Dubin-Johnson syndrome is a rare hereditary autosomal recessive disorder that was first described in 1954.1 Incidence of Dubin-Johnson syndrome in the general population is unclear, it appears to be slightly more common in males and its incidence varies widely with ethnicity and geography.2 Age at onset varies widely, between 10 weeks and 76 years.2 The syndrome is caused by a mutation in the ATP-binding cassette of subfamily C member 2/multidrug resistance-associated protein 2, which results in deficient canalicular multidrug resistance-associated protein 2 expression, leading to impaired secretion of conjugated bilirubin into the bile.3,4 Patients with Dubin-Johnson syndrome exhibit chronic, mild to moderate, recurrent jaundice caused by conjugated hyperbilirubinemia.5 Dubin-Johnson syndrome patients often have impaired secretion of conjugated bilirubin from hepatocytes into the bile, without other features of hepatobiliary disease.5 Since Dubin-Johnson syndrome is benign, nonpregnant patients with Dubin-Johnson syndrome generally require no specific therapy and usually have a normal life span. However, it is unclear whether the hyperbilirubinemia associated with Dubin-John syndrome in expectant mothers poses a risk to fetal health.
Studies of pregnant patients with Dubin-Johnson syndrome are extremely rare, and perinatal outcomes in women with Dubin-Johnson syndrome exacerbated by hyperbilirubin are controversial. For example, while some studies suggested potential deleterious effects,6–8 others2,9,10 have reported no clinically significant effects on the newborn. Here we report a case of maternal Dubin-Johnson syndrome exacerbated with jaundice during pregnancy. The patient was hospitalized because amniotic fluid depth was 2.9 cm, and the amniotic fluid index was 5.8 cm. Previous liver biopsy revealed pathological changes in hepatocytes, including intracytoplasmic accumulation of coarse, dark-brown pigment. However, both maternal and perinatal outcomes were favorable, which may be due to close monitoring of the bilirubin level and careful perinatal management. Our results, which are inconsistent with previous studies, suggest that Dubin-Johnson syndrome may be a benign condition in pregnancy.
A Chinese woman aged 19 years visited our hospital with a complaint of persistent yellow-stained skin and scleral icterus since the age of 4 years. These symptoms were usually stable but sometimes worsened during other sickness, for example, colds or insomnia. She had no history of fever, pruritus, or abdominal pain. She also denied smoking, alcohol, or drug abuse. Total serum bilirubin was 63 μmol/L (reference range: 5–21 μmol/L), conjugated bilirubin was 41.8 μmol/L (reference range: <7.8 μmol/L), and transaminase levels were normal. Upper abdominal computed tomography scan was normal. Further liver biopsy showed intracytoplasmic accumulation of coarse, dark-brown pigment in hepatocytes (Fig. 1). The patient was definitively diagnosed with Dubin-Johnson syndrome based on serum bilirubin levels and liver biopsy.
Later, at the age of 30 years, the same woman came as a primipara to our outpatient department at 12 weeks and 5 days of gestation for her first routine prenatal check. Her last menstrual period had occurred on 22 December 2018, and her expected date of confinement was 28 September 2019. She had gained 3.0 kg during the first trimester, and her body mass index was 19.53 kg/m2. Her skin and sclera were slightly yellow-stained, and liver size was normal on palpation. Lab analyses indicated alanine aminotransferase of 11 U/L (reference range: <49 U/L), aspartate aminotransferase of 23 U/L (reference range: <40 U/L), alkaline phosphatase of 73 U/L (reference range: 45–129 U/L), gamma-glutamyltranspeptidase of 40 U/L (reference range: <38 U/L), total serum bilirubin of 74.2 μmol/L (reference range: 5–21 μmol/L), and conjugated bilirubin at 53 μmol/L (reference range: <7.8 μmol/L). Urobilinogen was not detected in the urinalysis. Abdominal ultrasound revealed normal liver size and echotexture. Markers were not detected for Epstein-Barr virus, cytomegalovirus, or hepatitis A, B, C, or E viruses. Serum antinuclear antibodies and anti-smooth muscle antibodies were absent. Hemoglobin was 107 g/L (reference range: 110–160 g/L). The patient refused referral to a genetic counselor, trio-exome sequencing, and prenatal diagnosis.
During the pregnancy, she had 13 prenatal visits. Exacerbation of jaundice was observed from gestational week 25. Liver function tests were always normal, and urinary urobilinogen was always negative. Bilirubin levels showed isolated conjugated hyperbilirubinemia, and this increased with gestational age. Unconjugated bilirubin levels were slightly higher than normal, in the range of 17.1–34.3 μmol/L (reference range: <17 μmol/L) (Fig. 2). Despite oral iron supplementation throughout pregnancy, her iron-deficiency anemia was not corrected, and the hemoglobin level remained at 95–105 g/L.
