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Aktuelle Neurologie 2018; 45(03): 187-199
DOI: 10.1055/s-0043-124430
Übersicht
© Georg Thieme Verlag KG Stuttgart · New York

Differenzialdiagnose der CK-Erhöhung

Differential Diagnosis of HyperCKemia
Rudolf Andre Kley
1   Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil, Heimer Institut für Muskelforschung an der Neurologischen Universitätsklinik, Bochum
,
Tobias Schmidt-Wilcke
2   St. Mauritius Therapieklinik Meerbusch, Neurologische Klinik
3   Heinrich-Heine-Universität Düsseldorf, Institut für Klinische Neurowissenschaften und Medizinische Psychologie
,
Matthias Vorgerd
1   Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil, Heimer Institut für Muskelforschung an der Neurologischen Universitätsklinik, Bochum
› Author Affiliations
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Publication History

Publication Date:
11 April 2018 (online)

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Zusammenfassung

Eine erhöhte Aktivität der Kreatinkinase (CK) im Serum ist in der Regel ein Indikator für eine Muskelschädigung. Eine HyperCKämie ist häufig ein Zufallsbefund und sollte, insbesondere bei asymptomatischen Patienten, zunächst nach mehrtägiger Vermeidung körperlicher Belastung kontrolliert werden. Zudem sprechen Daten aus neueren Studien dafür, dass die aktuellen Normwerte nach oben hin korrigiert werden müssen. Diese Übersichtsarbeit enthält einen Algorithmus zur differenzialdiagnostischen Abklärung einer CK-Erhöhung bei Patienten ohne muskuläre Beschwerdesymptomatik. Auf neurologischem Fachgebiet können insbesondere Myopathien und Neuropathien mit Beteiligung des 2. Motoneurons Ursache für eine symptomatische HyperCKämie sein, wobei CK-Werte über 1000 U/L (16,7 μkat/L) eher für eine primäre Muskelerkrankung sprechen. Zu den Erkrankungen mit sehr hohen CK-Werten zählen einige Formen der Muskeldystrophien, idiopathischen Myositiden und metabolischen Myopathien. Andererseits schließt ein normaler oder nur leicht erhöhter CK-Wert eine Myopathie nicht aus. Das individuelle diagnostische Vorgehen (z. B. Bildgebung der Muskulatur, spezielle Laboruntersuchungen, Muskelbiopsie und genetische Analysen) hängt vom klinischen Phänotyp und den Ergebnissen der elektrophysiologischen Untersuchungen ab. Eine HyperCKämie kann auch als Nebenwirkung bei zahlreichen Medikamenten, einschließlich Statinen, auftreten. Bei asymptomatischen Patienten kann eine Statin-assoziierte CK-Erhöhung bis zum 5-Fachen des oberen Grenzwertes toleriert werden. Bei höheren CK-Werten und/oder assoziierten muskulären Beschwerden sollte die LDL-Cholesterin-senkende Therapie neu festgelegt werden. Eine Rhabdomyolyse ist ein potentiell lebensgefährlicher Zustand und geht mit deutlichen CK-Erhöhungen einher. Zur Therapie in der akuten Phase gehören eine Sicherstellung der Nierenfunktion und ein Ausgleich von metabolischen Störungen.

Abstract

Elevated serum creatine kinase (CK) activity is usually an indicator of muscle damage. HyperCKemia is often an incidental finding and should be controlled after refraining from physical activity for some days, especially in asymptomatic patients. Furthermore, data from recent studies indicate that the upper limits of normal (ULN) need to be revised upward. This review includes an algorithm for differential diagnosis of CK elevation in patients without muscular symptoms. In the field of neurology, in particular myopathies and neuropathies with affection of the lower motoneuron, can cause symptomatic hyperCKemia, with CK values > 1000 U/l (16.7 µkat/l) being indicative of a primary muscle disorder. Diseases with very high CK values include subtypes of muscular dystrophies, idiopathic inflammatory myopathies and metabolic myopathies. However, a normal or only slightly elevated CK value does not exclude the presence of a myopathy. The individual diagnostic procedure (e.g. muscle imaging, special laboratory studies, muscle biopsy and genetic testing) depends on the clinical phenotype and the results of electrophysiological studies. HyperCKemia can also be an adverse effect of several drugs including statins. In asymptomatic patients, a statin-associated CK elevation < 5-fold of ULN can be tolerated. In patients with higher CK values and/or muscle symptoms, LDL cholesterol-lowering therapy should be changed. Rhabdomyolysis is a potentially life- threatening condition and is accompanied by highly elevated CK values. Acute-phase treatment includes preserving renal function and restoring metabolic balance.

