Recurrent pruritus, jaundice, and pancreatitis in an adult due to a rare etiology: A case report

Abstract

BACKGROUND

Benign recurrent intrahepatic cholestasis type 1 (BRIC1) is an autosomal recessive disorder linked to mutations in ATP8B1. We report a case of BRIC1 with the unusual combination of recurrent pancreatitis and hearing loss, features that extend beyond the classic hepatic phenotype.

CASE SUMMARY

An adult male with recurrent jaundice, pruritus, and pancreatitis from 2019 to 2025 underwent laboratory and imaging studies, liver biopsy, and genetic sequencing. Histology confirmed intrahepatic cholestasis. An ATP8B1 minigene plasmid was constructed to assess splicing effects in vitro. Sequencing identified compound heterozygous ATP8B1 variants: c.1214_1215delAT (p.Y405Cfs*24) and c.3015G>A (p.Q1005Q). Functional studies provided the evidence for reclassifying the c.3015G>A variant from uncertain significance to likely pathogenic (LP) in BRIC1. In addition, the patient appeared to show a favorable response to glucocorticoids therapy.

CONCLUSION

An adult with BRIC1 and relatively rare extrahepatic phenotype had functional evidence for the LP of a novel ATP8B1 variant.

Key Words: Benign recurrent intrahepatic cholestasis type 1; Progressive familial intrahepatic cholestasis type 1; Adenosine triphosphatase phospholipid transporting 8B1; FIC1; Cholestasis; Case report

Core Tip: This case represents the first report of potential pathogenicity for the c.3015G>A variant, providing novel support for clinical screening in benign recurrent intrahepatic cholestasis type 1 (BRIC1). The patient presented with a relatively rare phenotype of BRIC1, characterized by recurrent pancreatitis and hearing loss alongside hepatic involvement. The clinical course suggests a potential role for glucocorticoids in the personalized management of patients with such phenotypes.

INTRODUCTION

Benign recurrent intrahepatic cholestasis type 1 (BRIC1) is an autosomal recessive disorder caused by mutations in ATP8B1, which encodes FIC1. FIC1 interacts with CDC50A to create a heterodimer. This complex maintains an asymmetric phospholipid structure and membrane fluidity on the canalicular membrane of the hepatocytes to facilitate normal excretion of bile[1]. Indirectly, the mutations in ATP8B1 can impair the bile salt export pump[2,3].

BRIC1 is characterized by intermittent pruritus and jaundice. Despite cholestasis, gamma-glutamyl transferase (GGT) levels remain normal or only mildly elevated. Bile duct imaging is typically unremarkable, and liver histology shows reversible cholestatic changes. Between episodes, symptoms resolve fully and liver function returns to normal. Episode frequency and duration vary widely. ATP8B1 mutations also underlie progressive familial intrahepatic cholestasis type 1 (PFIC1)[4]. Some patients initially diagnosed with BRIC1 may later develop a PFIC1-like course. BRIC1 usually presents in adolescence or adulthood, whereas PFIC1 manifests in infancy. BRIC1 patients retain partial FIC1 function, correlating with a generally favorable prognosis and low risk of end-stage liver disease, in contrast to the poor outcomes seen in PFIC1.

We report an adult male who presented with intermittent episodes of pruritus, jaundice, and recurrent pancreatitis, ultimately leading to a genetic finding highly suggestive of BRIC1. This finding highlights the need for a high index of suspicion for hereditary cholestasis in patients with such a clinical syndrome.

CASE PRESENTATION

Chief complaints

A 47-year-old male presents with a 6-year history of recurrent episodes of pruritus, jaundice, and pancreatitis.

History of present illness

First presented in early July 2019, the patient with an episode of pruritus, jaundice, and abdominal pains, which are caused by the consumption of alcohol and seafood. The first symptom was pruritus. About 20 days after, jaundice was observed, and another month later, abdominal pain. Other symptoms were associated, such as anorexia, nausea, clay-colored stools, and tea-colored urine. Laboratory results showed that there was cholestatic liver dysfunction. Additional examination eliminated viral hepatitis, liver injury caused by drugs, autoimmune liver diseases, and Wilson disease. Liver biopsy showed acute cholestatic hepatitis and moderate-severe intrahepatic cholestasis (Supplementary Figure 1). Acute pancreatitis was diagnosed based on the elevated level of serum amylase (AMY) and lipase (LIP) and computed tomography (CT) results (Supplementary Figure 2A). The patient received ursodeoxycholic acid (UDCA), glucocorticoids (GCs), plasmapheresis (PE), and supportive care. His symptoms improved slowly and after 3 months, liver functions came back to normal. He stayed well until another relapse occurred.

