Navigating cholestasis: identifying inborn errors of bile acid metabolism for precision diagnosis.

Inborn errors of bile acid metabolism (IEBAM) cause cholestasis during the neonatal period, and 8 types of IEBAM have been reported to date. IEBAM accounts for approximately 2% of cases of cholestasis of unknown cause. As only 10 patients have been identified in Japan, IEBAM presents diagnostic challenges due to the similarity of clinical symptoms with biliary atresia, thus necessitating precise differentiation to avoid unnecessary invasive procedures. Laboratory tests in IEBAM are characterized by normal γ-glutamyltransferase (GGT) and serum total bile acid (STBA) levels despite the presence of cholestasis; therefore, measuring STBA and GGT is essential to distinguishing biliary atresia from IEBAM. With suspected IEBAM, liquid chromatography-mass spectrometry (LC/MS) analysis of urinary bile acids is needed to optimize diagnostic and therapeutic efficacy and avoid open cholangiography and initiate treatment for primary bile acids such as cholic acid or chenodeoxycholic acid. This prospective report aims to increase awareness of IEBAM by highlighting the characteristics of general blood test and bile acid profiles from LC/MS analyses of blood, urine, and stool samples.

Rapid in vivo evaluation system for cholestasis-related genes in mice with humanized bile acid profiles.

BACKGROUND: Pediatric cholestatic liver diseases (Ped-CLD) comprise many ultrarare disorders with a genetic basis. Pharmacologic therapy for severe cases of Ped-CLD has not been established. Species differences in bile acid (BA) metabolism between humans and rodents contribute to the lack of phenocopy of patients with Ped-CLD in rodents and hinder the development of therapeutic strategies. We aimed to establish an efficient in vivo system to understand BA-related pathogenesis, such as Ped-CLD. METHODS: We generated mice that express spCas9 specifically in the liver (L-Cas9Tg/Tg [liver-specific Cas9Tg/Tg] mice) and designed recombinant adeno-associated virus serotype 8 encoding small-guide RNA (AAV8 sgRNA) targeting Abcc2, Abcb11, and Cyp2c70. In humans, ABCC2 and ABCB11 deficiencies cause constitutional hyperbilirubinemia and most severe Ped-CLD, respectively. Cyp2c70 encodes an enzyme responsible for the rodent-specific BA profile. Six-week-old L-Cas9Tg/Tg mice were injected with this AAV8 sgRNA and subjected to biochemical and histological analysis. RESULTS: Fourteen days after the injection with AAV8 sgRNA targeting Abcc2, L-Cas9Tg/Tg mice exhibited jaundice and phenocopied patients with ABCC2 deficiency. L-Cas9Tg/Tg mice injected with AAV8 sgRNA targeting Abcb11 showed hepatomegaly and cholestasis without histological evidence of liver injury. Compared to Abcb11 alone, simultaneous injection of AAV8 sgRNA for Abcb11 and Cyp2c70 humanized the BA profile and caused higher transaminase levels and parenchymal necrosis, resembling phenotypes with ABCB11 deficiency. CONCLUSIONS: This study provides proof of concept for efficient in vivo assessment of cholestasis-related genes in humanized bile acid profiles. Our platform offers a more time- and cost-effective alternative to conventional genetically engineered mice, increasing our understanding of BA-related pathogenesis such as Ped-CLD and expanding the potential for translational research.

Clinical symptoms, biochemistry, and liver histology during the native liver period of progressive familial intrahepatic cholestasis type 2.