Schlüsselwörter

Kreatinkinase - CK-Erhöhung - Myopathie - Neuropathie - Algorithmus

Keywords

creatine kinase - CK elevation - myopathy - neuropathy - algorithm
 

  • Literatur

  • 1 Urdal P, Urdal K, Strømme JH. Cytoplasmic creatine kinase isoenzymes quantitated in tissue specimens obtained at surgery. Clin Chemistry 1983; 29: 310-313
    PubMedGoogle Scholar
  • 2 Nicholson GA, McLeod JG, Morgan G. et al. Variable distributions of serum creatine kinase reference values. Relationship to exercise activity. J Neurol Sci 1985; 71: 233-245
    CrossrefPubMedGoogle Scholar
  • 3 Schumann G, Bonora R, Ceriotti F. et al. IFCC primary reference procedures for the measurement of catalytic activity concentrations of enzymes at 37 degrees C. Part 2. Reference procedure for the measurement of catalytic concentration of creatine kinase. Clin Chem Lab Med 2002; 40: 635-642
    PubMedGoogle Scholar
  • 4 Hørder M, Elser RC, Gerhardt W. et al. International Federation of Clinical Chemistry, Scientific Division Committee on Enzymes: approved recommendation on IFCC methods for the measurement of catalytic concentration of enzymes. Part 7. IFCC method for creatine kinase (ATP: creatine N-phosphotransferase, EC 2.7.3.2). Eur J Clin Chem Clin Biochem 1991; 29: 435-456
    PubMedGoogle Scholar
  • 5 Moghadam-Kia S, Oddis CV, Aggarwal R. Approach to asymptomatic creatine kinase elevation. Cleve Clin J Med 2016; 83: 37-42
    CrossrefPubMedGoogle Scholar
  • 6 Lev EI, Tur-Kaspa I, Ashkenazy I. et al. Distribution of serum creatine kinase activity in young healthy persons. Clin Chim Acta 1999; 279: 107-115
    CrossrefPubMedGoogle Scholar
  • 7 Brewster LM, Mairuhu G, Sturk A. et al. Distribution of creatine kinase in the general population: implications for statin therapy. Am Heart J 2007; 154: 655-661
    CrossrefPubMedGoogle Scholar
  • 8 Kyriakides T, Angelini C, Schaefer J. et al. EFNS guidelines on the diagnostic approach to pauci- or asymptomatic hyperCKemia. Eur J Neurol 2010; 17: 767-773
    CrossrefPubMedGoogle Scholar
  • 9 Lilleng H, Johnsen SH, Wilsgaard T. et al. Are the currently used reference intervals for creatine kinase (CK) reflecting the general population? The Tromsø Study. Clin Chemistry Laboratory Med 2012; 50: 879-884
    PubMedGoogle Scholar
  • 10 Nardin RA, Zarrin AR, Horowitz GL. et al. Effect of newly proposed CK reference limits on neuromuscular diagnosis. Muscle Nerve 2009; 39: 494-497
    CrossrefPubMedGoogle Scholar
  • 11 Lilleng H, Abeler K, Johnsen SH. et al. Variation of serum creatine kinase (CK) levels and prevalence of persistent hyperCKemia in a Norwegian normal population. The Tromsø Study. Neuromuscul Disord 2011; 21: 494-500
    CrossrefPubMedGoogle Scholar
  • 12 D'Adda E, Sciacco M, Fruguglietti ME. et al. Follow-up of a large population of asymptomatic/oligosymptomatic hyperckemic subjects. J Neurol 2006; 253: 1399-1403
    CrossrefPubMedGoogle Scholar
  • 13 Reijneveld JC, Notermans NC, Linssen WH. et al. Benign prognosis in idiopathic hyper-CK-emia. Muscle Nerve 2000; 3: 575-579
    PubMedGoogle Scholar
  • 14 Malandrini A, Orrico A, Gaudiano C. et al. Muscle biopsy and in vitro contracture test in subjects with idiopathic HyperCKemia. Anesthesiology 2008; 109: 625-628
    CrossrefPubMedGoogle Scholar
  • 15 Weglinski MR, Wedel DJ, Engel AG. Malignant hyperthermia testing in patients with persistently increased serum creatine kinase levels. Anesth Analg 1997; 84: 1038-1041