He experienced another such incident on October 23, 2020 after taking antipyretic medication. Laboratory tests once again showed abnormal liver functioning and increased pancreatic enzymes. This episode was controlled in the same way as PE, GCs, and supportive care. It took approximately 3 months and completely healed. There were two additional similar episodes in May 2022 and March 2025 and no apparent triggers. The patient has experienced no intercritical symptoms and can function normally in terms of liver.

History of past illness

The patient has had 10 years of bilateral sensorineural tinnitus and hearing loss.

Personal and family history

The patient had a history of smoking and alcohol use lasting more than ten years. He stopped both habits when the first episode occurred. His parents and younger sister do not exhibit any comparable symptoms, and no family history of genetic disorders.

Physical examination

There were positive physical provisional findings of scleral and cutaneous icterus, and multiple scattered excoriations.

Laboratory examinations

During the initial episode in July 2019, laboratory investigations revealed cholestatic liver dysfunction: Alanine transaminase: 28 (reference range 7-40) U/L; aspartate transaminase: 29 (reference range 13-35) U/L; GGT: 87 (reference range 7-45) U/L; alkaline phosphatase (ALP): 309 (reference range 50-135) U/L; total bilirubin (TBIL): 601.6 (reference range 5.0-21.0) µmol/L; direct bilirubin (DBIL): 430 (reference range < 6.0) µmol/L; and total bile acids (TBA): 216.1 (reference range < 15.0) µmol/L. Concurrently, pancreatic enzymes were markedly elevated, with an AMY level of 432 (reference range 30-110) IU/L and a LIP level of 1425 (reference range 23-300) IU/L.

In the second episode in October 2020, laboratory tests again indicated abnormal liver function, demonstrating a GGT of 76 U/L, ALP of 232 U/L, TBIL of 388.4 μmol/L, DBIL of 289.9 μmol/L, and TBA of 184 μmol/L. Pancreatic enzyme levels were also significantly increased, with AMY reaching 418 IU/L and LIP peaking at 1650 IU/L.

Supplementary Figure 3 displays the trends of key laboratory markers (TBIL, TBA, AMY, and LIP) over this 6-year period.

Imaging examinations

CT: During the initial episode, CT revealed pancreatic enlargement with peripancreatic stranding (Supplementary Figure 2A).

Magnetic resonance cholangiopancreatography: Magnetic resonance cholangiopancreatography showed no evidence of intrahepatic or extrahepatic bile duct dilation (Supplementary Figure 2B).

FINAL DIAGNOSIS

The final diagnosis was BRIC1.

TREATMENT

The patient was treated with UDCA, GCs, and PE, along with other supportive measures for symptoms such as pruritus and pancreatitis. Methylprednisolone was initiated at a daily dose of 40-48 mg, which was then tapered by 4-8 mg every few days based on the recovery of liver function.

OUTCOME AND FOLLOW-UP

After the March 2025 recurrence, GCs therapy was discontinued on June 4, 2025, and the patient remains clinically stable to date.

DISCUSSION

The patient had recurrent episodes of pruritus, jaundice, and pancreatitis, with only mild GGT elevation during flares. We ruled out viral hepatitis, drug-induced liver injury, autoimmune liver disease, and Wilson’s disease. Serial imaging revealed no evidence of bile duct abnormalities or cirrhosis. Between episodes, the patient was symptom-free and all liver function tests returned to normal. Genetic testing revealed compound heterozygous ATP8B1 variants: c.1214_1215delAT (p.Y405Cfs*24) of maternal origin and c.3015G>A (p.Q1005Q) of paternal origin (Figure 1). ATP8B1 mutations can also cause PFIC1. Nevertheless, PFIC1 normally implies total protein deficiency. That leads to progressive cholestasis and fibrosis. We did not observe that pattern here. Therefore, we diagnosed BRIC1 based on the clinical and genetic data. This is equivalent to an autosomal recessive type of inheritance.

Figure 1 Two-site mutations in the ATP8B1 gene. Sequencing chromatograms showing compound heterozygous ATP8B1 variants. A: c.1214_1215delAT (p.Y405Cfs*24) of maternal origin; B: c.3015G>A (p.Q1005Q) of paternal origin.

