin to convert to ferrihaemate, nephrotoxic, and precipitates causing physical obstruction)
* ...uricaemia (purine → urate and intrarenal deposition)
* ... increases urine concn and tubular obstruction by myoglobin casts, uric acid casts products
* Myoglobin is NOT directly **nephrotoxic** but 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
28
_Renal failure in rhabdomyolysis_
* ... is NOT directly nephrotoxic but renal failure in rhabdomyolysis caused by:
* Hypov...
* ... acidosis (hypovol., release of organic acids)
* Aciduria (causes myoglobin to convert to ferrihaemate, nephrotoxic, and precipitates causing physical obstruction)
* Hyperuricaemia (... → urate and intrarenal deposition)
* Dehydration increases urine concn and tubular obstruction by myoglobin casts, uric acid casts products
* **Myoglobin** is NOT directly nephrotoxic but 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
29
_Renal failure in rhabdomyolysis_
* Myoglobin is NOT directly ... but renal failure in rhabdomyolysis caused by:
* Hypovolaemia
* Metabolic acidosis (hypovol., release of ... acids)
* Aciduria (causes myoglobin to convert to ferrihaemate, nephrotoxic, and precipitates causing ... obstruction)
* Hyperuricaemia (purine → ... and intrarenal deposition)
* Dehydration increases urine concn and tubular obstruction by myoglobin casts, uric acid casts products
* Myoglobin is NOT directly **nephrotoxic** but 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
30
_Renal failure in rhabdomyolysis_
* Myoglobin is NOT directly nephrotoxic but 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 ... and tubular ... by myoglobin casts, uric acid casts products
* Myoglobin is NOT directly nephrotoxic but 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
31
_Renal protection in rhabdomyolysis_
* Identify those at risk e.g. ... age, higher ...
* Fluid status/BP etc – proactive management of hypovolaemia
* Less common:
* Mannitol – osmotic ...
* Urine alkalinisation – pHu \>8 with bicarb infusion
* Early haemofiltration
* Note compartment syndrome is another complication of 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
32
_Renal protection in rhabdomyolysis_
* Identify those at risk e.g. older age, higher CK
* Fluid status/BP etc – proactive management of hypovolaemia
* Less common:
* m... – osmotic diuretic
* Urine alkalinisation – pHu \>... with bicarb infusion
* Early haemo...
* Note ... syndrome is another complication of 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
33
_Renal protection in rhabdomyolysis_
* Identify those at risk e.g. ... age, higher CK
* ... status/... etc – proactive management of hypo...
* Less common:
* Mannitol – osmotic diuretic
* Urine alkalinisation – pHu \>8 with bicarb infusion
* Early haemofiltration
* Note compartment syndrome is another complication of 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
34
_Renal protection in rhabdomyolysis_
* Identify those at risk e.g. older age, higher CK
* Fluid status/BP etc – proactive management of hypovolaemia
* Less common:
* Mannitol – .. diuretic
* Urine ... – pHu \>8 with bicarb infusion
* ... haemofiltration
* Note ... syndrome is another complication of 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
35
_Biochemical investigation of muscle disease_
* Routine ... studies (plasma s..., p..., chloride, urea, bicarbonate, glucose, calcium, phosphate, simple endocrine function tests)
* Plasma creatine kinase activity
* [Other enzymes (ALT, AST)]
* ... in urine, not offered anymore, serum CK is more ...
* Highly ... biochemical investigations (carnitine, fatty acids, etc.)
* Routine **biochemical** studies (plasma **sodium**, **potassium**, chloride, urea, bicarbonate, glucose, calcium, phosphate, simple endocrine function tests)
* Plasma creatine kinase activity
* [Other enzymes (ALT, AST)]
* **Myoglobin** in urine, not offered anymore, serum CK is more **sensitive**
* Highly **specialised** biochemical investigations (carnitine, fatty acids, etc.)
36
_Biochemical investigation of muscle disease_
* Routine biochemical studies (plasma sodium, potassium, c..., u..., bicarbonate, glucose, calcium, phosphate, simple endocrine function tests)
* Plasma ... ... activity
* [Other enzymes (ALT, AST)]
* ... in urine, not offered anymore, serum CK is more ...
* Highly ... biochemical investigations (carnitine, fatty acids, etc.)
* Routine biochemical studies (plasma sodium, potassium, **chloride, urea,** bicarbonate, glucose, calcium, phosphate, simple endocrine function tests)
* Plasma **creatine kinase** activity
* [Other enzymes (ALT, AST)]
* **Myoglobin** in urine, not offered anymore, serum CK is more **sensitive**
* Highly **specialised** biochemical investigations (carnitine, fatty acids, etc.)
