RARE DISEASE
Congenital bile acid synthesis defect
Congenital bile acid synthesis defect
Congenital bile acid synthesis defect
Synonyms: BASD
Synonyms: BASD
Synonyms: BASD
Drug discovery
0
drugs
With orphan designations
Overview
Congenital bile acid synthesis defects (BASDs) are rare autosomal recessive disorders caused by enzymatic deficiencies in bile acid production, leading to cholestasis, fat-soluble vitamin malabsorption, and progressive liver injury. Key features include neonatal jaundice, hepatomegaly, coagulopathy, and steatorrhea. Diagnosis relies on urine mass spectrometry to detect atypical bile acids and genetic testing. Early intervention with oral bile acid replacement (e.g., cholic acid) improves outcomes, while delayed treatment risks cirrhosis and liver failure [1][6][13].
Therapies
Primary therapy: Oral cholic acid (FDA-approved) to restore bile flow and suppress toxic metabolites [1][6][15].
Alternatives: Ursodeoxycholic acid (UDCA) in select cases, though less effective for toxin suppression [3][11].
Transplant: Required for end-stage liver disease unresponsive to medical therapy [5][7].
Categories: rare genetic diseases, rare hepatic diseases, rare inborn errors of metabolism, rare transplant-related disorders
Research Papers
43 drug discovery papers about Congenital bile acid synthesis defect, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
43 drug discovery papers about Congenital bile acid synthesis defect, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-02 | Integrated genomic and biochemical diagnosis of a novel homozygous start-loss variant in AKR1D1 associated with neonatal cholestasis.
Congenital bile acid synthesis defects are rare autosomal recessive disorders that typically present in early infancy with cholestasis, progressive liver dysfunction, and, in severe cases, acute liver failure. These conditions may mimic other metabolic diseases detected in newborn screening, complicating early diagnosis. The AKR1D1 gene encodes Δ4-3-oxosteroid 5β-reductase, a key enzyme in primary bile acid synthesis, and pathogenic variants cause bile acid synthesis defect type 2 (OMIM #235555). We report a 3-month-old male infant with severe neonatal cholestasis and a history of elevated tyrosine levels in newborn screening. Pregnancy was high risk and unmonitored, with birth outside a hospital. Parental consanguinity was first-degree. Early metabolic evaluation showed transient normalization of tyrosine levels, but subsequent analyses revealed recurrent hyper-tyrosinemia. Urinary organic acids showed increased 4-hydroxyphenyl metabolites, with absent succinylacetone, excluding tyrosinemia type I. Progressive cholestasis developed, accompanied by coagulopathy, hyperbilirubinemia, hyperammonemia, and markedly elevated alpha-fetoprotein. Imaging revealed no structural liver abnormalities. Clinical exome sequencing identified a novel homozygous start-loss variant in AKR1D1, likely abolishing functional enzyme production. Metabolic studies confirmed increased urinary excretion of 3-oxocholenoic acids consistent with abnormal bile acid synthesis and supporting a diagnosis of bile acid synthesis defect type 2. Oral cholic acid therapy led to stabilization and improvement in clinical and biochemical parameters. This case illustrates the diagnostic complexity of neonatal cholestasis, particularly when initial metabolic findings suggest alternative etiologies. It highlights the importance of newborn screening as a tool for broader diagnostic suspicion and the critical role of early molecular diagnosis and multidisciplinary care. Timely recognition and targeted therapy can improve outcomes, prevent liver transplantation, and enable accurate genetic counseling, especially in consanguineous families.
2026-06-01 | OC38 Bile acid synthesis disorders in children: a case series from a tertiary paediatric hepatology centre
Bile Acid Synthesis Disorders (BASDs) are rare, autosomal recessive causes of progressive cholestatic liver disease in childhood. Early recognition is critical, as timely medical therapy can prevent progression to liver failure and transplantation. We present a case series of children diagnosed and managed at a tertiary paediatric hepatology centre. We retrospectively reviewed clinical, biochemical, and genetic data of children diagnosed with BASD between 2015–2025. Diagnosis was established using urinary bile acid profile analysis and confirmed with targeted genetic testing. Clinical course, management, and outcomes were evaluated. Children presented predominantly with cholestasis, hepatomegaly, and varying degrees of coagulopathy and growth impairment. The underlying diagnoses included 3β-hydroxy-Δ5-C27-steroid oxidoreductase deficiency and Δ4–3-oxosteroid 5β-reductase deficiency, confirmed by urinary bile acid profiling and genetic analysis. All patients received oral cholic acid therapy as first-line treatment. The majority demonstrated significant biochemical and clinical improvement, with resolution of jaundice and normalisation of liver enzymes. A smaller subset progressed to end-stage liver disease requiring transplantation. No deaths occurred during follow-up. This series highlights the phenotypic diversity of BASDs and reinforces the importance of early diagnosis using bile acid profiling and molecular testing. Prompt initiation of bile acid replacement therapy can result in significant clinical improvement and may obviate the need for transplantation in many patients.
