Salut George

It is quite common to have statin-induced myopathy *without* elevated
liver enzymes.

All from Annals of Internal Medicine:

Paul S. Phillips et al 2002
http://www.annals.org/cgi/content/abstract/137/7/581
Statin-Associated Myopathy with Normal Creatine Kinase Levels
"Conclusion:  Some patients who develop muscle symptoms while receiving
statin therapy have demonstrable weakness and histopathologic findings
of myopathy despite normal serum creatine kinase levels."

~~~~~

Dr. Phillips responding to other physicians, one of whom suffered
statin-induced myopathy.
http://www.annals.org/cgi/content/full/138/12/1008-a

In which he says:
"We agree that we know too little about the mechanism and
pathophysiology of statin myotoxicity and that further clinical
evaluations and biochemical description are essential."

http://www.annals.org/cgi/reprint/138/12/1007-b.pdf

Statin-Associated Myopathy with Normal Creatine
Kinase Levels
TO THE EDITOR: The article by Phillips and colleagues (1) and the
accompanying editorial by Grundy (2) highlight a clinical experience
many of us have had. Are the authors aware of any data, or in their
clinical experience have they found any other noninvasive testing,
such as serum aldolase level, that might identify patients who are
experiencing creatine kinase-negative statin myopathy?
Mark H. Hyman, MD
University of California, Los Angeles
Los Angeles, CA 90025
References
1. Phillips PS, Haas RH, Bannykh S, Hathaway S, Gray NL, Kimura BJ, et
al. Statinassociated
myopathy with normal creatine kinase levels. Ann Intern Med. 2002;137:
581-5. [PMID: 12353945]
2. Grundy SM. Can statins cause chronic low-grade myopathy? [Editorial]
Ann Intern
Med. 2002;137:617-8. [PMID: 12353951]

TO THE EDITOR: We read with interest the article by Phillips and
colleagues (1) and the accompanying editorial (2). One of us (Dr.
Torgovnick) developed low-grade myopathy while receiving statin
therapy. Atorvastatin, 5 mg (0.5 tablet), was started in September
1999. Nonspecific aches and pains were noticed, but no clear weakness
was evident and Dr. Torgovnick continued regular exercise. On
several occasions, a burning sensation beyond what was anticipated
developed in the muscles after exercise. Low-grade myopathy was
considered in June 2000, and creatine kinase level was checked. The
result, 3.14
kat/L, was normal (reference range, 0 to 3.34
kat/L),
and atorvastatin therapy was continued.

In early May 2002, 24 hours after exercise, creatine kinase level
was checked and was found to be 4.8
kat/L. Atorvastatin was withdrawn,
and the aches, pains, and burning sensation gradually resolved.
After vigorous exercise, several weeks after atorvastatin was
discontinued, the creatine kinase level was 3.19
kat/L. On a repeated
test, serum cholesterol level was significantly elevated and
pravastatin was introduced. Symptoms recurred but were tolerated.
While Dr. Torgovnick was taking pravastatin, the creatine kinase
level was 4.98
kat/L shortly after exercise.

Phillips and colleagues' patients ranged in age from 62 to 76
years, and no information was given on their level of activity or their
muscle mass, both of which can affect creatine kinase levels. In the
current author's case, it was clear that something was wrong, but the
creatine kinase level rose only with exercise provocation. The message
of the article by Phillips and colleagues is clear and important.
As more patients with this syndrome are identified, perhaps less
invasive evaluation might include the use of exercise provocation to
watch for an increase in creatine kinase level. Alternatively, simple
serial measurement of creatine kinase levels to establish a baseline
and subsequent reevaluation after a specified period (or withdrawal
of the agent and a demonstrated decrease in creatine kinase level,
particularly if associated with resolution of symptoms) would be
useful.
Josh Torgovnick, MD
St. Vincent's Hospital and Medical Center
New York, NY 10011
Edward Arsura, MD
Salem Veterans Affairs Medical Center
Salem, VA 24153
References
1. Phillips PS, Haas RH, Bannykh S, Hathaway S, Gray NL, Kimura BJ, et
al. Statinassociated
myopathy with normal creatine kinase levels. Ann Intern Med. 2002;137:
581-5. [PMID: 12353945]
2. Grundy SM. Can statins cause chronic low-grade myopathy? [Editorial]
Ann Intern
Med. 2002;137:617-8. [PMID: 12353951]

TO THE EDITOR: Phillips and colleagues (1) nicely documented
biopsy-confirmed myopathy in patients with normal creatine kinase
levels in association with statin therapy. As they mentioned in their
discussion, similar features are reported for coenzyme Q10 deficiency.
It is known that 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA)
reductase inhibition by statins influences not only the cholesterol
synthesis but also that of proteins such as farnesylated and
geranylgeranylated proteins and ubiquinones such as coenzyme Q10.