37
Other investigations for muscle disease (4)
* **Histological Studies**
* **Immunocytochemical studies**
* **Genetic analyses**
* **EMG**
38
_Metabolic Muscle Diseases_
* 1-Disorders of ... Metabolism
* 2-Defects of ... Chain (e.g. mitochondrial)
* 3-Defects of ... ... oxidation (FAOD)
* Defects are in enzymes involved in muscle metabolism leading to energy depletion or structural damage.
* 1-Disorders of **Carbohydrate** Metabolism
* 2-Defects of **Respiratory** Chain (e.g. mitochondrial)
* 3-Defects of **fatty acid** oxidation (FAOD)
* Defects are in enzymes involved in muscle metabolism leading to energy depletion or structural damage.
39
_Metabolic Muscle Diseases_
* 1-Disorders of Carbohydrate Metabolism
* 2-Defects of Respiratory Chain (e.g. mitochondrial)
* 3-Defects of fatty acid oxidation (FAOD)
* Defects are in enzymes involved in muscle ... leading to energy ... or ... damage.
* 1-Disorders of Carbohydrate Metabolism
* 2-Defects of Respiratory Chain (e.g. mitochondrial)
* 3-Defects of fatty acid oxidation (FAOD)
* Defects are in enzymes involved in muscle **metabolism** leading to energy **depletion** or **structural** damage.
40
_Symptoms of Metabolic Muscle Diseases_
* Symptoms vary; most present ... in life (... to ..) and can be mild (... intolerance) to fatal:
* Exercise intolerance, muscle pain (...) after exercise, cramps, muscle damage, myoglobinuria, rhabdomyolysis (..) leading to renal failure, proximal muscle weakness, ...tonia, other organs may be affected e.g. heart, lungs
* 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
41
_Causes of metabolic muscle disease - 1_
* Disorders of Carbohydrate Metabolism
* Chronic, ... weakness with atrophy, cardio..., hepato...y, macroglossia, respiratory dysfunction
* -Glycogen storage diseases (GSD): e.g. M... disease (GSD V, myophosphorylase deficiency) Pompe (GSD II, a-glucosidase deficiency)
* Disorders of Carbohydrate Metabolism
* Chronic, **progressive** weakness with atrophy, **cardiomegaly, hepatomegaly,** macroglossia, respiratory dysfunction
* -Glycogen storage diseases (GSD): e.g. **McArdle** disease (GSD V, myophosphorylase deficiency) Pompe (GSD II, a-glucosidase deficiency)
42
_Causes of metabolic muscle disease - 1_
* Disorders of Carbohydrate Metabolism
* Chronic, progressive weakness with a..., cardiomegaly, hepatomegaly, macroglossia, r... dysfunction
* -... ... diseases (GSD): e.g. McArdle disease (GSD V, myophosphorylase deficiency) P.. (GSD II, a-glucosidase deficiency)
* Disorders of Carbohydrate Metabolism
* Chronic, progressive weakness with **atrophy**, cardiomegaly, hepatomegaly, macroglossia, **respiratory** dysfunction
* **-Glycogen storage** diseases (GSD): e.g. McArdle disease (GSD V, myophosphorylase deficiency) **Pompe** (GSD II, a-glucosidase deficiency)
43
_Causes of metabolic muscle disease - 1_
* Disorders of Carbohydrate Metabolism
* C..., progressive weakness with atrophy, cardiomegaly, hepatomegaly, macro..., respiratory ...
* -Glycogen storage diseases (GSD): e.g. McArdle disease (GSD V, myophosphorylase deficiency) Pompe (GSD II, a-glucosidase deficiency)
* Disorders of Carbohydrate Metabolism
* **Chronic**, progressive weakness with atrophy, cardiomegaly, hepatomegaly, **macroglossia**, respiratory **dysfunction**
* -Glycogen storage diseases (GSD): e.g. McArdle disease (GSD V, myophosphorylase deficiency) Pompe (GSD II, a-glucosidase deficiency)
44
_Causes of metabolic muscle disease -2_
* Defects of ... ... (Mitochondrial Enzyme deficiencies/myopathies)
* ... disorders; very variable. Muscle weakness, exercise intolerance, hearing loss, seizures, ataxia, pigmentary retinopathy, cardiomyopathy
* Defects of **Respiratory Chain** (Mitochondrial Enzyme deficiencies/myopathies)
* **Multisystem** disorders; very variable. Muscle weakness, exercise intolerance, hearing loss, seizures, ataxia, pigmentary retinopathy, cardiomyopathy
45
_Causes of metabolic muscle disease -2_
* Defects of Respiratory Chain (Mitochondrial ... deficiencies/myopathies)
* Multisystem disorders; very .... Muscle ..., exercise ..., ... loss, seizures, ataxia, pigmentary retinopathy, cardio...
