Vanishing bile duct syndrome with hyperlipidemia after ibuprofen therapy in an adult patient: a case report

Drug-induced liver injury (DILI) is a term used to describe a spectrum of clinical presentations and severity that ranges from a mild elevation of liver enzymes to acute liver failure and death. The severe form of DILI leads to a long-term liver-related morbidity and mortality in 1% to 3% of cases [1]. Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently prescribed drugs and can cause DILI [2]. Although patients with DILI from NSAIDs often recover spontaneously, 3% of them required hospitalization and those with persistent cholestasis present a diagnostic challenge. Ibuprofen is a widely used antipyretic and analgesic NSAID. However, cases with sub-fulminant hepatitis requiring liver transplantation following ibuprofen overdose have been reported [3]. It has been suggested that ibuprofen can produce an unpredictable, idiosyncratic, type B reactions as a hypersensitivity reaction (HSR) in susceptible individuals [4]. The true HSR is a systemic disease defined by the triad of fever, rash, and internal organ involvement that starts 1 day to 12 weeks after the initiation of therapy [4]. Recently, several cases of children with persistent jaundice after taking ibuprofen have been linked to liver injury as the targeting organ damage from HSR and developed the vanishing bile duct syndrome (VBDS) [5‐8]. However, data on adult patients is limited.

A woman in her 40s presented with acute onset of marked jaundice that had become progressively worsening over the course of 30 days, after taking ibuprofen intermittently for menalgia. The associated symptoms included profound fatigue and dark urine. No other symptoms were present. Twelve months prior to the onset of jaundice, she had menorrhagia after receiving the diagnosis of adenomyosis of uterus. She started only on ibuprofen 300 mg bid by mouth for 2–3 days each month with a total of six months when menalgia occurred. Her medical history included type II diabetic for one year on oral acarbose 50 mg TID and metformin 500 mg three times daily. She had no other medications. She had a surgical resection for a right ovarian cyst about 20 years ago. At the time, she was a non-smoker and did not consume any alcoholic drinks or recreational drugs. Clinical examination revealed normal vital signs and mental status. Although she has scleral icterus and a soft, non-tender abdomen with a surgical scare, neither signs of ascites nor hepatomegaly were presented. Her spleen was palpable at 3 cm below the left costal margin. There was no asterixis.

VBDS is a severe cholestatic disease associated with toxic effects of medications [9, 11]. As a complication of acute drug-induced liver injury, VBDS generally manifests 1 to 6 months after the onset of the liver injury [9]. Several diseases or syndromes as the causes for VBDS have been discussed in the section of differential diagnosis. Although DILI is an uncommon etiology for the VBDS, several medications have been reported to be related to the development of VBDS after liver injury. These medications include: antifungals or antibiotics like terbinafine, [12] meropenem, [13] and azithromycin; [11] anti-seizure medications such as valproic acid, [14] carbamazepine, [15] and lamotrigine; [16] and NSAIDs such as loxoprofen, diclofenac, and ibuprofen in pediatric cases [5‐8, 17]. Five cases of ibuprofen-induced liver injury with the complication of VBDS have been reported by far and all were children. The first case was reported by Alam at el in 1996, which indicated that VBDS was temporally associated with ibuprofen [8]. Subsequently, Kim et al. reviewed three cases of VBDS from ibuprofen-induced liver injury in patients with ages ranging from 9 months to 10 years old [7]. Among them, two had completed clinical and biochemical recovery in 4 to 7 months after the onset of VBDS; one had persistent jaundice and required transplant evaluation. In a case recently reported by Bastuck et al. VBDS occurred in a 7-year-old child who had toxic epidermal necrolysis after oral ibuprofen intake. However, the patient had a complete recovery within 8 months [6]. These reports suggested that ibuprofen can cause acute VBDS, and weight-based ursodeoxycholic acid was commonly used for VBDS with supportive care, although steroids, immunosuppressive agents, or plasmapheresis were provided occasionally [12, 18]. Similar to the clinical presentations described in children, our case had acute onset of jaundice and VBDS developed approximately at weeks 4–6 from the ibuprofen-induced liver injury. However, unlike the outcomes of completed recovery in the majority of cases reported before, our patient had no significant improvement in biochemistry after a 10-month follow-up. Such different outcomes may be related to the lower liver stem cell or progenitor cell activity in the adult or aging liver when comparing to those in children [19]. In addition, hyperlipidemia was presented in our case. Although hyperlipidemia is an uncommon presentation in VBDS patients, it has been reported in a few pediatric patients. In the case presented by Basturk et al. the child was treated with supportive care, an steroid, and ursodeoxycholic acid, with complete normalization of lipid profile in 8 months [6]. Another case reported by Cho et al. was a 7-year-old boy with VBDS from trimethoprim-sulfamethoxazole combination therapy induced liver injury [20]. At the onset of VBDS, the patient’s total cholesterol level was 490 mg/dL and was improved to 385 mg/dL after nine weeks of ursodeoxycholic acid therapy (30 mg/kg/day) and returned to the normal range after one year. Lastly, Kim et al. reported a 7-month-old infant with ibuprofen associated toxic epidermal necrolysis, followed by severe and rapidly progressive VBDS [7]. She had a total cholesterol level of 760 mg/dL but recovered totally with supportive care in three months. The mechanism of hyperlipidemia in VBDS has not been fully understood. It has been suggested that cholestasis might affect cholesterol metabolism and lead to the formation of lipoprotein X, which is frequently mistaken for LDL on routine clinical tests [21]. Further studies are needed to explore the implications of hyperlipidemia in the setting of VBDS.

In summary, we report herein a case of an adult patient who had persistent cholestasis from the vanishing bile duct syndrome after ibuprofen use. The highlights of clinical features include acute onset of jaundice and severe hepatic impairment required hospitalization, followed by a very slow recovery with persistence of hyperbilirubinemia and hyperlipidemia. The clinical course differed from those previously reported in children, which was a completed clinical and biochemistry recovery. Clinicians need to be aware of VBDS as a serious consequence of ibuprofen use in adult patients, although ibuprofen is considered to be among the safest NSAIDs.