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Attention—grapefruit!
Case Report
Attention—grapefruit! Lucinda A Grande, Raul D Mendez, Richard T Krug, Evert-Jan Verschuyl Lancet 2009; 373: 1222 St Peter Family Medicine (L A Grande MD), Department of Medicine (R D Mendez MD), Department of Surgery (R T Krug MD), and Department of Interventional Radiology (E-J Verschuyl MD), Providence St Peter Hospital, Olympia, WA 98506 , USA Correspondence to: Dr Lucinda A Grande, St Peter Family Medicine, 525 Lilly Road NE, Olympia, WA 98506, USA [email protected]
A
In November, 2008, a 42-year-old woman presented to our emergency department with difficulty in walking, shortness of breath, and light-headedness. The day before, she had gone on a 1·5 h car journey, after which she felt pain in her lower back and left buttock radiating down to the ankle. The following morning, her left leg had turned purple. Medical history was unremarkable. Her medications included levothyroxine, which she had taken for 4 years, and a low-dose combined oral contraceptive containing drospirenone and ethinylestradiol, which she had taken for 1 year. She did not smoke and rarely drank alcohol. Slightly overweight, she had begun an aggressive weight-loss diet 3 days earlier, including 225 g grapefruit every morning; previously she had eaten grapefruit rarely. In the emergency department, her left leg was diffusely firm and swollen, with bluish discoloration and livedo reticularis throughout. There were palpable femoral, popliteal, and dorsalis pedis pulses. Duplex ultrasonography showed a deep venous thrombosis, which extended from the external iliac vein distal to the calf veins. Because of the presence of phlegmasia caerulea dolens, there was concern for potential irreversible venous gangrene and subsequent limb loss; an intravenous infusion of unfractionated heparin was immediately started, and the patient underwent catheterdirected thrombolysis with recombinant tissue plasminogen activator. On contrast radiography, stenosis was evident within the left common iliac vein at approximately the 5th lumbar vertebra (figure), suggestive of May-Thurner syndrome. A stent was placed across the stenosis. Leg pain and discoloration completely resolved by that evening; venography 24 h later confirmed a patent vein and stent. She was discharged home on bridging anticoagulation, after beginning a 6-month course of B
warfarin; she also stopped using her oral contraceptive. A thrombophilia screen done in the outpatient setting was positive for factor V Leiden mutation. When last seen in February, 2009, she was asymptomatic. The May-Thurner syndrome was described in 1957,1 but Virchow first hypothesised such a disorder in 1851 on the basis that the risk of deep venous thrombosis is more than three times higher in the left than in the right leg.2 The syndrome results from compression of the left common iliac vein between the overlying right common iliac artery and the underlying 5th lumbar vertebral body. Chronic pulsation of the artery results in intimal hyperplasia within the vein. Iliofemoral vein thrombosis eventually occurs. Left iliac vein stenosis is not rare, but for thrombosis to occur, all three components of Virchow’s triad must be present: stasis, endothelial injury, and hypercoagulability. Procoagulant contributors in our patient included factor V Leiden mutation and oestrogen contraceptive use.3 What tipped the balance toward acute venous thrombosis that day? It is likely that stasis occurred as our patient’s already stenosed iliac vein was compressed further by hip flexion during her car journey. We hypothesise that she also had enhanced hypercoagulability as a consequence of her new diet. Grapefruit juice can augment the bioavailability of ethinylestradiol4 by inhibiting CYP3A4, a cytochrome P450 enzyme densely expressed in the wall of the small bowel. The enzyme metabolises many drugs, including ethinylestradiol, dihydropyridines, and statins. Inhibition of CYP3A4 by grapefruit juice most likely occurs through increased enzyme degradation. With an effective half-life of about 12 h, a cumulative effect of daily grapefruit juice consumption can occur. The magnitude of effect varies; those with high inherent bowel wall enzyme content show the largest enzyme reduction with juice treatment, resulting in an increase in peak drug concentration of up to six times.4 Our patient had a constellation of potential risk factors for venous thrombosis; a heightened hypercoagulable state from increased ethinylestradiol serum concentration due to her 3 days of grapefruit for breakfast may well have tipped the balance. Contributors LAG prepared the report. RTK evaluated the patient in the emergency room. E-J V performed the catheterisation procedure; LAG and RDM managed the patient in the hospital after the procedure.
Figure: Contrast radiography showing stenosis within the left common iliac vein (A) The rough wall of the stenosed vessel is evidence of endothelial injury. (B) The stenosis is located at the 5th lumbar vertebra; this is the same view as (A) but with different contrast settings.