2026-05-11 | Delayed diagnosis of 3β-HSD7 deficiency in adolescence: Two case reports and review of the literature.
Congenital bile acid synthesis defects (BASD), the most common of which is 3β-hydroxy-Δ5-C27-steroid dehydrogenase oxidoreductase (3β-HSD7) deficiency, are a rare cause of fat-soluble vitamin malabsorption. We describe a 14-year-old girl who presented at 14 months with a left distal femur fracture and failure to thrive. It was not until 13 years of age that after several hospitalizations for bleeding and severe vitamin K deficiency, the patient was ultimately diagnosed with 3β-HSD7 deficiency. We also describe the case of an adolescent girl who was referred for treatment of Hepatitis C (HCV) and diagnosed with 3β-HSD7 deficiency after she failed to respond to therapy as expected. Finally, we review the diagnosis of BASD and highlight the challenges involved in our clinical cases. These cases demonstrate the importance of maintaining a broad differential when evaluating any patient with unexplained fat-soluble vitamin deficiencies and represent unique presentations of 3β-HSD7 deficiency in adolescent patients.
2025-12-19 | The Diagnostic Odyssey of Congenital Bile Acid Synthesis Defect Type 1: A Case Report
Congenital Bile Acid Synthesis Defects (BASDs) are rare, autosomal recessive metabolic conditions defined by defects in primary bile acid synthesis, leading to the accumulation of toxic intermediate sterols, a deficiency of normal primary bile acids (cholic and chenodeoxycholic acid), and subsequent cholestasis and fat-soluble vitamin malabsorption. Early diagnosis and targeted replacement therapy are vital to prevent progressive liver damage and fatal outcomes. This report describes a 6-year and 5-monthold male from a consanguineous marriage in Chennai, presenting late with right arm swelling, gum bleeding, and progressive pallor for one week. He had a significant history of neurodevelopmental delay and a sibling’s death from jaundice. Physical examination revealed severe malnutrition, icterus, widespread ecchymoses, ichthyosis, and spastic quadriparesis. Blood investigations confirmed severe microcytic hypochromic anaemia (Hb 1.6 g/dL) and severe coagulopathy {Prothrombin Time (PT)> 100, International Normalised Ratio (INR)>8}. A diagnosis of congenital BASD type 1 was established through abnormal urinary bile acid profiling Fast Atom Bombardment–Mass Spectrometry (FAB-MS) and was confirmed by genetic testing showing biallelic pathogenic variants in the HSD3B7 gene. The child was managed with aggressive supportive care, including blood and Fresh Frozen Plasma (FFP) transfusions and high-dose Vitamin K, alongside targeted therapy with oral cholic acid and fat-soluble vitamins. The child showed dramatic clinical improvement within six days, reinforcing the therapeutic benefit of even delayed intervention, although liver transplantation was advised for the advanced liver disease. This case underscores the challenges of late diagnosis and the lifethreatening coagulopathy associated with severe BASD type 1.
2025-09-20 | Pediatric Liver Transplant Complications: EBV-Associated Tumors and Infection Management Strategies.
