Rhabdomyolysis
Approach to evaluation of Rhabdomyolysis
The diagnostic approach to the evaluation of rhabdomyolysis involves:
Step 1: Evaluate for acquired causes of rhabdomyolysis: Alcohol/drugs, medications, metabolic, electrolyte disturbances, endocrine disease, toxic exposures, autoimmune disease.
If this fails the next step is to attempt in categorizing the patient into one of the following 5 groups to help guide subsequent testing for inherited muscle disease:
Glycogen storage disease: In these patients, rhabdomyolysis is often triggered by short periods of intense exercise, often accompanied by pain and cramping; contractures may occur with prolonged strenuous activity or isometric exercise; baseline CK level may be elevated.
Repeated history of second wind phenomena do genetic testing for the PGYM mutations.
Compensated hemolysis: Genetic testing for PF K mutations.
Skin rash and/or uterine stiffness: Genetic testing for LDH a mutation.
Mental retardation and hemolytic anemia: Genetic testing for the PGK mutations.
If no suggestive findings: Muscle biopsy for histochemical and enzymatic testing.
Disorders of fatty acid metabolism: Symptoms of pain and cramping are triggered by prolonged low-to-moderate intensity activity; contractures are not a prominent feature; CK is often normal between episodes.
Acylcarnitine profile
Genetic testing for CPT2 mutations
If no CPT2 mutation: Muscle biopsy for histochemical and enzymatic testing.
Mitochondrial myopathy: Muscle symptoms are triggered soon after exercise and/or after prolonged activity; excessive and early fatigue is a major complaint. The interictal CK level can be normal or abnormal; an elevated lactate level or lactate/pyruvate ratio may be found.
Muscle biopsy for histochemical and enzymatic testing.
Genetic testing for mitochondrial myopathy (specific gene vs panel vs exome).
Consider inherited myopathy such as muscular dystrophy or congenital myopathy.
Muscle biopsy with muscular dystrophy immunohistochemistry.
Genetic testing for RYR1 mutations.
Consider WES or gene panels.
LIPN1 mutation
Children less than 6 years old.
Triggers include fever
CK >10,000
Consider Benign Rhabdomyolysis
Diagnosis of exclusion if recurrent exertional rhabdomyolysis without evidence of inherited myopathy or clear acquired cause after thorough evaluation.
In patients in whom an acquired or intrinsic cause of rhabdomyolysis cannot be easily identified, the physician is faced with the question of the utility and cost of further evaluation (e.g., whole exome sequencing). In general, after a single episode of rhabdomyolysis in which no acquired cause can be identified, I do not necessarily pursue additional testing or muscle biopsy unless there is additional evidence suggesting an inherited muscle disease. However, in the case of recurrent rhabdomyolysis, I pursue genetic testing and/or muscle biopsy. In patients with recurrent rhabdomyolysis with no clear acquired cause or specific clinical features and with normal muscle biopsy and enzymatic testing, I consider gene panels and/or whole exome sequencing. Benign exertional rhabdomyolysis is a diagnosis of exclusion. As clinical genetic testing and whole exome sequencing become more widely available, I expect that additional genetic factors predisposing individuals to recurrent rhabdomyolysis will be identified.
TESTING IN PATIENTS WITH RHABDOMYOLYSIS
CBC, CMP, ESR, ANA, ENA, CK (>5 x nl), aldolase, urine myoglobin, EMG/NCS, muscle biopsy, molecular genetic studies, (molecular genetics/Invitae) PTH, TSH, Vit D, HIV, LFTs including GGT, RA, abnormal serum lactate:pyruvate ratio, forearm exercise test, total carnitine profile, serum acylcarnitine profile (interictal) and if possible (ictal), plasma amino-acids, uric acid, urine organic acids.
Elevation of plasma long-chain acylcarnitine species, particularly C16:0 and C18:1, on mass spectrometry strongly suggests CPT2 deficiency.
Anti-SRP, HMGCR autoantibodies
AChR-abs.
ACQUIRED CAUSES OF RHABDOMYOLYSIS
Definition of rhabdomyolysis: CK levels >5 - 10 x ULN.
