T3 L6 Clinical biochemistry; musculoskeletal system 2.5.23 KS (1).pptx

Clinical Biochemistry; Musculoskeletal System Kate Shipman Consultant Chemical Pathologist Learning outcomes Discuss common metabolic and non-metabolic causes of muscular diseases Discuss bone-turnover markers and their changes in metabolic bone diseases Understand the role of clinical biochemistr...

Clinical Biochemistry; Musculoskeletal System Kate Shipman Consultant Chemical Pathologist Learning outcomes Discuss common metabolic and non-metabolic causes of muscular diseases Discuss bone-turnover markers and their changes in metabolic bone diseases Understand the role of clinical biochemistry tests used to aid diagnosis and management of MSK disorders Understand the role of biochemistry in rheumatological diseases Muscle Disease 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 Some causes of skeletal muscle disease (taken from Marshall Clin Chem) Physical inj./ crush syndrome, ischaemic damage, snake venoms, external statins, steroids, fibrates, chloroquine agents Inflammatio Poly-, dermato-myositis, viral/bacterial, inclusion body n/ myositis Infection Metabolic 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 Terminology in muscle disease Terminolog Definition y Myalgia Pain attributed to muscle, with or without a risk in CK Myotonia Inability of muscle to relax after contraction Myositis Inflammation of muscle, often autoimmune Rhabdomyol Widespread breakdown of muscle fibres ysis with raised CK Myopathy General term to describe any disorder of muscles Marshall Clinical Chemistry 9E 2020 Elsevier Causes of increased CK >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) Rhabdomyolysis • Rapid destruction of striated muscle • Resulting in release of myoglobin and other muscle proteins and intracellular ions into the circulation 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). Causes of rhabdomyolysis • Severe exercise • Injury (trauma, electrocution, crush injuries, surgery) • Ischaemia • Metabolic (severe hypokalaemia or hypophosphataemia, malignant hyperpyrexia, McArdle disease, phosphofructokinase deficiency etc.) • Infections, toxins, drugs Rhabdomyolysis 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 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 concn and tubular 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 – osmotic diuretic – Urine alkalinisation – pHu >8 with bicarb infusion – Early haemofiltration – Note compartment syndrome is another complication of rhabdomyolysis Biochemical investigation of 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.) Myoglobin in urine, not offered anymore, serum CK is more sensitive Other investigations Histological Studies Immunocytochemical studies Genetic analyses EMG 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 metabolism leading to energy depletion or structural damage. Symptoms of Metabolic Muscle Diseases 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 Causes of metabolic muscle disease - 1 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) Causes of metabolic muscle disease -2 Defects of Respiratory Chain (Mitochondrial Enzyme deficiencies/myopathies) Multisystem disorders; very variable. Muscle weakness, exercise intolerance, hearing loss, seizures, ataxia, pigmentary retinopathy, cardiomyopathy Symptoms of Respiratory Chain Disorders: MELAS: mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes 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. Causes of metabolic muscle disease -3 Defects of fatty acid oxidation (Lipid storage disorders) Muscle weakness and pain, myoglobinuria, exercise intolerance. Symptoms usually present after prolonged period of exercise. Biochemical Abnormalities in Metabolic Muscle Diseases Clinical Investigations: • Elevated CK (intermittent) • Elevated troponin • Hypoglycaemia Family history, Neurological, Cardiac *Gastrointestinal, Ophthalmology, Audiology (*mitochondrial) • Abnormal LFTs (may be muscle damage)Plasma Urine CSF* • Myoglobinuria Lactate Amino acids Lactate • Increased plasma lactate Creatine kinase Organic acids • Increased cholesterol & triglycerides Amino Acids • Increased plasma urate Acylcarnitines • Abnormal acylcarnitines Free carnitine Abnormalities may be present only during an attack Structural muscle disease: Duchenne muscular dystrophy X-linked - dystrophin gene Proximal weakness, Progressive Gower sign, hypertrophy, contractures Lab - very high CK, biopsy, genetic tests Compare with fascioscapulohumeral which is benign with later presentation Myaesthenia Gravis Weakness, easy tiring - especially cranial nerves = diplopia and ptosis Due to antibodies AChR Occurs in young women OR a/w Lambert-Eaton myaesthenic thymoma syndrome Antibodies against the presynaptic voltage-gated calcium channels Rare paraneoplastic Rheumatological 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 disease Drug monitoring DMARDs-methotrexate: PIIINP (type III procollagen peptide) marker of liver fibrosis, serial measurements can indicate need for a liver biopsy in those on long term methotrexate. HOWEVER – methotrexate no longer thought to cause liver fibrosis (related to underlying autoimmune conditions or fatty liver). Therefore national guidance (2022) is to replace with FIB4 (calculated value to indicate fibroscan). Drug monitoring Immunosuppressant –azathioprine: TPMT (thiopurine methyl transferase) metabolises azathioprine to 6-methylxanthine (inactive). Thiopurine metabolites of azathioprine are myelotoxic. If enzyme activity low you use a lower dose. NOTE – the commonest mutation worldwide is actually NUDT15 therefore by only screening for TPMT (not both) potentially fatal drug reactions can still occur. NUDT15 is a genetic test so resource issues one reason affecting uptake. Biologic monitoring Infliximab and Adalimumab 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). 