Search Results (23)

Background: Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by progressive bile duct damage and cholestasis. While ursodeoxycholic acid (UDCA) is the first-line therapy, approximately 40% of patients have incomplete responses, necessitating alternative treatments. This systematic review and meta-analysis evaluate the efficacy and safety of novel oral anti-cholestatic agents for PBC. Methods: A systematic literature search was conducted in electronic databases up to September 2024. Randomized controlled trials, cohort studies, and case-control studies evaluating novel oral anti-cholestatic agents in adult PBC patients were included. The primary outcome was a change in alkaline phosphatase (ALP) levels. Safety was assessed by the incidence of serious adverse events. Random-effect meta-analyses were performed. Results: Ten studies involving 878 patients were analyzed. Novel agents included seladelpar, fenofibrate, saroglitazar, bezafibrate, elafibranor, and budesonide. The meta-analysis showed significant reductions in ALP levels with novel agents compared to the controls (SMD −2.80; 95% CI −3.56, −2.03; p < 0.00001), with high heterogeneity (I² = 93%). Saroglitazar achieved the largest effect size. There was no significant difference in serious adverse events between novel agents and controls (OR 1.21; 95% CI 0.81, 1.83; p = 0.35). Conclusions: Novel oral anti-cholestatic agents show promise in improving biochemical markers in PBC patients with suboptimal UDCA responses, with a safety profile comparable to controls. However, study heterogeneity and limited long-term data restrict direct comparisons. Larger standardized trials with extended follow-up are needed to confirm long-term efficacy and safety. Full article

During the coronavirus disease 2019 (COVID-19) pandemic, several studies highlighted a worse prognosis for patients with alterations in liver function tests, especially those with pre-existing liver diseases. However, further studies are needed to define the long-term impact of the COVID-19 pandemic on liver diseases. Long COVID-19 encompasses a wide range of signs and symptoms, including exacerbations of pre-existing chronic conditions or new onset conditions developed after the COVID-19 acute phase. Therefore, the long-term effects of COVID-19 extensively include hepatic manifestations. The co-expression of angiotensin-converting receptor 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) has been demonstrated also in enterocytes, cholangiocytes, and hepatocytes. Studies on the post-COVID-19 sequelae have shown the presence of steatosis and necroinflammation in the liver, concomitantly with an alteration of inflammation, cytolysis and cholestasis indices. Some studies also demonstrated an increased risk for hepatobiliary pathologies, including secondary biliary cholangitis and worsening of the severity of metabolic-associated fatty liver disease (MASLD). Based on these premises, this review aims to provide an overview of the pathophysiological mechanisms contributing to COVID-19-related liver and hepatobiliary damage; explore its implications for liver inflammation and fibrosis, with a particular focus on MASLD and metabolic dysfunction-associated steatohepatitis (MASH); and analyze the short- and long-term COVID-19 sequelae. A literature search was conducted using the PubMed database for relevant studies published in English. Full article

Background: Patients with progressive familial intrahepatic cholestasis (PFIC) experience cholestasis-associated symptoms, including severe pruritus. Odevixibat is an ileal bile acid transporter inhibitor indicated for treatment of PFIC in the European Union and for the treatment of pruritus in PFIC in the United States. The aim of the current study was to characterize the real-world effectiveness and safety of odevixibat in patients with PFIC. Methods: This retrospective study included 9 patients with PFIC treated with odevixibat in a single center in Tübingen, Germany. Data were recorded using case report forms. Results: Of the 9 patients (PFIC1, n = 2; PFIC2, n = 7), 5 had improved serum bile acid levels, pruritus, liver function tests, and sleep with odevixibat treatment. Two siblings with periodic relapses of PFIC symptoms also had improved pruritus and sleep within 4 months of treatment. Two siblings with complete loss of bile salt export pump (BSEP) protein did not respond to treatment; both underwent liver transplantation (indications: hepatocellular carcinoma [HCC] manifestation [n = 1] and severe failure to thrive and refractory pruritus [n = 1]). Four patients reported abdominal complaints that were transient or responded to dose reduction; no other safety issues were reported. Conclusions: In this case series, clinical benefits were observed in most patients with PFIC1 and PFIC2 treated with odevixibat. In patients with periodic relapse of PFIC symptoms, ≥3 months of treatment with odevixibat may be required for symptom control. Patients with complete loss of BSEP did not have consistent symptom relief and require careful monitoring. Effectiveness and feasibility results from our cohort demonstrate potential for long-term benefits with odevixibat in real-world treatment of patients with PFIC. Full article

