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1. Successful pregnancy outcome in a woman presenting with Wilson’s disease complicated by liver cirrhosis: a case report Lucinda Ryan, Tina Kapoor, Ida MuslimEaling Hospital NHS Trust, Uxbridge Road, Southall, UB1 3HW, United Kingdom OPTIONALLOGO HERE OPTIONALLOGO HERE Discussion Discussion Objectives Conclusion To report a successful pregnancy outcome in a lady with Wilson’s disease, managed in a UK District General Hospital setting. A review of literature is presented along with the case. Wilson’s disease is a rare condition caused by impaired copper metabolism. It is an autosomal recessive condition that results in multi-organ dysfunction. The ATP7B gene codes for a transmembraneATPase, which transports copper out of cells in response to elevated intracellular copper levels. It is expressed mainly in hepatocytes and absent or reduced function leads to decreased hepatocellular excretion of copper into bile1-3. This results in hepatic copper accumulation and injury. Eventually, copper is released into the bloodstream and deposited progressively in other organs4. The clinical presentation can vary but it usually manifests itself as hepatic dysfunction, progressive neurological disorder and as psychiatric disease4 either in isolation or combination. Less cited, but important consequences of the disease are its effects upon reproduction and fertility. The literature on this topic is scarce, however it has been noted that symptomatic women with Wilson’s disease may have oligomenorrhoea or amenorrhoea, the cause of which is largely unknown. The endocrine profile of four such cases were investigated by Kaushanskyet al.9, who noted low estradiol levels, likely to be the cause of disturbed ovarian function. The mechanism proposed for this hormonal imbalance was copper intoxication causing an interference of ovarian follicular aromatase activity9. Undoubtedly, the direct effects of hepatic dysfunction are also likely to be a major factor causing hormonal disturbance. Recurrent miscarriages also seem to be more common in untreated patients with Wilson’s disease, according to a cohort study in India10, which analyzed data from 16 patients and detected a 40% miscarriage rate. The achievement of a successful pregnancy to term in our patient is likely to be attributable to the fact that her disease was stable at the time of conception with the appropriate therapy. Until the discovery of chelating agents, this condition was fatal. Penicillamine was the first oral chelating agent to be introduced followed by trientine. These bind copper and result in increased excretion in the urine. Zinc is another treatment that is used which helps prevent the absorption of copper from the gut. The most important point about treatment during pregnancy is that the patient must stay on her anticopper therapy to protect her own health and she must be made aware of the importance of this. During the period when penicillamine was the only available drug, many women stopped taking it because of the teratogenic effects of penicillamine, and many became seriously ill with acute hepatic failure5. Although penicillamine is the most widely used medication, the teratogenic effects to the fetus have been documented in case reports6 describing congenital diffuse cutis laxa, severe micrognathia, limb contractures, and central nervous system abnormalities including agenesis of the corpus callosum in it’s most severe form6. The other therapies are also not without risk. Once again all documented evidence is from small case series and reports. A case series of 26 pregnancies in 19 women who were on zinc therapy throughout their pregnancy showed that zinc does protect the health of the mother but there were two fetal abnormalities: one baby had a surgically correctable cardiac septal defect and one had a lethal microcephaly8. Whether these can be directly attributed to the zinc is unknown. Due to lack of evidence it is not clear which treatment is safest in Wilson’s disease during pregnancy and there appears to be a lack of consensus between clinicians4,5. The other difficulty with treatment during pregnancy is that over-treatment resulting in copper deficiency is also teratogenic9. Animal studies, as analysed by Keen et al.9 in their literature review, have shown that copper deficiency can produce effects ranging from intrauterine growth retardation and teratogenesis to embryonic or fetal death. The mechanisms are not well understood but a few proposed by Keen et al.9 include the copper deficiency–induced changes in maternal metabolism; altered extracellular matrix; excessive oxidative damage; and impaired energy production9. This case serves