Creatine Phosphokinase


Article Author:
Ravinder Aujla


Article Editor:
Roshan Patel


Editors In Chief:
Ishwarlal Jialal


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Avais Raja
Orawan Chaigasame
Khalid Alsayouri
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Radia Jamil
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Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
9/13/2019 12:32:30 PM

Introduction

Creatine phosphokinase (CPK), also known by the name creatine kinase (CK) is the enzyme that catalyzes the reversible reaction of creatine and adenosine triphosphate (ATP) to phosphocreatine and adenosine diphosphate (ADP). The phosphocreatine created from this reaction is used to supply tissues and cells that require substantial amounts of ATP like the brain, skeletal muscles, and the heart with their required ATP. The normal CPK level is considered to be 20 to 200 IU/L. Many conditions can cause derangement in CPK levels, including rhabdomyolysis, heart disease, kidney disease, or even certain medications.[1][2][3]

Pathophysiology

Molecular

There exist four major isoenzymes of CPK with two in the cytosol and two in the mitochondria. The cytosol variants are the muscle type (M chain) and the brain type (B chain). The cytosol variants can produce the heterodimer CK-MB or homodimers CK-MM and CK-BB. CK-MB is mostly present in cardiac muscle, CK-MM in skeletal muscle and CK-BB in smooth muscle and most non-muscle tissues such as the brain. The mitochondrial variants are an octamer of Mi-CK in the brain and a dimer of Mi-CK in muscle. CK-MB further subdivides into two types, CK-MB1 and CK-MB2 when it is in the bloodstream.[4][5]

Normally, creatine phosphokinase occurs in heart tissue, skeletal muscles, the brain, etc. However, upon muscular injury, there is leakage of CPK into the bloodstream. Thus, CPK is indicative of muscular damage. CK-MB is a more specific indicator of myocardial muscle damage, while CK-MM is more indicative of skeletal muscle damage.[6]

Clinical Significance

Creatine kinase activity is one of the oldest markers of acute myocardial infarction (AMI). Creatine kinase activity begins to rise within 12 hours of AMI symptoms, peaks at 24 to 36 hours and normalizes after 48 to 72 hours. The issue with measuring creatine kinase activity for AMI is that it is not specific to the heart. CK activity can increase in several conditions such as rhabdomyolysis, chronic muscle diseases, burns, and even after strenuous exercise. Thus, the CK-MB isoenzyme started being used to aid in the diagnosis of AMI. Although the CK-MB measurement is an improvement over just CK, it can still become increased in other conditions such as acute muscle injury, congestive cardiac failure, and arrhythmias.[7]

Elevated levels of CK-MB have long been used to diagnose a case of AMI. Although many centers are now going by troponin levels instead of CK-MB, there exists a newer, more specific CK-MB method as well. The new testing method involves measuring the values of the CK-MB1 and CK-MB2 isoforms. In a normal patient, the ratio of CK-MB2 to CK-MB1 should be at 1:1. In the case of AMI, the ratio will be at its peak within 4 hours of the infarction. However, some evidence of AMI can be detected as early as 1-2 hours after the infarction. To diagnose AMI, the ratio of CK-MB2 to CK-MB1 should be greater than 1.7 to 1. However, even a ratio of more than or equal to 1.5 to 1 points strongly to a diagnosis of AMI.[7][4][8]

Patients with Alzheimer disease and Pick disease may have decreased CPK activity in the brain. The BB-CK activity is primarily decreased in these patients, resulting in an overall decrease in total CPK activity as well.[5]

CPK levels also elevate in patients with rhabdomyolysis. Rhabdomyolysis may result from a crush injury, drug use, viral infections, and strenuous exercise. It typically presents with muscle pain and weakness alongside dark colored urine. There is a breakdown of skeletal muscle which leads to a release of CPK along with alanine aminotransferase (ALT), aspartate aminotransferase (AST) and electrolytes. The reason for the dark urine is due to myoglobinuria. A CPK level which increases to more than 1000 IU/L is indicative of rhabdomyolysis; values over 5000 IU/L indicate severe rhabdomyolysis. Patients with sickle cell trait who suddenly start a new strenuous exercise program such as spin class are also at an increased risk of rhabdomyolysis, with reported levels of creatine kinase higher than 70000 IU/L in some cases. The most common complication resulting from rhabdomyolysis is acute kidney injury. Therefore, any patient that comes with suspected rhabdomyolysis should receive prompt treatment with intravenous fluids to preserve kidney function.[9][10][11]

Patients on statins such as simvastatin may have an adverse effect of significantly elevated CPK levels which can also lead to rhabdomyolysis. This adverse effect becomes amplified if the patient also receives a concurrent drug that inhibits cytochrome P450-3A4 (CYP3A4). Some common medications to avoid in patients on statin therapy include clarithromycin, erythromycin, verapamil, tamoxifen, and many antifungal agents.[11][12]

Suggestions also exist that the guidelines for high CPK levels being above 200 IU/L may not apply to all populations. In black men specifically, the CPK levels may be as high as 1200 IU/L even in a healthy person. Therefore, some studies have tried to set some new thresholds for upper limits of CPK as follows: White women: 325 IU/L, White men: 504 IU/L, Black women: 621 IU/L, Black men: 1200 IU/L.[3]

Low levels of CPK can be present in patients with connective tissue diseases such as rheumatoid arthritis or systemic lupus erythematosus. There may also be low levels in patients that have reduced physical activity such as elderly bed-ridden patients.[13]

