Progressive Familial Intrahepatic Cholestasis Research Articles

Progressive familial intrahepatic cholestasis type 2 on the example of one family. Liver transplantation as an effective treatment method. Case report

The article presents the structure of diseases that led to the need for liver sector transplantation in children living in the Novosibirsk region. The paper provides a detailed description of progressive familial intrahepatic cholestasis, principles of modern diagnosis and treatment. A description of the medical history of family members and, in particular, a clinical case in a young child with type 2 PFIC (Byler's syndrome) is given.

WED-282 - Analysis of safety in maralixibat-treated participants with progressive familial intrahepatic cholestasis: data from MARCH-PFIC

WED-282 - Analysis of safety in maralixibat-treated participants with progressive familial intrahepatic cholestasis: data from MARCH-PFIC

OS-072 - Maralixibat leads to significant reductions in bilirubin for patients with progressive familial intrahepatic cholestasis: data from MARCH-PFIC

OS-072 - Maralixibat leads to significant reductions in bilirubin for patients with progressive familial intrahepatic cholestasis: data from MARCH-PFIC

LBP-35 - Long-term maintenance of response and improved liver health with maralixibat in patients with progressive familial intrahepatic cholestasis (PFIC): data from the MARCH-ON study

LBP-35 - Long-term maintenance of response and improved liver health with maralixibat in patients with progressive familial intrahepatic cholestasis (PFIC): data from the MARCH-ON study

TOP-057 - Long-term efficacy and safety of odevixibat in patients with progressive familial intrahepatic cholestasis: results with 96 weeks or more of treatment

TOP-057 - Long-term efficacy and safety of odevixibat in patients with progressive familial intrahepatic cholestasis: results with 96 weeks or more of treatment

WED-252 - Maralixibat leads to significant reductions in pruritus and improvements in sleep for children with progressive familial intrahepatic cholestasis: data from MARCH-PFIC

WED-252 - Maralixibat leads to significant reductions in pruritus and improvements in sleep for children with progressive familial intrahepatic cholestasis: data from MARCH-PFIC

THU-289 - Analysis of long-term treatment effects of odevixibat on clinical outcomes in children with progressive familial intrahepatic cholestasis in odevixibat clinical studies vs external controls from the NAPPED database

THU-289 - Analysis of long-term treatment effects of odevixibat on clinical outcomes in children with progressive familial intrahepatic cholestasis in odevixibat clinical studies vs external controls from the NAPPED database

THU-378 - Outcomes in adult patients with progressive familial intrahepatic cholestasis treated with odevixibat: subgroup analysis from the PEDFIC 2 study

THU-378 - Outcomes in adult patients with progressive familial intrahepatic cholestasis treated with odevixibat: subgroup analysis from the PEDFIC 2 study

THU-313 - Odevixibat therapy following liver transplantation in patients with FIC1-deficient progressive familial intrahepatic cholestasis: a retrospective case series

THU-313 - Odevixibat therapy following liver transplantation in patients with FIC1-deficient progressive familial intrahepatic cholestasis: a retrospective case series

THU-270 - Clinical characteristics and pathogenic mechanism of five new ABCB4 missense mutations in progressive familial intrahepatic cholestasis type 3

THU-270 - Clinical characteristics and pathogenic mechanism of five new ABCB4 missense mutations in progressive familial intrahepatic cholestasis type 3

Surgical versus Medical Management of Progressive Familial Intrahepatic Cholestasis-Case Compilation and Review of the Literature.

(1) Background: Progressive familial intrahepatic cholestasis (PFIC) is a rare cause of liver failure. Surgical biliary diversion (SBD) and ileal bile salt inhibitors (IBAT) can delay or prevent liver transplantation (LTX). A comparison of the two methodologies in the literature is lacking. The combination has not been investigated. (2) Methods: We performed a literature survey on medical and surgical treatments for PFIC and reviewed the charts of our patients with PFIC of a tertiary hospital. The end points of our analysis were a decrease in serum bile acid (sBA) levels, reduction of pruritus and delay or avoidance of (LTX). (3) Results: We included 17 case series on SBD with more than 5 patients and a total of 536 patients. External or internal SBD, either conventional or minimally invasive, can reduce pruritus and sBA, but not all PFIC types are suitable for SBD. Six publications described the use of two types of IBAT in PFIC with a total of 118 patients. Treatment response was dependent on genetic type and subtype. Patients with PFIC 2 (nt-BSEP) showed the best response to treatment. Four out of eleven PFIC patients underwent SBD at our centre, with two currently receiving IBAT. (4) Conclusions: Limited data on IBAT in selected patients with PFIC show safety and effectiveness, although surgical methods should still be considered as a successful bridging procedure. Further studies to evaluate a possible combination of IBAT and SBD in PFIC are warranted and treatment decision should be discussed in an interdisciplinary board.

