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Colchicine myopathy in a patient with familial mediterranean fever and normal renal functionArthritis & Rheumatism (Arthritis Care & Research)Vol. 49, No. 4, August 15, 2003, pp 614 – 616DOI 10.1002/art.11185 2003, American College of Rheumatology Colchicine Myopathy in a Patient With Familial
Mediterranean Fever and Normal Renal Function
EUGENE Y. KISSIN,1 JOSEPH C. CORBO,2 FRANCIS A. FARRAYE,1 AND PETER A. MERKEL1
trexate, and infliximab. At the time of her presentation Patients with familial Mediterranean fever (FMF) rou- with weakness, the Crohn’s disease was under good con- tinely take large daily doses of colchicine to both prevent trol with balsalazide alone. Other medical conditions in- and abort acute attacks (1,2) and to reduce the risk of cluded gastroesophageal reflux disease and irritable bowel developing amyloidosis (3). Unfortunately, colchicine can syndrome. In October 2001 her medications included ome- also cause a number of toxic side effects, including neu- prazole (20 mg/day), balsalazide (2.25 gm 3 times per day), romyopathy. Almost all cases of colchicine neuromyopa- colchicine (1.8 mg/day), calcium carbonate (500 mg 3 thy previously described have been associated with renal times per day), and amitriptyline (50 mg/day).
insufficiency (4). We report the first case of biopsy-con- Physical examination revealed a weight of 48 kg, blood firmed myopathy due to chronic colchicine administration pressure of 100/70 mm Hg and pulse of 80 beats/minute.
in an adult with FMF and normal renal function.
Neurologic examination revealed 5–/5 strength in theproximal upper extremity muscle groups and 4ϩ/5strength in the proximal lower extremity muscle groups Case report
bilaterally. She had great difficulty performing 1 deep knee A 38-year-old woman with FMF and Crohn’s disease pre- bend (squat). Distal muscle groups had normal strength.
sented in October 2001 for evaluation of worsening muscle Deep tendon reflexes were absent in the biceps, triceps, weakness over the previous 3 years. She had difficulty knees, and ankles bilaterally. Sensation to light touch, gait, walking up stairs or doing overhead work. She reported no and cranial nerve examination were normal. The results of muscle pain, rash, fevers, Raynaud’s phenomenon, joint the remainder of her physical examination were normal.
The patient’s laboratory studies were notable for the The patient has carried the diagnosis of FMF (homozy- following values: creatine phosphokinase (CPK) enzyme gous for mutation V726A) since childhood. She had recur- level 889 U/liter (normal 30 –250 U/liter), aldolase 9.5 rent attacks every 3– 4 weeks lasting 24 – 48 hours accom- U/liter (normal 1.2–7.6 U/liter), white cell count 4,200/ panied by fevers to 40°C and abdominal or chest pains. Her mm3, hematocrit 31%, platelet count 161,000/l, blood symptoms had responded to treatment with 1.8 –2.4 mg of urea nitrogen 6 mg/dl, creatinine 0.3 mg/dl, albumin 4.0 colchicine daily and she has been maintained on this gm/dl (normal 3.5– 4.8 gm/dl), urinalysis results were nor- dosage since her teenage years. She had not had any at- mal. Abdominal fat aspirate was negative for amyloid.
Nerve conduction and electromyography studies re- In 1997 the patient developed diarrhea and was diag- vealed moderately severe denervation in the proximal nosed with Crohn’s disease for which she was treated with muscles of the upper and lower extremities, as well as combinations of mesalamine, oral glucocorticoids, metho- absent superficial peroneal sensory responses and low am-plitude sural sensory responses.
Muscle biopsy of the right quadriceps revealed central Dr. Merkel is supported in part by a Mid-Career Develop-
rimmed vacuoles and endomysial fibrosis (Figure 1). There ment Award in Clinical Investigation (NIH-NIAMS: K24
was marked variability of fiber size with atrophic fibers AR-2224-01A1).