BACKGROUND EBV-associated smooth muscle tumors (EBV-SMTs) are rare malignancies in pediatric transplant recipients under chronic immunosuppression, with fewer than100 cases reported globally. Diagnosis is challenging due to nonspecific imaging findings and overlapping features with other post-transplant malignancies, necessitating histopathological confirmation. This underscores the need for heightened clinical suspicion in high-risk cohorts. CASE REPORT Here, we present a pediatric case from our liver transplant (LT) center involving a patient who developed both post-transplant lymphoproliferative disorder (PTLD) and EBV-SMT following liver transplantation. Clinical data and comprehensive treatment details of this rare case were retrospectively reviewed. The patient, diagnosed with a congenital bile acid synthesis defect, underwent liver transplantation at the age of 5 months. Pre-transplant screening confirmed that both the donor and recipient were negative for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections. However, EBV DNA became detectable in peripheral blood at 22.5 months after transplantation and showed a progressive increase over time. At 30.9 months after LT, PTLD and hepatic EBV-SMT were simultaneously diagnosed through histopathological examination. Treatment strategies included stepwise immunosuppression reduction, administration of rituximab targeting PTLD, and subsequent sirolimus therapy for EBV-SMT and surgical resection of the liver and splenic tumor. This multidisciplinary approach successfully achieved complete remission. CONCLUSIONS EBV-SMT necessitates multidisciplinary management balancing immunosuppression with targeted therapies. mTOR inhibitors are a strategic option for concurrent rejection prevention and tumor control. Sirolimus, a mechanistic target of rapamycin (mTOR) inhibitor, demonstrates promise by simultaneously preventing rejection and inhibiting tumor progression.
cell therapies
2022-03-24 | Characteristics of SOX9-positive progenitor-like cells during cholestatic liver regeneration in biliary atresia.
The progression of Biliary Atresia (BA) is associated with the number of reactive ductular cells (RDCs) whose heterogeneity in origin and evolution in humans remains unknown. SOX9-positive liver progenitor-like cells (LPLCs) have been shown to participate in RDCs and new hepatocyte formation during cholestatic liver regeneration in an animal model, which implies the possibility that hepatocyte-reprogrammed LPLCs could be a source of RDCs in BA. The present study aimed to elucidate the characteristics of SOX9-positive LPLCs in BA for exploring new possible therapeutic targets by manipulating the bi-differentiation process of LPLCs to prevent disease progression. Twenty-eight patients, including 24 patients with BA and 4 patients with Congenital Choledochal Cyst as the control group, were retrospectively recruited. Liver biopsy samples were classified histologically using a 4-point scale based on fibrosis severity. LPLCs were detected by SOX9 and HNF4A double positive staining. Single immunohistochemistry, double immunohistochemistry, and multiple immunofluorescence staining were used to determine the different cell types and characteristics of LPLCs. The prognostic predictors of BA, namely total bile acid (TBA), RDCs, and fibrosis, were correlated to the emergence of LPLCs. SOX9 and HNF4A double-positive LPLCs co-stained rarely with relevant markers of portal hepatic progenitor cells (portal-HPCs), including CK19, CK7, EPCAM, PROM1 (CD133), TROP2, and AFP. Under cholestasis conditions, LPLCs acquired superior proliferation and anti-senescence ability among hepatocytes. Moreover, LPLCs arranged as a pseudo-rosette structure appeared from the periportal parenchyma to the portal region, which implied the differentiation from hepatocyte-reprogrammed LPLCs to RDCs with the progression of cholestasis. LPLCs are associated with disease progression and prognostic factors of BA. The bipotent characteristics of LPLCs are different from those of portal-HPCs. As cholestasis progresses, LPLCs appear to gain superior proliferation and anti-senescence ability and continually differentiate to RDCs.
2019-05-29 | Hepatocyte-like cells derived from human amniotic epithelial, bone marrow, and adipose stromal cells display enhanced functionality when cultured on decellularized liver substrate
Transplantation of primary hepatocytes has been used in treatments for various liver pathologies and end-stage liver disease. However, shortage of donor tissue and the inability of hepatocyte proliferation in vitro have lead to alternative methods such as stem cell-derived hepatocyte-like cells (HLCs). Mesenchymal stromal/stem cells, and amniotic epithelial cells were isolated from human bone marrow (BM-MSCs), lipoaspirates (ASCs), and amniotic tissue (AECs) respectively. All cells were differentiated into HLCs on plates coated with Type I collagen or Porcine Liver Extracellular Matrix (PLECM-AA) matrix. Flow cytometry of BM-MSCs and ASCs, and AECs showed high expression of MSC-specific and embryonic stem cell markers respectively. All cell types differentiated into osteocytes, chondrocytes, and adipocytes. All cell type-derived HLCs presented the typical cuboidal primary hepatocyte morphology on PLECM-AA and fewer vacuoles (AECs) compared to HLCs cultured on type I collagen. Gene analysis of all cell type-derived HLCs cultured on PLECM-AA revealed higher upregulation of genes involved in drug transportation and metabolism compared to HLCs cultured on type I collagen. Although, HLCs cultured on PLECM-AA displayed some hepatocyte-related function and bioactivity, overall gene expression was lower compared to that of primary hepatocytes suggesting that caution should be taken when considering using HLCs to replace total hepatocyte functionality.