Trauma (crush injury), prolonged immobilization, post-surgical ischemia
Protracted vigorous exercise .
Sickle cell trait military recruits were reported to have non-traumatic rhabdomyolysis following vigorous exercise.
Seizures, tetany, neuroleptic malignant syndrome, serotonin syndrome
Hyperthermia: Heat stroke, malignant hyperthermia
Acute or Chronic alcohol intoxication
Illicit substances
Heroin, methamphetamine, cocaine, LSD, alcohol, amphetamines, loxapine, hemlock, mercuric chloride, phencyclidine, strychnine,
Statins (increased risk with hypothyroidism, certain genetic polymorphisms, liver disease, and diabetes)
Risk of statin-triggered myopathy is particularly increased in patients with a single-nucleotide polymorphism located within the SLCO1B1 gene, which encodes organic anion transporting polypeptide 1B1, or OATP1B1 , involved in regulation of hepatic statin uptake.
Statin + fibrates
Statin + CYP450 inhibitors
Statin + DPP-4 Inhibitors
Statin + CYP3A4 inhibitors
Diltiazem/amiodarone/verapamil
Macrolide antibiotics (erythromycin/clarithromycin)
Patients taking statins who were also prescribed the antibiotics clarithromycin or erythromycin were twice as likely to be hospitalized with muscle breakdown, called rhabdomyolysis.
Protease inhibitors
Stiglaglipin and other DPP-4 Inhibitors
Colchicine
Statin+ daptomycin
Statin + fluconazole
Statin + tacrolimus/cyclosporine
Amino-caproic acid
Antidepressants
Tricyclic antidepressants
Venlafaxine
Sertraline
Escitalopram
Antihistamines
Antipsychotics
Aripriprazole
Clozapine
Haloperidol
Olanzapine
Risperidone
Quetiapine
Anti-retrovirals
Tenofovir/abicavir
Raltegravir
Pentamidine
Colchicine
Colchicine + clarithromycin
Colchicine + cyclosporine/tacrolimus
Colchicine in the setting of renal insufficiency (colchicine has renal excretion and thus tends to build up to toxic levels in these set of patients).
Daptomycin
Depakote, lamotrigine
Interferon-a
Lithium
Ofloxacin/levofloxacin
Strychnine
Terbutaline
Propofol, PPI
Neuroleptic malignant syndrome
Metabolic abnormalities
Hypokalemia, hypophosphatemia, hyponatremia, and hypernatremia in the setting of diabetes, thyroid dysfunction, primary hyperaldosteronism, primary adrenal insufficiency, central diabetes insipidus, postpartum hypernatremia, and pituitary dysfunction.
Hypokalemia and hyponatremia in the setting of laxative and diuretic misuse/abuse.
Rhabdomyolysis can be the presenting event in cases of inherited or acquired renal tubular dysfunction with profound hypokalemia, or it can be triggered by illness or discontinuation of medical treatment. These causes can be screened for with serum and urine electrolyte panels and studies of endocrine
Venoms, toxins, pesticides, and poisons
Snake venom can cause rhabdomyolysis
Wasp stings and spider bites
Ingestion of European quail that feed on hemlock seeds.
Haff disease, a rare sporadic syndrome of rhabdomyolysis, develops after eating buffalo fish that are thought to contain an unidentified toxin.
Ingestion of certain mushroom species
Pesticides and chemical poisonings
Autoimmune Myopathies.
Dermatomyositis and polymyositis
Immune-mediated necrotizing myopathy
Antibodies associated with autoimmune necrotizing myopathies (i.e., anti–SRP), anti–HMG-CoA reductase autoantibodies (HMGCR-ab).
Infectious agents
Tetanus, salmonella, legionella, group-A-beta hemolytic, inflluenza, EBV, CMV, HIV, COVID-19, malaria, rickettsial
Miscellaneous
Seizures, DTs, electrocution, lightening strike, excessive exercise in the conditioned. Prolonged dystonia or chore.
Inherited metabolic myopathies
Disorders of Glycogen Metabolism.
Muscle Phosphorylase Deficiency caused by a mutation in the muscle phosphorylase gene PYGM.