Enhancing Healthcare Team Outcomes

Creatine phosphokinase is an important enzyme more so in the diagnosis of rhabdomyolysis than AMI in the current medical setting. It is especially important in patients with sickle cell anemia or sickle cell trait. It requires careful management with an interprofessional team consisting of a pediatrician and geneticist. The geneticist should assess the type of sickle cell disease during newborn screening. The pediatrician should advise the parents of the child that there exist increased chances of rhabdomyolysis from strenuous exercise in children with sickle cell anemia and sickle cell trait. In a patient that already presents with rhabdomyolysis after an increased Creatine phosphokinase level, an interprofessional team consisting of a nephrologist, surgeon, and nurse may have involvement in managing the condition. The nephrologist would be working to increase the kidney function in such patients as acute kidney injury is the most common complication of rhabdomyolysis. The surgeon may need to surgically repair any damaged muscle or tissue that lead to the condition. The nurse should teach the patient about managing their condition and how to avoid having an attack of rhabdomyolysis again. The healthcare team can also consult with the pharmacist to verify that any of the patient's mediations are not potential sources for elevated CPK. Any hospital staff members working in the emergency department should be aware that in patients with suspected rhabdomyolysis, intravenous fluid therapy should be started promptly to curb acute kidney injury.[10][11]


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Creatine Phosphokinase - Questions

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There were 20 patients with decreased creatine phosphokinase activity. Further investigation into these patients revealed that they all had decreased creatine phosphokinase activity. Alzheimer disease was found to be present in all of these patients. The brains of the 20 with Alzheimer disease were studied after it was found that they all had a decreased level of creatine phosphokinase. The results of the brain studies most likely revealed which of the following?



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A72-year-old male patient presents to the hospital after crush injury to his legs. He takes simvastatin for hyperlipidemia. His heart rate is 140/mins and blood pressure is 140/110 mm of hg. Physical examination is unremarkable except for bruises and laceration on left leg. Laboratory exam is significant for creatine kinase level of 30,000 IU/L. He is admitted to the hospital and prescribed intravenous 0.9% saline at 250 cc/hr. What should be monitored in the hospital relavant to his diagnosis?



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A 14-year-old boy presents with complaints of pain in his lower limb muscles after intense football practice. Previously, the boy had not been very physically active, and this is the first day of practice. He also notices a dark discoloration in his urine. No other player on the team has any similar symptoms. What genetic condition is most likely to be present in this patient?



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A 68-year-old man presented to the hospital with a crush injury to his lower limbs. A creatine phosphokinase lab test was returned with a level of 13,000 IU/L. What is the next best step in the management of this patient?



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A 51-year-old male presents to the hospital with myalgia and dark-colored urine after a crush injury. Initial labs reveal a creatine phosphokinase level of 6000 IU/L. What is the most likely diagnosis?



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A 65-year-old male patine was brought to the emergency department by the paramedics. The patient was involved in a road traffic crushing accident. Upon running lab tests, it is found that his CPK (creatine phosphokinase) level is 7000 IU/L, with a creatinine of 1.4 mg/dL. An electrocardiogram is done, which turns out to be normal. Which of the following is the next step in the management of this patient?



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Creatine Phosphokinase - References

References

Bong SM,Moon JH,Nam KH,Lee KS,Chi YM,Hwang KY, Structural studies of human brain-type creatine kinase complexed with the ADP-Mg2 -NO3- -creatine transition-state analogue complex. FEBS letters. 2008 Nov 26;     [PubMed]
Chanson JB,Dakayi C,Lannes B,Echaniz-Laguna A, Benign acute myositis in an adult patient. BMJ case reports. 2018 May 29;     [PubMed]
Moghadam-Kia S,Oddis CV,Aggarwal R, Approach to asymptomatic creatine kinase elevation. Cleveland Clinic journal of medicine. 2016 Jan;     [PubMed]
Aydin S,Ugur K,Aydin S,Sahin İ,Yardim M, Biomarkers in acute myocardial infarction: current perspectives. Vascular health and risk management. 2019;     [PubMed]
Aksenov MY,Aksenova MV,Payne RM,Smith CD,Markesbery WR,Carney JM, The expression of creatine kinase isoenzymes in neocortex of patients with neurodegenerative disorders: Alzheimer's and Pick's disease. Experimental neurology. 1997 Aug;     [PubMed]
Rawson ES,Clarkson PM,Tarnopolsky MA, Perspectives on Exertional Rhabdomyolysis. Sports medicine (Auckland, N.Z.). 2017 Mar;     [PubMed]
Al-Hadi HA,Fox KA, Cardiac markers in the early diagnosis and management of patients with acute coronary syndrome. Sultan Qaboos University medical journal. 2009 Dec;     [PubMed]
Swaanenburg JC,Dejongste MJ,Volmer M,Kema IP, Analytical aspects of the automated CKMB1,2 and CKMM1,2,3 isoform determination and its relation to other biochemical markers. Scandinavian journal of clinical and laboratory investigation. 1998 Apr;     [PubMed]
Chavez LO,Leon M,Einav S,Varon J, Beyond muscle destruction: a systematic review of rhabdomyolysis for clinical practice. Critical care (London, England). 2016 Jun 15;     [PubMed]
Longo T,Shaines M, Case Report: Exertional rhabdomyolysis in a spin class participant with sickle cell trait. F1000Research. 2018;     [PubMed]
Ezad S,Cheema H,Collins N, Statin-induced rhabdomyolysis: a complication of a commonly overlooked drug interaction. Oxford medical case reports. 2018 Mar;     [PubMed]
Stolcpart RS,Olson KL,Delate T,Rasmussen J,Rehring TF,Merenich JA, The risk for significant creatine kinase elevation with statins. American journal of cardiovascular drugs : drugs, devices, and other interventions. 2010;     [PubMed]
Wei N,Pavlidis N,Tsokos G,Elin RJ,Plotz PH, Clinical significance of low creatine phosphokinase values in patients with connective tissue diseases. JAMA. 1981 Oct 23-30;     [PubMed]

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