Background: Liver cirrhosis presents significant challenges in the pediatric population due to a complex interplay of etiological factors, clinical manifestations, and limited therapeutic options. The leading contributors to cirrhosis among pediatric patients are chronic cholestasis, metabolic disorders present from birth, and long-term hepatitis. Materials and method: Our narrative review aimed to synthesize literature data on the etiology, clinical picture, diagnostic techniques, optimal management of complications, and timely transplantation. Results: The epidemiology of liver cirrhosis in pediatric patients is evolving. The introduction of a universal vaccination and effective long-term viral suppression in viral hepatitis have significantly decreased complications rates. Liver transplantation programs worldwide have also improved the management of cirrhosis complications. Conclusions: Early diagnosis, comprehensive management strategies, and advancements in treatment modalities are critical for improving outcomes. Understanding these differences is crucial in providing age-appropriate care and support for those affected by cirrhosis. Full article

The unclear pathogenesis of chronic itch originating from several systemic disorders poses challenges to clinical intervention. Recent studies recapitulate the spinal neurocircuits associated with neuroinflammation and synaptic plasticity responsible for pruriceptive sensations. The resolution of nociception and inflammation by Annexin 1 (ANXA1) has been identified. Given that pain and itch share many neural mechanisms, we employed two mice models of chronic itch to study the underlying targets and therapeutic potential of ANXA1, comprising allergic contact dermatitis-induced itch and cholestatic itch. Herein, we report that spinal expression of ANXA1 is down-regulated in mice with dermatitis-induced itch and cholestatic itch. Repetitive injections of ANXA1-derived peptide Ac2-26 (intrathecal, 10 μg) reduce itch-like scratching behaviors following dermatitis and cholestasis. Single exposure to Ac2-26 (intrathecal, 10 μg) alleviates the established itch phenotypes. Moreover, systemic delivery of Ac2-26 (intravenous, 100 μg) is effective against chronic dermatitis-induced itch and cholestatic itch. Strikingly, Ac2-26 therapy inhibits transferrin receptor 1 over-expression, iron accumulation, cytokine IL-17 release and the production of its receptor IL-17R, as well as astrocyte activation in the dorsal horn of spinal cord in mouse with dermatitis and cholestasis. Pharmacological intervention with iron chelator deferoxamine impairs chronic itch behaviors and spinal iron accumulation after dermatitis and cholestasis. Also, spinal IL-17/IL-17R neutralization attenuates chronic itch. Taken together, this current research indicates that ANXA1 protects against the beginning and maintenance of long-term dermatitis-induced itch and cholestatic itch, which may occur via the spinal suppression of IL-17-mediated neuroinflammation, astrocyte activation and iron overload. Full article

