ToxCard: Colchicine Toxicity

Authors: Travis Barlock, MD (Emergency Medicine Resident, Carolinas Medical Center, Charlotte, NC); Kathryn T Kopec, DO (Emergency Medicine Attending; Medical Toxicologist, Carolinas Medical Center, Charlotte, NC) // Reviewed by: Cynthia Santos, MD (@Cynthia Santos, MD); Alex Koyfman, MD (@EMHighAK); and Brit Long, MD (@long_brit)

 

Case Presentation:

A 55-year-old male presents to the emergency department (ED) complaining of fatigue, abdominal pain, vomiting, and bloody diarrhea 6 hours after ingesting a handful of his “gout medicine.” Initial vital signs were HR 155 bpm, BP 95/65mmHg, RR 24 breaths/minute, 97% RA, and 100.3ºF. The patient was cool and clammy to touch, tachycardic and had a tender abdomen on exam.

 

Question:

What gout medication are you most concerned about in his presentation?

A. Indomethacin

B. Colchicine

C. Allopurinol

D. Ibuprofen

 

 

Answer:

B. Colchicine

What is Colchicine?

  • Colchicine is a natural alkaloid originally derived from the plants Autumn Crocus (Colchicum autumnale) and Glory Lilly (Gloriosa superba) that has been used as a treatment for gout since 1820. [1,2] Colchicine is a controversial drug, with a narrow therapeutic index and well documented cases of severe toxicity and death. Currently, there is no approved antidote. [3]

 

Pathophysiology of Overdose

Colchicine is rapidly absorbed in the jejunum, but it is only 25-50% bioavailable. It is approximately 50% protein bound and highly lipophilic giving it a large volume of distribution. These factors make it non-dialyzable. [4]

Mechanism of Action:

  • Colchicine is a potent inhibitor of microtubule formation. Binding of tubulin interferes with cellular division, intracellular transport, and cellular migration. [4]
  • At low concentrations, colchicine halts microtubule growth, but at higher concentrations it depolymerizes microtubules resulting in cell dysfunction and death.
  • Colchicine accumulates in rapidly dividing cells, in particular, leukocytes. Leukocyte adhesion, mobility, chemotaxis, degranulation, and phagocytosis are all disrupted. [4]

Colchicine is metabolized in the liver by CYP3A4 and is ultimately excreted in the biliary tract and in stool, however, it does undergo some degree of enterohepatic circulation. Secondary to its’ hepatic metabolism patients with underlying liver disease or those on CYP3A4 inhibitors will more readily accumulate toxic levels of colchicine. [4]

 

Clinical Presentation:

At toxic doses, colchicine will preferentially inhibit mitosis of rapidly dividing cells (leukocytes, enterocytes, stem cells, skin cells)

  • In mild poisoning, the GI tract is predominately affected resulting in nausea, vomiting, diarrhea and abdominal pain. [4]
  • With severe poisoning, there is a well described “Triphasic Response” [5]
    • Phase I (0 – 24 hrs): GI symptoms (nausea, vomiting, bloody diarrhea, abdominal pain), dehydration with hypotension, leukocytosis (often >30,000/mm3)
    • Phase II (1 to 7 days): Multiorgan system failure, profound leukopenia, hypovolemic shock, dysrhythmias, rhabdomyolysis, renal failure, liver failure, acute lung injury with respiratory failure, seizures
    • Phase III (> 7 days): Recovery or Death: can develop sensory neuropathies and areflexia, myopathies, alopecia, respiratory failure, cardiovascular collapse, dysrhythmia, intractable shock, death

 

How do you make the diagnosis?

  • Colchicine toxicity is a clinical diagnosis.
  • Colchicine concentration levels are not routinely available
    • However, concentrations over 3.0ng/mL are associated with mild toxicity while cases over 24.0ng/mL are associated with severe toxicity [4]
  • Any patient taking colchicine presenting with gastrointestinal complaints should be asked about their dosing
  • A marked leukocytosis on presentation may suggest potential toxicity
  • Patients who present later will appear to be in undifferentiated shock
  • Initial labs should include CBC, BMP, LFTs, CK, phosphate, calcium, magnesium, PT/INR, aPTT, and a UA.
  • Troponin, arterial blood gases, lactate, fibrinogen, and fibrin split products, are helpful in guiding care if cardiotoxicity, ARDS, or coagulopathies develop [4]
    • A troponin level should be checked every 6 to 12 hours during the first 48 hours because increasing levels suggest an increased risk of cardiotoxicity and cardiovascular collapse [6]
    • Blood cell counts should be followed daily to monitor for cytopenias [4]
  • Any patient in undifferentiated shock should undergo RUSH exam with POCUS, and these patients should also have a documented chest x-ray as ARDS can develop as well. [4]

Management:

As there is no antidote for colchicine toxicity the mainstay of treatment is good systematic and supportive care.

