When Birth Control Turns Biliary: A Rare Case of Profound Hyperbilirubinemia From Oral Contraceptives

Abstract

Oral contraceptives (OCs) are extensively utilized and generally considered safe (reference); nonetheless, infrequent hepatobiliary complications such as cholestasis and hyperbilirubinemia have been documented, particularly among individuals with a genetic predisposition. We present a case involving a 19-year-old female who exhibited significant conjugated hyperbilirubinemia shortly after the commencement of OC therapy. Comprehensive investigations ruled out alternative causes, and the findings from liver biopsy, in conjunction with the clinical context, indicated an estrogen-induced cholestatic injury, likely revealing an underlying Dubin–Johnson syndrome. This case underscores the critical necessity of acknowledging hepatic adverse effects associated with estrogen as well as the influence of genetic susceptibility in drug-related adverse events.

Introduction

Oral contraceptives (OCs) are extensively utilized for birth control and are generally regarded as safe, with a favorable risk-benefit profile. Nonetheless, in rare cases, they have been associated with hepatobiliary complications, including drug-induced cholestasis and hyperbilirubinemia.^1,2 These effects are primarily attributed to the estrogenic components, which may interfere with the hepatic transport and excretion of bile acids, particularly in individuals with underlying genetic susceptibilities such as Dubin-Johnson Syndrome.^3,4

Most commercially available OCs consist of a combination of an estrogen, commonly ethinyl estradiol or mestranol, and a synthetic progestin derived from 19-nortestosterone. ⁵ Upon oral administration, these hormones undergo extensive first-pass hepatic metabolism, resulting in high intrahepatic concentrations of sex steroids.^3,5 While generally well tolerated, this can predispose susceptible individuals to liver injury. ⁶

Hepatic complications may range from self-limited cholestasis to more severe outcomes, including hepatic adenomas and, rarely, hepatocellular carcinoma.^2,5 Estrogen-induced cholestasis typically presents within the initial 6 cycles of OC use, with nonspecific symptoms such as pruritus, anorexia, nausea, and fatigue. ⁷ Fortunately, these symptoms usually resolve with discontinuation of the offending agent. ²

In more severe or prolonged cases, histological findings may include sinusoidal dilation, bile duct injury, or ductopenia. The risk of complications appears to correlate with the dose and duration of estrogen exposure and may be increased in the presence of predisposing conditions like genetic cholestatic syndromes. ¹

In this report, we describe a young woman who developed marked conjugated hyperbilirubinemia and cholestatic liver injury following initiation of a combined OC.

Case Presentation

A 19-year-old woman with no significant past medical history presented to the outpatient clinic with a 2-week history of progressive jaundice, severe generalized pruritus, and fatigue. She denied dark urine, pale stools, abdominal pain, or gastrointestinal symptoms. Her symptoms began ~1 month after initiating a combined OC containing ethinyl estradiol and levonorgestrel. The OC had been initiated for contraceptive purposes and not for menstrual regulation. This was her first exposure to hormonal contraception. She denied any prior episodes of jaundice or pruritus; however, review of outside records revealed a total bilirubin level of 7.4 mg/dL measured 2 weeks prior to presentation. The patient denied alcohol use, herbal supplements, or over-the-counter medications and reported no recent travel or known exposure to hepatotoxins. She reported no family history of liver disease, cholestasis, or Dubin-Johnson syndrome.

On examination, she was icteric but hemodynamically stable. There were no stigmata of chronic liver disease, including spider angiomas or palmar erythema, and no hepatomegaly or splenomegaly was appreciated on abdominal examination. Laboratory tests showed marked conjugated hyperbilirubinemia with a total bilirubin of 26.0 mg/dL (direct: 22.5 mg/dL). Aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase were within normal limits. Viral serologies for hepatitis A, B, and C, Epstein-Barr virus, and cytomegalovirus were negative. Autoimmune screening, including antinuclear antibody, anti-smooth muscle antibody, and antimitochondrial antibody, was also negative. Chronological liver function test results are depicted in Table 1.

Table 1.

Chronological Liver Function Test Results From 2 Weeks Prior to Admission Through 3 Months of Follow-Up.