Fetus loss in early pregnancy is of major concern to both humans and animals, and this issue is largely influenced by embryo implantation. Chenodeoxycholic acid (CDCA), a primary bile acid, contributes to metabolic improvements and protects against intrahepatic cholestasis of pregnancy. However, the effect of CDCA on embryo implantation during early pregnancy has not been investigated. The present study demonstrated that CDCA administration during early pregnancy improved embryo implantation in sows and rats, thereby improving the pregnancy outcomes of sows. CDCA significantly reduced inflammation, oxidative stress, and insulin resistance. The metabolomics analysis indicated significant differences in the fecal metabolome, especially regarding the level of secondary bile acids, between the control and CDCA-treated sows. CDCA also influenced the serum metabolite profiles in sows, and the serum L-Histidine level was significantly correlated with the abundance of 19 differential fecal metabolites. Importantly, L-Histidine administration improved embryo implantation and metabolic health in rats during early pregnancy. Moreover, CDCA administration during early pregnancy also led to long-term metabolic improvements in sows. Our data indicated that CDCA improved embryo implantation by alleviating inflammation and oxidative stress, improving insulin sensitivity, and modulating the interaction between the gut microbiota and host metabolites. Therefore, CDCA intervention is a potential therapeutic strategy regarding embryo loss during pregnancy. Full article

Severe hemolytic disease of the fetus and newborn (HDFN) requiring intrauterine transfusions (IUTs) may cause iron accumulation, resulting in liver damage, which may lead to cholestasis and coagulation disorders. In this article, we reported a case of a female neonate who underwent chelation therapy with a positive outcome, and we reviewed the English and Polish literature on chelation therapy in HDFN available in PubMed. The patient with maximum ferritin concentration above 33,511.2 ng/mL developed liver dysfunction with coagulation disorders requiring multiple transfusions of fresh frozen plasma (FFP), Octaplex^® and cryoprecipitate, and hypoalbuminemia treated with numerous albumin infusions. Furthermore, severe cholestasis was observed with direct bilirubin levels up to 33.14 mg/dL. Additionally, the child developed transient myelosuppression with neutropenia, thrombocytopenia, and low reticulocyte count due to several blood transfusions. The differential diagnosis tests were conducted to rule out any causes of hepatic failure other than hemolytic disease of the newborn. This case proves that adequate treatment of severe HDFN with anemia requiring IUT and hepatic failure can lead to positive outcomes with no long-term consequences. Full article

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. Full article

The aims of our study were to evaluate the maternal and fetal outcomes of intrahepatic cholestasis of pregnancy (ICP). In this observational, retrospective case–control study, we included all pregnant women who gave birth with a diagnosis of ICP between January 2010 and December 2020 at the Unit of Obstetrics and Gynecology, University Hospital of Messina. The data were compared with those from a control group of pregnant women who did not have ICP. One hundred twenty-nine and eighty-five patients were included, respectively, in the study and in the control group. There was a significant difference between the two groups in the incidence of hypothyroidism, thrombophilia, gestational diabetes, gestational hypertension, postpartum hemorrhage, and preterm delivery, which were more frequent in the ICP patients. No neonatal adverse events were recorded, although a significant difference in the meconium-stained amniotic fluid condition was noted. After a 24-month follow-up, 48/129 patients with ICP accepted to be reassessed by liver ultrasound, elastographic examination, and liver function blood tests. No patient showed signs of chronic liver disease. This study confirmed a higher probability of adverse short-term maternal outcomes in ICP pregnant patients, but a lower probability of adverse short-term fetal outcomes and the absence of a long-term maternal risk of chronic liver disease. Full article

Graft versus host disease (GVHD) is one of the most serious complications following stem cell transplant in children and is a major cause of morbidity and mortality. Corticosteroids remain the mainstay of treatment, and although a majority of children respond to systemic steroids, those refractory to or dependent upon corticosteroids suffer from complications secondary to long-term steroid administration. This problem has prompted consideration of steroid-sparing treatment strategies, although the time to clinical remission can be variable. Intraarterial corticosteroid delivery has been used in adults as a rescue therapy in steroid-resistant patients, but its use in children has been limited. We investigated the feasibility of intraarterial steroid administration into the bowel and/or liver in a cohort of six pediatric patients with acute GVHD. All patients successfully underwent treatment with no serious adverse effects. Five of five (100%) patients with gastrointestinal bleeding due to GVHD had rapid symptom improvement by 48 h, which was durable up to three weeks. Three of four (75%) patients with hepatic GVHD had improved cholestasis following intraarterial steroid administration. Our experience with this small cohort preliminarily demonstrated the feasibility and safety of intraarterial steroid administration in children with acute GVHD. This approach warrants consideration as a rescue therapy in steroid-refractory cases and as a “bridge” therapy for children with severe acute GVHD who are transitioning to steroid-sparing regimens. Full article