Similar to cholesterol synthesis, the primary regulation of coenzyme
Q10 biosynthesis is the HMG-CoA reductase reaction, providing its
isoprenyl side chain deriving from mevalonate. Decreased plasma
levels of coenzyme Q10 have been reported in statin-treated patients
(2, 3), and in one of them this decrease was dose related (3).
Furthermore,
in one study (4), statin-induced coenzyme Q10 reduction
was prevented by exogenous coenzyme Q10 supplementation.
On the other hand, similar histopathologic findings of myopathy
are well documented in patients with carnitine deficiency. A
16-week trial of treatment with lovastatin significantly altered
carnitine
status in rabbits with decreased tissue levels of carnitine and
increased serum levels of acylcarnitine (5). Use of HMG-CoA reductase
inhibitors leads to increased levels of acyl-CoA and, therefore, to
higher requirements of carnitine for the buffering of acyl-CoA
moieties.
Assessing the acylcarnitine-free carnitine ratio before and during
therapy with statins might identify the patients who are most
vulnerable to this possible myopathic complication. Although the
incidence of statin-associated myopathy (with abnormal or normal
creatine kinase levels) is low, studies on pathogenic roles of coenzyme
Q10 and carnitine are imperative. Finally, well-done clinical trials
addressing the preventive or therapeutic effects of coenzyme Q10 and
L-carnitine are worthy, since millions of people are receiving statins.
Emil Toma, MD, DSc, FRCP(C)
Maude Loignon, BSc
Hoˆtel-Dieu Hospital
Montreal, Quebec H2W 1T8, Canada
References
1. Phillips PS, Haas RH, Bannykh S, Hathaway S, Gray NL, Kimura BJ, et
al. Statinassociated
myopathy with normal creatine kinase levels. Ann Intern Med. 2002;137:
581-5. [PMID: 12353945]
2. Watts GF, Castelluccio C, Rice-Evans C, Taub NA, Baum H, Quinn PJ.
Plasma
coenzyme Q (ubiquinone) concentrations in patients treated with
simvastatin. J Clin
Pathol. 1993;46:1055-7. [PMID: 8254097]
3. Mortensen SA, Leth A, Agner E, Rohde M. Dose-related decrease of
serum coenzyme
Q10 during treatment with HMG-CoA reductase inhibitors. Mol Aspects
Med.
1997;18 Suppl:S137-44. [PMID: 9266515]
4. Bargossi AM, Grossi G, Fiorella PL, Gaddi A, Di Giulio R, Battino M.
Exogenous
CoQ10 supplementation prevents plasma ubiquinone reduction induced by
HMGCoA
reductase inhibitors. Mol Aspects Med. 1994;15 Suppl:s187-93. [PMID:
7752830]
5. Bhuiyan J, Seccombe DW. The effects of
3-hydroxy-3-methylglutaryl-CoA reductase
inhibition on tissue levels of carnitine and carnitine acyltransferase
activity in the
rabbit. Lipids. 1996;31:867-70. [PMID: 8869889]

TO THE EDITOR: Phillips and colleagues (1) posited that myopathy
with normal creatine kinase levels may occur in patients receiving
statin therapy. Patients with muscular pain or weakness but without
elevated enzyme levels pose an important clinical problem, although
the exact incidence of this disorder is not known. Phillips and
colleagues
did not discuss a potential mechanism or mechanisms. However,
they reported 3-methylglutaconic aciduria consistent with respiratory
chain dysfunction and pathologic findings similar to those
found in coenzyme Q10 deficiency (2). The American College of
Cardiology/American Heart Association/National Heart, Lung, and
Blood Institute clinical advisory states that ubiquinone (coenzyme
Q10) deficiency could be a possible mechanism, although no conclusive
data support this hypothesis (3). The synthesis of coenzyme Q10
in cells involves pathways that are blocked by the statins. A recent
review of statin myopathy (4) discusses this and other topics.
Members of the complementary and alternative medicine community
have been advocating the concomitant use of coenzyme Q10
with statins, although this practice has not been accepted by most
mainstream physicians. Data on whether statins lower coenzyme Q10
levels are contradictory. However, certain persons with a genetic,
biochemical, or other cause of decreased levels of coenzyme Q10
levels in tissue, such as increasing age (5), may experience
statininduced
decreases in muscle coenzyme Q10 levels as a cause of the
myopathy. Of note, the patients in Phillips and colleagues' study
were 62 to 76 years of age. Do the authors have any information on
serum or muscle coenzyme Q10 levels or coenzyme Q10 use in these
patients?

I believe the clinical and pathologic data in Phillips and
colleagues'
study, coupled with other reports in the peer-reviewed literature,
suggest an etiologic role of coenzyme Q10 deficiency in some
patients with statin-induced myopathy. Although isolated case reports
have supported this hypothesis, we need large randomized,
controlled studies studying the concomitant administration of coenzyme
Q10 and statins to prevent or treat muscle symptoms, with or
without muscle enzyme elevations. Only then will we be able to
address this important controversy.
