PEDIATRICS Vol. 109 No. 5 May 2002, pp. 971-973
EXPERIENCE AND REASON |
Late Diagnosis of Severe Colchicine Intoxication
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
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A 4-year-old Turkish girl was referred to our hospital with the findings of encephalopathy and pancytopenia. She had a history of severe abdominal cramps and gastrointestinal bleeding. A confused state, muscle pain and weakness, erythema-bullous and erythema-nodosum–like skin lesions, and alopecia were observed at her hospitalization. All of these symptoms resolved on follow-up. On laboratory investigation severe thrombocytopenia and leukopenia, mild anemia, a moderate increase in aspartate aminotransferase and alanine aminotransferase levels were detected. After reevaluating her medical history, it was learned that she had accidentally taken 1.3 to 1.5 mg/kg of colchicine 3 to 4 days before her first hospitalization.
The possibility of misdiagnosis of colchicine intoxication should be borne in mind, and pediatricians must be aware of its toxic effects, especially in areas where patients with familial Mediterranean fever are present.
Key Words: colchicine • intoxication • children • late diagnosis
Abbreviations: FMF, familial Mediterranean fever
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
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Familial Mediterranean fever (FMF) is a relatively common disease in the Mediterranean and in the Middle East. Colchicine has been routinely used for the prevention of acute attacks of FMF and of amyloid formation.1–3 Despite its wide use in children with FMF, few cases of colchicine intoxication have been reported, including a child with a fatal outcome.4–7 Symptoms related to its toxic effects could be observed even with the usage of therapeutic doses.
We here report a child with the symptoms of severe colchicine intoxication who was misdiagnosed with pancreatitis and febrile neutropenia.
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CASE REPORT |
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TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
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A 4-year-old Turkish girl was referred to our center with the findings of encephalopathy and pancytopenia. Before admission to the city hospital with the complaints of abdominal pain, diarrhea, and vomiting, she had the past history of a confused state for few days, which was explained by the fact that she fell down the stairs. She had been hospitalized for 10 days in that hospital with the suspicion of pancreatitis. She had blood transfusions because of severe gastrointestinal bleeding, petechiae, and ecchymoses.
On admission to our center, she was pale and lethargic. Her blood pressure was 90/70 mm Hg, body temperature was 37.8°C, heart rate was 154 beats per minute, and respiratory rate was 44 breaths per minute. There were a necrotizing area on her left alar cartilage, painful enanthemae on her buccal mucosa, and petechiae on upper and lower extremities. Muscles on the distal part of her lower extremities were painful when pressure was applied. The rest of her physical examination was unremarkable.
Severe thrombocytopenia (24 000 and 18 100/mm3), leukopenia (680 and 850/mm3) and mild anemia (9.6 g/dL) were detected on admission. A decrease in the whole series was observed on bone morrow aspiration. Protrombin time and partial thromboplastine time were found within normal limits. Granulocyte colony-stimulating factor (Filgrastim pITN, Roche, Switzerland) and antibiotics were administered with the diagnosis of febrile neutropenia.
On the second day of hospitalization, the patient developed errythematous skin lesions with the bullous central areas of 1 to 2 cm diameter on her trunk and on extremities (Fig 1). In a few days, painful, subcutaneous erythema nodosum-like nodules were noticed on her pretibial regions. Skin lesions were defined as Sweet syndrome-like eruptions by dermatologists and biopsy showed neutrophilic infiltration.
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On laboratory evaluation, a moderate increase in aspartate aminotransferase and alanine aminotransferase was detected (326 IU/mL and 194 IU/mL, respectively). C-reactive protein, erythrocyte sedimentation rate, lactic (acid) dehydrogenase,
-glutamyltransferase, kidney function tests, calcium, phosphorus, and plasma ammonia levels were substantially normal. Creatine phosphokinase was found to be 25 U (normal limits: 6–206). Throughout her hospitalization, serum sodium and potassium levels ranged between 136 and 147 mEq/L and between 2.6 and 4.6 mEq/L, respectively.
Occipital alopecia was noted on the second day and progressed to almost total alopecia (Fig 2). After the second day of hospitalization, her confused state gradually improved; but weakness on her lower extremities sustained. Deep tendon reflexes were found to be normal. Sensory loss could not be sufficiently examined.
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Her cerebral tomography and electromyography did not show any abnormality. Echocardiography was normal.
On clinical follow-up, her abdominal pain resolved in a week; consciousness normalized on the 12th day, muscle weakness improved in 2 weeks, and dermatologic lesions healed within 20 days. Her outpatient follow-up for the last 6 months was normal.