2015-09-01 | Two Effective Routes for Removing Lineage Restriction Roadblocks: From Somatic Cells to Hepatocytes
The conversion of somatic cells to hepatocytes has fundamentally re-shaped traditional concepts regarding the limited resources for hepatocyte therapy. With the various induced pluripotent stem cell (iPSC) generation routes, most somatic cells can be effectively directed to functional stem cells, and this strategy will supply enough pluripotent material to generate promising functional hepatocytes. However, the major challenges and potential applications of reprogrammed hepatocytes remain under investigation. In this review, we provide a summary of two effective routes including direct reprogramming and indirect reprogramming from somatic cells to hepatocytes and the general potential applications of the resulting hepatocytes. Through these approaches, we are striving toward the goal of achieving a robust, mature source of clinically relevant lineages.
2005-10-07 | Deconjugation of bile acids with immobilized genetically engineeredLactobacillus plantarum80 (pCBH1)
Bile acids are important to normal human physiology. However, bile acids can be toxic when produced in pathologically high concentrations in hepatobileary and other diseases. This study shows that immobilized genetically engineered Lactobacillus plantarum 80 (pCBH1) (LP80 (pCBH1)) can efficiently hydrolyze bile acids and establishes a basis for their use. Results show that immobilized LP80 (pCBH1) is able to effectively break down the conjugated bile acids into glycodeoxycholic acid (GDCA) and taurodeoxycholic acid (TDCA) with bile salt hydrolase (BSH) activities of 0.17 and 0.07 μmol DCA/mg CDW/h, respectively. The deconjugation product, deoxycholic acid (DCA), was diminished by LP80 (pCBH1) within 4 h of initial BSH activity. This in-vitro study suggests that immobilized genetically engineered bacterial cells have important potential for deconjugation of bile acids for lowering of high levels of bile acids for therapy.
2005-09-11 | Living Donor Liver Transplantation for Pediatric Patients with Inheritable Metabolic Disorders
Forty-six pediatric patients who underwent living donor liver transplantation (LDLT) using parental liver grafts for inheritable metabolic disorders (IMD) were evaluated to determine the outcomes of the surgery, decisive factors for post-transplant patient survival and the impact of using donors who were heterozygous for the particular disorder. Disorders included Wilson disease (WD, n = 21), ornithine transcarbamylase deficiency (OTCD, n = 6), tyrosinemia type I (TTI, n = 6), glycogen storage disease (GSD, n = 4), propionic acidemia (PPA, n = 3), methylmalonic acidemia (MMA, n = 2), Crigler-Najjar syndrome type I (CNSI, n = 2), bile acid synthetic defect (BASD, n = 1) and erythropoietic protoporphyria (EPP, n = 1). The post-transplant cumulative patient survival rates were 86.8 and 81.2% at 1 and 5 years, respectively. Post-transplant patient survival and recovery of the growth retardation were significantly better in the liver-oriented diseases (WD, OTCD, TTI, CNSI and BASD) than in the non-liver-oriented diseases (GSD, PPA, MMA and EPP) and pre-transplant growth retardation disadvantageously affected post-transplant outcomes. Although 40 of 46 donors were considered heterozygous for each disorder, neither mortality nor morbidity related to the heterozygosis has been observed. LDLT using parental donors can be recommended as an effective treatment for pediatric patients with IMD. In the non-liver-oriented diseases, however, satisfactory outcomes were not obtained by hepatic replacement alone.
