Correspondence |
Norethisterone-induced cholestasis
Sir,Combination oral contraceptive steroids are (rarely) associated with cholestasis that resembles intrahepatic cholestasis of pregnancy. The incidence of cholestasis due to oral contraceptive steroids is approximately 1:10 000 women exposed in Western Europe, but as high as 1:4000 women exposed in Chile and Scandinavia.1 The oestrogenic component of the combined oral contraceptive pill is believed to be responsible. However, we report two cases of cholestasis induced by norethisterone, a progestogen contraceptive, which resolved after withdrawal of these pills.
An 18-year-old schoolgirl developed jaundice, pruritus, fatigue and anorexia 2 weeks after starting norethisterone. She had taken 5 mg norethisterone three times daily for 10 days to delay menstruation during a skiing holiday. She was on no other medication and did not drink alcohol. Examination revealed icterus with a palpable liver edge. Blood tests showed alanine transaminase was 540 U/l, alkaline phosphatase was 102 U/l and bilirubin was 42 µmol/l. During the subsequent weeks her jaundice deepened, with bilirubin peaking at 256 µmol/l. Blood tests for viral hepatitis (hepatitis A and B, cytomegalovirus, Epstein Barr virus) and autoimmune liver disease (antinuclear antibody, smooth muscle antibody, antimitochondrial antibody) were all negative. Biochemical screening for Wilson's disease was negative. Ultrasound scanning did not reveal any biliary obstruction. Her pruritus failed to respond to antihistamines or cholestyramine. An empirical course of oral prednisolone 25 mg daily for 1 week, with gradually tapering doses for the following 3 weeks, led to clinical and biochemical improvement. Liver biopsy was not done. Her symptoms subsided completely and her liver biochemistry was normal after 4 months.
A 34-year-old woman whose sole medication was 350 µg norethisterone (‘Micronor’, Janssen-Cilag) as a contraceptive, for 4 years, presented with pruritus and a cholestatic blood picture. She had mild icterus and scratch marks over her body, but no other abnormal findings. Bilirubin was 33 µmol/l, aspartate transaminase 179 U/l, and alkaline phosphatase 532 U/l. Hepatobiliary ultrasound and subsequently magnetic resonance scanning revealed two small incidental hepatic haemangiomata. Serological tests for hepatitis A, B and C, and Epstein-Barr virus, were all negative. Liver auto antibodies were negative. Her norethisterone pill was stopped, and there was rapid symptomatic and slower biochemical improvement.
Interestingly, this patient had also developed cholestatic jaundice 5 years earlier, while taking a combined contraceptive pill containing 500 µg norethisterone and 35 µg ethinyl oestradiol (‘Brevinor’, Pharmacia). At that time, full investigation revealed no other cause for her jaundice, and her combined oral contraceptive pill was deemed to be responsible. Her symptoms resolved and her liver biochemistry normalized on stopping the pill. She had been advised to change to a progestogen-only pill.
The oestrogen component of combination oral contraceptive steroids is usually blamed for the rare development of intrahepatic cholestasis. Oestrogen-induced cholestasis can occur in women with previous obstetric cholestasis, and has also been described in sisters. These observations indicate a genetic susceptibility. Studies in rats suggest that canalicular bile transporters, particularly multidrug resistant protein 2 (MRP-2), responsible for biliary secretion of several organic anions including bilirubin glucuronides, may be implicated in oestrogen-induced cholestasis.2 By lowering bile canalicular Na-K-ATPase activity, ethinyl oestradiol decreases bile acid transport independent of bile flow.
In distinction to oestrogens, progestogens are not typically implicated in cholestasis. In women with a previous history of intrahepatic cholestasis due to combined oestrogen-progestogen contraceptives and/or pregnancy, it is generally assumed that ‘progesterone-only’ contraceptives are safe, and will avoid recurrence of this hepatic problem. However, the serum concentration of sulphated metabolites of progesterone is known to be elevated in patients with obstetric cholestasis,3 and progesterone metabolites may have a more important role than oestradiol metabolites in the pathogenesis of obstetric cholestasis. Patients with obstetric cholestasis have an increased ratio of 3-
to 3-ß hydroxysteroids, and excrete large amounts of sulphated progesterone metabolites in their urine.3 Furthermore, there are reports of intrahepatic cholestasis when high doses of the progesterones norethisterone4 or megestrol acetate5 have been used to treat women with breast cancer. In rats, norethisterone can induce hepatic cholestasis associated with bile staining of hepatocytes.6
The mechanism of cholestasis induced by progestogens is unknown. These case reports indicate that progestogens alone can also cause cholestatic jaundice and that ‘progesterone–only’ contraceptive pills are not necessarily trouble-free in women who have experienced cholestasis with the combined (oestradiol-containing) contraceptive pill.
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Wycombe Hospital High Wycombe UK e-mail: david.gorard{at}sbucks.nhs.uk
References
1. Kreek MJ. Female sex steroids and cholestasis. Semin Liver Dis 1987; 7:8–23.[ISI][Medline]
2. Huang L, Smit JW, Meijer DK, Vore M. MRP 2 is essential for estradiol-17beta (beta-D-glucuronide) – induced cholestasis in rats. Hepatology 2000; 32:66–72.[CrossRef][ISI][Medline]
3. Meng LJ, Reyes H, Axelson M, Palma J, Hernandez I, Ribalta J, Sjovall J. Progesterone metabolites and bile acids in serum of patients with intrahepatic cholestasis of pregnancy: effects of ursodeoxycholic acid therapy. Hepatology 1997; 26:1573–9.[Medline]
4. Langlands AO, Martin WM. Jaundice associated with norethisterone-acetate treatment of breast cancer. Lancet 1975; i:584–5.
5. Foitl DR, Hyman G, Lefkowitch JH. Jaundice and intrahepatic cholestasis following high–dose megestrol acetate for breast cancer. Cancer 1989; 63:438–9.[CrossRef][Medline]
6. Zaki K, Rizk M, Kira L, Nour H, Guirguis R. Studies on the effects of ethinyl estradiol and norethisterone acetate on the adrenal cortex and some other tissues in the rat. Endokrinologie. 1979; 73:66–76.[Medline]
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