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 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: Monitoring therapy, Predicting fracture risk, Malignancy of bone Focus on P1NP and CTX 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). 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 (formation and resorption) –If secondary causes suspected • Gonadotrophins, testosterone, oestrogen • +/- myeloma screen, Coeliac screen, urine calcium, tryptase (systemic mastocytosis) • Radiology: DEXA, XR Secondary Osteoporosis Causes Endocrine Malignanc y Connective Tissue Disease 1° and 2° Hypogonadi sm Myeloma Osteogenesis imperfecta Thyrotoxicos Mastocytos is is Hyperparathyroidism Lymphoma Drugs Misc Glucocortico Gastrointesti ids nal disease Marfan syndrome Alcohol Chronic liver disease – PBC Ehlers Danlos syndrome Heparin Chronic Renal Failure Cushing Leukaemia Homocystinur Anticonvulsa Syndrome ia nts Also immobilisation and disuse atrophy Post Organ Transplant Osteoporosis in clinical chemistry Therapies can be anabolic or anti-resorptive so BTM can support therapy monitoring (BMD – bone mineral density - 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 Gout 1% of adults; aim to get urate <300 µmol/L A/W 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… Urate • Urate is a by-product of purine metabolism but can precipitate 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 pre-eclampsia and premature birth http://www.med.unibs.it/~marchesi/nucmetab.html Generation of Uric Acid Increased production: Cell breakdown, Diet Drugs, Enzyme defects DNA, RNA breakdown & Diet Adenosine Adenosine deaminase Inosine Pi Ribose -1P Guanosine Pi Ribose -1P Purine nucleoside phosphorylase Hypoxanthine Xanthine (more soluble than urate) Xanthine oxidase Uric Acid Allopurinol Febuxostat Guanine Guanase Decreased Excretion: Renal impairment (treatments probenecid & sulphinpyrazone inhibit urate reabsorp in kidney) Vitamin D • 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) Osteomalacia Causes 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 Diagnosis of Osteomalacia Clinically present: • Malaise, Bone pain, Proximal muscle weakness / myopathy • Alk phosphatase raised, [Ca2+] low/N, [PO42-] low/N (L:low, H:high, N: normal, VDR: vit D receptor) • Looser zones in X-rays Cause 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) Ca L L Vit D L N PT H H H L N H Pho other s L H ALP L/H H ALP, L 1,25D L H ALP, H 1,25D Osteomalacia differentials • It is rare, therefore consider differentials: • Other metabolic bone disease: Osteoporosis / PTH bone disease / Neoplastic • Proximal muscle weakness: PMR, Muscular dystrophy • Bone pain: Paget, Rheumatological, Leukaemia, Myeloma • Unexplained fractures: Osteoporosis, Paget Causes of hypophosphataemia Common Causes Less Common Less common cont Respiratory alkalosis Neuroleptic malignant syndrome Cystinosis Infusion of carbohydrate Hungry bone syndrome Wilson disease Parenteral nutrition Heat stroke Monoclonal gammopathy Refeeding syndrome Oncogenic osteomalacia Post hepatic surgery Problem drinking Chronic obstructive pulmonary disease Thyrotoxic periodic paralysis Antacids Gout Rapidly growing tumours DKA Respiratory distress syndrome Septicaemia Severe burns Hypothermia Treatment of pernicious anaemia Paget Disease 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% Paget Disease: Features Asymptomatic Incidental finding on XR / LFT’s with raised ALP Symptomatic Bone pain Bone enlargement / deformity May be Degenerative joint disease complicated by Fractures gout, and is a Auditory complications differential for Neurological complications metastases Immobilisation hypercalcaemia High output cardiac failure (multifactorial) 76 yo female 19/10/20 15 12/1/16 Na 142 AST 22 14/3/16 AST 22 TSH 1.3 Clinical details: SOB, pallor. Is there a unifying diagnosis? 2/11/16 Na 139 AST 90 (5-40) CK 1336 (25-200) TSH 37.5 (0.355) FT4 <5 (9-19) Hypothyroidism and Muscle 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. Kocher-DebréSémélaigne syndrome; called Herculean appearance in children 76 yo female 19/10/201 5 12/1/16 Na 142 AST 22 TSH 1.3 mIU/L 14/3/16 AST 22 2/11/16 Na 139 AST 90 (5-40) CK 1336 (25-200) TSH 37.5 (0.355) FT4 <5 (9-19) Replacing thyroid hormone should reverse the condition. However histological/structural changes may not entirely reverse. Questions? [email protected] Thank You