BACKGROUND: Progressive familial intrahepatic cholestasis type 2 (PFIC2) is an ultra-rare disease caused by mutations in the ABCB11 gene. This study aimed to understand the course of PFIC2 during the native liver period. METHODS: From November 2014 to October 2015, a survey to identify PFIC2 patients was conducted in 207 hospitals registered with the Japanese Society of Pediatric Gastroenterology, Hepatology, and Nutrition. Investigators retrospectively collected clinical data at each facility in November 2018 using pre-specified forms. RESULTS: Based on the biallelic pathogenic variants in ABCB11 and/or no hepatic immunohistochemical detection of BSEP, 14 Japanese PFIC2 patients were enrolled at seven facilities. The median follow-up was 63.2 [47.7-123.3] months. The median age of disease onset was 2.5 [1-4] months. Twelve patients underwent living donor liver transplantation (LDLT), with a median age at LDLT of 9 [4-57] months. Two other patients received sodium 4-phenylbutyrate (NaPB) therapy and survived over 60 months with the native liver. No patients received biliary diversion. The cases that resulted in LDLT had gradually deteriorated growth retardation, biochemical tests, and liver histology since the initial visit. In the other two patients, jaundice, growth retardation, and most of the biochemical tests improved after NaPB therapy was started, but pruritus and liver fibrosis did not. CONCLUSIONS: Japanese PFIC2 patients had gradually worsening clinical findings since the initial visit, resulting in LDLT during infancy. NaPB therapy improved jaundice and growth retardation but was insufficient to treat pruritus and liver fibrosis.

Healthy Patients With AKR1D1 Mutation Not Requiring Primary Bile Acid Therapy: A Case Series.

Δ4-3-Oxosteroid 5ß-reductase (AKR1D1) deficiency typically causes severe cholestasis occurs in newborns, leading to death unless patients are treated with primary bile acids. However, we encountered an AKR1D1 deficiency patient treated with only ursodeoxycholic acid who had cholestasis until about 1 year of age but then grew up healthy without further treatment. We also have been following other healthy patients with AKR1D1 mutation who have never developed cholestasis and have not been treated. However, reports are few, involving 3 patients. To better understand and clinically manage a diverse group of patients with AKR1D1 mutation who do not develop potentially fatal cholestasis in the neonatal period, ongoing accumulation and study of informative cases is needed.

Intestinal Atp8b1 dysfunction causes hepatic choline deficiency and steatohepatitis.

Choline is an essential nutrient, and its deficiency causes steatohepatitis. Dietary phosphatidylcholine (PC) is digested into lysoPC (LPC), glycerophosphocholine, and choline in the intestinal lumen and is the primary source of systemic choline. However, the major PC metabolites absorbed in the intestinal tract remain unidentified. ATP8B1 is a P4-ATPase phospholipid flippase expressed in the apical membrane of the epithelium. Here, we use intestinal epithelial cell (IEC)-specific Atp8b1-knockout (Atp8b1IEC-KO) mice. These mice progress to steatohepatitis by 4 weeks. Metabolomic analysis and cell-based assays show that loss of Atp8b1 in IEC causes LPC malabsorption and thereby hepatic choline deficiency. Feeding choline-supplemented diets to lactating mice achieves complete recovery from steatohepatitis in Atp8b1IEC-KO mice. Analysis of samples from pediatric patients with ATP8B1 deficiency suggests its translational potential. This study indicates that Atp8b1 regulates hepatic choline levels through intestinal LPC absorption, encouraging the evaluation of choline supplementation therapy for steatohepatitis caused by ATP8B1 dysfunction.

Dried blood spot-based newborn screening for bile acid synthesis disorders, Zellweger spectrum disorder, and Niemann-Pick type C1 by detection of bile acid metabolites.

