Colchicine-Induced Bone Marrow Aplasia in an Elderly Female with Renal
Insufficiency
Chen-Sen Huang1, Jen-Pi Tsai2, Horng-Rong Chang3
1
Division of Nephrology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
2
Division of Nephrology, Buddhist Dalin Tzu Chi General Hospital, Chiayi, Taiwan
3
Division of Nephrology, Department of Internal Medicine, Chung Shan Medical
University Hospital, Taichung, Taiwan
Correspondence and reprint request to:
Horng-Rong Chang M.D. & Ph.D.
Division of Nephrology, Department of Internal Medicine, Chung-Shan Medical
University Hospital
No.110, Section 1, Jianguo N. Road, Taichung 402, Taiwan.
Tel: +886-424739595 ext 32630
Fax: +886-424739595 ext 32624
E-mail: chr@csmu.edu.tw
慢性腎臟病患者因使用秋水仙素造成骨髓再生不全:病例報
告
黃振森 1 蔡任弼 2 張浤榮 3
1
新光吳火獅紀念醫院腎臟科
2
佛教慈濟綜合醫院大林分院腎臟科
3
中山醫學大學附設醫院腎臟科
秋水仙素常被用來治療及預防痛風的發作，以及使用在一些疾病，如家族性
地中海型風濕熱、貝西氏症以及類澱粉沈著症。因使用治療劑量的秋水仙素所造
成的全血球低下症實屬罕見。所以目前仍沒有建議的治療方式。
我們報告一位 78 歲慢性腎臟病的女性，因服用秋水仙素引起全血球低下症
及骨髓再生不全,在使用顆粒球聚落刺激因子及紅血球生成素後血球恢復的個
案。 藉由此個案，我們回顧文獻後，了解年老及有肝腎疾病都是容易引起秋水
仙素的血球毒性，以及此副作用可以給予顆粒球聚落刺激因子及紅血球生成素來
治療。
關鍵詞：秋水仙素，慢性腎臟病，骨髓再生不全，顆粒球聚落刺激因子，紅
血球生成素
Abstract
Colchicine has long been used to treat and prevent acute attacks of gout and also
used in a variety of conditions such as familial Mediterranean fever, Behcet’s disease,
and amyloidosis. Therapeutic oral colchicine induced severe pancytopenia have been
reported but rarely. However, there is no recommended treatment currently.
We described a 78 years old female with pancytopenia and bone marrow aplasia
induced by oral colchicines and treatments with granulocyte colony-stimulating factor
(G-CSF) and erythropoietin (EPO). Pancytopenia and bone marrow aplasia recovered
after treatment.
Severe side effect of colchicine is rare, but maybe more frequent in elderly,
patient with renal insufficiency and hepatic dysfunction. Treat colchicines induced
pancytopenia with combination of GCS-F and EPO may be effective.
Key word: colchicine, pancytopenia, EPO, G-CSF
Introduction
Colchicine has long been used to treat and prevent acute attacks of gout and also
used in a variety of conditions such as familial Mediterranean fever, Behcet’s disease,
and amyloidosis. Under therapeutic oral dose, the most common side effects of oral
colchicine are gastrointestinal symptoms including diarrhea, nausea, vomiting and
abdominal pain.[1] But severe side effects such as pancytopenia or bone marrow
aplasia, especially in elderly are reported.[2-5] There is no recommended treatment
for pancytopenia caused by colchicine currently. We described a case with
pancytopenia and bone marrow aplasia diagnosed by bone marrow biopsy induced by
oral colchicine and recovered gradually with granulocyte colony-stimulating factor
(G-CSF) and erythropoietin (EPO).
