Unsuspected colchicine overdose in a female patient presenting as an acute abdomen.
We report a case of multi-system organ failure as a result of unsuspected colchicine overdose in a patient with known gout and bulimia nervosa. The patient had initially presented with mild gastrointestinal symptoms with rapid progression to fulminant hepatic failure and multiple organ dysfunction before the causative agent was identified. The patient survived with aggressive intensive care support and ongoing medical treatment. Physicians should be aware of the risk assessment based on the ingested dose, that the clinical presentation of colchicine in toxic doses may be nonspecific with high potential for severe morbidity or death and that survival may occur despite multiple organ failure requiring aggressive support.
Key Words: colchicine, overdose, toxicology, poisoning, hepatic failure
Colchicine is a drug traditionally used in the treatment of acute gout. Toxicity is uncommon but has a high risk of mortality. Suicide attempts with colchicine are uncommon; however, therapeutic overdose can occur in patients with hepatic, renal or gastrointestinal disease. We report the case of a female presenting with diffuse gastrointestinal symptoms progressing to acute hepatic failure and multiple organ dysfunction, diagnosed as resulting from colchicine overdose after being listed for liver transplant for four days. Further history revealed access to colchicine. The patient survived after a 62-day admission.
A 34-year-old woman presented to hospital with a seven-hour history of nausea, vomiting and generalised abdominal pain of sudden onset. She was previously investigated for a three-month history of bloatedness and constipation, and was on triple therapy for suspected H. pylori without endoscopic biopsy diagnosis. She had a past history of gout and active bulimia. She was taking eight paracetamol tablets per day plus tramadol and was taking up to 20 docusate and senna tablets per day. She had never been prescribed colchicine. She had a moderate alcohol habit.
On examination she was euvolaemic, temperature 38[degrees]C, blood pressure of 109/76 mmHg and oxygen saturations of 100% on room air. Her abdomen was soft and non-distended with 'sluggish' bowel sounds and right-sided generalised tenderness. The examination was otherwise unremarkable.
The initial clinical impression was that of viral gastroenteritis with intravenous fluids and antiemetics prescribed and the patient was admitted for observation. Her haematology and biochemistry results showed neutrophilia with a white cell count of 15.8 x [10.sup.9]/l, potassium of 2.4 mEq/l and derangement of liver function tests (bilirubin<20 [micro]mol/l, ALP (N<135) 161 U/l, GGT (N<60) 43 U/l, ALT (N<40) 108 U/l, albumin 43 g/l) and amylase of 141 U/l. A serum paracetamol level performed on her presentation blood sample five days after her admission was less than 10 mg/l. The patient's pain had localised to the right upper quadrant with guarding. A general surgeon was consulted and an urgent ultrasound demonstrated a thick-walled gall bladder without evidence of obstruction. She was admitted with the diagnosis of biliary sepsis and commenced on intravenous antibiotics.
Approximately 24 hours after admission the patient became tachycardic (105/bpm) and hypotensive (80/56 mmHg) with crampy abdominal pain and ongoing vomiting. A laparotomy was performed at which an acutely oedematous and enlarged liver was the major finding with normal-looking gall bladder, bowel and spleen. The diagnosis at this stage was of acute hepatic/renal failure. The patient was transferred ventilated to the intensive care unit (ICU) and was listed for liver transplant due to suspected paracetamol-induced acute liver failure. A liver biopsy (taken at the time of laparotomy) showed acute zone-2 hepatocyte necrosis, marked steatosis and moderate fibrosis.
Her investigations on admission to ICU demonstrated deterioration in hepatic function with an ALT 1420 U/l, AST 4040 U/l, ALP 161 U/l, GGT 32 U/l and an INR of 4.8. An arterial blood gas showed mixed acidosis with a pH of 7.13, base excess of -13 and a lactate of 4.5.
Over the course of the next three days her condition deteriorated. On presentation she was placed on continuous haemodiafiltration for renal failure and significant metabolic derangement. It was apparent that she had progressive dysfunction of all systems with vasodilatory shock requiring extremely high doses of vasopressor agents, renal and metabolic dysfunction and progressive lung injury. Her CK peaked at 91400 U/l and her LFT peaked with ALT 280 U/l, AST 17000 U/l, ALP 297 U/l, GGT 303 U/l and bilirubin of 43 [micro]mol/l. On day six she developed pancytopenia with platelets of 53 and neutrophil count of 0.2X [10.sup.9]/l. Bone marrow biopsy proved pronounced synchronisation, with virtually no maturation beyond the myelocyte stage and marrow hypoplasia.