Necrotizing enterocolitis (NEC), spontaneous intestinal perforation (SIP) and meconium-related ileus (MI) requiring surgical intervention are associated with a high risk of severe short- and long-term complications in very-low-birth-weight (VLBW) infants including poor growth, cholestasis and neurodevelopmental impairment. This retrospective study aimed to identify risk factors for such complications in a cohort of 55 VLBW preterm infants requiring surgery with enterostomy creation due to NEC, SIP or MI. Long-term follow-up was available for 43 (78%) infants. Multiple regression analyses revealed that the duration of inflammation and longitudinal growth determined the risk of cholestasis and neurodevelopmental outcome at 2 years corrected age independent of the aetiology of the intestinal complication. Direct bilirubin increased by 4.9 μmol/L (95%CI 0.26–9.5), 1.4 μmol/L (95%CI 0.6–2.2) and 0.8 μmol/L (95%CI 0.22–1.13) with every day of elevated (Interleukin-6) IL-6, (C-reactive protein) CrP and parenteral nutrition. The mental development index at 2 years corrected age decreased by 3.8 (95%CI −7.3–−0.36), 0.4 (95%CI 0.07–0.80) and 0.3 (95%CI 0.08–0.57) with every day of elevated IL-6 and every 1 point decrease in weight percentile at discharge and 2 years. These data stress the importance of optimal timing for the initial surgery in order to prevent prolonged inflammation and an early reversal of the enterostomy in case of poor growth or insufficient enteral nutrition. Full article

Previous studies showed that rats with long-term bile duct ligation have reduced coenzyme A stores per g of liver but maintained mitochondrial CoA stores. Based on these observations, we determined the CoA pool in the liver homogenate, liver mitochondria, and liver cytosol of rats with bile duct ligation for 4 weeks (BDL rats, n = 9) and sham-operated control rats (CON rats, n = 5). In addition, we tested the cytosolic and mitochondrial CoA pools by assessing the metabolism of sulfamethoxazole and benzoate in vivo and of palmitate in vitro. The hepatic total CoA content was lower in BDL than CON rats (mean ± SEM; 128 ± 5 vs. 210 ± 9 nmol/g), affecting all subfractions equally (free CoA (CoASH), short- and long-chain acyl-CoA). In BDL rats, the hepatic mitochondrial CoA pool was maintained, and the cytosolic pool was reduced (23.0 ± 0.9 vs. 84.6 ± 3.7 nmol/g liver; CoA subfractions were affected equally). The urinary excretion of hippurate after i.p. benzoate administration (measuring mitochondrial benzoate activation) was reduced in BDL rats (23.0 ± 0.9 vs. 48.6 ± 3.7% of dose/24 h), whereas the urinary elimination of N-acetylsulfamethoxazole after i.p. sulfamethoxazole administration (measuring the cytosolic acetyl-CoA pool) was maintained (36.6 ± 3.0 vs. 35.1 ± 2.5% of dose/24 h BDL vs. CON rats). Palmitate activation was impaired in the liver homogenate of BDL rats but the cytosolic CoASH concentration was not limiting. In conclusion, BDL rats have reduced hepatocellular cytosolic CoA stores, but this reduction does not limit sulfamethoxazole N-acetylation or palmitate activation. The hepatocellular mitochondrial CoA pool is maintained in BDL rats. Impaired hippurate formation in BDL rats is explained best by mitochondrial dysfunction. Full article