Case report
A 78 year-old female who lives at nursing home was admitted to our hospital in
August 2007 because of general weakness for two days. She has the history of old
cerebrovascular accident (CVA), hypertension and chronic gouty arthritis under
medical treatment. Three days prior to admission, the patient was brought to
emergency room (ER) because of watery diarrhea and fresh bloody stool for five
times. She also had nausea and vomiting, but denied abdominal pain or fever. Other
residents of nursing home had no similar symptoms. The patient denied taking any
medication except those from out-patient department. Medications for gouty arthritis
were prednisolon 5 mg daily, colchicine 0.5 mg daily, allopurinol 100 mg daily, and
celebrex 200 mg daily since June 26th 2006 to August 13 2006. One week before
admission, medications were adjusted because of more episodes of gouty arthritis.
(prednisolon 20mg daily , colchicine 1.5 mg daily, allopurinol 100 mg daily,
diclofenac 50 mg daily and cimetidine 600 mg daily). Acute gastroenteritis and
hemorrhoid bleeding were considered in ER and she was brought home after
treatment. Medications for gouty arthritis were discontinued since then.
The patient was brought to ER again two days later due to progressively general
weakness. Her blood pressure was 164/117 mmHg, body temperature was 36℃, pulse
rate was 105 (beats/min), and respiratory rate was 14 (times/min). Physical
examination disclosed clear consciousness, pale conjunctivae and tophi over right
hand. Complete cell count disclosed white blood cell (WBC) count 2410/mm3 with
75% neutrophils, hemoglobin 10.7 g/dL and platelet 50 x 103/ul at admission (Table
1). Blood urea nitrogen was 59 mg/dl and creatinine 2.9 mg/dl (estimated glomerular
filtration rate (eGFR) was 16.68 ml/min calculated by Modification of Diet in Renal
Disease formula). Urinalysis revealed pyuria with bacteruria. Abdominal echo
revealed bilateral contracted kidney with degenerative cystic lesions and no
hepato-bilillary problems. Brain CT images revealed hypodense lesion over the right
parietal lobe which was compatible with diagnosis of old CVA.
After admission, cefazolin 1 g was administered intravenously every 12 hours
under the suspicion of urinary tract infection. The followed hematological data at day
4 revealed WBC 1.63 x 103/ul , RBC 3.21 x 106/ul and platelet 53 x 103/ul. Bone
marrow biopsy was performed for the evalaution of pancytopenia and disclosed
aplastic bone marrow. (Figure 1 and 2). Because of infectious disease and
pancytopenia, GCS-F 250μg subcutaneously was prescribed for her at day 5,day 8
and day 12 after hospitalization. EPO 2000 IU subcutaneously was given to her
sequentially for three days since day 6 after hospitalization. She was discharged at day
13 with the hematological data revealing WBC 6.78 x 103/ul, hemoglobin 9.2 g/dl and
platelet 137 x 103/ul.
Discussion
Colchicine is a neutral and liposoluble alkaloid. Colchicine interferes with
microtubule growth and affects mitosis. It is absorbed mainly in the ileum, partially
metabolized in the liver and its metabolites are excreted through the biliary tract.
Kidneys excreted about 20% of unchanged colchicine. After oral ingestion, maximal
plasma concentration occurs is 1.1 to 1.5 hours and the mean half-life for its
elimination is about 9 to 16 hours in pharmacological conditions. Patient with hepatic
or renal impairment may have prolonged elimination.[1]
Colchicine toxicity and death is usually a consequence of oral colchicine
overdosage exceeding 0.5 mg/kg, the lowest reported overdose fatality being 7.5mg.
Bismuth and colleagues reported minor toxicity with 100% survival after ingestion of
less than 0.5 mg/kg, major toxicity (myelosuppression) with 10% mortality after
ingestion of 0.5 to 0.8 mg/kg, and 100% mortality (cardiogenic shock and death) after
ingestions of doses more than 0.8 mg/kg.[6] The risk factors for colchicines toxicity
include (a) intravenous use, (b) use of loading dose, (c) use in elderly patients, (d)
renal insufficiency, (e) hepatic dysfunction, (f) drug interaction (cimetidine,
erythromycin, tolbutamide).[7]
The course of colchicines toxicity can be divided into three sequential and usually
overlapping stages. The first stage occurs during the first 24 hours after ingestion and
is dominated by the gastrointestinal symptoms, including diarrhea, nausea and
vomiting, leading volume depletion and leukocytosis. The second stage develops from
24 to 72 hours after ingestion and is dominated by multiorgan failure. There may
include bone marrow failure, renal failure, acute respiratory distress syndrome,
arrhythmia, disseminated intravascular coagulation and neuromuscular disturbance.
