Bile Acid Synthesis Defect, Congenital, 1

Oral cholic acid therapy is an effective therapy in children with primary bile acid synthesis deficiencies. Most reported patients with this treatment have 3β-hydroxy-Δ⁵-C₂₇-steroid oxidoreductase deficiency. The aim of the study was the evaluation of cholic acid therapy in a cohort of patients with the rarer Δ⁴-3-oxosteroid 5β-reductase (Δ⁴-3-oxo-R) deficiency.

Sixteen patients with Δ⁴-3-oxo-R deficiency confirmed by AKR1D1 gene sequencing who received oral cholic acid were retrospectively analyzed.

First symptoms were reported early in life (median 2 months of age), with 14 and 3 patients having cholestatic jaundice and severe bleeding respectively. Fifteen patients received ursodeoxycholic acid before diagnosis, with partial improvement in 8 patients. Four patients had liver failure at the time of cholic acid initiation. All 16 patients received cholic acid from a median age of 8.1 months (range 3.1-159) and serum liver tests normalized in all within 6-12 months of treatment. After a median cholic acid therapy of 4.5 years (range 1.1-24), all patients were alive with their native liver. Median daily cholic acid dose at last follow-up was 8.3 mg/kg of body weight. All patients, but one, had normal physical examination and all had normal serum liver tests. Fibrosis, evaluated using liver biopsy (n = 4) or liver elastography (n = 9), had stabilized or improved. Cholic acid therapy enabled a 12-fold decrease of 3-oxo-∆⁴ derivatives in urine. Patients had normal growth and quality of life. The treatment was well tolerated without serious adverse events and signs of hepatotoxicity.

Oral cholic acid therapy is a safe and effective treatment for patients with Δ⁴-3-oxo-R deficiency.

The truncating mutations in tight junction protein 2 (TJP2) cause progressive cholestasis, liver failure, and hepatocyte carcinogenesis. Due to the lack of effective model systems, there are no targeted medications for the liver pathology with TJP2 deficiency. We leveraged the technologies of patient-specific induced pluripotent stem cells (iPSC) and CRISPR genome-editing, and we aim to establish a disease model which recapitulates phenotypes of patients with TJP2 deficiency.

We differentiated iPSC to hepatocyte-like cells (iHep) on the Transwell membrane in a polarized monolayer. Immunofluorescent staining of polarity markers was detected by a confocal microscope. The epithelial barrier function and bile acid transport of bile canaliculi were quantified between the two chambers of Transwell. The morphology of bile canaliculi was measured in iHep cultured in the Matrigel sandwich system using a fluorescent probe and live-confocal imaging.

The iHep differentiated from iPSC with TJP2 mutations exhibited intracellular inclusions of disrupted apical membrane structures, distorted canalicular networks, altered distribution of apical and basolateral markers/transporters. The directional bile acid transport of bile canaliculi was compromised in the mutant hepatocytes, resembling the disease phenotypes observed in the liver of patients.

Our iPSC-derived in vitro hepatocyte system revealed canalicular membrane disruption in TJP2 deficient hepatocytes and demonstrated the ability to model cholestatic disease with TJP2 deficiency to serve as a platform for further pathophysiologic study and drug discovery.

We investigated a genetic liver disease, progressive familial intrahepatic cholestasis (PFIC), which causes severe liver disease in newborns and infants due to a lack of gene called TJP2. By using cutting-edge stem cell technology and genome editing methods, we established a novel disease modeling system in cell culture experiments. Our experiments demonstrated that the lack of TJP2 induced abnormal cell polarity and disrupted bile acid transport. These findings will lead to the subsequent investigation to further understand disease mechanisms and develop an effective treatment.

3β-hydroxy-Δ5-C27-steroid dehydrogenase deficiency is a rare autosomal recessive condition. So far fewer than 100 cases have been reported and the factors affecting the prognosis are not yet established. The objective of this study is to explore a possible prediction of the outcome of this rare condition.

This review was undertaken and reported in accordance with the preferred reporting items for systematic review and meta-analyses guidelines. Demographics, clinical features, gene data, treatment strategies and prognoses at the last follow-up were extracted and summarized. Patients were divided into 2 groups (alive with native liver and liver transplantation/died). Risk factors for the different clinical features were identified.

87 patients that were taken from 7 case reports and 9 case series were included. 38 (38/63, 63.0%) of them presented initial symptoms when they were younger than 1 month and 55 (55/63, 87.3%) less than 1 year. There is a larger proportion of patients younger than 1 month or 1 year at the age of symptom onset in the liver transplantation /died group than patients in alive with the native liver group. The majority of patients (53/62, 85.5%) were diagnosed before the age of 5 year. In all cases, 65 (predicted) pathogenic variants have been identified. Over 70% of patients carried an HSD3B7 variant on exon 1, 4, 5 or 6. 71 (81.6%) were alive at the last follow-up, 16 (18.4%) underwent liver transplantation or died. No significance was found between the group alive with native liver and group liver transplantation /died.

Age of onset of the symptoms may be a potential factor that determines the outcome of patients with 3β-HSD deficiency, patients presented with symptoms and signs at an age younger than 1 month or even 1 year may have a worse prognosis. Since there is no difference between clinical outcome and zygosity of gene mutation, we recommend a further study about any possible relationship between mutation site and clinical characteristics or prognosis.