Her medical history was reevaluated for drug poisoning and family members were questioned. The patient’s 8 year-old sister, who has been diagnosed with FMF, was also taking colchicine remembered that the patient had taken her bottle of colchicine and eaten almost 45 to 48 pills 3 to 4 days before her first admission to the hospital.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
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Colchicine is a neutral and liposoluble alkaloid. It is absorbed mainly in the ileum. It is partially metabolized in the liver through deacetylation mediated by cytochrome P 3A4, and its metabolites are excreted through the biliary tract.1 Kidneys are responsible for the excretion of 20% of unchanged colchicine. After oral ingestion, the mean half-life for its elimination is 9 to 16 hours in pharmacologic conditions and may prolong with the toxic doses. An overdose of colchicine inhibits cell division on affected organs. Colchicine displays its effect by fixating the intracellular tubuli and arresting their polymerization into microtubules; thus, mitosis and transport systems within the cells are disrupted. The most effected organs are those that have a high rate of cell turnover, such as the gastrointestinal tract and bone marrow. First symptoms of acute toxicity occur within the first 24 hours of ingestion and include nausea, vomiting, diarrhea, and abdominal pain. Multiorgan failure develops after 24 to 72 hours after ingestion. Bone marrow depression, hemolytic anemia, liver damage, renal failure, respiratory distress syndrome, arrhythmias, neuromuscular disturbances (myopathy, proximal weakness, dysthesia, diminished deep tendon reflexes, paralysis) and disseminated intravascular coagulation can be detected in the second stage.1 Hyponatremia, hypocalcemia, and metabolic acidosis can occur.
Our patient presented most of the acute and subacute symptoms of colchicine intoxication such as gastrointestinal, hematologic, and dermatologic disturbances. The patient’s confused state mimicking encephalopathy and muscle weakness were suggestive for the colchicine-induced nervous system involvement. Myoneuropathy manifested by distal areflexia, sensory abnormalities, and numbness attributable to colchicine ingestion have been described.8 In our patient, longstanding muscle weakness has been observed, while her deep tendon reflexes, creatine phosphokinase level, and electromyograph were found to be normal. Transient hypokalemic state can also be the reason for the muscle weakness.
Dermatologic findings of this patient were erythema-bullous lesions and erythema nodosum-like painful nodules. Those lesions could be attributable to the drugs given to the patient such as granulocyte colony-stimulating factor and antibiotics and also to colchicine. These lesions have not been described in colchicine intoxication before; and it may possibly be related to the late stage of colchicine toxicity.
In our case, cardiovascular, pulmonary, or renal involvement of colchicine intoxication could not be determined during her hospitalization while alopecia, which has been described as a finding of the recovery stage, was detected.9
In literature, the youngest patient with colchicine intoxication was a 3-year-old child who ingested an inappropriate dose and recovered completely.4 A fatal pediatric case of colchicine poisoning has also been reported.7 Death usually occurs 36 to 72 hours after ingestion resulting from hypovolemic shock, central nervous system damage, or cardiopulmonary failure.7 The risk of colchicine intoxication can be correlated to the dose administered. The toxic dose decreases when the colchicine is taken acutely.5 A high fatality rate was reported to be associated with oral doses of colchicine exceeding 40 mg. However, there are adult patients who survived even after ingesting 350 mg of colchicine.9 Our patient might have consumed 1.3 to 1.5 mg/kg of colchicine acutely. Unfortunately, the serum colchicine level could not be determined. A good outcome has been reported after ingestion of 0.6 mg/kg body weight of colchicine. Severe intoxication with cardiovascular and central nervous system involvement with prophylactic colchicine doses to treat FMF has also been reported.5 Erythromycine and ketoconazole are specific inhibitors of cytochrome P3A4.1
Treatment is symptomatic and supportive. An antidotal effect of glutamate or aspartate has been reported in animal studies.1 Recently, an effective and lifesaving treatment with F (ab) fragments of anticolchicine antibodies was reported in a patient with cardiovascular failure.10
In this case, severe gastrointestinal and hematologic disturbances that developed at the beginning had led the pediatrician to a misdiagnosis. Although we do not know the exact dose of colchicine ingested by this patient, fortunately she had an early nonspecific supportive therapy and recovered completely.
In regions where the patients with FMF are seen more often and colchicine use is common, either mild or severe symptoms of colchicine poisoning may be overlooked, and intoxication may be misdiagnosed.
Department of Pediatrics
Akdeniz University Medical Faculty
07070 Antalya, Turkey
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FOOTNOTES |
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Received for publication Dec 14, 2000; Accepted Oct 29, 2001.
Reprint requests to (A.G.G.) Department of Pediatrics, Akdeniz University Medical Faculty, Dumlupinar Blvd, 07070 Antalya, Turkey. E-mail: gur{at}med.akdeniz.edu.tr
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REFERENCES |
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