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Vullierme MP, Desterke C, Hillaire S, Parfait B, Vilgrain V, Rebours V, Lewin M. Primary intrahepatic lithiasis in western countries: role of ultrasound and comparison with MRI with MRCP. Eur J Gastroenterol Hepatol 2025:00042737-990000000-00521. [PMID: 40359291 DOI: 10.1097/meg.0000000000002984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/15/2025]
Abstract
OBJECTIVES To study hepatobiliary expert ultrasound (US) in a cohort of suspected primary intrahepatic lithiasis (IHL) and to compare these findings with MRI/MRCP data. METHODS All patients with a diagnosis of primary-IHL based upon biological and, or, clinical symptoms who underwent US between 2008 and 2023 were retrospectively enrolled in two tertiary hepatobiliary centers. Clinical characteristics, available genetic and radiological features (expert US and MRCP) were recorded. Data were compared for the presence of comet-tail images or stones on US, between US and MRCP features and between imaging and patients' genetic status. Statistical analyses were performed with R software environment version 4.2.1, by univariate and multivariate analysis. RESULTS A total of 112 primary-IHL patients were included (mean age 43 years old ±14 and 55% women). US identified primary-IHL in 92/112 (82%) patients including intrahepatic biliary comet-tail in 82/112 (73%) and stones in 51/112 (46%). Among these, 66/112 (68%) had both US and MRCP. Lithiasis was identified in 60/76 US (79%) and 44/76 MRCP (58%). MRCP showed only stones in 22/76, 29%. Genetic testing was performed in 66/112 (58%) patients. Thirty-two (49%) of these patients had pathogenic ABCB4/MDR3 gene variants, 14/66 (21%) other pathogenic variants and 5/66 (5%) had unknown significant variants. No genetic abnormalities were found in 19/66 (29%). A multivariate logistic model with the comet-tail sign as an outcome showed that there was a significant negative correlation between other pathogenic genetic variants and the comet-tail phenotype (P-value = 0.049). CONCLUSION US, and not MRCP, should be the primary diagnostic tool in suspected primary-IHL patients.
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Affiliation(s)
- Marie-Pierre Vullierme
- Department of Radiology, Paul Brousse University Hospital, Paris-Cité University, Villejuif, France
| | - Christophe Desterke
- INSERM U1310, Paris-Saclay University, Medicine Faculty, Paul Brousse University Hospital, Villejuif, France
| | - Sophie Hillaire
- Department of Hepatology, Beaujon University Hospital, Clichy, AP-HP, Paris-Cité University, Clichy, France
| | - Béatrice Parfait
- Department of Genomic Medicine, Cochin University Hospital, Paris, AP-HP Paris-Cité University, Paris, France
| | - Valérie Vilgrain
- Department of Radiology, Beaujon University Hospital, Clichy, AP-HP, Paris-Cité University, Clichy, France
| | - Vinciane Rebours
- Department of Pancreatology and digestive oncology, Beaujon University Hospital, Clichy, AP-HP, Paris-Cité University, Clichy, France
| | - Maïté Lewin
- Department of Radiology, Paul Brousse University Hospital, Villejuif, AP-HP, Paris-Saclay University, Villejuif, France
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Zhang D, Li Y, He S, Shu J, Li T, Sun Q. Association between ABCB4 variants and intrahepatic cholestasis of pregnancy. Sci Rep 2025; 15:3300. [PMID: 39865141 PMCID: PMC11770179 DOI: 10.1038/s41598-025-87909-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Accepted: 01/22/2025] [Indexed: 01/28/2025] Open
Abstract
The ABCB4 gene encodes multidrug resistance protein 3(MDR3), which is a phosphatidylcholine(PC) transfer enzyme that transfers lecithin from the inner part of the phospholipid bilayer to the extracellular bile. The occurrence of intrahepatic cholestasis of pregnancy(ICP) is closely related to ABCB4 variants, but there is limited research on this topic in southern Anhui, China. We sequenced ABCB4 in pregnant women with ICP and healthy pregnant women to explore the relationship. A total of 30 patients diagnosed with ICP were selected as the study objects and 90 healthy pregnant women were selected as the control group. DNA was extracted from peripheral blood of ICP patients and healthy pregnant women, 27 exons were sequencing by Sanger sequencing. Polymerase chain reaction (PCR) was used to amplify those exons. PolyPhen2, Mutation Taster, Provean, SIFT and Mutpred2 were used to predict protein structure, and Pymol software was used to predict the impact of missense variant c.1954 A > G(p.Arg652Gly) on proteins. Four exonic variants of ABCB4 gene were detected in ICP patients and healthy pregnant women, including synonymous variants c.175 C > T, c.504 C > T,c.711 A > T and missense variant c.1954 A > G(p.Arg652Gly). The incidence of the missense variant c.1954 A > G(p.Arg652Gly) was 6/90 in healthy pregnant