  • Decontamination
    • Gastric lavage should be strongly considered if the patient is not vomiting and presents within 2 hours of ingestion. [4]
    • Activated charcoal should also be considered if the patient is not actively vomiting
  • Treatment
    • Supportive Care
      • IV fluid resuscitation to maintain adequate urine output and sufficient intravascular volume,
      • Vasopressors should be employed to maintain adequate mean arterial pressure and systemic perfusion
      • In cases of acute renal failure, hemodialysis should be employed as a supportive measure, but it is important to remember hemodialysis will minimally affect toxin removal
    • Granulocyte-colony Stimulating Factors (G-CSF)
      • May be useful for colchicine-induced leukopenia and thrombocytopenia, and should be dosed according to manufacturer’s instructions [7]
    • Antibiotics
      • Patients with coexisting infections or who potentially have underlying septic shock should still be treated with early goal directed therapy
    • Extracorporeal Membranous Oxygenation (ECMO)
      • Can be considered in cases of severe refractory poisoning [8]
    • Experimental Colchicine Antibodies
      • Colchicine specific antibodies have been shown to restore tubulin activity in animal models and has been noted to reverse colchicine-induced diarrhea [9]
      • One case report of a patient with colchicine overdose treated with anti-colchicine antibodies demonstrated a dramatic improvement in clinical and hemodynamic status [10]

 

Key Points/Bedside Pearls:

  • Colchicine has a very narrow therapeutic index, and has high mortality in overdose
  • Colchicine is metabolized by the liver, so patients with liver disease, and those on CYP3A4 inhibitors like erythromycin, clarithromycin, and grapefruit juice are more likely to develop toxicity
  • Initial manifestation of overdose are GI symptoms, but patients can present later with multi-organ failure and septic or hypovolemic shock
  • Gastric lavage is rarely warranted in overdoses, however, colchicine poisoning is an exception
  • There is no antidote, so supportive care is the mainstay of treatment

 

References:

  1. Graham W, Roberts JB (March 1953). “Intravenous colchicine in the management of gouty arthritis” (PDF). Annals of the Rheumatic Diseases. 12 (1): 16–9. doi:10.1136/ard.12.1.16. PMC 1030428. PMID 13031443
  2. Goldfrank’s toxicologic emergencies. Nelson, Lewis, 1963- (Eleventh ed.). New York. 2019-04-11. ISBN 978-1-259-85961-8. OCLC 1020416505
  3. Bronstein  AC, et al. 2010 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 28th annual report. Clin Toxicol (Phila). 2011;49:910–941.  [PubMed: 22165864]
  4. Santos C, Schier CG. Colchicine, Podophyllin, and the Vinca Alkaloids. In: Nelson LS, Howland M, Lewin NA, Smith SW, Goldfrank LR, Hoffman RS. eds. Goldfrank’s Toxicologic Emergencies, 11e. McGraw-Hill; Accessed November 17, 2020. https://accessemergencymedicine-mhmedical-com.libproxy.lib.unc.edu/content.aspx?bookid=2569&sectionid=210270571
  5. Hobson  CH, Rankin  AP. A fatal colchicine overdose. Anaesth Intensive Care. 1986;14: 453–455.  [PubMed: 3565732]
  6. Gaze  DC, Collinson  PO. Cardiac troponins as biomarkers of drug- and toxin-induced cardiac toxicity and cardioprotection. Expert Opin Drug Metab Toxicol. 2005;1:715–725.  [PubMed: 16863435]
  7. Critchley  JA, et al. Granulocyte-colony stimulating factor in the treatment of colchicine poisoning. Hum Exp Toxicol. 1997;16:229–232.  [PubMed: 9154449]
  8. Kerns W.P., Heffner A.C. (2017) Extracorporeal Membrane Oxygenation and Cardiopulmonary Bypass in the Poisoned Patient. In: Brent J. et al. (eds) Critical Care Toxicology. Springer, Cham. https://doi.org/10.1007/978-3-319-17900-1_91
  9. Peake  PW, et al. Fab fragments of ovine antibody to colchicine enhance its clearance in the rat. Clin Toxicol (Phila). 2015;53:427–432.  [PubMed: 25858137]
  10. Baud  FJ, et al. Brief report: treatment of severe colchicine overdose with colchicine-specific Fab fragments. N Engl J Med. 1995;332:642–645.  [PubMed: 7845428]

 

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