OBJECTIVE: To examine whether it is possible to screen for bile acid synthesis disorders (BASDs) including peroxisome biogenesis disorder 1a (PBD1A) and Niemann-Pick type C1 (NPC1) at the time of newborn mass screening by measuring the intermediary metabolites of bile acid (BA) synthesis. METHODS: Patients with 3ß-hydroxy-ΔSuchy et al. (2021)5-C27-steroid dehydrogenase/isomerase (HSD3B7) deficiency (n = 2), 3-oxo-ΔPandak and Kakiyama (n.d.)4-steroid 5ß-reductase (SRD5B1) deficiency (n = 1), oxysterol 7α-hydroxylase (CYP7B1) deficiency (n = 1), PBD1A (n = 1), and NPC1 (n = 2) with available dried blood spot (DBS) samples collected in the neonatal period were included. DBSs from healthy neonates at 4 days of age (n = 1055) were also collected for the control. Disease specific BAs were measured by newly optimized liquid chromatography-tandem mass spectrometry with short run cycle (5-min/run). The results were validated by comparing with those obtained by the conventional condition with longer run cycle (76-min/run). RESULTS: In healthy specimens, taurocholic acid and cholic acid were the two major BAs which constituted approximately 80% in the measured BAs. The disease marker BAs presented <10%. In BASDs, the following BAs were determined for the disease specific markers: Glyco/tauro 3ß,7α,12α-trihydroxy-5-cholenoic acid 3-sulfate for HSD3B7 deficiency (>70%); glyco/tauro 7α,12α-dihydroxy-3-oxo-4-cholenoic acid for SRD5B1 deficiency (54%); tauro 3ß-hydroxy-5-cholenoic acid 3-sulfate for CYP7B1 deficiency (94%); 3α,7α,12α-trihydroxy-5ß-cholestanoic acid for PBD1A (78%); and tauro 3ß,7ß-dihydroxy-5-cholenoic acid 3-sulfate for NPC1 (26%). *The % in the parenthesis indicates the portion found in the patient's specimen. CONCLUSIONS: Early postnatal screening for BASDs, PBD1A and NPC1 is feasible with the described DBS-based method by measuring disease specific BAs. The present method is a quick and affordable test for screening for these inherited diseases.

Clinicopathologic Features, Genetics, Treatment, and Long-Term Outcomes in Japanese Children and Young Adults with Benign Recurrent Intrahepatic Cholestasis: A Multicenter Study.

BACKGROUND: Few reports of benign recurrent intrahepatic cholestasis (BRIC) have focused on East Asian patients. We describe the clinicopathologic features, genetics, treatment, and outcomes in Japanese BRIC patients. METHODS: We recruited patients with BRIC type 1 (BRIC-1) or 2 (BRIC-2) treated at four pediatric centers and one adult center between April 2007 and March 2022. Demographics, clinical course, laboratory results, molecular genetic findings concerning ATP8B1 and ABCB11 genes, histopathology, and treatment response were examined retrospectively. RESULTS: Seven Japanese patients with BRIC were enrolled (four male, three female; four BRIC-1 and three BRIC-2). The median age at onset for BRIC-1 was 12 years; for BRIC-2, it was 1 month. Intermittent cholestatic attacks numbered from one to eight during the 11 years of median follow-up. Six patients received a mainstream education; only one patient attended special education. None developed cirrhosis. Three with BRIC-1 showed compound heterozygosity for a variant ATP8B1 gene, while one was heterozygous; two BRIC-2 patients showed compound heterozygosity in ABCB11 and one was heterozygous. Liver biopsy specimens obtained during cholestatic attacks showed fibrosis varying from none to moderate; inflammation was absent or mild. Rifampicin administered to three patients for cholestatic attacks was effective in all, as was cholestyramine in two of three. CONCLUSIONS: To our knowledge, this is the first East Asian multicenter study of BRIC patients. Onset age and number of cholestatic attacks varied. Rifampicin and cholestyramine were effective against attacks. No patient developed cirrhosis; most had normal growth and development. The long-term outcomes were satisfactory.

Serum Fibrinogen Level and Cytokine Production as Prognostic Biomarkers for Idiopathic Sudden Sensorineural Hearing Loss.

OBJECTIVES: No clinically useful prognostic factors have been identified for idiopathic sudden sensorineural hearing loss (ISSNHL). The current study therefore sought to identify useful prognostic factors for idiopathic sudden sensorineural hearing loss from blood biomarkers while attempting to classify the pathogenic mechanism and formulate treatment strategies based on these results. STUDY DESIGN: Prospective cohort study. SETTING: Tertiary referral center. METHODS: A total of 47 patients with acute phase ISSNHL were treated with steroid at an initial dose of 1 mg/kg/day and hyperbaric oxygen therapy and followed up for 6 months. Serum fibrinogen levels, peripheral blood mononu- clear cells (PBMCs), and interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α production levels from PBMCs were measured, after which patient's pre- and post- treatment hearing was compared. RESULTS: In the overall cohort, the mean improvement level, mean recovery rate, and mean fibrinogen level was 20.3 dB, 46.2%, 292.0 mg/mL, respectively. The mean levels of IL-1ß, IL-6, and TNF-α produced by peripheral blood mononu- clear cells cultured under lipopolysaccharide stimulation were 318.4, 498.1, and 857.6 pg/mL, respectively. High fibrinogen levels were associated with poor hearing progno- sis. Lipopolysaccharide-stimulated cytokine production by PBMCs did not correlate with hearing changes; however, the prognosis was significantly better in patients with low fibrinogen levels and high IL-1ß levels produced by PBMCs than in other patients. CONCLUSIONS: Our results suggest that patients with simple inflammatory-type ISSNHL responded well to standard therapy. Therefore, serum fibrinogen levels and PBMCs cytokine production may help determine the management of ISSNHL based on its pathogenic mechanism.

