Residency Program - Case of the Month

Answer:

The gastric biopsy shows antral-type gastric mucosa with numerous epithelial metaphase mitotic figures (“ring” mitoses), which are most prominent in the proliferative zone of the glands. There is hyperplasia of the surface epithelium with some epithelial pseudostratification and loss of polarity.

This patient has a history of gout for which he was taking colchicine. The findings in the gastric biopsy are consistent with colchicine toxicity.

Discussion:

Colchicine is an alkaloid derived from Colchicum autmnale  (autumn crocus or meadow saffron) that is FDA-approved for the treatment of gout and familial Mediterranean fever. It produces an anti-inflammatory effect by binding to tubulin and preventing  microtubular formation, leading to inhibition of leukocyte migration, phagocytosis and formation of leukotriene B4.  This inhibition of microtubular formation and function also results in mitotic arrest in dividing cells and is the mechanism of its toxicity.

Colchicine toxicity affects multiple organs, and the effects may occur hours or several days after the exposure. Symptoms of acute toxicity include nausea, vomiting, abdominal pain, and bloody diarrhea. Other observed effects include hepatic necrosis, acuter renal failure, disseminated intravascular coagulation, seizures, and later complications, like bone marrow suppression and alopecia. Chronic poisoning is often subtle and is seen in patients with renal insufficiency and liver disease as well as in patients taking certain medications (e.g., erythromycin, cimetidine, cyclosporine) that result in drug interactions that inhibit colchicine clearance.

Iacobuzio-Dohahue et al have described distinct histopathologic findings in gastrointestinal biopsies of patients with clinical evidence of colchine toxicity: metaphase mitoses, epithelial pseudostratification, loss of polarity, and abundant apoptotic bodies (majority of cases reported).¹ These findings were most obvious in the gastric antrum and duodenum, with Ki-67 staining revealing marked expansion of the proliferative neck region.1 Other studies, including autopsy studies of patients who died of colchicine toxicity, have also described increased mitotic figures in the liver, genitourinary tract, bone marrow, lymph nodes, and respiratory tract.¹-²

References:

1. Iacobuzio-Donahue DA et al. Colchicine toxicity: distinct morphologic findings in gastrointestinal biopsies. Am J Surg Pathol 2001;25:1067-1073.
2. Kamath A, Mehal W, Dhanpat J. Colchicine-associated ring mitosis in liver biopsy and their clinical implications. J Clin Gastroenterol 2008;42:1060-1062.
3. Katzung BG et al (eds). Basic & Clinical Pharmacology, Twelfth edition. New York: McGraw-Hill, 2012.
4. Olson KR (ed). Poisoning & Drug Overdose. Sixth edition.  New York: McGraw-Hill, 2012.