At her visit on gestational week 38, the patient complained about dark urine, likely due to a cold. Urine urobilinogen was positive, total serum bilirubin was at 127.7 μmol/L, with conjugated bilirubin at 101.8 μmol/L and unconjugated bilirubin at 25.9 μmol/L. Decreased amniotic fluid was detected by ultrasonography. The patient was hospitalized because amniotic fluid depth was 2.9 cm and amniotic fluid index was 5.8 cm. At 7 hours after admission, the patient experienced a gush of fluid from the vagina. Premature rupture of amniotic membranes was diagnosed using nitrazine pH paper. Labor was induced by intravenous oxytocin. After 15 hours and 25 minutes in total labor, she delivered a female infant 49 cm long and weighing 3 220 g. Apgar score was 10 at 1 minute, 10 at 5 minutes, and 10 at 10 minutes after birth. The placenta appeared to be normal based on gross and microscopic inspection. Postpartum hemorrhage volume was about 370 mL in 24 hours. The level of transcutaneous bilirubin in the newborn was 2.9–3.1 mg/dL within 24 hours of birth, 5.9–6.5 mg/dL at 24–48 hours, and 6.8–9.6 mg/dL at 48–72 hours. The patient was discharged 3 days after giving birth because of unremarkable postpartum course. At 2 weeks after delivery, jaundice was observable but less obvious, and total serum bilirubin had decreased to 73.6 μmol/L (conjugated: 50.2 μmol/L; unconjugated: 23.4 μmol/L).
Several disorders may lead to jaundice in pregnancy, including viral hepatitis, intrahepatic cholestasis, acute fatty liver, hemolysis, elevated liver enzymes levels, and low platelet levels (HELLP) syndrome, and hereditary disorders (Gilbert syndrome, Crigler-Najjar syndrome, Rotor syndrome, and Dubin-Johnson syndrome).5 Therefore, a detailed medical history and certain laboratory tests can help identify the cause of hyperbilirubinemia.5 In our patient, jaundice occurred without pruritis or cholestasis, and Dubin-Johnson syndrome was diagnosed based on characteristic pigmentation on liver biopsy.
The majority of patients with Dubin-Johnson syndrome are asymptomatic. Laboratory test results are usually normal except for mild conjugated hyperbilirubinemia. Illness (such as sepsis), exercise, alcohol, drugs (especially oral contraceptives), surgery, trauma, hemolysis, and pregnancy may exacerbate subclinical hyperbilirubinemia into symptomatic jaundice.2 Approximately half of mothers with Dubin-Johnson syndrome have overt jaundice.11 Estrogen is believed to cause jaundice.12 Jaundice becomes overt or exacerbated with gestational age and returns to its pre-pregnancy level rapidly after delivery. For example, in a study of nine pregnant women with Dubin-Johnson syndrome, jaundice was noted for the first time in four patients and pre-existing mild scleral icterus was exacerbated in the other five; serum bilirubin concentrations in all women decreased rapidly during the first week postpartum and returned to pre-pregnancy levels by approximately 10 days postpartum.13 Consistent with this, jaundice in our patient improved with gestational age and resolved quickly after delivery.
Perinatal outcomes of Dubin-Johnson syndrome have been described in a few previous reports (summarized in Table 1), some of which were published half a century ago. For example, a study of 7 pregnant women with Dubin-Johnson syndrome showed eight abortions, one stillbirth, one neonatal death, one premature delivery, and six normal deliveries.6 Another study described one case of Dubin-Johnson syndrome in which the patient suffered jaundice early in pregnancy, and stillbirth occurred 3 months before term.7 In a study of two patients with Dubin-Johnson syndrome, one had a normal baby, two abortions, and one nonviable anomalous fetus in four pregnancies, while the other patient had one spontaneous abortion, one normal premature infant, and nonviable immature twins in three pregnancies.8 In another patient with Dubin-Johnson syndrome, the first pregnancy was uncomplicated, while the second was complicated by vaginal bleeding, and the newborn showed restricted growth.14 A study of four pregnancies in one woman with Dubin-Johnson syndrome resulted in four live newborns, including two healthy babies, a baby with giant encephalocele who died 15 days later, and a baby who died of severe diarrhea at 6 months.5 These studies may demonstrate increased fetal mortality and poor newborn prognosis born from mothers with Dubin-Johnson syndrome. However, other reports showed uncomplicated pregnancies with normal newborns.2,9,10 Our case report suggests that, generally, Dubin-Johnson syndrome in pregnant women is associated with exacerbated jaundice but has minimal adverse effects on fetal health.