    CrossrefPubMedGoogle Scholar
  • 16 Dabby R, Sadeh M, Herman O. et al. Asymptomatic or minimally symptomatic hyperCKemia: histopathologic correlates. Isr Med Assoc J 2006; 8: 110-113
    PubMedGoogle Scholar
  • 17 Fernandez C, Paula AM de, Figarella-Branger D. et al. Diagnostic evaluation of clinically normal subjects with chronic hyperCKemia. Neurology 2006; 66: 1585-1587
    CrossrefPubMedGoogle Scholar
  • 18 Prelle A, Tancredi L, Sciacco M. et al. Retrospective study of a large population of patients with asymptomatic or minimally symptomatic raised serum creatine kinase levels. J Neurol 2002; 249: 305-311
    CrossrefPubMedGoogle Scholar
  • 19 Joy JL, Oh SJ. Asymptomatic hyper-CK-emia: an electrophysiologic and histopathologic study. Muscle Nerve 1989; 12: 206-209
    CrossrefPubMedGoogle Scholar
  • 20 Filosto M, Tonin P, Vattemi G. et al. The role of muscle biopsy in investigating isolated muscle pain. Neurology 2007; 68: 181-186
    CrossrefPubMedGoogle Scholar
  • 21 Simmons Z, Peterlin BL, Boyer PJ. et al. Muscle biopsy in the evaluation of patients with modestly elevated creatine kinase levels. Muscle Nerve 2003; 27: 242-244
    CrossrefPubMedGoogle Scholar
  • 22 Norwood FLM, Harling C, Chinnery PF. et al. Prevalence of genetic muscle disease in Northern England: in-depth analysis of a muscle clinic population. Brain 2009; 132: 3175-3186
    Google Scholar
  • 23 Zhang Y, Huang J, Wang Z. et al. Value of muscle enzyme measurement in evaluating different neuromuscular diseases. Clin Chim Acta 2012; 413: 520-524
    CrossrefPubMedGoogle Scholar
  • 24 Deschauer M, Wieser T, Zierz S. Muscle carnitine palmitoyltransferase II deficiency: clinical and molecular genetic features and diagnostic aspects. Arch Neurol 2005; 62: 37-41
    CrossrefPubMedGoogle Scholar
  • 25 Leverenz D, Zaha O, Crofford LJ. et al. Causes of creatine kinase levels greater than 1000 IU/L in patients referred to rheumatology. Clin Rheumatol 2016; 35: 1541-1547
    CrossrefPubMedGoogle Scholar
  • 26 McGrowder DA, Fraser YP, Gordon L. et al. Serum creatine kinase and lactate dehydrogenase activities in patients with thyroid disorders. Niger J Clin Pract 2011; 14: 454-459
    CrossrefPubMedGoogle Scholar
  • 27 Stroes ES, Thompson PD, Corsini A. et al. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J 2015; 36: 1012-1022
    CrossrefPubMedGoogle Scholar
  • 28 Parker BA, Capizzi JA, Grimaldi AS. et al. Effect of statins on skeletal muscle function. Circulation 2013; 127: 96-103
    CrossrefPubMedGoogle Scholar
  • 29 Talameh JA, Kitzmiller JP. Pharmacogenetics of statin-induced myopathy: a focused review of the clinical translation of pharmacokinetic genetic variants. J Pharmacogenomics Pharmacoproteomics 2014; DOI: 10.4172/2153-0645.1000128.
    PubMedGoogle Scholar
  • 30 Ahmad Z. Statin intolerance. Am J Cardiol 2014; 113: 1765-1771
    CrossrefPubMedGoogle Scholar
  • 31 Riphagen IJ, van der Veer E, Muskiet FAJ. et al. Myopathy during statin therapy in the daily practice of an outpatient cardiology clinic: prevalence, predictors and relation with vitamin D. Curr Med Res Opin 2012; 28: 1247-1252
    CrossrefPubMedGoogle Scholar
  • 32 Limaye V, Bundell C, Hollingsworth P. et al. Clinical and genetic associations of autoantibodies to 3-hydroxy-3-methyl-glutaryl-coenzyme a reductase in patients with immune-mediated myositis and necrotizing myopathy. Muscle Nerve 2015; 52: 196-203