gene therapies
2024-04-02 | Primary Bile Acid Disorders: A Largely Unknown Group of Rare Genetic Diseases in Newborns
Primary bile acid disorders (BASD) in newborns are rarely found with a prevalence of 1-9/1,000,000 and include 1-2 % of all cases with neonatal cholestasis. Causes are different gene defects, which lead to liver enzyme defects, which play a major role in both cholic acid pathways, the classical with production of cholic acid and the alternative one with chenodeoxycholic acid. They are found in both genders in the same distribution. Early diagnosis is very important to introduce a bile acid replacement therapy as soon as possible as the treatment of choice to date. Diagnosis will be confirmed by molecular trsting, liver biopsy and different forms of mass spectrometry methods. Differential diagnosis includes progressive familial intrahepatic cholestasis, neonatal hepatitis and biliary atresia. Further gene therapy approaches must be developed, like CRISP Cas9 technology, to repair the spontaneous point mutations on DNA of these patients to cure and not to treat them their whole life finally.
small molecules
2026-07-02 | Integrated genomic and biochemical diagnosis of a novel homozygous start-loss variant in AKR1D1 associated with neonatal cholestasis.
Congenital bile acid synthesis defects are rare autosomal recessive disorders that typically present in early infancy with cholestasis, progressive liver dysfunction, and, in severe cases, acute liver failure. These conditions may mimic other metabolic diseases detected in newborn screening, complicating early diagnosis. The AKR1D1 gene encodes Δ4-3-oxosteroid 5β-reductase, a key enzyme in primary bile acid synthesis, and pathogenic variants cause bile acid synthesis defect type 2 (OMIM #235555). We report a 3-month-old male infant with severe neonatal cholestasis and a history of elevated tyrosine levels in newborn screening. Pregnancy was high risk and unmonitored, with birth outside a hospital. Parental consanguinity was first-degree. Early metabolic evaluation showed transient normalization of tyrosine levels, but subsequent analyses revealed recurrent hyper-tyrosinemia. Urinary organic acids showed increased 4-hydroxyphenyl metabolites, with absent succinylacetone, excluding tyrosinemia type I. Progressive cholestasis developed, accompanied by coagulopathy, hyperbilirubinemia, hyperammonemia, and markedly elevated alpha-fetoprotein. Imaging revealed no structural liver abnormalities. Clinical exome sequencing identified a novel homozygous start-loss variant in AKR1D1, likely abolishing functional enzyme production. Metabolic studies confirmed increased urinary excretion of 3-oxocholenoic acids consistent with abnormal bile acid synthesis and supporting a diagnosis of bile acid synthesis defect type 2. Oral cholic acid therapy led to stabilization and improvement in clinical and biochemical parameters. This case illustrates the diagnostic complexity of neonatal cholestasis, particularly when initial metabolic findings suggest alternative etiologies. It highlights the importance of newborn screening as a tool for broader diagnostic suspicion and the critical role of early molecular diagnosis and multidisciplinary care. Timely recognition and targeted therapy can improve outcomes, prevent liver transplantation, and enable accurate genetic counseling, especially in consanguineous families.
2026-06-01 | OC38 Bile acid synthesis disorders in children: a case series from a tertiary paediatric hepatology centre
Bile Acid Synthesis Disorders (BASDs) are rare, autosomal recessive causes of progressive cholestatic liver disease in childhood. Early recognition is critical, as timely medical therapy can prevent progression to liver failure and transplantation. We present a case series of children diagnosed and managed at a tertiary paediatric hepatology centre. We retrospectively reviewed clinical, biochemical, and genetic data of children diagnosed with BASD between 2015–2025. Diagnosis was established using urinary bile acid profile analysis and confirmed with targeted genetic testing. Clinical course, management, and outcomes were evaluated. Children presented predominantly with cholestasis, hepatomegaly, and varying degrees of coagulopathy and growth impairment. The underlying diagnoses included 3β-hydroxy-Δ5-C27-steroid oxidoreductase deficiency and Δ4–3-oxosteroid 5β-reductase deficiency, confirmed by urinary bile acid profiling and genetic analysis. All patients received oral cholic acid therapy as first-line treatment. The majority demonstrated significant biochemical and clinical improvement, with resolution of jaundice and normalisation of liver enzymes. A smaller subset progressed to end-stage liver disease requiring transplantation. No deaths occurred during follow-up. This series highlights the phenotypic diversity of BASDs and reinforces the importance of early diagnosis using bile acid profiling and molecular testing. Prompt initiation of bile acid replacement therapy can result in significant clinical improvement and may obviate the need for transplantation in many patients.