The third stage is recovery of bone marrow with rebound leukocytosis, resolution of
organ system derangement and development of alopecia.[8]
Colchicine causes bone marrow depression, particularly when associated with acute
intoxication and also been reported after intravenous and oral administration of
therapeutic doses.[2,3] Most patients had gastrointestinal and neurologic toxicities
before or at onset of severe hematopoietic suppression. A typical arrest of marrow
function includes leucopenia, reticulocytopenia, thrombocytopenia and hypocellular
bone marrow. Although oral administration of therapeutic dose colchicines induced
pancytopenia had been reported.[6] The majority had received colchicine
intravenously,[1] and oral administration seems safer.[9] Characteristically,
leucopenia lasts for 2-5 days after colchicine is given; leukocytosis appears at the
seventh or eighth day and may persist for two weeks.
In this patient, she received therapeutic dose of colchicine and recovered from
pancytopenia more than two weeks. The possible causes of intoxication under
therapeutic dose are aged, decrease of excretion due to renal insufficiency (eGRF
16.68 to 38.65 ml/min) and combination of cimetidine. Although allopurinol is
another possible cause of leukocytopenia and aplastic anemia, but allopurinol dose is
not titrated and patient’s clinical course was compatible to colchicines intoxication.
The management of severe colchicines poisoning is mainly supportive. Because of
colchicine’s rapid tissue distribution and highly binding affinity at intercellular site,
hemodialysis, charcoal hemoperfusion and plasma exchange are not effective. A
colchicine specific Fab fragment have been reported to treat a life-threatening
overdose.[10] Fab fragment infusion has been shown to increase urinary excretion of
colchicines in patients by six-fold, and at least 98% of the colchicines was bound to
Fab fragments during the first 16 hours after the start of the infusion. Despite their
efficacy, the use of specific Fab fragments is still highly experimental and they are not
easily available clinically. G-CSF is reported effectively to treat the bone marrow
depression or pencytopenia which follows colchicine poisoning.[3-5] G-CSF is
known to promote the proliferation and maturation of neutrophil granulocytes
specificall and works with interleukins to support megakaryocyte-mediated platelet
production.[11] EPO is used to treat anemia in end-stage renal disease, anemia in
myelodysplastic syndrome and aplastic anemia to increase erythroid response.[11,12]
Combination of EPO and G-CSF also is used to treat meylodysplastic
syndrome[12-15] and has a synergistic effect.[14] In this patient, change of RBC
count is small after using EPO. Not enough dosage of EPO was supposed due to
report of Mundle et al. that high dose EPO between 60,000 to 80,000 U/week is used
to treat myelodysplastic syndrome.[13]
In conclusion, clinical using colchicine is safe and severe side effect of
colchicine is rare, but probably more frequent in elderly, patients with renal
insufficiency and hepatic dysfunction. To treat colchicine-induced pancytopenia with
combination of GCS-F and EPO may be effective, but definitive dose and duration
still need further investigation.
References
1
Levy M, Spino M, Read SE: Colchicine: A state-of-the-art review.
Pharmacotherapy 1991;11:196-211.
2
Liu YK, Hymowitz R, Carroll MG: Marrow aplasia induced by colchicine. A
case report. Arthritis Rheum 1978;21:731-735.
3
Yoon KH: Colchicine induced toxicity and pancytopenia at usual doses and
treatment with granulocyte colony-stimulating factor. J Rheumatol
2001;28:1199-1200.