1Eugene Y. Kissin, MD, Francis A. Farraye, MD, MSc,
and few basophilic regenerating fibers. There was a noted Peter A. Merkel, MD, MPH: Boston University School of
absence of necrotic fibers and a paucity of inflammatory Medicine, Boston, Massachusetts; 2Joseph C. Corbo, MD,
infiltrate. Electron microscopy showed central longitudi- PhD: Children’s Hospital and Harvard Medical School, Bos-
nal autophagic vacuoles containing aggregates of cellular ton, Massachusetts.
degradation products and exhibiting areas of myofibrillar Address correspondence to Peter A. Merkel, MD, MPH,
Arthritis Center E5, Boston University School of Medicine,
715 Albany Street, Boston, MA 02118. E-mail: [email protected]
Colchicine was discontinued following the muscle bi- opsy in early November 2001 and no other medication Submitted for publication August 8, 2002; accepted in
changes occurred. By March 2002 her strength gradually revised form December 6, 2002.
improved, but her CPK enzyme level had only decreased cause bone marrow failure and death (5). Myopathy andneuropathy are well recognized but rare toxicities of treat-ment with oral colchicine. Colchicine may lead to myop-athy by causing a toxic accumulation of lysosomal andautophagic vacuoles in myocytes through disruption of thecytoskeletal network by which these vacuoles are excreted(6).
Colchicine is bound by tissues in the extravascular space because its volume of distribution is greater thantotal body water (7). Studies in mice have determined that,4 hours after intravenous administration, significantamounts of colchicine accumulate in the intestines, kid-neys, and spleen but not in blood, the brain, or muscles (8).
However, colchicine concentrations in these tissues werenot evaluated at later time points. Others have found leu-kocytes to contain significant concentrations of colchicine10 days following intravenous administration (9). Colchi-cine and its metabolites are cleared through the bile (10)and urine (11), thus renal or hepatic dysfunction may leadto elevation of plasma colchicine levels and increase therisk of toxicity (12). Interestingly, the mean elimination Figure 1. Conventional histology of muscle biopsy from right
thigh. Hematoxylin-eosin stain a,b and trichrome stain c,d dem-
half-life for colchicine in patients with FMF is more than onstrate variation in muscle fiber size (double arrow), centraliza-
twice as long as in healthy individuals, despite normal tion of nuclei (small arrow), endomysial fibrosis (white arrow),
renal function and no evidence of amyloidosis (13).
and central vacuoles (arrowhead) in several myofibers. There is a
Kuncl et al described the characteristic features of col- paucity of inflammatory cells and no necrosis of myofibrils.
chicine neuromyopathy in 12 patients (4). These features to 482 U/liter. Normalization of CPK (138 U/liter) and include proximal weakness, an elevation of creatine ki- return of normal strength occurred by June 2002, 8 months nase, proximal myopathic changes on electromyography, after discontinuation of colchicine. The patient has not axonal polyneuropathy on nerve conduction velocities, had any attacks of FMF over these 8 months.
and vacuolar myopathy on muscle biopsy, all of which ourpatient exhibited. However, unlike the patients presented Discussion
by Kuncl et al, our patient had persistently normal renal Our patient presented with an insidious onset of muscle function. Furthermore, our patient’s CPK levels did not weakness, CPK elevation, peripheral neuropathy, and a return to normal for 8 months following discontinuation of vacuolar myopathy on muscle biopsy. The resolution of the offending drug, while normalization typically occurs her symptoms with normalization of CPK enzymes follow- ing discontinuation of colchicine further implicates col- Three prior cases of colchicine-associated neuromyopa- chicine as the cause of her myopathy. Colchicine is well thy in patients with normal renal function have been re- known for its toxic side effects. Even at low doses it can ported (14,15). Two of these cases occurred in children commonly cause gastrointestinal distress. When given via with FMF. However, neither of these cases had evidence of the intravenous route in doses greater than 2 mg, espe- muscle involvement, with symptoms consisting only of cially to patients with renal or hepatic insufficiency, it can neuropathy. The third case occurred in a patient onchronic suppressive therapy for gout who, similar to ourpatient, also required a prolonged, 4-month period forresolution of myopathic toxicity (14).
Treatment of patients with FMF after the development of colchicine myopathy is problematic. Over 9 years, 49%of patients with FMF will develop proteinurea due to renalamyloidosis if colchicine is not used, compared with just1.7% in patients compliant with colchicine therapy (3).