Case Report: Intrahepatic cholestasis: a diagnostic dilemma

Cholestasis is an impairment of bile formation or bile flow. The mechanisms of cholestasis can be broadly classified into intrahepatic and extrahepatic. Most of the time, etiology can be determined with proper history, physical examination and diagnostic testing including laboratory and imaging tests. This is a case report of a patient with severe cholestasis who underwent extensive evaluation to determine the etiology of intrahepatic cholestasis. This Case Report details a 28-year-old male who presented with seven days’ history of yellowish discoloration of eyes, passage of dark colored urine, generalized body itching, and passage of clay colored stool. Patient had no similar episode in the past. Laboratory investigations showed unconjugated hyperbilirubinemia and increased alkaline phosphatase. Magnetic resonance cholangiopancreaticography was unremarkable and liver biopsy was suggestive of cholestatic pattern and negative for acute hepatitis. The bilirubin level started decreasing after a month. The etiology of intrahepatic cholestasis remained unknown. Genotyping could not be done due to limited available resources. It may have helped to diagnose familial hepatocellular cholestasis such as benign recurrent intrahepatic cholestasis (BRIC) and progressive familial intrahepatic cholestasis. Gamma glutamyl transferase is normal or mildly elevated in patients with BRIC. A similar picture was seen in our case as well. If the patient presents again with similar symptoms and findings, we can consider the diagnosis of BRIC.

Cholestatic Pruritus in Children: Conventional Therapies and Beyond.

Pruritus in the setting of cholestatic liver disease is difficult to treat and occurs in patients ranging in age from infancy to adulthood. Likely multifactorial in etiology, this symptom often involves multimodal therapy targeting several pathways and mechanisms proposed in the underlying etiology of cholestatic pruritus. Many patients in both the pediatric and adult populations continue to experience unrelenting pruritus despite maximal conventional therapy. Options are further limited in treating pediatric patients due to sparse data regarding medication safety and efficacy in younger patients. Conventional therapies for the treatment of cholestatic pruritus in children include ursodeoxycholic acid, cholestyramine, hydroxyzine, and rifampin. Certain therapies are more routinely used in the adult populations but with limited data available for use in child and adolescent patients, including opioid antagonists and selective serotonin reuptake inhibitors. Recently, ileal bile acid transport inhibitors have been shown to alleviate pruritus in many children with Alagille syndrome and progressive familial intrahepatic cholestasis and is an additional therapy available for consideration for these patients. Ultimately, surgical options such as biliary diversion or liver transplantation are considered in specific circumstances when medical therapies have been exhausted and pruritus remains debilitating. While further investigation regarding underlying etiologies and effective therapies are needed to better understand itch pathogenesis and treatment in pediatric cholestasis, current considerations beyond conventional management include the use of opioid antagonists, selective serotonin reuptake inhibitors, ileal bile acid transport inhibitors, and surgical intervention.

Interim results from an ongoing, open-label, single-arm trial of odevixibat in progressive familial intrahepatic cholestasis

Background & AimsPEDFIC 2, an ongoing, open-label, 72-week study, evaluates odevixibat, an ileal bile acid transporter inhibitor, in patients with progressive familial intrahepatic cholestasis. MethodsPEDFIC 2 enrolled and dosed 69 patients across two cohorts; all received odevixibat 120 μg/kg per day. Cohort 1 comprised children from PEDFIC 1, and cohort 2 comprised new patients (any age). We report data through 15 July 2020, with Week 24 of PEDFIC 2 the main time point analysed. This represents up to 48 weeks of cumulative exposure for patients treated with odevixibat from the 24-week PEDFIC 1 study (cohort 1A) and up to 24 weeks of treatment for those who initiated odevixibat in PEDFIC 2 (patients who received placebo in PEDFIC 1 [cohort 1B] or cohort 2 patients). Primary endpoints for this prespecified interim analysis were change from baseline to Weeks 22–24 in serum bile acids (sBAs) and proportion of positive pruritus assessments (≥1-point drop from PEDFIC 2 baseline in pruritus on a 0–4 scale or score ≤1) over the 24-week period. Safety monitoring included evaluating treatment-emergent adverse events (TEAEs). ResultsIn cohort 1A, mean change from PEDFIC 1 baseline to Weeks 22–24 of PEDFIC 2 in sBAs was -201 μmol/L (p <0.0001). For cohort 1B and cohort 2, mean changes from odevixibat initiation to weeks 22–24 in sBAs were -144 and -104 μmol/L, respectively. The proportion of positive pruritus assessments in the first 24-week period of PEDFIC 2 was 33%, 56%, and 62% in cohorts 1A, 1B, and 2, respectively. Most TEAEs were mild or moderate. No drug-related serious TEAEs occurred. ConclusionsOdevixibat in patients with progressive familial intrahepatic cholestasis was generally well tolerated and associated with sustained reductions in sBAs and pruritus. Clinical Trials RegistrationThis study is registered at ClinicalTrials.gov (NCT03659916). Impact and ImplicationsDisrupted bile flow is a hallmark feature of patients with progressive familial intrahepatic cholestasis and can result in build-up of bile constituents in the liver with spill over into the bloodstream; other effects that patients can experience include extremely itchy skin, and because not enough bile reaches the gut, patients can have problems digesting food, which may lead to poor growth. Odevixibat is an orally administered medication that shunts bile acids away from the liver. The current study, called PEDFIC 2, suggested that odevixibat can improve the problematic signs and symptoms of progressive familial intrahepatic cholestasis and was generally safe for patients.