Clinical and genetic features of congenital bile acid synthesis defect with a novel mutation in AKR1D1 gene sequencing: Case reports.

RATIONALE: Congenital bile acid synthesis defect (BASD) is a rare disease caused by mutations in the aldo-keto reductase 1D1 gene, which encodes the primary Δ4-3-oxosteroid 5ß-reductase enzyme. Early disease diagnosis is critical for early treatment with bile acid replacement therapy, with an excellent chance for recovery. In contrast, protracted diagnosis and treatment may lead to poor outcomes, including decompensated hepatic cirrhosis, liver transplant, and even death. PATIENT CONCERNS: Three clinical congenital bile acid synthesis defect cases in the Vietnamese population are herein reported. These pediatric patients presented with symptoms of prolonged postpartum jaundice and abnormal loose stool (mucus, lipids, and white). The clinical examinations showed hepatosplenomegaly. Urinalysis showed a very low fraction of primary bile acids and atypical 3-oxo-Δ4- bile acids in all three patients. DIAGNOSES: The patients were diagnosed with primary Δ4-3-oxosteroid 5ß-reductase deficiency. Next-generation gene sequencing revealed two homozygous mutations in the aldo-keto reductase family 1 member D1 gene. The first is a documented variant, c.797G>A (p.Arg266Gln), and the second is a novel mutation at c.155T>C (p.Ile52Thr). INTERVENTIONS: Immediately after diagnosis, patients were treated with oral chenodeoxycholate 5 mg/kg/d. OUTCOMES: The patients' symptoms, signs, and primary bile acids levels improved significantly. LESSONS: Clinicians should consider genetic disorders related to cholestasis for effective and life-saving treatment. A prompt genetic analysis by next-generation gene sequencing enables patients to access bile acid replacement therapy earlier, significantly improving short- and long-term outcomes.

Human iPSC-derived hepatocyte system models cholestasis with tight junction protein 2 deficiency.

Background & Aims: 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. Methods: 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. Results: 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. Conclusions: 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. Lay summary: 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.

Influence of food on pharmacokinetics and pharmacodynamics of 4-phenylbutyrate in patients with urea cycle disorders.

Urea cycle disorders (UCDs), inborn errors of hepatocyte metabolism, cause hyperammonemia and lead to neurocognitive deficits, coma, and even death. Sodium 4-phenylbutyrate (NaPB), a standard adjunctive therapy for UCDs, generates an alternative pathway of nitrogen deposition through glutamine consumption. Administration during or immediately after a meal is the approved usage of NaPB. However, we previously found that preprandial oral administration enhanced its potency in healthy adults and pediatric patients with intrahepatic cholestasis. The present study evaluated the effect of food on the pharmacokinetics and pharmacodynamics of NaPB in five patients with UCDs. Following an overnight fast, NaPB was administered orally at 75 mg/kg/dose (high dose, HD) or 25 mg/kg/dose (low dose, LD) either 15 min before or immediately after breakfast. Each patient was treated with these four treatment regimens with NaPB. With either dose, pre-breakfast administration rather than post-breakfast administration significantly increased plasma PB levels and decreased plasma glutamine availability. Pre-breakfast LD administration resulted in a greater attenuation in plasma glutamine availability than post-breakfast HD administration. Plasma levels of branched-chain amino acids decreased to the same extent in all tested regimens. No severe adverse events occurred during this study. In conclusion, preprandial oral administration of NaPB maximized systemic exposure of PB and thereby its efficacy on glutamine consumption in patients with UCDs.