Louis Evan Teichholz, MD
Hackensack University Medical Center
Hackensack, NJ 07601
References
1. Phillips PS, Haas RH, Bannykh S, Hathaway S, Gray NL, Kimura BJ, et
al. Statinassociated
myopathy with normal creatine kinase levels. Ann Intern Med. 2002;137:
581-5. [PMID: 12353945]
2. Ogasahara S, Engel AG, Frens D, Mack D. Muscle coenzyme Q deficiency
in
familial mitochondrial encephalomyopathy. Proc Natl Acad Sci U S A.
1989;86:2379-
82. [PMID: 2928337]
3. Pasternak RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, Cleeman JI,
Lenfant C,
et al. ACC/AHA/NHLBI clinical advisory on the use and safety of
statins. J Am Coll
Cardiol. 2002;40:567-72. [PMID: 12142128]
4. Baker SK, Tarnopolsky MA. Statin myopathies: pathophysiologic and
clinical perspectives.
Clin Invest Med. 2001;24:258-72. [PMID: 11603510]
5. Rosenfeldt FL, Pepe S, Ou R, Mariani JA, Rowland MA, Nagley P, et
al. Coenzyme
Q10 improves the tolerance of the senescent myocardium to aerobic and
ischemic
stress: studies in rats and in human atrial tissue. Biofactors.
1999;9:291-9. [PMID:
10416043]

IN RESPONSE: Dr. Hyman asks whether other biochemical markers
might identify patients with statin-induced myopathy. Levels of
aldolase
and myoglobin, which would be released by disrupted myocyte
membranes, have been normal whenever we have tested them in
our patients. We are currently testing other indicators of the
metabolic
defect associated with this muscle toxicity (1).

Drs. Torgovnick and Arsura inquire about the relation of this
toxicity to exercise. Postexercise creatine kinase level is more
sensitive
than resting creatine kinase level in assessing muscle toxicity. The
latter is related to membrane disruption but has not met with much
success in assessing statin toxicity (2, 3). We required that all study
patients maintain a consistent exercise and dietary regimen during
the 5-month evaluation. Although all of the creatine kinase evaluations
were performed after exercise, they were not performed late
enough (6 to 12 hours later) to make this a sensitive test. We believe
that the preoccupation with muscle membrane abnormalities and
elevation of creatine kinase levels as indicators of toxicity has
delayed
the detection of the metabolic toxicity we described. Other afflictions
with similar pathologic characteristics-mitochondrial myopathies,
for example-cause significant abnormalities in muscle function
without disrupting membranes sufficiently to elevate creatine kinase
levels. We suspect that further evaluation of metabolic defects in
patients with statin myotoxicity will prove more fruitful than repeated
attempts to evaluate this abnormality from the perspective of
muscle membrane toxicities or rhabdomyolysis.

The comments of Dr. Toma and Ms. Loignon and Dr. Teichholz
regarding the possible relationships of carnitine and coenzyme
Q10 to statin myotoxicity are correct. While we found no depression
in either serum or muscle carnitine levels in our patients, measurement
of coenzyme Q10 may be more productive. Muscle coenzyme
Q10 levels correlated with toxicity in one of the three patients in our
study who underwent muscle biopsy, both while myopathic and
again when toxicity had resolved. We have a report in preparation
that discusses measurement of coenzyme Q10 level in a series of 50
muscle biopsy specimens from patients under evaluation for statin
myotoxicity. The results of that study should provide further impetus
for future trials assessing coenzyme Q10 and carnitine.

Statins are the best therapy available to reduce cardiovascular
end points in patients with atherosclerotic risks. The optimal use of
these agents requires a thorough understanding of their toxicities as
well as of their efficacy. We agree that we know too little about the
mechanism and pathophysiology of statin myotoxicity and that further
clinical evaluations and biochemical description are essential.
Paul S. Phillips, MD
Scripps Mercy Hospital
San Diego, CA 92103
Richard H. Haas, MD
University of California, San Diego
La Jolla, CA 92093-0935
References
1. Phillips P, Haas R, Barshop B, Bannykh S, Amjadi D. Utility of
abnormal 3-methylglutaconic
aciduria (3MGA) in diagnosing statin associated myopathy. Atheroscler
Thromb Vasc Biol Online Journal. 2002;22:878. Accessed at
http://aha.agora.com/
abstractviewer/av_view.asp.
2. Reust CS, Curry SC, Guidry JR. Lovastatin use and muscle damage in
healthy
volunteers undergoing eccentric muscle exercise. West J Med.
1991;154:198-200.
[PMID: 2006566]
3. Smit JW, Bar PR, Geerdink RA, Erkelens DW. Heterozygous familial
hypercholesterolaemia
is associated with pathological exercise-induced leakage of muscle
proteins,
which is not aggravated by simvastatin therapy. Eur J Clin Invest.
1995;25:79-84.
[PMID: 7737266]

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