womenand 8/30 in ICP patients.In healthy pregnant women with the missense variant c.1954 A > G(p.Arg652Gly), no other exonic variants were found. In ICP patients with missense variant c.1954 A > G(p.Arg652Gly), other exonic variants were found. PolyPhen2, Mutation Taster, Provean, SIFT and Mutpred2 were used to predict that the four exonic variants were benign, while Pymol was used to showed that the missense variant was located in the linker region of MDR3 and had a slight impact on protein function. Among ICP patients with missense variant c.1954 A > G(p.Arg652Gly), patients with three exonic variants(c.504 C > T, c.711 A > T, c.1954 A > G) had higher γ-GT, TBA, ALT and AST than those with two exonic variants. ABCB4 missense variant c.1954 A > G(p.Arg652Gly) requires the combination of other variants(c.175 C > T, c.504 C > T,c.711 A > T) to cause ICP symptoms, and when combined with other variants, it has a superimposed effect.
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Affiliation(s)
- Dekun Zhang
- Department of Gynecology and Obstetrics, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, People's Republic of China
- School of Basic Medical Sciences, Wannan Medical College, Wuhu, Anhui, People's Republic of China
| | - Yuhong Li
- Department of Gynecology and Obstetrics, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, People's Republic of China
- School of Basic Medical Sciences, Wannan Medical College, Wuhu, Anhui, People's Republic of China
| | - Shufeng He
- Department of Gynecology and Obstetrics, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, People's Republic of China
- School of Basic Medical Sciences, Wannan Medical College, Wuhu, Anhui, People's Republic of China
| | - Jing Shu
- School of Basic Medical Sciences, Wannan Medical College, Wuhu, Anhui, People's Republic of China
| | - Tiechen Li
- School of Basic Medical Sciences, Wannan Medical College, Wuhu, Anhui, People's Republic of China.
| | - Qing Sun
- Department of Gynecology and Obstetrics, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, People's Republic of China.
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Nishi Y, Funamizu N, Ito C, Shine M, Nagaoka T, Honjo M, Tamura K, Sakamoto K, Ogawa K, Takada Y. A Case of a Young Adult with Multiple Intrahepatic Stones Diagnosed as Low Phospholipid-Associated Cholelithiasis Showing <i>ABCB4</i> Gene Mutation. KANZO 2024; 65:566-571. [DOI: 10.2957/kanzo.65.566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/19/2025]
Affiliation(s)
- Yusuke Nishi
- Department of HBP and Transplantation Surgery, Ehime University Hospital
| | - Naotake Funamizu
- Department of HBP and Transplantation Surgery, Ehime University Hospital
| | - Chihiro Ito
- Department of HBP and Transplantation Surgery, Ehime University Hospital
| | - Mikiya Shine
- Department of HBP and Transplantation Surgery, Ehime University Hospital
| | - Tomoyuki Nagaoka
- Department of HBP and Transplantation Surgery, Ehime University Hospital
| | - Masahiko Honjo
- Department of HBP and Transplantation Surgery, Ehime University Hospital
| | - Kei Tamura
- Department of HBP and Transplantation Surgery, Ehime University Hospital
| | - Katsunori Sakamoto
- Department of HBP and Transplantation Surgery, Ehime University Hospital
| | - Kohei Ogawa
- Department of HBP and Transplantation Surgery, Ehime University Hospital
| | - Yasutsugu Takada
- Department of HBP and Transplantation Surgery, Ehime University Hospital
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Zöllner J, Williamson C, Dixon PH. Genetic issues in ICP. Obstet Med 2024; 17:157-161. [PMID: 39262913 PMCID: PMC11384815 DOI: 10.1177/1753495x241263441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 06/05/2024] [Indexed: 09/13/2024] Open
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is the commonest gestational liver disorder with variable global incidence. Genetic susceptibility, combined with hormonal and environmental influences, contributes to ICP aetiology. Adverse pregnancy outcomes linked to elevated serum bile acids highlight the importance of comprehensive risk assessment. ABCB4 and ABCB11 gene variants play a significant role in about 20% of severe ICP cases. Several other genes including ATP8B1, NR1H4, ABCC2, TJP2, SERPINA1, GCKR and HNF4A have also been implicated with ICP. Additionally, ABCB4 variants elevate the risk of drug-induced intrahepatic cholestasis, gallstone disease, gallbladder and bile duct carcinoma, liver cirrhosis and abnormal liver function tests. Genetic variations, both rare and common, intricately contribute to ICP susceptibility. Leveraging genetic insights holds promise for personalised management and intervention strategies. Further research is needed to elucidate variant-specific phenotypic expressions and therapeutic implications, advancing precision medicine in ICP management.