Diagnostic workup of suspected hereditary cholestasis in adults: a case report

Hereditary cholestasis comprises a broad spectrum of clinical phenotypes of varying severity. Severe forms such as progressive familial intrahepatic cholestasis (PFIC) mostly affect children with disease onset within their first years. Nevertheless, late-onset PFIC forms are increasingly diagnosed. Most adults present with less severe forms of hereditary cholestasis, often suffering from pruritus, gallstone disease, jaundice, or elevated liver enzymes. To identify the underlying genetic background and to rule out potential differential diagnoses, a broad genetic analysis like whole exome sequencing (WES) is recommended. Knowledge of the affected gene may have an impact not only on patient surveillance due to risk for disease progression or tumor development but also on potential therapeutic strategies. This case of the adult patient illustrates the importance of broad genetic analysis, which brought up the potentially relevant rare multidrug resistance protein 3 (MDR3) missense variant p.(Asn489Tyr) underlying the patient’s clinical phenotype of low phospholipid-associated cholelithiasis (LPAC). Patients with MDR3 disease may have an increased risk for cholangiocarcinoma (CCA) development and therefore need an individualized surveillance strategy. Most MDR3-affected patients benefit from life-long therapy with ursodeoxycholic acid (UDCA), which is well tolerated. Bezafibrate treatment can reduce pruritus, one of the main symptoms affecting the quality of life. Whether the administration of ileal bile acid transporter (IBAT) inhibitors is beneficial in adult patients with MDR3 disease is so far unknown.

Native liver survival in bile salt export pump deficiency: results of a retrospective cohort study.

Bile salt export pump (ABCB11) deficiency [Progressive familial intrahepatic cholestasis (PFIC2)] is the most common genetic cause of PFIC and is associated with pruritus and progressive liver disease. Surgical biliary diversion or pharmacological [ileal bile acid transporter inhibitor (IBATi)] approaches can be used to block the recirculation of bile acids to the liver. There is a paucity of detailed data on the natural history and, in particular, the longitudinal evolution of bile acid levels to predict treatment response. Cross-sectional data from large international consortia suggested a maximum cutoff value of bile acids after the intervention to predict a successful outcome. This retrospective, single-center, cohort study included all patients with confirmed biallelic pathogenic ABCB11 genotype PFIC2 treated at our institution with ≥2 years follow-up. The outcomes of interventions and predictors of long-term health were analyzed. Forty-eight cases were identified with PFIC2. Eighteen received partial external biliary diversion (PEBD) surgery, and 22 patients underwent liver transplantation. Two patients developed HCC and 2 died. Improved survival with native liver was closely associated with genotype, complete normalization of serum bile acids following PEBD, and alleviation of pruritus. Persistence of mild-to-moderate elevation of bile acids or a secondary rise following normalization was associated with liver disease progression and led to transplantation, suggesting that any prolonged elevation of bile acids worsens the chance of native liver survival. Higher-grade fibrosis at the time of PEBD was not associated with reduced long-term native liver survival. Patients with PFIC2 benefit from PEBD even at a stage of advanced fibrosis. Serum bile acid levels are an early predictor of treatment response and might serve as the gold standard in the evaluation of novel therapies including IBATi.