2026-05-11 | Delayed diagnosis of 3β-HSD7 deficiency in adolescence: Two case reports and review of the literature.
Congenital bile acid synthesis defects (BASD), the most common of which is 3β-hydroxy-Δ5-C27-steroid dehydrogenase oxidoreductase (3β-HSD7) deficiency, are a rare cause of fat-soluble vitamin malabsorption. We describe a 14-year-old girl who presented at 14 months with a left distal femur fracture and failure to thrive. It was not until 13 years of age that after several hospitalizations for bleeding and severe vitamin K deficiency, the patient was ultimately diagnosed with 3β-HSD7 deficiency. We also describe the case of an adolescent girl who was referred for treatment of Hepatitis C (HCV) and diagnosed with 3β-HSD7 deficiency after she failed to respond to therapy as expected. Finally, we review the diagnosis of BASD and highlight the challenges involved in our clinical cases. These cases demonstrate the importance of maintaining a broad differential when evaluating any patient with unexplained fat-soluble vitamin deficiencies and represent unique presentations of 3β-HSD7 deficiency in adolescent patients.
2025-12-19 | The Diagnostic Odyssey of Congenital Bile Acid Synthesis Defect Type 1: A Case Report
Congenital Bile Acid Synthesis Defects (BASDs) are rare, autosomal recessive metabolic conditions defined by defects in primary bile acid synthesis, leading to the accumulation of toxic intermediate sterols, a deficiency of normal primary bile acids (cholic and chenodeoxycholic acid), and subsequent cholestasis and fat-soluble vitamin malabsorption. Early diagnosis and targeted replacement therapy are vital to prevent progressive liver damage and fatal outcomes. This report describes a 6-year and 5-monthold male from a consanguineous marriage in Chennai, presenting late with right arm swelling, gum bleeding, and progressive pallor for one week. He had a significant history of neurodevelopmental delay and a sibling’s death from jaundice. Physical examination revealed severe malnutrition, icterus, widespread ecchymoses, ichthyosis, and spastic quadriparesis. Blood investigations confirmed severe microcytic hypochromic anaemia (Hb 1.6 g/dL) and severe coagulopathy {Prothrombin Time (PT)> 100, International Normalised Ratio (INR)>8}. A diagnosis of congenital BASD type 1 was established through abnormal urinary bile acid profiling Fast Atom Bombardment–Mass Spectrometry (FAB-MS) and was confirmed by genetic testing showing biallelic pathogenic variants in the HSD3B7 gene. The child was managed with aggressive supportive care, including blood and Fresh Frozen Plasma (FFP) transfusions and high-dose Vitamin K, alongside targeted therapy with oral cholic acid and fat-soluble vitamins. The child showed dramatic clinical improvement within six days, reinforcing the therapeutic benefit of even delayed intervention, although liver transplantation was advised for the advanced liver disease. This case underscores the challenges of late diagnosis and the lifethreatening coagulopathy associated with severe BASD type 1.
2025-09-20 | Pediatric Liver Transplant Complications: EBV-Associated Tumors and Infection Management Strategies.
BACKGROUND EBV-associated smooth muscle tumors (EBV-SMTs) are rare malignancies in pediatric transplant recipients under chronic immunosuppression, with fewer than100 cases reported globally. Diagnosis is challenging due to nonspecific imaging findings and overlapping features with other post-transplant malignancies, necessitating histopathological confirmation. This underscores the need for heightened clinical suspicion in high-risk cohorts. CASE REPORT Here, we present a pediatric case from our liver transplant (LT) center involving a patient who developed both post-transplant lymphoproliferative disorder (PTLD) and EBV-SMT following liver transplantation. Clinical data and comprehensive treatment details of this rare case were retrospectively reviewed. The patient, diagnosed with a congenital bile acid synthesis defect, underwent liver transplantation at the age of 5 months. Pre-transplant screening confirmed that both the donor and recipient were negative for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections. However, EBV DNA became detectable in peripheral blood at 22.5 months after transplantation and showed a progressive increase over time. At 30.9 months after LT, PTLD and hepatic EBV-SMT were simultaneously diagnosed through histopathological examination. Treatment strategies included stepwise immunosuppression reduction, administration of rituximab targeting PTLD, and subsequent sirolimus therapy for EBV-SMT and surgical resection of the liver and splenic tumor. This multidisciplinary approach successfully achieved complete remission. CONCLUSIONS EBV-SMT necessitates multidisciplinary management balancing immunosuppression with targeted therapies. mTOR inhibitors are a strategic option for concurrent rejection prevention and tumor control. Sirolimus, a mechanistic target of rapamycin (mTOR) inhibitor, demonstrates promise by simultaneously preventing rejection and inhibiting tumor progression.
cell therapies
2022-03-24 | Characteristics of SOX9-positive progenitor-like cells during cholestatic liver regeneration in biliary atresia.