Time Point	TB (mg/dL)	DB (mg/dL)	AST (U/L)	ALT (U/L)	Alk phos (U/L)	GGT (U/L)
Ref	0.2-1	0-0.4	15-37	12-78	47-176	5-55
2 wk prior admission	7.4	5.4	41	42	161	18
Admission date	30.5	26.5	-	-	-	-
Hospitalization day 2	29.2	26.3	46	33	321	24
Hospitalization day 5/discharge date	25.7	23.7	46	30	305	-
2 mo follow-up	21.7	-	50	37	317	-
3 mo follow-up	7.1	-	37	47	206	-

Abbreviations: Alk phos, alkaline phosphate; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DB, direct bilirubin; GGT, gamma-glutamyl transferase; Ref, reference number; TB, total bilirubin.

Abdominal ultrasound and computed tomography revealed no evidence of biliary obstruction, hepatic masses, or other acute pathology. Magnetic resonance cholangiopancreatography confirmed the absence of both intrahepatic and extrahepatic biliary obstruction (Figure 1). Given the persistence of symptoms and unclear etiology, an endoscopic ultrasound was performed, followed by a liver biopsy. Histopathology demonstrated moderate sinusoidal dilatation, hepatocyte biliary metaplasia, and mild ductopenia without fibrosis or malignancy.

Figure 1.

Magnetic resonance cholangiopancreatography demonstrating patent intrahepatic and extrahepatic bile ducts with no obstructive pathology.

The temporal relationship between symptom onset and initiation of OCs, combined with the exclusion of other hepatic diseases and the biopsy findings, supported a diagnosis of estrogen-induced cholestasis. The presence of conjugated hyperbilirubinemia and pigment retention in hepatocytes raised suspicion for underlying, previously undiagnosed Dubin-Johnson syndrome. Genetic testing was deferred due to the patient’s clinical stability and favorable response to treatment.

The OC was discontinued immediately, and the patient was started on cholestyramine and ursodeoxycholic acid (ursodiol). Over several weeks, her symptoms improved, with gradual normalization of bilirubin levels as depicted in Table 1. At 3-month follow-up, total bilirubin had decreased to 7.1 mg/dL, and pruritus and fatigue had resolved completely. Given the suspected estrogen-induced cholestasis, reinitiation of combined estrogen-containing OCs was not recommended. The patient was counseled regarding alternative nonestrogen-based contraceptive options and was advised to consider progesterone-only contraception.

Discussion

Despite the widespread prescription of OCs on a global scale, the potential hepatobiliary adverse effects associated with their use remain insufficiently acknowledged within the medical community. The influence of estrogen on bile acid metabolism is extensively documented; it inhibits both the expression and functionality of the bile salt export pump as well as other canalicular transporters, thereby disrupting the normal flow of bile and predisposing individuals to intrahepatic cholestasis.^3,8,9

Cholestasis induced by estrogen shares similarities with various other cholestatic disorders, including intrahepatic cholestasis of pregnancy. ¹⁰ In individuals with underlying genetic predispositions, such as Dubin-Johnson syndrome, an autosomal recessive condition characterized by mutations in the ABCC2 (MRP2) gene, there is a notable impairment in the hepatocellular excretion of conjugated bilirubin, which may lead to significant hyperbilirubinemia when the influence of exogenous hormones further compromise hepatic clearance.^11-13

The biochemical profile of our patient, characterized by isolated conjugated hyperbilirubinemia accompanied by normal transaminase levels, along with histopathological findings such as ductopenia and sinusoidal dilatation, in conjunction with a favorable response to the cessation of OCs, substantiates a diagnosis of estrogen-induced cholestasis and raises the possibility of Dubin-Johnson syndrome. ² While such occurrences are infrequent, analogous cases have been documented in the literature, indicating that the utilization of OCs can reveal previously latent genetic hepatic disorders.^1,14

This clinical presentation further underscores the necessity of a comprehensive diagnostic strategy. The preliminary laboratory evaluations effectively excluded prevalent infectious and autoimmune etiologies. Imaging studies successfully ruled out the presence of obstructive pathologies, while liver biopsy provided critical insights into hepatocellular and ductal pathologies that were not discernible through noninvasive diagnostic modalities.^15,16

Management predominantly entails the cessation of the causative agent.^2,16 Complementary therapies, including ursodeoxycholic acid and bile acid sequestrants (such as cholestyramine), may help mitigate pruritus and facilitate recovery.^15,17 The prognosis for reversible cholestatic liver injury is highly favorable if the detrimental agent is eliminated promptly. ¹⁶

Conclusion

This case underscores the potential for OCs to cause significant hepatic injury, particularly in individuals with underlying predispositions such as Dubin-Johnson syndrome. Clinicians should maintain a high index of suspicion when evaluating unexplained jaundice in young female patients on estrogen-containing medications. Early recognition and cessation of the causative agent can lead to complete clinical recovery.