A 44-year-old woman presented to the hospital for evaluation of progressive jaundice and generalized itching during the previous 6 weeks. On physical exam her temperature was 36.5°C (97.7°F), the pulse was 72/min, and blood pressure was 125/80 mmHg. The liver was normal and there was no ascites. Examination of the skin revealed scratch lesions with crusts and erythema over the entire body with areas of minor injury in the mid-dorsal region that cannot be reached by hands (Fig. 1, Panel 1, dotted line). The grandmother and an aunt of this patient had had similar symptoms at the age of 40 with spontaneous resolution after several weeks. The patient had had an uneventful pregnancy 6 years earlier. She reported having suffered from gastroenteritis and having taken 500 mg acetaminophen twice during a stay in Tunisia 2 weeks before the development of jaundice.
Laboratory studies revealed a total bilirubin of 155 μmol/L (6.7 mg/dL), alanine aminotransferase (ALT) 226 U/L, alkaline phosphatase 231 U/L, and gamma glutamyl transferase 36 U/L. Serum bile acids were elevated at 120 μmol/L (normal values <30 μmol/L). Ultrasound showed a normal liver parenchyma with a common bile duct diameter of 6 mm. An extensive diagnostic work-up including viral, autoimmune, and metabolic markers was negative. A computed tomography (CT) scan showed normal bile ducts and a large number of stones in the gallbladder (Fig. 1, Panel 2, arrow). The patient was administered antihistamine medication (hydroxyzine), rifampicin, and naltrexone without a significant improvement of her symptoms. Liver biopsy showed a normal parenchyma with major intrahepatocytic and intracanalicular cholestasis (Fig. 1, Panel 3, arrows), without inflammatory infiltrates, fibrosis, or steatosis. Over the subsequent weeks the patient spontaneously recovered and was completely asymptomatic.
Cholestasis with normal gamma glutamyl transferase is a key feature of functional deficiencies in the gene ATP8B1, encoding a P-type ATPase1 or ABCB11, which encodes the bile salt export pump (BSEP), a liver specific adenosine triphosphate (ATP)-binding cassette transporter.2 Depending on their localization, mutations in ABCB11 may result in promoter changes affecting transcription or new splice acceptor sites leading to nonsense mediated decay of the messenger RNA.3 As a result the protein can be quantitatively or functionally insufficient. Sequence analysis in this patient revealed a heterozygote ABCB11 mutation c.221T>C. This nucleotide change results in an amino acid change p.Ile74Arg in the first transmembrane domain of the ABCB11 protein.
Immunohistochemical staining of the liver biopsy showed a normal (canalicular) expression of BSEP (Fig. 1, Panel 4). However, there was a gradual decrease from zone 1 to zone 3 of the liver lobule with a very low expression of BSEP in the zone around the central vein (Fig. 1, Panel 4, arrow). In contrast, we observed in a control patient a homogeneous distribution of BSEP throughout the liver parenchyma, including the pericentral area (Fig. 1, Panel 5, arrow).
Two years later the patient continued to show marginally elevated levels of serum bile acids (33 μmol/L) and alkaline phosphatase (110 U/L), indicating the persistence of a mild cholestasis. ABCB11 deficiency has been described in association with numerous mutations and represents a clinical continuum from very mild to progressive forms of cholestasis, including benign recurrent intrahepatic cholestasis type 2, intrahepatic cholestasis of pregnancy, and progressive familial cholestasis 2. This patient had biliary stones, a distinguishing feature of ABCB11 deficiency, probably due to the low bile salt concentration secondary to impaired BSEP function.
The attack of cholestasis in this patient was preceded by nausea and vomiting for a few days. Episodes of minor infections or drugs taken shortly before the cholestatic event are considered possible trigger factors in patients carrying mutations in the ABCB11 gene and may explain the intermittent character of intrahepatic cholestasis.4 In our case sequence analysis revealed only one heterozygous single nucleotide mutation, but we cannot exclude the possibility that other mutations have been missed. The immunohistochemical findings suggest that the mutation identified here may predispose patients to cholestasis through a regulatory mechanism of BSEP not at the canalicular, but at the lobular level. Further investigation will be needed to confirm these findings and to understand the role of BSEP in the different liver lobule zones.