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References 1 May R, Thurner J. The cause of predominantly sinistral occurrence of thrombosis of the pelvic veins. Angiology 1957; 8: 419–27. 2 Virchow R. Uber die Erweiterung kleiner Gefasse. Arch Pathol Anat 1851; 3: 427. 3 Vandenbroucke JP, Rosing J, Bloemenkamp KW, et al. Oral contraceptives and the risk of venous thrombosis. N Engl J Med 2001; 344: 1527–35. 4 Bailey DG, Arnold MO, Spence JD. Grapefruit juice-drug interactions. Br J Clin Pharmacol 1998; 46: 101–10.
www.thelancet.com Vol 373 April 4, 2009
Attention—grapefruit! Lucinda A Grande, Raul D Mendez, Richard T Krug, Evert-Jan Verschuyl Lancet 2009; 373: 1222 St Peter Family Medicine (L A Grande MD), Department of Medicine (R D Mendez MD), Department of Surgery (R T Krug MD), and Department of Interventional Radiology (E-J Verschuyl MD), Providence St Peter Hospital, Olympia, WA 98506 , USA Correspondence to: Dr Lucinda A Grande, St Peter Family Medicine, 525 Lilly Road NE, Olympia, WA 98506, USA [email protected]
A
In November, 2008, a 42-year-old woman presented to our emergency department with difficulty in walking, shortness of breath, and light-headedness. The day before, she had gone on a 1·5 h car journey, after which she felt pain in her lower back and left buttock radiating down to the ankle. The following morning, her left leg had turned purple. Medical history was unremarkable. Her medications included levothyroxine, which she had taken for 4 years, and a low-dose combined oral contraceptive containing drospirenone and ethinylestradiol, which she had taken for 1 year. She did not smoke and rarely drank alcohol. Slightly overweight, she had begun an aggressive weight-loss diet 3 days earlier, including 225 g grapefruit every morning; previously she had eaten grapefruit rarely. In the emergency department, her left leg was diffusely firm and swollen, with bluish discoloration and livedo reticularis throughout. There were palpable femoral, popliteal, and dorsalis pedis pulses. Duplex ultrasonography showed a deep venous thrombosis, which extended from the external iliac vein distal to the calf veins. Because of the presence of phlegmasia caerulea dolens, there was concern for potential irreversible venous gangrene and subsequent limb loss; an intravenous infusion of unfractionated heparin was immediately started, and the patient underwent catheterdirected thrombolysis with recombinant tissue plasminogen activator. On contrast radiography, stenosis was evident within the left common iliac vein at approximately the 5th lumbar vertebra (figure), suggestive of May-Thurner syndrome. A stent was placed across the stenosis. Leg pain and discoloration completely resolved by that evening; venography 24 h later confirmed a patent vein and stent. She was discharged home on bridging anticoagulation, after beginning a 6-month course of B
warfarin; she also stopped using her oral contraceptive. A thrombophilia screen done in the outpatient setting was positive for factor V Leiden mutation. When last seen in February, 2009, she was asymptomatic. The May-Thurner syndrome was described in 1957,1 but Virchow first hypothesised such a disorder in 1851 on the basis that the risk of deep venous thrombosis is more than three times higher in the left than in the right leg.2 The syndrome results from compression of the left common iliac vein between the overlying right common iliac artery and the underlying 5th lumbar vertebral body. Chronic pulsation of the artery results in intimal hyperplasia within the vein. Iliofemoral vein thrombosis eventually occurs. Left iliac vein stenosis is not rare, but for thrombosis to occur, all three components of Virchow’s triad must be present: stasis, endothelial injury, and hypercoagulability. Procoagulant contributors in our patient included factor V Leiden mutation and oestrogen contraceptive use.3 What tipped the balance toward acute venous thrombosis that day? It is likely that stasis occurred as our patient’s already stenosed iliac vein was compressed further by hip flexion during her car journey. We hypothesise that she also had enhanced hypercoagulability as a consequence of her new diet. Grapefruit juice can augment the bioavailability of ethinylestradiol4 by inhibiting CYP3A4, a cytochrome P450 enzyme densely expressed in the wall of the small bowel. The enzyme metabolises many drugs, including ethinylestradiol, dihydropyridines, and statins. Inhibition of CYP3A4 by grapefruit juice most likely occurs through increased enzyme degradation. With an effective half-life of about 12 h, a cumulative effect of daily grapefruit juice consumption can occur. The magnitude of effect varies; those with high inherent bowel wall enzyme content show the largest enzyme reduction with juice treatment, resulting in an increase in peak drug concentration of up to six times.4 Our patient had a constellation of potential risk factors for venous thrombosis; a heightened hypercoagulable state from increased ethinylestradiol serum concentration due to her 3 days of grapefruit for breakfast may well have tipped the balance. Contributors LAG prepared the report. RTK evaluated the patient in the emergency room. E-J V performed the catheterisation procedure; LAG and RDM managed the patient in the hospital after the procedure.
Figure: Contrast radiography showing stenosis within the left common iliac vein (A) The rough wall of the stenosed vessel is evidence of endothelial injury. (B) The stenosis is located at the 5th lumbar vertebra; this is the same view as (A) but with different contrast settings.
1222
References 1 May R, Thurner J. The cause of predominantly sinistral occurrence of thrombosis of the pelvic veins. Angiology 1957; 8: 419–27. 2 Virchow R. Uber die Erweiterung kleiner Gefasse. Arch Pathol Anat 1851; 3: 427. 3 Vandenbroucke JP, Rosing J, Bloemenkamp KW, et al. Oral contraceptives and the risk of venous thrombosis. N Engl J Med 2001; 344: 1527–35. 4 Bailey DG, Arnold MO, Spence JD. Grapefruit juice-drug interactions. Br J Clin Pharmacol 1998; 46: 101–10.
www.thelancet.com Vol 373 April 4, 2009