We analyzed the long-term survival rate and development of progressive familial intrahepatic cholestasis (PFIC) patients after liver transplantation (LT). From October 2007 to May 2019, 41 patients were diagnosed as PFIC (type I-III) and received LT in Ren Ji Hospital due to end-stage liver diseases. The median age at LT was 2.93 years, with 75.6% of patients receiving living donor liver transplantation (LDLT). The 5- and 10-year patient survival rates after LT were 92.7% and 92.7%, respectively, and no difference was found among the three subtypes of PFIC. Two PFIC type II patients received re-transplantation due to vascular complications. Liver function and bile acid metabolism returned to normal levels in all living recipients. Catch-up growth was recorded as the height and weight Z scores increased from −2.53 and −1.54 to −0.55 and −0.27 with a median follow-up time of 5.55 years. Improved psychomotor ability and age-appropriate study ability was also observed. A total of 72.4% of school-aged recipients exhibited average academic performance. Diarrhea was reported in all PFIC type I recipients but resolved after resin absorptive treatment. However, allograft steatosis occurred in one PFIC type I patient and exhibited a “remission–relapse circle” under the treatment of cholestyramine. In conclusion, LT is an effective treatment for end-stage PFIC patients with encouraging long-term survival rate and development. However, allograft steatosis should be closely monitored in PFIC type I patients even if diarrhea has been well treated. Full article

Cholestatic diseases can be caused by the dysfunction of transporters involved in hepatobiliary circulation. Although pharmacological treatments constitute the current standard of care for these diseases, none are curative, with liver transplantation being the only long-term solution for severe cholestasis, albeit with many disadvantages. Liver-directed gene therapy has shown promising results in clinical trials for genetic diseases, and it could constitute a potential new therapeutic approach for cholestatic diseases. Many preclinical gene therapy studies have shown positive results in animal models of both acquired and genetic cholestasis. The delivery of genes that reduce apoptosis or fibrosis or improve bile flow has shown therapeutic effects in rodents in which cholestasis was induced by drugs or bile duct ligation. Most studies targeting inherited cholestasis, such as progressive familial intrahepatic cholestasis (PFIC), have focused on supplementing a correct version of a mutated gene to the liver using viral or non-viral vectors in order to achieve expression of the therapeutic protein. These strategies have generated promising results in treating PFIC3 in mouse models of the disease. However, important challenges remain in translating this therapy to the clinic, as well as in developing gene therapy strategies for other types of acquired and genetic cholestasis. Full article

Background and Objectives: Progressive familial intrahepatic cholestasis (PFIC) is a rare autosomal recessive inherited disease divided into five types (PFIC 1-5). Characteristic for all types is early disease onset, which may result clinically in portal hypertension, fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and extrahepatic manifestations. Liver transplantation (LT) is the only successful treatment approach. Our aim is to present the good long-term outcomes after liver transplantation for PFIC1, focusing on liver function as well as the occurrence of extrahepatic manifestation after liver transplantation. Materials and Methods: A total of seven pediatric patients with PFIC1 underwent liver transplantation between January 1999 and September 2019 at the Department of Surgery, Charité Campus Virchow Klinikum and Charité Campus Mitte of Charité-Universitätsmedizin Berlin. Long-term follow-up data were collected on all patients, specifically considering liver function and extrahepatic manifestations. Results: Seven (3.2%) recipients were found from a cohort of 219 pediatric patients. Two of the seven patients had multilocular HCC in cirrhosis. Disease recurrence or graft loss did not occur in any patient. Two patients (male, siblings) had persistently elevated liver parameters but showed excellent liver function. Patient and graft survival during long-term follow-up was 100%, and no severe extrahepatic manifestations requiring hospitalization or surgery occurred. We noted a low complication rate during long-term follow-up and excellent patient outcome. Conclusions: PFIC1 long-term follow-up after LT shows promising results for this rare disease. In particular, the clinical relevance of extrahepatic manifestations seems acceptable, and graft function seems to be barely affected. Further multicenter studies are needed to analyze the clinically inhomogeneous presentation and to better understand the courses after LT. Full article