Differences in responsiveness of intratympanic steroid injection for intractable vertigo in Meniere's disease.

OBJECTIVES: The efficacy of intratympanic steroid (ITS) injection for intractable Meniere's disease has been reported; however, its differences in responsiveness are not fully understood. This study investigated the clinical characteristics of patients who responded to ITS injection treatment. METHODS: This retrospective study included 32 patients with Meniere's disease who were unable to control frequent vertigo attacks despite conservative treatment for at least 3 months. They received an intratympanic injection of dexamethasone (3.3 mg/mL) in the affected side at least three times. We measured hearing threshold, subjective symptom scores, cervical and ocular vestibular evoked myogenic potential (cVEMP and oVEMP), and performed glycerol and bithermal caloric tests. RESULTS: Satisfactory control of vertigo for 1 year after the first round of injection was found in 18 patients (56.3%; the response group). However, the injections failed to control vertigo in the other 14 patients (43.8%; the non-response group), and they were then treated with middle ear micropressure therapy. The response group showed improvement in low-frequency hearing, whereas hearing acuity did not change in the non-response group. Significantly reduced amplitude of cVEMP on the affected side was found in 62.5% of patients in the response group; however, no patients in the non-response group showed reduced amplitude of cVEMP. CONCLUSIONS: ITS injection significantly improved the subjective symptoms for intractable Meniere's disease; however, the long-term effects were heterogeneous. Our results suggest that reduced amplitude in cVEMP is associated with the effectiveness of ITS injection treatment.

A randomized trial to examine the impact of food on pharmacokinetics of 4-phenylbutyrate and change in amino acid availability after a single oral administration of sodium 4-phenylbutyrarte in healthy volunteers.

Urea cycle disorders (UCDs), inborn errors of hepatocyte metabolism, result in the systemic accumulation of ammonia to toxic levels. Sodium 4-phenylbutyrate (NaPB), a standard therapy for UCDs for over 20 years, generates an alternative pathway of nitrogen deposition through glutamine consumption. Administration during or immediately after a meal is the accepted use of NaPB. However, this regimen is not based on clinical evidence. Here, an open-label, single-dose, five-period crossover study was conducted in healthy adults to investigate the effect of food on the pharmacokinetics of NaPB and determine any subsequent change in amino acid availability. Twenty subjects were randomized to one of four treatment groups. Following an overnight fast, NaPB was administered orally at 4.3 g/m2 (high dose, HD) or 1.4 g/m2 (low dose, LD) either 30 min before or just after breakfast. At both doses, compared with post-breakfast administration, pre-breakfast administration significantly increased systemic exposure of PB and decreased plasma glutamine availability. Pre-breakfast LD administration attenuated plasma glutamine availability to the same extent as post-breakfast HD administration. Regardless of the regimen, plasma levels of branched-chain amino acids (BCAA) were decreased below baseline in a dose-dependent manner. In conclusion, preprandial oral administration of NaPB maximized systemic exposure of the drug and thereby its potency to consume plasma glutamine. This finding may improve poor medication compliance because of the issues with odor, taste, and pill burden of NaPB and reduce the risk of BCAA deficiency in NaPB therapy.

Modeling Human Bile Acid Transport and Synthesis in Stem Cell-Derived Hepatocytes with a Patient-Specific Mutation.

The bile salt export pump (BSEP) is responsible for the export of bile acid from hepatocytes. Impaired transcellular transport of bile acids in hepatocytes with mutations in BSEP causes cholestasis. Compensatory mechanisms to regulate the intracellular bile acid concentration in human hepatocytes with BSEP deficiency remain unclear. To define pathways that prevent cytotoxic accumulation of bile acid in hepatocytes, we developed a human induced pluripotent stem cell-based model of isogenic BSEP-deficient hepatocytes in a Transwell culture system. Induced hepatocytes (i-Heps) exhibited defects in the apical export of bile acids but maintained a low intracellular bile acid concentration by inducing basolateral export. Modeling the autoregulation of bile acids on hepatocytes, we found that BSEP-deficient i-Heps suppressed de novo bile acid synthesis using the FXR pathway via basolateral uptake and export without apical export. These observations inform the development of therapeutic targets to reduce the overall bile acid pool in patients with BSEP deficiency.

