Postgrad Med J: first published as 10.1136/pgmj.45.521.196 on 1 March 1969. Downloaded from Postgrad. med. J. (March 1969) 45, 196-201. Developments in jaundice R. P. H. THOMPSON ROGER WILLIAMS B.M., M.R.C.P. M.D., M.R.C.P. JAUNDICE is a large subject, but two topical aspects OH OH are the potential hepatic toxicity of oral contracep- 8eH3 vt OH3 C-CH tives, and the possible use of hepatic enzyme induction in therapy. Hepatic effects of oral contraceptives Oral contraceptives are usually prescribed as a Testosterone cH3 Norethisterone cH3 combined pill containing 1-4 mg of a progestagen, C=o (ond 19-norprogestogens) C=0 and 0-05-0-15 mg of an oestrogen, taken for 3 weeks sH-OHCHH15 from the 5th day of each menstrual cycle. Less commonly sequential administration is used, when CH-OH OHC -COH oestrogen is taken for the first 2 weeks, and oestrogen OCH3~I -H_o^^^ CH-Cho^ modinone plus progestagen for the next week. These doses are ozzwJ^ Nomestronl)(and small compared to the normal production of pro- Hydroxyprogesterone OH gesterone and oestradiol, for the corpus luteum of menstruation secretes 20-30 mg/day of the former and 1 mg/day of the latter, and in late pregnancy the copyright. placenta up to 300 mg, and 15-30 mg/day, respec- tively. HO HO The progestagens used in contraceptive pills are Oestradiol Ethynyl oestrodiol synthetic and of two types (Fig. 1). Most are derivatives of testosterone but, lacking its C19methyl group, are called 19-norsteroids. They include OH norethisterone (norethindrone), norethynodrel and CH3CH2CH3 ethynodiol; and lynoestrenol. The two other pro- gestagens used, megestrol and chlormadinone, are http://pmj.bmj.com/ derivatives of hydroxyprogesterone, and have a or different structure. Either ethynyloestradiol Norethondrolone ('nilevor') mestranol are used for the oestrogen component. None of these steroids are 17c-alkyl-substituted, but FIG. 1. The structure of some steroid molecules. the 19-norprogestagens and these oestrogens do have unsaturated hydrocarbon groups in the 17a position. women developed raised serum transaminase levels Unlike testosterone, 19-norprogestagens are partly and retention of bromsulphthalein (BSP) after on October 4, 2021 by guest. Protected converted to oestrogens in vivo (Bishop, 1968). 1 month's treatment with an oral contraceptive pre- About 10 % of norethisterone acetate is metabolized paration for menstrual irregularities. Since then to urinary 17a-ethynyloestradiol (Brown & Blair, approximately 100 cases of jaundice have been 1960) which has twenty times the oestrogenic effect recorded in the world literature, although this of oestradiol, and although Paulsen (1966) found reaction probably occurs in less than 1 in 10,000 of that it produced gynaecomastia, other oestrogenic the millions of women taking the pill (Schaffner, effects surprisingly are not marked. Megestrol and 1966). Initial symptoms of vague nausea and pruritus chlormadinone are not so metabolized (Cooper & are followed by jaundice which is usually slight, but Kellie, 1968). occasionally severe. Biochemically and histologically the picture is of a mixed hepatocellular and chole- Occurrence ofimpaired hepatic function static lesion. This syndrome usually occurs in the In 1964 Eisalo, Jarvinen & Luukkainen reported first few weeks of treatment and rapidly regresses from Helsinki that twelve elderly post-menopausal when the pill is withdrawn. Postgrad Med J: first published as 10.1136/pgmj.45.521.196 on 1 March 1969. Downloaded from Developments in jaundice 197 Minor abnormalities of liver function and histo- 1964), while the serum transaminase levels and logy probably occur in a much higher percentage of routine liver histology were unaffected. In rats, women on the pill. Kleiner, Kresch & Arias (1965) Gallagher, Mueller & Kappas (1966) have demon- used the infusion test of Wheeler et al. (1960) to strated abnormal BSP retention with oestradiol and measure both the hepatic storage capacity and the mestranol, but progesterone and norethynodrel were transport maximum (Tm) for bromsulphthalein. inactive, as was progesterone in man (Kappas, Both these are concerned in the hepatic excretion of 1968). this dye, and this test may detect changes in liver Further information comes from the relationship function when the routine BSP test (measurement of contraceptive liver damage to recurrent intra- of retention in blood 30-45 min after intravenous hepatic cholestasis of pregnancy (Haemmerli, 1966). injection) is within normal limits. They found that In this condition pruritus alone, or pruritus and contraceptive doses of norethynodrel and mestranol moderate obstructive jaundice develop in the last given for several months impaired BSP transport trimester of succeeding pregnancies, returning to maxima