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Trinh A, Tjandra D, Park YA, Sood S, Thomson B, Speer T, Buchanan D, Boussioutas A, Metz AJ. Searching for low phospholipid associated cholelithiasis among patients with post-cholecystectomy biliary pain. ANZ J Surg 2024; 94:1102-1107. [PMID: 38361311 DOI: 10.1111/ans.18904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 01/28/2024] [Indexed: 02/17/2024]
Abstract
INTRODUCTION Low phospholipid associated cholelithiasis (LPAC) is associated with variants of the adenosine triphosphate-binding cassette subfamily B, member 4 (ABCB4) gene and is characterized by reduced phosphatidylcholine secretion into bile, impairing the formation of micelles and thus exposing bile ducts to toxic bile acids and increasing cholesterol saturation. LPAC is present in 1% of patients with gallstones and post-cholecystectomy pain is common in this group. LPAC is an under-appreciated cause of post-cholecystectomy pain. The aim of this study is to assess a cohort of patients with post-cholecystectomy pain to identify those with clinical features suggesting that further investigations for LPAC would be beneficial. METHODS A retrospective chart review was performed of the first 2 years of post-operative follow-up for all patients under 40 years of age undergoing cholecystectomy for symptomatic gallstones at a tertiary centre between January 2016 and December 2017. RESULTS 258 patients under the age of 40 underwent a cholecystectomy. 50 patients (19.4%) reported abdominal pain post-cholecystectomy. Five patients (1.9%) fulfilled the criteria for suspected LPAC. Family history of gallstones was documented in 33 of 258 (12.8%) of cases. Obstetric history was obtained in 69 of 197 (35%) female patients. None of the five patients identified above who satisfied the criteria of LPAC had the diagnosis of LPAC considered by their treating clinicians. CONCLUSION LPAC is an under-recognized cause of post-cholecystectomy pain. Treatment can avoid long-term symptoms and complications. Clinicians should take a family history and obstetric history to alert them to the diagnosis of LPAC.