The progression of Biliary Atresia (BA) is associated with the number of reactive ductular cells (RDCs) whose heterogeneity in origin and evolution in humans remains unknown. SOX9-positive liver progenitor-like cells (LPLCs) have been shown to participate in RDCs and new hepatocyte formation during cholestatic liver regeneration in an animal model, which implies the possibility that hepatocyte-reprogrammed LPLCs could be a source of RDCs in BA. The present study aimed to elucidate the characteristics of SOX9-positive LPLCs in BA for exploring new possible therapeutic targets by manipulating the bi-differentiation process of LPLCs to prevent disease progression. Twenty-eight patients, including 24 patients with BA and 4 patients with Congenital Choledochal Cyst as the control group, were retrospectively recruited. Liver biopsy samples were classified histologically using a 4-point scale based on fibrosis severity. LPLCs were detected by SOX9 and HNF4A double positive staining. Single immunohistochemistry, double immunohistochemistry, and multiple immunofluorescence staining were used to determine the different cell types and characteristics of LPLCs. The prognostic predictors of BA, namely total bile acid (TBA), RDCs, and fibrosis, were correlated to the emergence of LPLCs. SOX9 and HNF4A double-positive LPLCs co-stained rarely with relevant markers of portal hepatic progenitor cells (portal-HPCs), including CK19, CK7, EPCAM, PROM1 (CD133), TROP2, and AFP. Under cholestasis conditions, LPLCs acquired superior proliferation and anti-senescence ability among hepatocytes. Moreover, LPLCs arranged as a pseudo-rosette structure appeared from the periportal parenchyma to the portal region, which implied the differentiation from hepatocyte-reprogrammed LPLCs to RDCs with the progression of cholestasis. LPLCs are associated with disease progression and prognostic factors of BA. The bipotent characteristics of LPLCs are different from those of portal-HPCs. As cholestasis progresses, LPLCs appear to gain superior proliferation and anti-senescence ability and continually differentiate to RDCs.
2019-05-29 | Hepatocyte-like cells derived from human amniotic epithelial, bone marrow, and adipose stromal cells display enhanced functionality when cultured on decellularized liver substrate
Transplantation of primary hepatocytes has been used in treatments for various liver pathologies and end-stage liver disease. However, shortage of donor tissue and the inability of hepatocyte proliferation in vitro have lead to alternative methods such as stem cell-derived hepatocyte-like cells (HLCs). Mesenchymal stromal/stem cells, and amniotic epithelial cells were isolated from human bone marrow (BM-MSCs), lipoaspirates (ASCs), and amniotic tissue (AECs) respectively. All cells were differentiated into HLCs on plates coated with Type I collagen or Porcine Liver Extracellular Matrix (PLECM-AA) matrix. Flow cytometry of BM-MSCs and ASCs, and AECs showed high expression of MSC-specific and embryonic stem cell markers respectively. All cell types differentiated into osteocytes, chondrocytes, and adipocytes. All cell type-derived HLCs presented the typical cuboidal primary hepatocyte morphology on PLECM-AA and fewer vacuoles (AECs) compared to HLCs cultured on type I collagen. Gene analysis of all cell type-derived HLCs cultured on PLECM-AA revealed higher upregulation of genes involved in drug transportation and metabolism compared to HLCs cultured on type I collagen. Although, HLCs cultured on PLECM-AA displayed some hepatocyte-related function and bioactivity, overall gene expression was lower compared to that of primary hepatocytes suggesting that caution should be taken when considering using HLCs to replace total hepatocyte functionality.