A study showed that ATP8B1, a P4 type ATPase, works as a flippase for PIP2 and can bind PIP2 directly[5]. The ATP8B1 is expressed in multiple tissues, including the cochlea, liver, pancreas, kidneys, and small intestine. Besides keeping bile acid balance, ATP8B1 also helps keep the hair cell structure in the cochlea stable and supports pancreatic exocrine function. Some researchers have suggested it could be a target for treating chronic pancreatitis[6,7]. It also regulates several key pathways, including glucose, cholesterol, and phosphatidylinositol phosphate metabolism, and it influences inflammatory signaling[5,8]. Together, these functions may explain why ATP8B1 mutations lead to such a wide range of intrahepatic and extrahepatic features. These include intrahepatic cholestasis, hearing loss, pancreatitis, and diarrhea[7,9,10]. Extrahepatic findings are uncommon in BRIC1 because it involves only a partial loss of FIC1 function. In PFIC1, by contrast, these findings are well documented[10]. Although the patient had a history of alcohol use and the initial episode was alcohol related, the recurrent pancreatitis is more likely attributable to BRIC1. Following the onset of pruritus, the patient stopped drinking, and pancreatitis developed roughly one month later. Imaging and laboratory evaluation excluded biliary, metabolic, and autoimmune causes. Given the confirmed pathogenic ATP8B1 variant and the absence of alternative explanations, the recurrent pancreatitis probably reflects multisystem involvement from this genetic defect.

According to the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) guidelines, the c.1214_1215delAT variant was classified as likely pathogenic (LP) and has been reported in some PFIC1 patient[11]. The c.3015G>A variant was initially designated a variant of uncertain significance (VUS) due to insufficient evidence and has not been previously documented[12]. To clarify the splicing effect of c.3015G>A, we performed a minigene splicing assay. Detailed methods are described in the Supplementary material, and primers are listed in Supplementary Table 1. We ran a minigene assay for the ATP8B1 variant c.3015G>A. It produced two different transcripts: MT-A and MT-B. On the gel, the wild type and MT-B both gave a band at 625 bp. MT-A showed a shorter band at 541 bp, which suggested an 84 bp deletion. Sanger sequencing then confirmed that the WT and MT-B minigenes made full-length transcripts that included exons 23 through 25. MT-B is a synonymous mutation and thus the protein made remains the same. But MT-A deleted exon 24 completely (84 bp) as was the case in the gel (Figure 2). It is predicted that, the MT-A transcript (c.2932_3015del) will encode a truncated protein (p.Thr978_Gln1005del). The c.3015G>A variant was then reclassified using the ACMG/AMP guidelines. It was changed to VUS to LP[12]. The primary evidence was PS3_Moderate. Exon 24 skipping occurred in the minigene assay, and the skipped product appeared to be more abundant compared to full-length. That provided us with a moderate functional evidence of the variant being harmful (Supplementary Figure 4). Two other pieces of evidence that are given include: PM2 (the type is very uncommon in population databases) and PP4 (the phenotype of the patient is very congruent with the disease). More research is required to differentiate the pathogenic mechanism of this variant. In general, the clinical picture of BRIC1 can be attributed to a partial loss of FIC1 activity due to these ATP8B1 mutations.

Figure 2 Two mutational outcomes of the c.3015G>A locus. Minigene splicing assay of the c.3015G>A variant. The mutant minigene produced two transcripts, MT-A and MT-B. MT-A exhibited complete skipping of exon 24.

The treatment of BRIC1 is predominantly aimed at alleviating symptoms. Treatment options contain UDCA, cholestyramine, rifampicin, PE, and emerging targeted therapy[13]. It is possible that GCs can stimulate bile secretion and decrease inflammation, but it is still uncertain whether they have a place in BRIC1. A study has indicated that a sub-group of BRIC1 patients may respond to GCs therapy[14]. The response of every episode in this patient improved steadily after GCs treatment. Subsequent episodes were less intense and shorter in duration (Supplementary Figure 3). Spontaneous improvement cannot be completely eliminated. However, the identified pattern suggests the potential reaction to GCs. GCs can be taken into consideration as an option in BRIC1 patients with severe disease or those who have not responded to standard therapy. More studies are needed to confirm this observation.

CONCLUSION

This report recommends BRIC1 as a possibility in case a patient has recurring cholestatic results with no other apparent cause, acute pancreatitis and hearing loss. Less frequent extrahepatic manifestations of BRIC1 should also be known to the clinicians. The c.3015G>A mutation of the ATP8B1 gene seems to be a novel LP mutation, and more studies are required. The GCs can be used as the method of treatment of BRIC1, though the advantages and disadvantages should be weighed.

ACKNOWLEDGEMENTS

We are particularly grateful to Professor De-Xin Yu from Department of Radiology, Qilu Hospital of Shandong University for his radiological support and Professor Jing-Min Zhao from Centre for Pathological Diagnosis and Research, The Fifth Medical Centre of PLA General Hospital for providing the original pathology slide images.