Phosphofructokinase Deficiency caused by mutations in the PFKM gene
Phosphoglycerate kinase deficiency X-linked
Muscle Lactate Dehydrogenase Deficiency (LDH) deficiency is a recessive condition caused by mutations in the LDHA gene.
Resting CK levels are usually elevated. After exercise, there is a large increase in CK, but a smaller than expected increase in serum LDH; this biochemical discrepancy is a unique feature of muscle LDH deficiency.
In a patient with rhabdomyolysis in the context of strenuous activity, no second wind phenomenon, presence of a seasonal erythematous rash on extensor surfaces, or uterine stiffness during pregnancy genetic testing for LDH deficiency is suggested.
Muscle Phosphorylase b Kinase Deficiency is associated with mutations in the PHKA1 gene, located on the X chromosome
Phosphoglycerate Kinase Deficiency (PGK) deficiency is an X-linked disorder caused by a mutation in the PGK1 gene, which encodes the enzyme catalyzing the final step in the glycolytic pathway with formation of 3-phosphoglycerate and ATP.
Phosphoglycerate mutase deficiency is caused by a mutation in the PGAM2 gene.
Phosphoglucomutase Deficiency deficiency is an autosomal recessive condition caused by a mutation in the PGM1 gene
Disorders of Fatty Acid Oxidation Associated with Rhabdomyolysis
Carnitine Palmitoyltransferase II Deficiency (CPT2 deficiency)
Elevation of plasma long-chain acylcarnitine species, particularly C16:0 and C18:1, on mass spectrometry strongly suggests CPTII deficiency. Normal C16:0 and C18:1 acylcarnitine levels should not necessarily preclude genetic testing if the clinical suspicion for a CPT2 mutation is high. CK is usually in 6 digits.
Carnitine translocase, acyl-CoA dehydrogenase deficiency (VLCFA, and L-3-hydroxyacyl-CoA dehydrogenase.
Intramitochondrial fatty acid oxidation can be impaired by mutations in the acyl-coenzyme A dehydrogenases.
The most commonly described is very-long-chain acyl-coenzyme A dehydrogenase deficiency (VLCAD)
CK is very high in 6 digits.
Mitochondrial Myopathies Associated with Rhabdomyolysis: Patients may have associated cardiomyopathy, endocrinopathy, ophthalmoparesis/plegia, pigmentary retinopathy, and encephalopathies.
Coenzyme Q10 Deficiency
Cytochrome c Mutations
Cytochrome b Mutation
COX I Mutation
Mitochondrial DNA tRNA Mutations
Mutation in the MT-CO2 Gene
Structural Myopathies.
Dystrophinopathy.
LGMD2I: mutations in the FKRP gene encoding fukutin-related protein.
Dysferlinopathy
Anoctamin-5 Myopathy
Sarcoglycanopathy
FHSD
Channelopathies
RYR1 gene mutations
SCN4A Gene Mutation
malignant hyperthermia I-VI
Hypokalemic periodic paralysis
Lipin-1. Mutations in the lipin-1 gene (LPIN1) have been described recently in pediatric patients with recurrent rhabdomyolysis
Sickle-Cell Disease/trait
“Benign Exertional Rhabdomyolysis.”
Exercise in excess of training. Military, body-builders, marathon runners, cross-country skiers, rowers.
Infections
Multisystem organ failure
CK is a nonspecific marker of muscle damage. CK is composed of monomer M (muscle), B (brain), resulting in MM, MB, BB isoenzymes. MM isoenzyme is from skeletal muscle and increased levels reflect muscle membrane integrity. An elevation of CK denotes muscle membrane leak or muscle necrosis. It is useful in the clinical context of myopathy. However, CK is not specific to myopathy and can be seen in neurogenic disorders, trauma, and exercise. Quite commonly both CK and adolase levels are ordered for investigation of a patient with suspected myopathy. When only aldolase levels are elevated and CK levels are normal, one should think liver disease or some inflammatory condition affecting the fascia overlying the weak muscle.
Metabolic role for CK: CK catalyzes the conversion of creatine and ATP to phosphocreatine and ADP.
It is important for patients to stop exercising 5 - 7 days before CK levels are checked.