* Defects of Respiratory Chain (Mitochondrial **Enzyme** deficiencies/myopathies)
* Multisystem disorders; very variable. **Muscle weakness, exercise intolerance, hearing loss, seizures, ataxia, pigmentary retinopathy, cardiomyopathy**
46
_Symptoms of Respiratory Chain Disorders:
MELAS: mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes_
* Recurrent ...-like episodes, ...-like headaches, V... and S....
* Other symp include: general muscle ..., exercise ..., hearing loss, D... and S... stature. ... inheritance.
* Others include MERRF, Kearns-Sayre.
* **Recurrent stroke-like episodes, migraine-like headaches, vomiting and seizures. Other symp include: general muscle weakness, exercise intolerance, hearing loss, diabetes and short stature. Maternal inheritance. Others include MERRF, Kearns-Sayre.**
47
_Causes of metabolic muscle disease -3_
* Defects of ... ... oxidation (Lipid storage disorders)
* Muscle ... and ..., myoglobinuria, exercise ...
* Symptoms usually present after prolonged period of exercise.
* Defects of **fatty acid** oxidation (Lipid storage disorders)
* Muscle **weakness** and **pain**, myoglobinuria, exercise **intolerance**.
* Symptoms usually present after prolonged period of exercise.
48
_Causes of metabolic muscle disease -3_
* Defects of fatty acid oxidation (... storage disorders)
* Muscle weakness and pain, myoglobinuria, exercise intolerance.
* Symptoms usually present after ... period of ....
* Defects of fatty acid oxidation (**Lipid** storage disorders)
* Muscle weakness and pain, myoglobinuria, exercise intolerance.
* Symptoms usually present after **prolonged period of exercise.**
49
_Biochemical Abnormalities in Metabolic Muscle Diseases_
* Elevated C... (intermittent)
* Elevated T...
* ...glycaemia
* Abnormal L... (may be muscle damage)
* ...globinuria
* Increased plasma L...
* Increased C... & triglycerides
* Increased plasma U...
* A... acylcarnitines
* **Elevated CK (intermittent)**
* **Elevated troponin**
* **Hypoglycaemia**
* **Abnormal LFTs (may be muscle damage)**
* **Myoglobinuria**
* **Increased plasma lactate**
* **Increased cholesterol & triglycerides**
* **Increased plasma urate**
* **Abnormal acylcarnitines**
50
_Biochemical Abnormalities in Metabolic Muscle Diseases - what tests?_
***Abnormalities may be present only during an attack***
51
_Clinical Investigations - Biochemical abnormalities in metabolic muscle diseases_
* ... history, n..., c...
* \*Gastrointestinal, Ophthalmology, a... (\*mitochondrial)
* **Family history, Neurological, Cardiac**
* **\*Gastrointestinal, Ophthalmology, Audiology (\*mitochondrial)**
52
_Structural muscle disease: Duchenne muscular dystrophy_
* ...-linked - dystrophin gene
* ... weakness, Progressive
* ...'s sign, hypertrophy, contractures
* Lab - very high ..., biopsy, genetic tests
* **X-linked** - dystrophin gene
* **Proximal** weakness, Progressive
* **Gower’s** sign, hypertrophy, contractures
* Lab - very high **CK**, biopsy, genetic tests
53
_Structural muscle disease: Duchenne muscular dystrophy_
* X-linked - d... gene
* Proximal w..., p...
* Gower’s sign, hypertrophy, contractures
* Lab - very ... CK, biopsy, genetic tests
* X-linked - **dystrophin** gene
* Proximal **weakness**, **Progressive**
* Gower’s sign, hypertrophy, contractures
* Lab - very **high** CK, biopsy, genetic tests
54
_Myaesthenia Gravis_
* Present with - Weakness, easy ...
* Especially cranial nerves - d.. and p...
* Due to antibodies AChR
* Occurs in young ... OR a/w thymoma
* Present with - Weakness, easy **tiring**
* Especially cranial nerves - **diplopia and ptosis**
* Due to antibodies AChR
* Occurs in young **women** OR a/w thymoma
55
_Myaesthenia Gravis_
* Present with - Weakness, easy tiring
* Especially ... nerves - diplopia and ptosis
* Due to antibodies A...
* Occurs in young women OR a/w t...
* Present with - Weakness, easy tiring
* Especially **cranial** nerves - diplopia and ptosis
* Due to antibodies **AChR**
* Occurs in young women OR a/w **thymoma**
56
_Lambert-Eaton myaesthenic syndrome_
* Antibodies against the pre-synaptic voltage-gated ... channels
* Rare para...