    CrossrefPubMedGoogle Scholar
  • 33 Mosshammer D, Schaeffeler E, Schwab M. et al. Mechanisms and assessment of statin-related muscular adverse effects. Br J Clin Pharmacology 2014; 78: 454-466
    PubMedGoogle Scholar
  • 34 Argov Z. Statins and the neuromuscular system: a neurologistʼs perspective. Eur J Neurology 2015; 22: 31-36
    CrossrefPubMedGoogle Scholar
  • 35 McKenney JM, Davidson MH, Jacobson TA. et al. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol 2006; 97: 89C-94C
    CrossrefPubMedGoogle Scholar
  • 36 Reiner Z, Catapano AL, Backer G de. et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011; 32: 1769-1818
    CrossrefPubMedGoogle Scholar
  • 37 Kley RA, Hellenbroich Y, van der Ven PF. et al. Clinical and morphological phenotype of the filamin myopathy: a study of 31 German patients. Brain 2007; 130: 3250-3264
    CrossrefPubMedGoogle Scholar
  • 38 Unger A, Dekomien G, Guttsches A. et al. Expanding the phenotype of BICD2 mutations toward skeletal muscle involvement. Neurology 2016; 87: 2235-2243
    CrossrefPubMedGoogle Scholar
  • 39 Dräger B, Young P. Pragmatische Diagnostik hereditärer Neuropathien. Akt Neurol 2016; 43: 256-266
    Article in Thieme ConnectPubMedGoogle Scholar
  • 40 Abraham A, Albulaihe H, Alabdali M. et al. Frequent laboratory abnormalities in CIDP patients. Muscle Nerve 2016; 53: 862-865
    CrossrefPubMedGoogle Scholar
  • 41 Ropper AH, Shahani BT. Pain in Guillain-Barre syndrome. Arch Neurol 1984; 41: 511-514
    CrossrefPubMedGoogle Scholar
  • 42 Lopate G, Streif E, Harms M. et al. Cramps and small-fiber neuropathy. Muscle Nerve 2013; 48: 252-255
    CrossrefPubMedGoogle Scholar
  • 43 Echaniz-Laguna A, Dubourg O, Carlier P. et al. Phenotypic spectrum and incidence of TRPV4 mutations in patients with inherited axonal neuropathy. Neurology 2014; 82: 1919-1926
    CrossrefPubMedGoogle Scholar
  • 44 Berciano J, Garcia A, Peeters K. et al. NEFL E396K mutation is associated with a novel dominant intermediate Charcot-Marie-Tooth disease phenotype. J Neurol 2015; 262: 1289-1300
    CrossrefPubMedGoogle Scholar
  • 45 Hattori N, Yamamoto M, Yoshihara T. et al. Demyelinating and axonal features of Charcot-Marie-Tooth disease with mutations of myelin-related proteins (PMP22, MPZ and Cx32): a clinicopathological study of 205 Japanese patients. Brain 2003; 126: 134-151
    CrossrefPubMedGoogle Scholar
  • 46 Rudnik-Schoneborn S, Lutzenrath S, Borkowska J. et al. Analysis of creatine kinase activity in 504 patients with proximal spinal muscular atrophy types I-III from the point of view of progression and severity. Eur Neurol 1998; 39: 154-162
    CrossrefPubMedGoogle Scholar
  • 47 Gibson SB, Kasarskis EJ, Hu N. et al. Relationship of creatine kinase to body composition, disease state, and longevity in ALS. Amyotroph Lateral Scler Frontotemporal Degener 2015; 16: 473-477
    CrossrefPubMedGoogle Scholar
  • 48 Ghosh PS, Lahoria R, Milone M. et al. Pearls & Oy-sters: HyperCKemia with limb-girdle weakness: Think beyond myopathies. Neurology 2014; 83: e209-12
    CrossrefPubMedGoogle Scholar
  • 49 Rhodes LE, Freeman BK, Auh S. et al. Clinical features of spinal and bulbar muscular atrophy. Brain 2009; 132: 3242-3251
    CrossrefPubMedGoogle Scholar