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Affiliation(s)
- Andrew Trinh
- Department of Medicine, Royal Melbourne Hospital and The University of Melbourne, Parkville, Victoria, Australia
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Victoria, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia
| | - Doug Tjandra
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Yeung-Ae Park
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Siddharth Sood
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Benjamin Thomson
- Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia
| | - Tony Speer
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Daniel Buchanan
- Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia
| | - Alex Boussioutas
- Department of Medicine, Royal Melbourne Hospital and The University of Melbourne, Parkville, Victoria, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia
- Department of Gastroenterology, The Alfred and Monash University, Melbourne, Victoria, Australia
| | - Andrew J Metz
- Department of Medicine, Royal Melbourne Hospital and The University of Melbourne, Parkville, Victoria, Australia
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Victoria, Australia
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Zheng Y, Rao Q, Han Y, He J. A novel heterozygous deletion in ABCB4 gene in a Chinese family with intrahepatic cholestasis of pregnancy, neonatal hyperbilirubinemia, and cholelithiasis: Case reports and literature review. Mol Genet Genomic Med 2024; 12:e2291. [PMID: 37787087 PMCID: PMC10767586 DOI: 10.1002/mgg3.2291] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 08/31/2023] [Accepted: 09/19/2023] [Indexed: 10/04/2023] Open
Abstract
BACKGROUND ABCB4 gene (OMIM *171060) variant is associated with a wide clinical spectrum of hepatobiliary diseases, including familial intrahepatic cholestasis of pregnancy (ICP), progressive familial intrahepatic cholestasis type 3 (PFIC3), and neonatal hyperbilirubinemia due to impaired protection of the bile duct. The majority of reported cases, however, were missense or nonsense variants, with few deletion variant findings in the Chinese population. METHOD We performed whole genome sequencing and confirmed it with Sanger sequencing of the proband infant and his families. Clinical courses and laboratory results were documented and collected from the proband infant and his mother. We also reviewed other published cases related to genetic variants in ABCB4 in the Chinese population. RESULTS A 26-year-old Chinese female (II.2) who had recurrent intrahepatic cholestasis of pregnancy and her 49-day-old son (III.4) who had hyperbilirubinemia, both presented with extremely elevated total bile acid, cholestatic dominant pattern liver function abnormalities. They were able to stay relatively stable with mild pruritus on ursodeoxycholic acid treatment. After ruling out other possibilities, genetic sequencing revealed a diagnosis of heterozygous deletion variant NM_018849.3:c.1452_1454del (NP_061337.1:p.Thr485del) in ABCB4, which was not reported before, in the symptomatic mother (II.2), index patient (III.4), and the symptomatic grandmother (I.2). This variant resulted in clinical spectrums of ICP, neonatal hyperbilirubinemia, and cholelithiasis in our pedigree. CONCLUSION We reported a novel heterozygous deletion variant of the ABCB4 gene in a Chinese family, as well as a literature review of ABCB4-related disorders. We aim to facilitate healthcare professionals to better understand genetic factors as an uncommon cause of hepatobiliary diseases, as well as improve therapeutic strategies in challenging clinical situations such as pregnancy and neonatal care.
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Affiliation(s)
- Yang Zheng
- Department of General Practice, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
| | - Qunfang Rao
- Department of Infectious Diseases, The First Affiliated HospitalNanchang UniversityNanchangChina
| | - Yiru Han
- Department of Health Care, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
| | - Jianqin He
- Department of Health Care, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
- Department of Infectious Diseases, The First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
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Qiao F, Ren F, Lu W, Yang H, Mo G, Wang S, Liu L, Xu X. A female of progressive familial intrahepatic cholestasis type 3 caused by heterozygous mutations of ABCB4 gene and her cirrhosis improved after treatment of ursodeoxycholic acid: a case report. BMC Med Genomics 2023; 16:171. [PMID: 37488596 PMCID: PMC10367406 DOI: 10.1186/s12920-023-01602-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 07/04/2023] [Indexed: 07/26/2023] Open
Abstract
BACKGROUND Progressive familial intrahepatic cholestasis (PFIC) is a group of rapidly progressive autosomal recessive disorders characterized by intrahepatic cholestasis. PFIC-3 is caused by mutations in the ATP-binding cassette subfamily B member 4 gene (ABCB4), which encodes multidrug resistance protein 3 (MDR3/ABCB4). Patients are usually in infancy or childhood, but cirrhosis and portal hypertension may be the first manifestation in older children or young adults. CASE PRESENTATION A 25-year-old young woman with recurrent abnormal hepatic function was mainly characterized by increased gamma glutamyl transpeptidase (GGT) and bile acid with cryptogenic cirrhosis. After 7 months of treatment with ursodeoxycholic acid (UDCA), her hepatic pathology suggested there were also obvious widening and venous fibrosis around the portal vein, and slight bile duct hyperplasia at the edge of the portal area. Infiltration of inflammatory cells around the portal vein and hepatocyte ABCB4/MDR3 protein was basically normal. Sequencing indicated the patient had heterozygous mutations in the ABCB4 gene: c.2696C > G and wes [hg19]7q21.12(87032513-87033422) × 1. Through SWISS-MODEL Predict for protein structures, the missense mutation results in protein side chain missing a methyl group (-CH3), and the deletion mutation results in the serious damage to the structure of MDR3 protein which lead to phosphatidylcholine deficiency of bile in the capillary bile ducts. The toxic effect of bile salts then damages the bile ducts, causing cholestasis and cholangitis, which can then develop into biliary cirrhosis. Through the analysis of pathogenicity prediction software, the mutations led to PFIC3. After treatment of UDCA for 29 months, her cirrhosis was improved, hepatic function was close to normal. CONCLUSION Novel heterozygous mutations are the molecular pathological cause of PFIC3 in this patient. All young adult patients with occult cirrhosis should be tested for ABCB4. Early diagnosis of PFIC3 and continued treatment with UDCA are key to improving prognosis and delaying the onset of end-stage liver disease.