Pregnancy increases mean serum conjugated bilirubin concentrations by approximately 100% above basal values, while mean serum unconjugated bilirubin concentration increases approximately 60% above basal levels in Dubin-Johnson syndrome patients.13 Conjugated bilirubin cannot pass efficiently through the placental barrier as well as fetal blood-brain barrier and so is unlikely to affect the fetus. Although unconjugated bilirubin may traverse the placenta and blood-brain barrier, its concentration in the fetus probably remains too low to cause kernicterus in the absence of other untoward fetal event.14 These considerations suggest that increased total bilirubin in Dubin-Johnson syndrome may have negligible adverse effects on the fetus. With close monitoring of the bilirubin level and careful perinatal management, newborns from mothers with Dubin-Johnson syndrome may have better prognosis, similar to the favorable outcomes we found in this case report.
We report a case of maternal Dubin-Johnson syndrome exacerbated by jaundice during pregnancy that nevertheless had favorable perinatal outcomes. This result is inconsistent with previous studies and, together with a review of relevant literature, suggests that Dubin-Johnson syndrome may be a benign condition in pregnancy in the presence of close monitoring and careful perinatal management.
Jie Ruan: Case file collection, conception, literature review, preparation, and writing of the manuscript. Mei-Fan Duan and Dong Liu: Helped to obstetrical history collection, postpartum follow-up interview. Qiang Wei: Conception, review and proofreading of the manuscript, coordination, and helped to draft the manuscript. All authors read and approved the final manuscript.
Conflicts of Interest
. Dubin IN, Johnson FB. Chronic idiopathic jaundice
with unidentified pigment in liver cells; a new clinicopathologic entity with a report of 12 cases. Medicine (Baltimore) 1954;33(3):155–197. doi:10.1097/00005792-195409000-00001.
. Di Zoglio JD, Cardillo E. The Dubin-Johnson syndrome and pregnancy. Obstet Gynecol 1973;42(4):560–563. doi:10.1097/00006250-197310000-00013.
. Morii K, Yamamoto T. Images in clinical medicine. Dubin-Johnson syndrome. N Engl J Med 2016;375(1):e1. doi:10.1056/NEJMicm1509529.
. Corpechot C, Barbu V, Chazouillères O, et al. Genetic contribution of ABCC2 to Dubin-Johnson syndrome and inherited cholestatic disorders. Liver Int 2019;1–12. doi:10.1111/liv.14260.
. Gupta A, Tiwari P, Sachdeva P. A case of Dubin-Johnson syndrome in pregnancy. Cureus 2019;11(2):e4048. doi:10.7759/cureus.4048.
. Dubin IN. Chronic idiopathic jaundice
; a review of fifty cases. Am J Med 1958;24(2):268–292. doi:10.1016/0002-9343 (58)90315-2.
. Friedlander P, Osler M. Icterus and pregnancy. Am J Obstet Gynecol 1967;97(7):894–900. doi:10.1016/0002-9378(67)90513-3.
. Ikonen E. Jaundice
in late pregnancy. Acta Obstet Gynecol Scand 1964;43(Suppl 5):1–130.
. Chopra SA, Harries JR. Dubin-Johnson syndrome: a case history and review of the literature. East Afr Med J 1971;48(7):313–317.
. Kularatnam GAM, Warawitage D, Vidanapathirana DM, et al. Dubin-Johnson syndrome and intrahepatic cholestasis of pregnancy in a Sri Lankan family: a case report. BMC Res Notes 2017;10(1):487. doi:10.1186/s13104-017-2811-6.
. Seligsohn U, Shani M. The Dubin Johnson syndrome and pregnancy. Acta Hepatogastroenterol (Stuttg) 1977;24(3):167–169.
. Pregnancy and “Pill” can lead to liver ailment. JAMA 1970;212(12):2046.
. Cohen L, Lewis C, Arias IM. Pregnancy, oral contraceptives, chronic familial jaundice
with predominantly conjugated hyperbilirubinemia
(Dubin-Johnson syndrome). Gastroenterology 1972;62(6):1182–1190.
. Cotton DB. Infantile hepatic cholestasis with maternal Dubin-Johnson syndrome. South Med J 1984;77(9):1213–1214. doi:10.1097/00007611-198409000-00050.