* Antibodies against the pre-synaptic voltage-gated **calcium** channels
* Rare **paraneoplastic**
57
_Rheumatological disease_
* More limited role of biochemistry in rheumatology
* 1. Drug monitoring -DMARDs, Cytotoxic agents, Biologics
* 2. Bone ... markers
* 3. G...
* 4. Vit ...
* 5. P... disease
* More limited role of biochemistry in rheumatology
* 1. Drug monitoring -DMARDs, Cytotoxic agents, Biologics
* **2. Bone turnover markers**
* **3. Gout**
* **4. Vit D**
* **5. Paget’s disease**
58
_Rheumatological disease_
* More limited role of biochemistry in rheumatology
* 1. Drug monitoring -D...s, C... agents, B...
* 2. ... turnover markers
* 3. Gout
* 4. Vit D
* 5. P... disease
* More limited role of biochemistry in rheumatology
* **1. Drug monitoring -DMARDs, Cytotoxic agents, Biologics**
* **2. Bone turnover markers**
* **3. Gout**
* **4. Vit D**
* **5. Paget’s disease**
59
_Drug monitoring_
* DMARDs-m...:
* measure ... is a marker of liver fibrosis and serial measurements can indicate need for a liver biopsy in those on long term methotrexate.
* Immunosuppressant –a...:
* TPMT (thiopurine methyl transferase) metabolises azathioprine to 6-methylxantrhine (inactive). Thiopurines are also metabolites of azathioprine that are myelotoxic. If levels low you use a lower dose
* DMARDs-**methotrexate**:
* **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.
* Immunosuppressant –**azathioprine**:
* TPMT (thiopurine methyl transferase) metabolises azathioprine to 6-methylxantrhine (inactive). Thiopurines are also metabolites of azathioprine that are myelotoxic. If levels low you use a lower dose
60
_Drug monitoring_
* D..-methotrexate:
* PIIINP (type III procollagen peptide) is a marker of liver ... and serial measurements can indicate need for a liver biopsy in those on long term methotrexate.
* I... –azathioprine:
* ... metabolises azathioprine to 6-methylxantrhine (inactive). Thiopurines are also metabolites of azathioprine that are myelotoxic. If levels low you use a ... ...
* **DMARDs**-methotrexate:
* 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.
* **Immunosuppressant** –azathioprine:
* **TPMT** (thiopurine methyl transferase) metabolises azathioprine to 6-methylxantrhine (inactive). Thiopurines are also metabolites of azathioprine that are myelotoxic. If levels low you use a **lower dose**
61
_Biologic monitoring_
* I... and Adalimumab for example
* Levels can be measured and ... to them can be detected.
* Antibodies to these drugs prevent them ....
* These analyses are available but, like TPMT, most of the use is within ... practice not so much in rheumatology (evidence base is in ... primarily).
* **Infliximab** and Adalimumab for example
* Levels can be measured and **antibodies** to them can be detected.
* Antibodies to these drugs prevent them **working**.
* These analyses are available but, like TPMT, most of the use is within **gastroenterology** practice not so much in rheumatology (evidence base is in **gastro** primarily).
62
_Bone Turnover Markers_
* A plethora, all have pitfalls including enzymes and crosslinks associated with C... etc.
* Serum CTX and urinary NTX: osteo...
* Serum bone ALP and PINP: osteo...
* 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**
63
_Features of Bone Turnover Markers (BTM)_
* Performance depends on:
* ... type (... versus urine)
* Marker ...
* Affected by ... (.. contains collagen), exercise, drugs, age, time of day
* Uses include:
* Monitoring therapy
* Predicting fracture risk
* Malignancy of bone
* Performance depends on:
* **Sample** type (**serum** versus urine)
* Marker **type**
* Affected by **nutrition** (**food** contains collagen), exercise, drugs, age, time of day
* Uses include:
* Monitoring therapy
* Predicting fracture risk
* Malignancy of bone
64
_Features of Bone Turnover Markers (BTM)_
* Performance depends on:
* Sample type (serum versus urine)
* Marker type
* Affected by nutrition (food contains collagen), exercise, drugs, age, time of day
* Uses include:
* ... therapy
* Predicting ... risk
* ... of bone
* Performance depends on:
* Sample type (serum versus urine)
* Marker type
* Affected by nutrition (food contains collagen), exercise, drugs, age, time of day
* Uses include:
* **Monitoring therapy**
* **Predicting fracture risk**
* **Malignancy of bone**
65
Uses of bone turnover markers (3)
* **Uses include:**
* **Monitoring therapy**
* **Predicting fracture risk**
* **Malignancy of bone**
66
_Focus on P1NP and CTX (Bone turnover markers)_
* Probably the commonest 2…
* CTX (carboxy-terminal collagen crosslinks):
* Specific and sensitive indicator of bone r..., low if anti-r... agents e.g. bisphosphonate working.