Assessment of Adenosine Triphosphatase Phospholipid Transporting 8B1 (ATP8B1) Function in Patients With Cholestasis With ATP8B1 Deficiency by Using Peripheral Blood Monocyte-Derived Macrophages.

Adenosine triphosphatase phospholipid transporting 8B1 (ATP8B1) deficiency, an ultrarare autosomal recessive liver disease, includes severe and mild clinical forms, referred to as progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis type 1 (BRIC1), respectively. There is currently no practical method for determining PFIC1 or BRIC1 at an early disease course phase. Herein, we assessed the feasibility of developing a diagnostic method for PFIC1 and BRIC1. A nationwide Japanese survey conducted since 2015 identified 25 patients with cholestasis with ATP8B1 mutations, 15 of whom agreed to participate in the study. Patients were divided for analysis into PFIC1 (n = 10) or BRIC1 (n = 5) based on their disease course. An in vitro mutagenesis assay to evaluate pathogenicity of ATP8B1 mutations suggested that residual ATP8B1 function in the patients could be used to identify clinical course. To assess their ATP8B1 function more simply, human peripheral blood monocyte-derived macrophages (HMDMs) were prepared from each patient and elicited into a subset of alternatively activated macrophages (M2c) by interleukin-10 (IL-10). This was based on our previous finding that ATP8B1 contributes to polarization of HMDMs into M2c. Flow cytometric analysis showed that expression of M2c-related surface markers cluster of differentiation (CD)14 and CD163 were 2.3-fold and 2.1-fold lower (95% confidence interval, 2.0-2.5 for CD14 and 1.7-2.4 for CD163), respectively, in patients with IL-10-treated HMDMs from PFIC1 compared with BRIC1. Conclusion: CD14 and CD163 expression levels in IL-10-treated HMDMs may facilitate diagnosis of PFIC1 or BRIC1 in patients with ATP8B1 deficiency.

Hearing loss is associated with hippocampal atrophy and high cortisol/dehydroepiandrosterone sulphate ratio in older adults.

OBJECTIVES: Hearing loss (HL) has been recognised as a prodromal symptom of cognitive disorder with aging. It is still uncertain if HL leads to cognitive impairment directly or through an indirect mechanism. DESIGN: Participants of this study underwent an auditory test, blood tests, and brain MRI. The atrophy rate of the hippocampus (HP) was calculated using voxel-based specific areas. A partial correlation analysis whilst controlling for the effect of age was performed to analyse the factors affecting hearing levels and HP atrophy rate (HP%). STUDY SAMPLE: Thirty-six older adults with hearing impairment. RESULTS: The group of participants with moderate or severe HL (n = 22) had higher cortisol/dehydroepiandrosterone sulphate (C/D) ratio, geriatric depression score (GDS) and HP% than the mild HL or normal hearing group (n = 14, p < 0.05). The HP% showed a significant positive correlation with the C/D ratio, GDS and the hearing level of high frequency (HF) (p < 0.05). The C/D ratio was positively correlated with the HP% and the hearing level of the HF (p < 0.05). CONCLUSIONS: Our results suggest that the HL is associated with the atrophy of HP and high C/D ratios in older adults; however, HL may not be causally related to hippocampal atrophy.

Long-term Outcomes of Living-donor Liver Transplantation for Progressive Familial Intrahepatic Cholestasis Type 1.

OBJECTIVES: Progressive familial intrahepatic cholestasis type 1 (PFIC-1), an autosomal recessive disorder, is characterized by cholestasis, jaundice, and refractory pruritus. In some patients with PFIC-1, liver cirrhosis and end-stage liver disease develop and lead to liver transplantation (LT). In this observational study, we sought to clarify the long-term outcomes of LT for PFIC-1 and predictors of favorable outcomes. METHODS: The study cohort constituted 12 patients with PFIC-1 who had undergone living donor liver transplantation (LDLT) during the previous 3 decades (1990-2019). We compared the clinical manifestations and type of ATP8B1 mutations between patients in whom LDLT had been successful and those in whom it had been unsuccessful. RESULTS: LDLT failed in 5 of the 12 patients and the 25-year survival rate was 58%. Comparison of physical growth after LDLT revealed significant retardation of stature in patients in whom LDLT had been unsuccessful; these patients developed severe and persistent diarrhea. ATP8B1 genotypic analysis revealed that frameshifting, splicing, and large deletion mutations occurred more commonly in successful cases, whereas missense mutations occurred more frequently in unsuccessful cases. No mutations were identical in the 2 groups. CONCLUSIONS: These results suggest an association between post-LT outcomes and extrahepatic manifestations, especially intestinal function. Further investigation of correlations between ATP8B1 genotypes and intestinal function could help to identify patients with PFIC-1 who will achieve favorable post-LT outcomes.