Cover Image

The cover image is based on the Case Report Type 3 of progressive familial intrahepatic cholestasis (PFIC-3): Case report by Mohammad Badr Almoshantaf et al., https://doi.org/10.1002/ccr3.7197

Socio-economic issues in the diagnostic approach and decision to treat of a child with familial cholestasis

Objectives. The diagnostic approach in familial cholestasis cases involves using expensive investigations. The need for complex therapeutic resources is predictable. Material and methods. We present the case of a 3 years 5 months old boy diagnosed with cholestasis and liver cirrhosis, admitted in the Pediatrics Department of “Grigore Alexandrescu” Children’s Hospital for evaluation in order to check the criteria for liver transplantation. Outcomes. The patient is known to our clinic since he was 1 year 3 months; he was admitted at that time for green jaundice. He comes from a family with nine children, low socio-economic status and low education. The first four children have a different father, two of them were stillborn. The next five come from a consanguineous union (the father is maternal uncle of the mother): three (the patient included) presented with the same symptoms, two of them died before 3 years of age with liver cirrhosis. In time, infectious causes, autoimmune, neoplastic and metabolic disease were excluded. The liver biopsy describes cholestasis and fibrosis. Alagille syndrome and progressive familial intrahepatic cholestasis are still debated, but the genetic testing necessary for a positive diagnosis are not financially available to the family. The patient presents with failure to thrive, developmental delay, intense jaundice and pruritus, hippocratic fingers, dyspnea, enlarged abdomen with visible collateral circulation, significant hepatosplenomegaly. The lab tests show anemia, thrombocytopenia, liver cytolysis, normal gamma-glutamyl transferase, low prothrombin activity, normal renal function, no inflammatory syndrome, increased ammonia level, very high bile acids level. The upper endoscopy describes first degree esophageal varices and portal hypertensive gastropathy. A PELD (Pediatric End-Stage Liver Disease) score is calculated – 13.6 (76.3% one year survival rate on the transplant list, 90.9% one year survival rate after liver transplantation). The patient is enrolled on the transplant waiting list provided we would expect suboptimal results considering the developmental delay and difficult post-transplant monitoring. Conclusions. The low education level of the family correlated with a postponed positive diagnosis due to financial reasons and the lack of genetic advice already lead to the demise of four brothers. In this setting, the prognosis of the patient is very likely to be poor.

Management of Clinically Significant Itch in Cholestatic Liver Disease

Cholestatic liver diseases include primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and progressive familial intrahepatic cholestasis (PFIC). In all of these conditions, cholestatic itch is a major symptom that can severely and chronically impact a person’s quality of life (QoL). At a satellite symposium presented at the 2022 meeting of the American Association for the Study of Liver Diseases (AASLD) in Washington, D.C., USA, leading experts discussed the importance of assessing itch in all patients with one of these cholestatic liver diseases. The experts presented patient cases to illustrate the challenges of managing itch in these cholestatic liver diseases. Studies show that many of these patients are not being adequately treated for this important symptom. However, while there are several treatments for itch, although not all are specifically approved medications, finding the right one for each patient may be a process of trial and error. In some cases, for people with severe, chronic, non-treatment-responsive cholestatic itch, a liver transplant may be the only treatment option.

Evaluating the non-invasive tools for assessment of liver fibrosis in children with intrahepatic cholestasis prior to partial biliary diversion: tertiary-center experience

BackgroundThe liver biopsy is an essential element of evaluating progression of liver disease in children with Progressive Familial Intrahepatic Cholestasis (PFIC) and Allagille Syndrome (AGS). Several noninvasive techniques, including radiological imaging and blood biomarkers assay, can be used to evaluate liver stiffness.ObjectivesTo identify whether liver Transient elastography (FibroScan) and AST/PLT Ratio Index (APRI) could be reliable tools to assess the degree of fibrosis prior to partial biliary diversion (PBD).MethodsA prospective cohort in which all patients with PFIC and AGS who underwent PBD from July 2019 to July 2021 were included. Preoperative liver functions, pelvic-abdominal ultrasonography and FibroScan assessments were performed while intraoperative liver biopsy was obtained.ResultsEight patients with chronic cholestatic liver disease who were candidates for PBD due to intractable pruritus were enrolled, including PFIC (n = 6; 75%), and AGS (n = 2; 25%). The liver FibroScan results were similar to the liver biopsy histopathological assessment in 87.5% of cases. APRI ranged from 0.1 to 3.2 (median = 1.2). In four cases (50%), APRI was consistent with histological evaluation of liver samples. The FibroScan results were in concordance with APRI results in three patients (37.5%).ConclusionThe current cohort demonstrated that fibroScan was consistent with histopathology in 87.5% of patients, highlighting its value in determining the degree of liver fibrosis prior to surgery, whereas the APRI was only consistent with histopathology in half of cases.