* P1NP (procollagen type I terminal peptide):
* Bone f... marker, fairly good marker of osteo... (higher being better).
* Probably the commonest 2…
* CTX (carboxy-terminal collagen crosslinks):
* Specific and sensitive indicator of bone **resorption**, low if anti-**resorptive** agents e.g. bisphosphonate working.
* P1NP (procollagen type I terminal peptide):
* Bone **formation** marker, fairly good marker of **osteogenesis** (higher being better).
67
_Osteoporosis in clinical chemistry_
* Diagnosis is via:
* ... and ...
* Laboratory investigations
* FBC, ESR, Creatinine, U & E, LFT ,s, Ca, P, TFT, PTH, 25(OH)D
* Bone ... markers (formation and resorption)
* If secondary causes suspected
* G..., testosterone, O..
* SPE, U-BJ/light chains etc, Coeliac screen, urine calcium, tryptase (systemic mastocytosis)
* Radiology: D.., XR
* Diagnosis is via:
* **History and Examination**
* 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
68
_Osteoporosis in clinical chemistry_
* Diagnosis is via:
* History and Examination
* Laboratory investigations
* FBC, ESR, Creatinine, U & E, LFT ,s, Ca, P, TFT, PTH, 25(OH)D
* Bone turnover markers (F... and R...)
* If secondary causes suspected
* Gonadotrophins, ..., ...
* SPE, U-BJ/light chains etc, ... screen, urine ..., tryptase (systemic mastocytosis)
* Radiology: DEXA, XR
* Diagnosis is via:
* History and Examination
* 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
69
_Secondary Osteoporosis Causes_
70
Secondary Osteoporosis Causes
71
Secondary Osteoporosis Causes
72
_Osteoporosis in clinical chemistry_
* Therapies can be A... or Anti... so BTM can support therapy monitoring (BMD not the most dynamic tool but frequency of DEXA can be guided by BTM)
* BTM can tell you about adherence and also help prevent treatment complications e.g. ... by supporting drug ...
* Therapies can be **anabolic or antiresorptive** so BTM can support therapy monitoring (BMD not the most dynamic tool but frequency of DEXA can be guided by BTM)
* BTM can tell you about adherence and also help prevent treatment complications e.g. **osteonecrosis** by supporting drug **holidays**
73
_Osteoporosis in clinical chemistry_
* Therapies can be anabolic or antiresorptive so ... can support therapy monitoring (BMD not the most dynamic tool but frequency of DEXA can be guided by ...)
* ... can tell you about adherence and also help prevent treatment complications e.g. osteonecrosis by supporting drug holidays
* Therapies can be anabolic or antiresorptive so **BTM** can support therapy monitoring (BMD not the most dynamic tool but frequency of DEXA can be guided by **BTM**)
* **BTM** can tell you about adherence and also help prevent treatment complications e.g. osteonecrosis by supporting drug holidays
74
Gout - affects ...% of adults; aim to get urate
Gout - affects **1%** of adults; aim to get urate \<**300** µmol/L
75
_Gout_
* 1% of adults; aim to get urate
* Associated with HTN, insulin resistance, hypercholesterolaemia and acute attacks with alcohol
* Two times more common in ...
* Mono/polyarticular ..., tophi, increase in renal ...
* Secondary causes include ...thyroidism, hyper..., d..., renal impairment etc…
* 1% of adults; aim to get urate \<**300** µmol/L
* Associated with HTN, insulin resistance, hypercholesterolaemia and acute attacks with alcohol
* Two times more common in **men**
* Mono/polyarticular **arthritis**, tophi, increase in renal **stones**
* Secondary causes include **hypothyroidism**, **hyperparathyroidism**, **diuretics**, renal impairment etc…
76
... 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 cystals)
**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 cystals)
77
_Urate_
* Urate is a by-product of ... metabolism but can precipitate out in soft tissues, kidneys (renal ...) and joints (... inflammation caused by monosodium urate ...)
* Solubility decreased by low pH, and lower temperatures and affected by concentration of other ions
* Also some IMD (inherited metabolic diseases) of purine metabolism
* A/W pre... and premature birth
* 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 **cystals**)
* Solubility decreased by low pH, and lower temperatures and affected by concentration of other ions
* Also some IMD (inherited metabolic diseases) of purine metabolism
* A/W **preeclampsia** and premature birth
78
_Urate_
* 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 cystals)
* Solubility decreased by low ..., and lower ... and affected by ... of other ions
* Also some IMD (inherited ... diseases) of purine ...