Proposal of a liver histology-based scoring system for bile salt export pump deficiency.

AIM: Bile salt export pump (BSEP) deficiency manifests a form of progressive intrahepatic cholestasis. This study aimed to establish a scoring system of liver histology for the uncommon genetic condition. METHODS: After a roundtable discussion and histology review, a scoring system for BSEP deficiency was established. Eleven tissue samples were independently evaluated by three pathologists based on the proposed standard for an interobserver agreement analysis. In four cases with serial tissue samples available, correlation between changes in histology scores and clinical outcome was examined. RESULTS: Of 14 initially listed histopathological findings, 12 were selected for scoring and grouped into the following four categories: cholestasis, parenchymal changes, portal tract changes and fibrosis. Each category consisted of two to four microscopic findings that were further divided into three to six scores; therefore, each category had a maximum score of 8-11. Interobserver agreement was highest for pericellular fibrosis (κ = 0.849) and lowest for hepatocellular cholestasis (κ = 0.241) with the mean and median κ values of the 12 parameters being 0.561 and 0.602, respectively. For two patients whose clinical features worsened, score changes between two time points were interpreted as deteriorated. In two patients, who showed a good clinical response to preprandial treatment with sodium 4-phenylbutyrate, histological changes were evaluated as improved or unchanged. CONCLUSIONS: The proposed histology-based scoring system for BSEP deficiency with moderate interobserver agreement may be useful not only for monitoring microscopic changes in clinical practice but also for a surrogate endpoint in clinical trials.

Brain Abscess Presenting as Prolonged Headache in a Patient with Amyotrophic Lateral Sclerosis under Mechanical Ventilation.

A 57-year-old woman with amyotrophic lateral sclerosis (ALS) receiving mechanical ventilation developed intractable right temporal headache. She was diagnosed with brain abscess secondary to chronic suppurative otitis media. In this case, the otitis media was caused by nasopharyngeal reflux associated with eustachian tube muscle weakness and a supine position. In addition, ALS patients under mechanical ventilation have a limited ability to convey their pain. Their complaints are often overlooked because many physicians do not know that pain is common in ALS. Physicians should recognize brain abscess as a severe complication of ALS and listen to the complaints of these patients.

The Long-Term Efficacy of Cochlear Implantation for Hearing Loss in Muckel-Wells Syndrome.

Muckle-Wells syndrome (MWS), a subclass of cryopyrin-associated periodic syndrome (CAPS), sometimes includes complications of bilateral progressive sensorineural hearing loss. A 48-year-old woman had been diagnosed with pediatric rheumatic arthritis at aged 6 years; however, systematic therapy with prednisolone and methotrexate showed limited efficacy for her general fatigue and arthritic pain, and it never improved the hearing level. She underwent a cochlear implant surgery for progressive profound bilateral hearing loss. After 7 years of cochlear implant surgery, she was diagnosed with MWS by genetic tests. Interleukin (IL)-1ß monoclonal antibody therapy (canakinumab) improved general fatigue and arthritic pain but showed no effect on cochlear symptoms. Owing to successful cochlear implant surgery, she reacquired the hearing and communication function while being able to understand over 90% of monosyllables and words in the sound field of her daily life at 65 dB SPL for the next 13 years of her life. This suggests that peripheral cochlear damage induced by chronic inflammation contributes to the sensorineural hearing loss in cases with MWS, and that cochlear implantation can provide long-term hearing efficacy for patients with MWS with irreversible profound hearing loss.