  • 50 Soraru G, D'Ascenzo C, Polo A. et al. Spinal and bulbar muscular atrophy: skeletal muscle pathology in male patients and heterozygous females. J Neurol Sci 2008; 264: 100-105
    CrossrefPubMedGoogle Scholar
  • 51 Zutt R, van der Kooi AJ, Linthorst GE. et al. Rhabdomyolysis: review of the literature. Neuromuscul Disord 2014; 24: 651-659
    CrossrefPubMedGoogle Scholar
  • 52 Lane R, Phillips M. Rhabdomyolysis. BMJ 2003; 327: 115-116
    CrossrefPubMedGoogle Scholar
  • 53 Bosch X, Poch E, Grau JM. Rhabdomyolysis and acute kidney injury. N Engl J Med 2009; 361: 62-72
    CrossrefPubMedGoogle Scholar
  • 54 Melli G, Chaudhry V, Cornblath DR. Rhabdomyolysis: an evaluation of 475 hospitalized patients. Medicine 2005; 84: 377-385
    CrossrefPubMedGoogle Scholar
  • 55 Koeks Z, Bladen CL, Salgado D. et al. Clinical outcomes in Duchenne muscular dystrophy: a study of 5345 patients from the TREAT-NMD DMD Global Database. J Neuromuscul Dis; 2017 4. 293-306
    PubMedGoogle Scholar
  • 56 Lee SH, Lee JH, Lee KA. et al. Clinical and genetic characterization of female dystrophinopathy. J Clin Neurol 2015; 11: 248-251
    CrossrefPubMedGoogle Scholar
  • 57 Villamar LópezM, Azpeitia GonzálezJ, Ayuso GarcíaC. et al. Modificación del cálculo de riesgo en posibles mujeres portadoras de distrofia muscular de Duchenne (DMD) basado en niveles de CPK. [Modification of the calculation of risk factors in women, possible carriers of Duchenne muscular dystrophy, based on CPK levels]. An Esp Pediatr 1992; 37: 191-194
    PubMedGoogle Scholar
  • 58 Cardon MW. 50 years ago in the Journal of Pediatrics: an assessment of the creatine kinase test in the detection of carriers of Duchenne muscular dystrophy. J Pediatrics 2017; 186: 63
    CrossrefPubMedGoogle Scholar
  • 59 Thompson MW, Murphy EG, McAlpine PJ. An assessment of the creatine kinase test in the detection of carriers of Duchenne muscular dystrophy. J Pediatrics 1967; 71: 82-93
    CrossrefPubMedGoogle Scholar
  • 60 Dubowitz V. The female carrier of Duchenne muscular dystrophy. Br Med J (Clin Res Ed) 1982; 284: 1423-1424
    CrossrefPubMedGoogle Scholar
  • 61 Molster CM, Lister K, Metternick-Jones S. et al. Outcomes of an international workshop on preconception expanded carrier screening: some considerations for governments. Front Public Health 2017; 5: 25
    PubMedGoogle Scholar
  • 62 Rommel O, Kley RA, Dekomien G. et al. Muscle pain in myophosphorylase deficiency (McArdleʼs disease): the role of gender, genotype, and pain-related coping. Pain 2006; 124: 295-304
    CrossrefPubMedGoogle Scholar
  • 63 Dobloug C, Garen T, Bitter H. et al. Prevalence and clinical characteristics of adult polymyositis and dermatomyositis; data from a large and unselected Norwegian cohort. Ann Rheum Dis 2015; 74: 1551-1556
    CrossrefPubMedGoogle Scholar
  • 64 Schneider C, Reiners K, Toyka KV. Myotone Dystrophie (DM/Curschmann-Steinert-Erkrankung) und proximale myotone Myopathie (PROMM/Ricker-Syndrom). Myotone Muskelerkrankungen mit multisystemischen Manifestationen. [Myotonic dystrophy (DM/Curschmann-Steinert disease) and proximal myotonic myopathy (PROMM/Ricker syndrome). Myotonic muscle diseases with multisystemic manifestations]. Nervenarzt 2001; 72: 618-624
    CrossrefPubMedGoogle Scholar
  • 65 Karabul N, Kruijshaar ME, Schober A. et al. Pain in adult patients with Pompe disease. Mol Gen Metab Rep 2014; 1: 139-140
    PubMedGoogle Scholar