* A/W preeclampsia and ... birth
* 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 cystals)
* Solubility decreased by low **pH**, and lower **temperatures** and affected by **concentration** of other ions
* Also some IMD (inherited **metabolic** diseases) of purine **metabolism**
* A/W preeclampsia and **premature** birth
79
_Urate_
* 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 ... cystals)
* Solubility ... by low pH, and lower temperatures and affected by concentration of other ions
* Also some IMD (inherited metabolic diseases) of purine metabolism
* A/W preeclampsia and premature birth
* 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** cystals)
* Solubility **decreased** by low pH, and lower temperatures and affected by concentration of other ions
* Also some IMD (inherited metabolic diseases) of purine metabolism
* A/W preeclampsia and premature birth
80
_Urate_
* Urate is a by-product of purine metabolism but can precipitate out in soft tissues, kidneys (renal stones) and joints (gout ... caused by monosodium urate cystals)
* Solubility decreased by low pH, and lower temperatures and affected by concentration of other ions
* Also some IMD (... .... diseases) of purine metabolism
* A/W ... and premature birth
* 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 cystals)
* Solubility decreased by low pH, and lower temperatures and affected by concentration of other ions
* Also some IMD (**inherited metabolic** diseases) of purine metabolism
* A/W **preeclampsia** and premature birth
81
_Generation of Uric Acid_
* A... and F... blocks Xanthine oxidase which converts xanthine to uric acid
* **Allopurinol and Febuxostat** blocks Xanthine oxidase which converts xanthine to uric acid - given as therapy for prevention of gout attacks
82
_Uric acid - Increased production:_
* Cell ..., D...
* D..., E... defects
* **Cell breakdown, Diet**
* **Drugs, Enzyme defects**
83
_Uric acid - Decreased Excretion:_
* Treatments P... & s... inhibit urate reabsorp in kidney
* Treatments **probenecid & sulphinpyrazone** inhibit urate reabsorp in kidney
84
_Vitamin D_
* R... and O...
* Osteomalacia – adult disease
* Delay in mineralisation as osteoid is laid down
* Rickets – paediatric version
* Main skeletal changes affects growing ends of long bone
* ... growth plate
* ... metaphysis
* Proximal myopathy (vitamin D deficient patients)
* **Rickets and osteomalacia**
* Osteomalacia – adult disease
* Delay in mineralisation as osteoid is laid down
* Rickets – paediatric version
* Main skeletal changes affects growing ends of long bone
* **Widened** growth plate
* **Widened** metaphysis
* Proximal myopathy (vitamin D deficient patients)
85
_Vitamin D_
* R... and O...
* Osteo... – adult disease
* Delay in M... as osteoid is laid down
* Rickets – paediatric version
* Main skeletal changes affects growing ends of long bone
* ... growth plate
* ... metaphysis
* Proximal myopathy (vitamin D deficient patients)
* **Rickets and osteomalacia**
* **Osteomalacia** – adult disease
* Delay in **mineralisation** as osteoid is laid down
* Rickets – paediatric version
* Main skeletal changes affects growing ends of long bone
* **Widened** growth plate
* **Widened** metaphysis
* Proximal myopathy (vitamin D deficient patients)
86
_Vitamin D_
* R... and O...
* Osteomalacia – adult disease
* Delay in mineralisation as osteoid is laid down
* Rickets – paediatric version
* Main skeletal changes affects growing ends of ... bone
* ... growth plate
* ... metaphysis
* Proximal myopathy (vitamin D deficient patients)
* **Rickets and osteomalacia**
* Osteomalacia – adult disease
* Delay in mineralisation as osteoid is laid down
* Rickets – paediatric version
* Main skeletal changes affects growing ends of **long** bone
* **Widened** growth plate
* **Widened** metaphysis
* Proximal myopathy (vitamin D deficient patients)
87
_Vitamin D_
* R... and O...
* Osteomalacia – adult disease
* Delay in mineralisation as osteoid is laid down
* Rickets – paediatric version
* Main skeletal changes affects growing ends of long bone
* ... growth plate
* ... metaphysis
* Proximal ... (vitamin D deficient patients)
* **Rickets and osteomalacia**
* Osteomalacia – adult disease
* Delay in mineralisation as osteoid is laid down
* Rickets – paediatric version
* Main skeletal changes affects growing ends of long bone
* **Widened** growth plate
* **Widened** metaphysis
* Proximal **myopathy** (vitamin D deficient patients)
88
_Osteomalacia Causes_
* ... deficiency: Low intake plus inadequate sunlight exposure; Malabsorption
* Abnormal ... ... ...: Liver disease; Renal disease; Drugs (anticonvulsants)
* Low ...: Low intake / Excess losses ; Vitamin D dependent rickets type I and II
* **Vit D** **deficiency**: Low intake plus inadequate sunlight exposure; Malabsorption
* Abnormal **vit D metabolism**: Liver disease; Renal disease; Drugs (anticonvulsants)
* Low **phosphate**: Low intake / Excess losses ; Vitamin D dependent rickets type I and II
89
_Osteomalacia Causes_
* Vit D deficiency: Low intake plus inadequate ... exposure; M...