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Affiliation(s)
- Fei Qiao
- Department of Hepatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Feng Ren
- First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China
| | - Weiting Lu
- Department of Hepatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Haoran Yang
- First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China
| | - Guiling Mo
- Medical Laboratory Science, Guangzhou KingMed Center For Clinical Laboratory Co, Ltd, Guangzhou, China
| | - Shuangshuang Wang
- Department of Pathology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Lina Liu
- Department of Hepatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
- College of Traditional Chinese Medicine and Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
| | - Xiangtao Xu
- Department of Hepatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
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Targeted liver ultrasound performed by an expert is the pivotal imaging examination for low phospholipid-associated cholelithiasis. Eur J Gastroenterol Hepatol 2023; 35:327-332. [PMID: 36708304 DOI: 10.1097/meg.0000000000002492] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
OBJECTIVES Low phospholipid-associatedcholelithiasis (LPAC) is a clinical syndrome that can be associated with variants in the adenosinetriphosphate-binding cassette subfamily B, member 4 (ABCB4) transporter gene, in a proportion of patients. The diagnosis of LPAC is defined by clinical as well as imaging criteria of intrahepatic hyperechoic foci or microlithiasis and biliary sludge on ultrasound. The aim of the study was to assess the role of imaging in investigating patients presenting with clinical features suggesting a diagnosis of LPAC. METHODS Imaging findings in 51 patients with clinical LPAC were retrospectively reviewed. Most patients had been referred with difficult-to-manage biliary pain postcholecystectomy and some with intrahepatic dilated ducts and stones. The diagnosis of LPAC was made on clinical features. RESULTS The patients were young with symptom onset at median age 24 years and were mainly female (75%). Ultrasound was performed by an expert in 48/51 and magnetic resonance cholangiopancreatography (MRCP) in 47/51 patients. Targeted liver ultrasound found small hyperechoic foci with comet tail artifacts or posterior acoustic shadowing typical of LPAC in 30/48 (63%) of examinations. However, ultrasound examinations performed before referral for investigation did not report these findings. Intrahepatic duct dilatation was seen in 26/51 (51%) of cases. MRCP did not reliably detect microlithiasis. CONCLUSIONS Targeted liver ultrasound performed by an expert aware of the possible diagnosis is the pivotal investigation for patients with clinical features suggesting LPAC. The findings in ultrasound performed before referral suggest LPAC is under-recognized and under-diagnosed.