to highlight the importance of medication compliance in women with Wilson’s disease who wish to become pregnant both pre-conceptually, peri-conceptually and antenatally. Those that have stable disease and good compliance may achieve a successful pregnancy outcome, even in those with end-organ damage. In our case, appropriate counselling and management from a multi-professional team were central to enabling our patient’s disease to remain stable throughout pregnancy and achieving the successful outcome. The case also serves to illustrate the difficulty in treatment during pregnancy and the fine line between overtreatment and undertreatment. Wilson’s disease is a rare condition with limited data to support management decisions and this undoubtedly makes decisions more difficult and underlines the importance of involving the patient in the decisions. Methods Prospective follow up of the index case throughout her pregnancy, birth and post natal period. A retrospective review of current evidence was undertaken using medline and embase databases. Index Case We report the case of a 28 year old primigravida with a history of Wilson’s disease diagnosed in her late teens. This was a planned pregnancy and she conceived spontaneously within one year of trying. She was referred to our clinic at 14 weeks gestation according to her last menstrual period, although she was menstruating irregularly. A scan within 1 week of booking confirmed her gestation as 9+4 weeks. Her booking bloods showed Hb 10.0 g/dL; WCC 2.8 x 109/L; neutrophils 1.9 x 109/L; platelets 55 x 109/L and normal liver function tests. Her other routine booking bloods were normal. Her low platelets were attributed to her hypersplenism and she was known to have liver cirrhosis. Preconceptually her disease was stable on zinc therapy and she continued on this medication initially on the advice of the hepatologists. She required a change in medication from zinc to trientine at 20 weeks gestation because of her iron deficiency, attributed partly to the zinc therapy. She was monitored regularly for the duration of her pregnancy by the Obstetricians, Haematologists and Hepatologists and the importance of taking her medication was frequently expressed. Her liver function tests remained normal throughout the pregnancy and her platelets remained stable. Her pregnancy was complicated initially with several episodes of self-terminating epistaxis, which settled by the third trimester. She had an induction of labour for suspected obstetric cholestasis at 38 weeks gestation. She had a spontaneous vaginal delivery of a healthy male infant weighing 3014g. The delivery was complicated by a severe post partum haemorrhage, losing 1500 mL blood. The aetiology was a mixed picture: atony, perineal trauma and impaired coagulation. The bleeding was controlled successfully with uterotonics, suturing to the perineal trauma and infusion of two pools of platelets. She developed mild ascites and bipedal pitting oedema post delivery. With the addition of furosemide, this gradually subsided and she has now returned to her pre-pregnancy condition. References [1] Bull PC, Thomas GR, Rommens JM, Forbes JR, Cox DW. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat Genet 1993;5:327-337. [2] Tanzi RE, Petrukhin K, Chernov I, Pellequer JL, Wasco W, Ross B, et al. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet 1993;5:344-350. [3] Yamaguchi Y, Heiny ME, Gitlin JD. Isolation and characterization of ahuman liver cDNA as a candidate gene for Wilson disease. BiochemBiophys Res Commun 1993;197:271-277. [4] Roberts, E. A. and Schilsky, M. L. (2008), Diagnosis and treatment of Wilson disease: An update. Hepatology, 47: 2089–2111. doi: 10.1002/hep.22261 [5] Brewer GK, Askari FK. Wilson’s disease: clinical management and therapy. J of Hepatology 2005; 42: S14-S21. [6] Pinter R.; Hogge W.A.; McPherson E. Infant with severe penicillamineembryopathy born to a woman with Wilson disease. Am J Med Genet 2004; 128A:294-8. [7] Solomon L, Abrams G, Dinner M, Berman L. Neonatal abnormalities associated with D-penicillamine treatment during pregnancy. N Engl J Med 1977;296:54–55. [8] Brewer GJ. Treatment of Wilson’s disease with zinc xvii: treatment during pregnancy. Hepatology2000;31:364–370. [9] Kaushansky A, Frydman M, Kaufman H, Homburg R. Endocrine studies of the ovulatory disturbances in Wilson’s disease (hepatolenticular degeneration). FertilSteril 1987; 47: 270–73. [10] Sinha S, Taly AB, Prashanth LK, Arunodaya GR, Swamy HS. Successful pregnancies and abortions in symptomatic and asymptomatic Wilson’s disease. J NeurolSci 2004; 217: 37–40. Figure 1 Documented fetal complications from penicillamine and zinc treatment and copper deficiency