A clinical toxicologist reviewed the patient five days after presentation to hospital and suspected colchicine toxicity on the basis of the patient's clinical course, considering the shock and multi-organ failure and pronounced marrow failure following presentation with a gastrointestinal illness. Given the patient's history of gout and on further questioning of relatives the discovery that she worked in a pharmacy as an assistant, a second search of the family home was made, An empty colchicine bottle was found, the contents of which the patient was not known to have taken previously.
The patient developed alopecia three days later and survived with multiple medical co-morbidities as a result of the overdose but is currently able to live independently. She later confirmed the overdose of colchicine.
This case report describes a patient with unrecognised near-lethal colchicine overdose who had symptoms and signs of severe toxicity and who was initially listed for liver transplantation using criteria for paracetamol-induced liver failure.
Colchicine is an alkaloid obtained from Colchicum autumnale and related species, a treatment used primarily in the setting of acute gout. However it may also be used in the management of familial Mediterranean fever, primary biliary cirrhosis, amyloidosis, dermatitis herpetiformis and Sweets syndrome. Its anti-inflammatory effects are mediated by its ability to inhibit microtubule and polymorphonuclear leucocyte activity. Colchicine is antimitotic, blocking mitosis in metaphase, thus preventing DNA synthesis. It also inhibits urate crystal deposition but does not prevent progression to chronic gouty arthritis.
The drug is rapidly absorbed from the gastrointestinal tract, with peak levels occurring within 0.5 to two hours following oral ingestion. It is partially deacetylated in the liver with extensive first-pass metabolism. The oral bioavailability of colchicine is between 25% and 50% and found in high concentrations in leucocytes, kidneys, liver and spleen'. Elimination is by hepatic metabolism and the elimination half-life is approximately 30 hours after an overdose Z.
Any intentional ingestion of colchicine should be considered potentially lethal. (2) In a French series of 84 patients admitted with colchicine poisoning in an 11-year period, all patients who had ingested less than 0.5 mg/kg survived, whereas all those who ingested greater than 0.8mg/kg died within 72 hours of the ingestion (8). There is a 10% mortality for those who ingested between 0.5-0.8 mg/kg of colchicine. Hence, where possible, risk assessment is made on the ingested dose Z.
The classic presentation of colchicine toxicity can be divided into three phases. The first phase, up to 24 hours after ingestion, is characterised by gastrointestinal symptoms, electrolyte imbalance, hypovolaemia and peripheral leucocytosis (2,3). The patient may experience a feeling of burning and rawness in the mouth and difficulty in swallowing'. Nausea, vomiting, diarrhoea, abdominal pain and anorexia can all mimic a primary abdominal process which may be referred to general surgery or gastroenterologists. Such symptoms correspond to gastrointestinal mucosal damage and impairment of secretion of normal mucosal enzymes (4). Significant fluid loss due to vomiting and diarrhoea may lead to hypovolaemic shock (5).
The life-threatening consequences of overdose occur in the second phase, 24 to 72 hours following ingestion, and can last up to seven days. Multiple organ dysfunction syndrome develops early in the second stage, with vasomotor failure and systemic inflammatory response leading to cardiovascular collapse and lung injury. Shock may occur as a result of hypovolaemia, profound vasodilatation resulting from systemic inflammation, or cardiac dysfunction and is clinically correlated with mortality (6). Cardiotoxicity commonly manifests as arrhythmias such as sinus bradycardia, sinus tachycardia, ventricular fibrillation and complete atrioventricular block. Renal failure and rhabdomyolysis can occur. Bone marrow suppression is initially indicated by lymphopenia, likely to be followed by agranulocytosis, leucopenia and thrombocytopenia peaking at four to eight days after ingestion. This may be complicated by disseminated intravascular coagulation (1). Fever and sepsis may be seen at this stage. Central nervous system toxicity and cerebral oedema may be indicated by mental confusion, delirium, seizures and muscular weakness; rhabdomyolysis may occur, as well as the development of ascending central nervous system paralysis with the patient remaining conscious (1). Metabolic derangements include metabolic acidosis, hyperglycaemia, hypokalaemia, hypokacaemia, hypophosphataemia and hypomagnesaemia (7).
Fulminant hepatic failure requiring liver transplantation has not been reported in colchicine overdose. Death may occur at this stage as a result of the multi-system insult.
If the patient survives the second stage the prognosis is markedly better. The third phase, from the seventh day onwards, is characterised by rebound leucocytosis due to renewed bone marrow activity, resolution of multiple organ failure, transient alopecia and stomatitis. Myopathy and neuropathy can occur. Complete recovery can be anticipated if the patient progresses to this stage.