4
Katz R, Chuang LC, Sutton JD: Use of granulocyte colony-stimulating factor in
the treatment of pancytopenia secondary to colchicine overdose. Ann Pharmacother
1992;26:1087-1088.
5
Critchley JA, Critchley LA, Yeung EA, Young RP, Young RJ, Chan TY, Goh VK:
Granulocyte-colony stimulating factor in the treatment of colchicine poisoning. Hum
Exp Toxicol 1997;16:229-232.
6
Bismuth C, Baud F, Dally S: Standardized prognosis evaluation in acute
toxicology its benefit in colchicine, paraquat and digitalis poisonings. J Toxicol Clin
Exp 1986;6:33-38.
7
Putterman C, Ben-Chetrit E, Caraco Y, Levy M: Colchicine intoxication: Clinical
pharmacology, risk factors, features, and management. Semin Arthritis Rheum
1991;21:143-155.
8
Simons RJ, Kingma DW: Fatal colchicine toxicity. Am J Med 1989;86:356-357.
9
Peters RS, Lehman TJ, Schwabe AD: Colchicine use for familial mediterranean
fever. Observations associated with long-term treatment. West J Med 1983;138:43-46.
10 Baud FJ, Sabouraud A, Vicaut E, Taboulet P, Lang J, Bismuth C, Rouzioux JM,
Scherrmann JM: Brief report: Treatment of severe colchicine overdose with
colchicine-specific fab fragments. N Engl J Med 1995;332:642-645.
11
Gabrilove JL: Introduction and overview of hematopoietic growth factors. Semin
Hematol 1989;26:1-4.
12 Geissler RG, Schulte P, Ganser A: Clinical use of hematopoietic growth factors in
patients with myelodysplastic syndromes. Int J Hematol 1997;65:339-354.
13 Mundle S, Lefebvre P, Vekeman F, Duh MS, Rastogi R, Moyo V: An assessment
of erythroid response to epoetin alpha as a single agent versus in combination with
granulocyte- or granulocyte-macrophage-colony-stimulating factor in myelodysplastic
syndromes using a meta-analysis approach. Cancer 2009;115:706-715.
14 Hellstrom-Lindberg E: Efficacy of erythropoietin in the myelodysplastic
syndromes: A meta-analysis of 205 patients from 17 studies. Br J Haematol
1995;89:67-71.
15 Moyo V, Lefebvre P, Duh MS, Yektashenas B, Mundle S:
Erythropoiesis-stimulating agents in the treatment of anemia in myelodysplastic
syndromes: A meta-analysis. Ann Hematol 2008;87:527-536.
Table 1 Hematological data
Date
ER
Day
1
Day
4
Day
6
Day
10
Day
12
Day
19
Day
26
WBC(103/ul)
N(%)
L(%)
B(%)
2.8
87.2
6.4
0
2.41
75
14
1.63
1.35
74
16
2.41
1.39
14
7
12
3
3.73
63
10
5
6.78
92.2
5
0
Mono(%)
Eosin.(%)
Hb(g/dL)
Hct(%)
RBC(106/ul)
RDW(%)
PL(103/ul)
6.4
0
10.3
8
9
10
31
7.9
24.2
2.80
16.5
50
9.2
29.2
3.23
18.3
69
9.2
29.6
3.25
18.2
82
18
0
10
31.6
3.49
18.9
107
2.8
0
9.2
28.1
3.23
18.1
137
84
10.7
32.6
16.1
50
9.1
27.2
3.21
15.9
53
Figure 1. Bone marrow contained less than 10 % cellularity (Bone marrow, PAS stain,
40 X)
Figure 2. The precursors of hematopoietic series were markedly decreased and with
inappropriate ratio of erythrocytes and granulocytes. (Black arrow represent
erythrocyte precursor; red arrow granulocyte precursor)(Bone marrow, PAS stain, 400
X)