* Abnormal vit D metabolism: L... disease; R... disease; Drugs (a...)
* Low phosphate: Low intake / Excess losses ; Vitamin D dependent rickets type ... and ...
* Vit D deficiency: Low intake plus inadequate **sunlight** exposure; **Malabsorption**
* Abnormal vit D metabolism: **Liver** disease; **Renal** disease; Drugs (**anticonvulsants**)
* Low phosphate: Low intake / Excess losses ; Vitamin D dependent rickets type **I and II**
90
_Diagnosis of Osteomalacia_
* Clinically present:
* m..., B... pain, Proximal muscle ... / myopathy
* Alk phosphatase raised, [Ca2+] low/N, [PO42-] low/N
* ... zones in X-rays
* (L:low, H:high, N: normal, VDR: vit D receptor)
* Clinically present:
* **Malaise, Bone pain, Proximal muscle weakness** / myopathy
* Alk phosphatase raised, [Ca2+] low/N, [PO42-] low/N
* **Looser** zones in X-rays
* (L:low, H:high, N: normal, VDR: vit D receptor)
91
_Diagnosis of Osteomalacia_
* Clinically present:
* Malaise, Bone pain, Proximal muscle weakness / Myo...
* Alk ... raised, [Ca2+] low/N, [PO42-] low/N
* Looser zones in X-rays
* (L:low, H:high, N: normal, VDR: vit D receptor)
* Clinically present:
* Malaise, Bone pain, Proximal muscle weakness / **myopathy**
* Alk **phosphatase** raised, [Ca2+] low/N, [PO42-] low/N
* Looser zones in X-rays
* (L:low, H:high, N: normal, VDR: vit D receptor)
92
_Osteomalacia differentials_
* It is rare therefore consider differentials:
* Other metabolic bone disease: Osteo... / PTH bone disease / Neoplastic
* Proximal muscle weakness: PMR, Muscular ...
* Bone pain: P..., Rheumatological, L..., Myeloma
* Unexplained fractures: O..., P... disease
* Psychological illness
* **It is rare therefore consider differentials:**
* **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**
93
_Osteomalacia differentials_
* It is rare therefore consider differentials:
* Other metabolic bone disease: Osteoporosis / PTH bone disease / Neoplastic
* Proximal muscle ...: PMR, Muscular dystrophy
* Bone ...: Paget’s, Rheumatological, Leukaemia, Myeloma
* Unexplained ...: Osteoporosis, Paget’s disease
* P... illness
* It is rare therefore consider differentials:
* 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
94
_Osteomalacia differentials_
* It is rare therefore consider differentials:
* Other metabolic bone disease: Osteoporosis / P... bone disease / Neo...
* Proximal muscle weakness: P..., Muscular dystrophy
* Bone pain: Paget’s, r..., Leukaemia, Myeloma
* Unexplained fractures: Osteoporosis, Paget’s disease
* Psychological illness
* It is rare therefore consider differentials:
* 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
95
_Osteomalacia differentials_
* It is rare therefore consider differentials:
* Other ... bone disease: Osteoporosis / PTH bone disease / Neoplastic
* ... muscle weakness: PMR, Muscular dystrophy
* ... ...: Paget’s, Rheumatological, Leukaemia, Myeloma
* ... fractures: Osteoporosis, Paget’s disease
* Psychological illness
* It is rare therefore consider differentials:
* 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
96
_Paget’s Disease_
* 1st described by Sir James Paget in 1876
* Focal disorder of bone R... ?Cause
* Characterised by
* ... bone ...
* Initiated by increased ... mediated resorption
* Abnormal bone remodelling – weakened, disorganised, enlarged
* Monostotic / polyostotic: pelvis, femur, tibia, skull, spine
* Malignant complications: Sarcoma \<1%
* 1st described by Sir James Paget in 1876
* Focal disorder of bone **remodelling**?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%
97
_Paget’s Disease_
* 1st described by Sir James Paget in 1876
* Focal disorder of bone remodelling ?Cause
* Characterised by
* Accelerated bone ...
* Initiated by increased osteoclast mediated resorption
* ... bone remodelling – weakened, d..., e...