Treatment consists primarily of early risk assessment of the colchicine overdose, decontamination and supportive therapy.
Aggressive decontamination is attempted early, using activated charcoal, as even a small reduction in amount of colchicine absorbed may make a difference','. Repeated oral charcoal dosing may enhance elimination but has not been shown to affect outcome and is not routinely recommended'. Management is then supportive and any patient with an ingested dose >0.5 mg/kg or gastrointestinal symptoms should be admitted to an intensive care unit as dialysis, inotropes and ventilation may be required (2).
Granulocyte colony-stimulating factor has been used in patients to assist regeneration of suppressed bone-marrow seen in overdose patients; however it is unknown whether this is due to therapeutic response or predetermined recovery of the patient (5,9). Anticolchicine monoclonal antibodies are the only therapy specifically targeted to colchicine toxicity. There have been cases in which severe overdose has been successfully treated with experimentally produced colchicine-specific Fab fragments (10). Currently they are not produced commercially.
In conclusion, this 34-year-old female survived an unrecognised colchicine overdose, after an admission to an ICU with shock and multiorgan failure presenting with initially dominant liver failure. Clinicians should have a high index of suspicion for this diagnosis in patients with this presentation and with access to colchicine. Risk assessment is made on an ingested dose and the assumption that any intentional colchicine overdose is potentially lethal. Management involves early, aggressive decontamination and supportive care and often will require intensive care admission. Death usually occurs in ingestions greater than 0.8 mg/kg.
Accepted for publication on January 19, 2007.
(1.) MIMS Australia. Colchicine-MIMS Abbreviated Prescribing Information. Section 5(e) Agents used in gout and hyperuricaemia--Musculoskeletal system. MIMS 2005.
(2.) Murray L, Daly F, Little M, Cadogan M. Colchicine In: Toxicology Handbook. 1st ed. Australia 2007; 182-184.
(3.) Maxwell MJ, Muthu P, Pritty PE. Accidental colchicine overdose-A case report and literature review. Emerg Med J 2002; 19:265-267.
(4.) Stemmermann GN, Hayashi T Colchicine intoxication. A reappraisal of its pathology based on a study of three fatal cases. Hum Pathol 1971; 2:321-332.
(5.) Murray L, Harris R. Colchicine. In: Cameron P, Jelinek G, Kelly A, Murray L, Brown A, Heyworth J, eds. Textbook of Adult Emergency Medicine, 2nd ed. Australia, 2004; 820-822.
(6.) Sander P, Kopferschmitt J, Jaeger A, Mantz JM. Haemodynamic studies in eight cases of acute colchicine poisoning. Hum Toxicol 1983; 2:169-173.
(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.) Bismuth C Gautier M, Conso E Aplaise medullaire aprbs intoxication aigue a la colchicine. Nouv Presse Med 1977; 6:1625-1629.
(9.) Folpini A, Furfori P Colchicine toxicity-clinical features and treatment. Massive overdose case report. J Toxicol Clin Toxicol 1995; 33:71-77.
(10.) Baud FJ, Sabouraud A, Vicaut E, Taboulet P, Lang J, Bismuth C et al. Brief report: treatment of severe colchicine overdose with colchicine-specific Fab fragments. N Engl J Med 1995; 332:642-645.
R. E. BLACKHAM *, M. LITTLE ([dagger]), S. BAKER *, B. M. AUGUSTSON ([section]), G. C. MACQUILLAN **
Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
* M.B., B.S., Medical Officer, Emergency Department.
([dagger]) M.B., B.S., D.T.M.&H. (London), F.A.C.E.M., M.PH.&T.M., Staff Specialist and Clinical Toxicologist, Emergency Department and Clinical Senior Lecturer, University of Western Australia.
([double dagger]) M.B., B.S., F.J.F.R.C.M., Staff Specialist, Intensive Care Unit.
([section]) M.B., B.S., F.R.A.C.P, F.R.C.P.A., Clinical Haematologist.
** B.Sc. (Hons), M.B.Ch.B., M.R.C.P, Ph.D., F.R.A.C.P, Staff Specialist, Department of Gastroenterology and Hepatology and Clinical Senior Lecturer, University of Western Australia.
Address for reprints: Dr R. Blackham, Sir Charles Gairdner Hospital, Nedlands, W.A. 6009.
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|Author:||Blackham, R.E.; Little, M.; Baker, S.; Augustson, B.M.; Macquillan, G.C.|
|Publication:||Anaesthesia and Intensive Care|
|Article Type:||Clinical report|
|Date:||Jun 1, 2007|
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