Nonblack males and black females and Hispanics 110 - 150s IU/L
If CK in black women is >620: investigate further
If CK in white man is >500: investigate further.
White females 60 - 100s IU/L
If CK in white women is >325: investigate further.
Investigate only if CK levels are >3 x ULN.
Myopathies
Carrier state (dystrophinopathies)
Channelopathies
Drug/toxin-induced (statin, alcohol, chloroquine, cocaine)
Inflammatory myopathies (PM, sIBM, IMNM)
Metabolic myopathies (myophosphorylase deficiency, CPTII deficiency, mitochondrial cytopathies)
Congenital myopathies
Muscular dystrophies
Myotonic dystrophies
Motor neuron diseases (rarely elevated above 1000 IU/mL, except SBMA)
ALS
Postpolio syndrome
Spinal muscular atrophy
SBMA (Kennedy's disease): >1000 to several thousand IU/L
Neuropathies
Charcot-Marie-Tooth
Guillain-Barre´ syndrome
Radiculopathy
MMN
Mononeuritis multiplex
Others
Infectious myositis: Viral, bacterial, parasitic.
"Idiopathic hyper-CKemia’’
Increased muscle mass
Hypothyroid myopathy is associated with elevated CK. Normal CK is usually seen in most cases of myopathy associated with Hyperthyroidism.
Hypoparathyroidism
Hypophosphatemia
Medications
Race
Sex
Strenuous exercise
Surgery
MI, myocarditis
Trauma (EMG studies, intramuscular or subcutaneous injections)
CK level can be normal:
FSHD, milder LGMD, some metabolic myopathies at rest, rarely in DM
CK level can be mildly increased (<5-10 times the ULN):
Exercise, neurogenic causes, Becker muscular dystrophy, FSHD, many types of LGMD, myotonic dystrophy, advanced DMD, drug-induced, Inflammatory myopathies, congenital and metabolic myopathies, congenital myasthenic syndromes.
Dystrophinopathies must be considered as a likely cause of an asymptomatic to mildly symptomatic hyperCKemia.
CK level is markedly increased (>20 times the ULN):
DMD, BMD, some types of LGMD (types 2B, 2D, 2G), DM, IMNM, inherited and acquired causes of rhabdomyolysis and myoglobinuria
Kennedy’s disease (SBMA): CK levels are usually elevated, ranging from about 1000 to several thousand IU/L and sometimes incorrectly implicate a diagnosis of myopathy.
Creatine kinase (CK; creatine phosphokinase) is found in skeletal muscle, cardiac muscle, and the brain, bladder, stomach, and colon. Isoenzyme fractions identify the type of tissue damaged. CK-BB (CK1) is found in the brain, bladder, stomach, and colon; CK-MB (CK2) is found in cardiac tissue; and CK-MM (CK3) is found in skeletal muscle. CK-MB is detectable in the blood within 3 to 5 hours after myocardial infarction; levels peak at about 10 to 20 hours and normalize within about 3 days.
Treatment of Rhabdomyolysis and myoglobinuria
IVF 6-12 liters in 24 hours in the absence of contraindications. IVF should not be hypotonic
Urine output: 200 - 300 mL/24 h
Furosemide - diuresis
Sodium bicarbonate and mannitol may be used - limited evidence of alkalinzation
High index of suspicion for compartment syndrome
Fasciotomy
Hypocalcemia, hypokalemia, and hypophosphatemia should be screened for and treated PRN
ARDS, DIC and ishemic bowel monitoring.
Elevated CK in the setting of myalgia localizes to muscle. He may have an underlying myopathy. Based on his clinical picture as well as labs and immune necrotizing myopathy and myositis are unlikely to be causing his symptoms. He has exercise intolerance. DDx is broad and includes acquired: toxic, endocrine (thyroid, adrenal dysfunction), metabolic causes, sarcoid DNMT: LEMS, vs inherited: acid-maltase, metabolic myopathies, muscular dystrophies, muscle channelopathies including non-dystrophic myotonias, mitochondrial disorders; rheumatological: MCTD; sickle cell trait/disease are also a consideration.
It is important for patients to stop exercising 5 - 7 days before CK levels are checked. It is not uncommon for black males to have CK 270s - 480s IU/L.