2015-09-01 | Two Effective Routes for Removing Lineage Restriction Roadblocks: From Somatic Cells to Hepatocytes
The conversion of somatic cells to hepatocytes has fundamentally re-shaped traditional concepts regarding the limited resources for hepatocyte therapy. With the various induced pluripotent stem cell (iPSC) generation routes, most somatic cells can be effectively directed to functional stem cells, and this strategy will supply enough pluripotent material to generate promising functional hepatocytes. However, the major challenges and potential applications of reprogrammed hepatocytes remain under investigation. In this review, we provide a summary of two effective routes including direct reprogramming and indirect reprogramming from somatic cells to hepatocytes and the general potential applications of the resulting hepatocytes. Through these approaches, we are striving toward the goal of achieving a robust, mature source of clinically relevant lineages.
2005-10-07 | Deconjugation of bile acids with immobilized genetically engineeredLactobacillus plantarum80 (pCBH1)
Bile acids are important to normal human physiology. However, bile acids can be toxic when produced in pathologically high concentrations in hepatobileary and other diseases. This study shows that immobilized genetically engineered Lactobacillus plantarum 80 (pCBH1) (LP80 (pCBH1)) can efficiently hydrolyze bile acids and establishes a basis for their use. Results show that immobilized LP80 (pCBH1) is able to effectively break down the conjugated bile acids into glycodeoxycholic acid (GDCA) and taurodeoxycholic acid (TDCA) with bile salt hydrolase (BSH) activities of 0.17 and 0.07 μmol DCA/mg CDW/h, respectively. The deconjugation product, deoxycholic acid (DCA), was diminished by LP80 (pCBH1) within 4 h of initial BSH activity. This in-vitro study suggests that immobilized genetically engineered bacterial cells have important potential for deconjugation of bile acids for lowering of high levels of bile acids for therapy.
2005-09-11 | Living Donor Liver Transplantation for Pediatric Patients with Inheritable Metabolic Disorders
Forty-six pediatric patients who underwent living donor liver transplantation (LDLT) using parental liver grafts for inheritable metabolic disorders (IMD) were evaluated to determine the outcomes of the surgery, decisive factors for post-transplant patient survival and the impact of using donors who were heterozygous for the particular disorder. Disorders included Wilson disease (WD, n = 21), ornithine transcarbamylase deficiency (OTCD, n = 6), tyrosinemia type I (TTI, n = 6), glycogen storage disease (GSD, n = 4), propionic acidemia (PPA, n = 3), methylmalonic acidemia (MMA, n = 2), Crigler-Najjar syndrome type I (CNSI, n = 2), bile acid synthetic defect (BASD, n = 1) and erythropoietic protoporphyria (EPP, n = 1). The post-transplant cumulative patient survival rates were 86.8 and 81.2% at 1 and 5 years, respectively. Post-transplant patient survival and recovery of the growth retardation were significantly better in the liver-oriented diseases (WD, OTCD, TTI, CNSI and BASD) than in the non-liver-oriented diseases (GSD, PPA, MMA and EPP) and pre-transplant growth retardation disadvantageously affected post-transplant outcomes. Although 40 of 46 donors were considered heterozygous for each disorder, neither mortality nor morbidity related to the heterozygosis has been observed. LDLT using parental donors can be recommended as an effective treatment for pediatric patients with IMD. In the non-liver-oriented diseases, however, satisfactory outcomes were not obtained by hepatic replacement alone.
gene therapies
2024-04-02 | Primary Bile Acid Disorders: A Largely Unknown Group of Rare Genetic Diseases in Newborns
Primary bile acid disorders (BASD) in newborns are rarely found with a prevalence of 1-9/1,000,000 and include 1-2 % of all cases with neonatal cholestasis. Causes are different gene defects, which lead to liver enzyme defects, which play a major role in both cholic acid pathways, the classical with production of cholic acid and the alternative one with chenodeoxycholic acid. They are found in both genders in the same distribution. Early diagnosis is very important to introduce a bile acid replacement therapy as soon as possible as the treatment of choice to date. Diagnosis will be confirmed by molecular trsting, liver biopsy and different forms of mass spectrometry methods. Differential diagnosis includes progressive familial intrahepatic cholestasis, neonatal hepatitis and biliary atresia. Further gene therapy approaches must be developed, like CRISP Cas9 technology, to repair the spontaneous point mutations on DNA of these patients to cure and not to treat them their whole life finally.
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