* Monostotic / polyostotic: pelvis, femur, tibia, skull, spine
* Malignant complications: S... \<1%
* 1st described by Sir James Paget in 1876
* Focal disorder of bone remodelling ?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%
98
_Paget’s Disease_
* 1st described by Sir James Paget in 1876
* Focal disorder of bone remodelling ?Cause
* Characterised by
* ... bone turnover
* Initiated by increased osteoclast mediated resorption
* Abnormal bone remodelling – W..., disorganised, E...
* Monostotic / polyostotic: pelvis, femur, tibia, skull, spine
* Malignant complications: Sarcoma
* 1st described by Sir James Paget in 1876
* Focal disorder of bone remodelling ?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**%
99
_Paget’s Disease: Features_
* Asymptomatic
* Incidental finding on XR / LFT’s with raised ALP
* Symptomatic
* Bone p...
* Bone e... / d...
* D... joint disease
* F...
* Auditory complications
* Neurological complications
* Immobilisation hypercalcaemia
* High output cardiac failure (multifactorial)
* May be complicated by gout, and is a differential for metastases
* Asymptomatic
* Incidental finding on XR / LFT’s with raised ALP
* Symptomatic
* **Bone pain**
* **Bone enlargement / deformity**
* **Degenerative joint disease**
* **Fractures**
* Auditory complications
* Neurological complications
* Immobilisation hypercalcaemia
* High output cardiac failure (multifactorial)
* May be complicated by gout, and is a differential for metastases
100
_Paget’s Disease: Features_
* Asymptomatic
* Incidental finding on XR / LFT’s with raised ALP
* Symptomatic
* Bone pain
* Bone enlargement / deformity
* Degenerative joint disease
* Fractures
* A... complications
* N... complications
* I... hypercalcaemia
* High output cardiac failure (multifactorial)
* May be complicated by g..., and is a differential for metastases
* Asymptomatic
* Incidental finding on XR / LFT’s with raised ALP
* Symptomatic
* Bone pain
* Bone enlargement / deformity
* Degenerative joint disease
* Fractures
* **Auditory complications**
* **Neurological complications**
* **Immobilisation hypercalcaemia**
* High output cardiac failure (multifactorial)
* May be complicated by **gout**, and is a differential for metastases
101
_Paget’s Disease: Features_
* Asymptomatic
* Incidental finding on XR / LFT’s with raised ALP
* Symptomatic
* Bone pain
* Bone enlargement / deformity
* Degenerative ... disease
* Fractures
* Auditory complications
* Neurological complications
* Immobilisation hyper...
* High output ... failure (multifactorial)
* May be complicated by gout, and is a differential for m...
* Asymptomatic
* Incidental finding on XR / LFT’s with raised ALP
* Symptomatic
* Bone pain
* Bone enlargement / deformity
* Degenerative **joint** disease
* Fractures
* Auditory complications
* Neurological complications
* Immobilisation **hypercalcaemia**
* High output **cardiac** failure (multifactorial)
* May be complicated by gout, and is a differential for **metastases**
102
_Paget’s Disease: Features_
* Asymptomatic
* Incidental finding on ... / LFT’s with raised ...
* Symptomatic
* Bone ...
* Bone ... / deformity
* Degenerative joint disease
* Fractures
* Auditory complications
* Neurological complications
* Immobilisation hypercalcaemia
* High output cardiac failure (multifactorial)
* May be complicated by gout, and is a differential for metastases
* Asymptomatic
* Incidental finding on **XR** / LFT’s with raised **ALP**
* Symptomatic
* Bone **pain**
* Bone **enlargement** / deformity
* Degenerative joint disease
* Fractures
* Auditory complications
* Neurological complications
* Immobilisation hypercalcaemia
* High output cardiac failure (multifactorial)
* May be complicated by gout, and is a differential for metastases
103
_Case study - MSK Biochem_
* What is indicated?
* Hypothyroidism indicated - unifying diagnosis
* 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.
* Also some rare syndromic presentations
104
_Hypothyroidism and Muscle_
* Muscle conditions/symptoms with hypothyroidism are common (30-80%) – usually m..., w..., c..., f... and s....
* Get delay in tendon ..., proximal muscle weakness and rarely hyper... (legs, tongue).
* CK ...-...\*normal, no correlation to weakness. R... is rare.
* Also some rare syndromic presentations
* 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.
* Also some rare syndromic presentations
105
_Kocher-Debré-Sémélaigne syndrome; called Herculean appearance in children._
* Kocher Debre Semelaigne syndrome is a rare condition of muscular pseudohypertrophy and long standing moderate to severe ... in children
* Kocher Debre Semelaigne syndrome is a rare condition of muscular pseudohypertrophy and long standing moderate to severe **hypothyroidism** in children