in all nine normal women studied, storage normal soon after delivery. Serum alkaline phos- capacities remaining normal (Fig. 2). The electron phatase levels are raised and retention of BSP occurs. Centrizonal cholestasis in needle liver biopsies is 8 surprisingly mild. These women are particularly liable to develop jaundice with oral contraceptives, and they account for about half of the cases of such The condition is commoner in 7~ - jaundice reported. E Scandinavia and where the incidence of 60 Chile, C' contraceptive jaundice is also highest (Orellana- Alcade & Dominguez, 1966). In addition, abnor- ->' _ 50 5 malities of liver function without jaundice are commoner in women on the in these Cu,LcoE C probably pill g2 4040 -4 areas for serum transaminase levels are raised in c.rs VQa~ up L0 to 18% of pre-menstrual women in some Scandi- copyright. o C' ~E30 - navian series (Eisalo, Jarvinen & Luukkainen, 1965), but are normal in series from Mexico (Rice-Wray, E 1964), Holland (Swaab, 1964), London (Swyer & a~~~~~2I0 2 Little, 1965) and Los Angeles (Tyler, 1964). There is C some or e3a co 0 presumably genetic environmental factor 10 behind this geographical variation. Kreek et al. (1967) treated seven patients with 0 - OL previous pruritus or jaundice of pregnancy with FIG. 2. The effect of norethynodrel and mestranol on 0-5-1-5 mg of 17a-ethynyloestradiol alone for up to http://pmj.bmj.com/ BSP storage capacity and maximum excretory rates of two weeks, but did not try a progestagen. This dose normal women. Open columns, Before; stippled columns, is ten times that in the pill, but in six control women norethynodrel + mestranol; solid columns, after. it produced only nausea. In the seven patients their previous symptoms in pregnancy were reproduced, microscope will also often show changes of choles- liver function was variably impaired, and one tasis in the liver during contraceptive treatment, with patient became temporarily jaundiced. dilated canaliculi, distortion and loss of canalicular microvilli, and increased numbers of abnormal on October 4, 2021 by guest. Protected mitochondria. Light microscopy is usually normal Progestagens (Larsson-Cohn & Stenram, 1967). In most studies, administration of progestagens has had little effect. Adlercreutz & Ikonen (1964) Cause of abnormalities gave the progestagen lynoestrenol to a patient with It is uncertain whether the progestagen, the previous pruritus of pregnancy without change, but oestrogen component, or both are responsible. two progestagen and oestrogen contraceptive com- Combes et al. (1963) have shown selective impair- binations induced jaundice before and after. In the ment of the BSP transport maxima in the last original twelve patients of Eisalo et al. (1964) trimester of pregnancy, when large amounts of lynoestrenol was inactive, and Borglin (1965) had progesterone and oestrogen circulate. When equiva- similar results. In other studies, however, the 19- lently large amounts of oestradiol were given to norprogestagens without oestrogens have been thirty-one non-pregnant women, retention of BSP shown to impair liver function and rarely to cause frequently occurred (Mueller, Kappas & Damgaard, jaundice (Perez-Mera & Shields, 1962). In a recent Postgrad Med J: first published as 10.1136/pgmj.45.521.196 on 1 March 1969. Downloaded from 198 R. P. H. Thompson and Roger Williams report, remarkably prolonged and deep jaundice Oral contraceptives should not be given to developed in two sisters, one treated with norethis- patients with a previous history of jaundice or terone alone, the other with norethisterone plus pruritus ofpregnancy, nor to patients with hereditary ethynyloestradiol (Somayaji et al., 1968). hepatic excretory defects, nor with any of the diff- Other 19-norsteroids, such as methyltestosterone erent varieties of intrahepatic cholestasis. It is and norethandrolone, are well known to impair probably best not to prescribe them to patients with BSP excretion (Marquardt et al., 1961) and to cause hepatitis or other liver disease within recent months, cholestatic jaundice. These steroids have an alkyl although opinions on this are divided (Ockner & group in the 17cc-position (Fig. 1), which increases Davidson, 1967). their cholestatic action (Gallagher et al., 1966). Contraceptive pills which have a progesterone- There is some evidence that the similar but un- derived progestagen such as megestrol or chlor- saturated substitution groups in the 17a-position in madinone, rather than the testosterone-derived 19- 19-norprogestagens do likewise, and Eisalo, Heino nor-progestagens may be safer, and the long term & Rasanen (1968), for example, have recently found contraceptive use ofchlormadinone alone (Martinez- that the 19-norprogestagen lynoestrenol induced