One report of 10 patients describes interferon alfa beingused in an effort to abort attacks of FMF instead of colchi-cine (16). However, it is unknown whether interferon alfawill prevent the development of amyloidosis. As there issome evidence that colchicine can reverse or stabilizerenal amyloidosis, the risks of colchicine could potentially Figure 2. Electron microscopy of muscle biopsy from right thigh.
be avoided until proteinuria first develops. Patients with a, There are numerous autophagic vacuoles centrally located
previous myopathy could be then rechallenged with a within the muscle fibers and containing heterogeneous material.
lower dose of colchicine (0.6 mg/day). This case illustrates b, Numerous autophagic vacuoles produce extensive myofibrillar
the importance of continued clinical monitoring for col- chicine toxicity in patients on long-term treatment, even 8. Back A, Walaszek E, Uyeki E. Distribution of radioactive when renal and hepatic function is normal.
colchicine in some organs of normal and tumor-bearing mice.
Proc Soc Exp Biol Med 1951;77:667–9.
9. Ertel NH, Mittler JC, Akgun S, Wallace SL. Radioimmunoas- REFERENCES
say for colchicine in plasma and urine. Science 1976;193:233–5.
1. Zemer D, Revach M, Pras M, Modan B, Schor S, Sohar E, et al.
10. Hunter AL, Klaassen CD. Biliary excretion of colchicine.
A controlled trial of colchicine in preventing attacks of famil- J Pharmacol Exp Ther 1975;192:605–17.
ial Mediterranean fever. N Engl J Med 1974;291:932– 4.
11. Wallace SL, Omokoku B, Ertel NH. Colchicine plasma levels: 2. Dinarello CA, Wolff SM, Goldfinger SE, Dale DC, Alling DW.
implications as to pharmacology and mechanism of action.
Colchicine therapy for familial Mediterranean fever: a double- blind trial. N Engl J Med 1974;291:934 –7.
12. Achtert G, Scherrmann JM, Christen MO. Pharmacokinetics/ 3. Zemer D, Pras M, Sohar E, Modan M, Cabili S, Gafni J. Col- bioavailability of colchicine in healthy male volunteers. Eur J chicine in the prevention and treatment of the amyloidosis of Drug Metab Pharmacokinet 1989;14:317–22.
familial Mediterranean fever. N Engl J Med 1986;314:1001–5.
13. Halkin H, Dany S, Greenwald M, Shnaps Y, Tirosh M. Col- 4. Kuncl RW, Duncan G, Watson D, Alderson K, Rogawski MA, chicine kinetics in patients with familial Mediterranean fever.
Peper M. Colchicine myopathy and neuropathy. N Engl J Med 14. Pirzada NA, Medell M, I. AI. Colchicine induced neuromy- 5. Bonnel RA, Villalba ML. Deaths associated with the intrave- nous administration of colchicine [abstract]. Arthritis Rheum opathy in a patient with normal renal function. J Clin Rheu- 6. Shinde A, Nakano S, Abe M, Kohara N, Akiguchi I, Shibasaki 15. Harel L, Mukamel M, Amir J, Straussberg R, Cohen AH, H. Accumulation of microtubule-based motor protein in a Varsano I. Colchicine-induced myoneuropathy in childhood.
patient with colchicine myopathy. Neurology 2000;55: 16. Tunca M, Tankurt E, Akbaylar Akpinar H, Akar S, Hizli N, 7. Putterman C, Ben-Chetrit E, Caraco Y, Levy M. Colchicine Gonen O. The efficacy of interferon alpha on colchicine- intoxication: clinical pharmacology, risk factors, features, and resistant familial Mediterranean fever attacks: a pilot study.
management. Semin Arthritis Rheum 1991;21:143–55.
New Technologies and Alternative Feedstocks in Petrochemistry and Refining DGMK Conference October 9 – 11, 2013, Dresden, Germany Improved Performance of Nb-doped Vanadyl Pyrophosphate, Catalyst for n - butane Oxidation to Maleic Anhydride G. Pavarelli*, A. Caldarelli*, F. Cavani*, C. Cortelli**, S. Luciani** * Università di Bologna, Dipartimento di Chimica Industriale “Toso Montanar