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Cherraqi A, Imrani K, Andour H, Messaoud O, Benelhosni K, Billah NM, Nassar I. Low phospholipids associated cholelithiasis syndrome in a young women: A rare case report. Radiol Case Rep 2022; 18:11-16. [PMID: 36324844 PMCID: PMC9619147 DOI: 10.1016/j.radcr.2022.09.072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 09/18/2022] [Accepted: 09/21/2022] [Indexed: 11/07/2022] Open
Abstract
Low phospholipid-associated cholelithiasis (LPAC) is a rare, still poorly understood genetic disorder characterized by the association of an ABCB4 mutation and low biliary phospholipid concentration with recurrent cholelithiasis, responsible for the development of intrahepatic lithiasis in adults. The mutation of the ABCB4 gene, which codes for the ABCB4/MDR3 ductal protein, a biliary transporter, leads to precipitation of cholesterol crystals in the bile ducts leading to the formation of intrahepatic stones. The diagnosis should be suspected when at least 2 of the following criteria are present: onset of symptoms before age 40; recurrence of biliary symptoms (biliary colic, jaundice, cholangitis, acute pancreatitis) after cholecystectomy; presence of echogenic foci in the liver indicative of intrahepatic stones or biliary sludge; previous episode(s) of intrahepatic cholestasis during pregnancy; and a family history of gallstones in first degree relatives. Imaging techniques, especially ultrasound, play an important role in the detection of intrahepatic stones. The majority of clinical situations are simple and not serious, often managed by medical treatment with ursodeoxycholic acid, but certain complicated forms may require more invasive endoscopic or surgical treatment. We report a case of a 43-year-old woman, cholecystectomized 5 years ago, who presented with liver colic-like pain with cytolysis and biological cholestasis. Ultrasound and MRI showed the presence of intrahepatic calculi disseminated along the bile duct pathway creating a comet tail appearance and generating a posterior shadow cone. The interrogation of the patient showed that her sister was being followed for LPAC syndrome. The diagnosis of LPAC syndrome was retained and the patient was put under medical treatment with ursodeoxycholic acid with regular clinical, biological and radiological follow-up.
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Biyoukar M, Corpechot C, El Mouhadi S, Chambenois E, Vanderbecq Q, Barbu V, Dong C, Lemoinne S, Tordjman M, Jomaah R, Chazouilleres O, Arrivé L. ABCB4 variant is associated with hepatobiliary MR abnormalities in people with low phospholipid associated cholelithiasis syndrome. JHEP Rep 2022; 4:100590. [PMID: 36277956 PMCID: PMC9582794 DOI: 10.1016/j.jhepr.2022.100590] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 08/09/2022] [Accepted: 08/29/2022] [Indexed: 11/18/2022] Open
Affiliation(s)
- Moustafa Biyoukar
- Department of Radiology, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP) and Sorbonne University, Paris, France
| | - Christophe Corpechot
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN Rare-Liver, Department of Hepatology, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP), and INSERM, UMRS 938 Sorbonne University, Paris, France
| | - Sanaâ El Mouhadi
- Department of Radiology, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP) and Sorbonne University, Paris, France
| | - Edouard Chambenois
- Department of Radiology, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP) and Sorbonne University, Paris, France
| | - Quentin Vanderbecq
- Department of Radiology, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP) and Sorbonne University, Paris, France
| | - Véronique Barbu
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN Rare-Liver, Department of Hepatology, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP), and INSERM, UMRS 938 Sorbonne University, Paris, France
| | - Catherine Dong
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN Rare-Liver, Department of Hepatology, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP), and INSERM, UMRS 938 Sorbonne University, Paris, France
| | - Sara Lemoinne
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN Rare-Liver, Department of Hepatology, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP), and INSERM, UMRS 938 Sorbonne University, Paris, France
| | - Mickael Tordjman
- Department of Radiology, Raymond Poincaré Hospital, Assistance Publique – Hôpitaux de Paris (APHP), Garches, France
| | - Raphel Jomaah
- Faculty of Arts and Science, University of Toronto, Toronto, ON, Canada
| | - Olivier Chazouilleres
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN Rare-Liver, Department of Hepatology, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP), and INSERM, UMRS 938 Sorbonne University, Paris, France
| | - Lionel Arrivé
- Department of Radiology, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP) and Sorbonne University, Paris, France
- Corresponding author. Address: Department of Radiology, Saint-Antoine Hospital, 184 rue du Faubourg Saint-Antoine, 75012 Paris, France. Tel.: +33-149282257.
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Halleb Y, Ben Jazia E, Akkari I, Zaghouani H, Hmila F, Ghrissi R, Saad A, Gribaa M. Clinical, biological, radiological, and genetic study of LPAC syndrome in Tunisian patients. Arab J Gastroenterol 2022; 23:210-217. [PMID: 35922258 DOI: 10.1016/j.ajg.2022.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 05/12/2022] [Accepted: 06/07/2022] [Indexed: 10/16/2022]
Abstract
BACKGROUND AND STUDY AIMS Low phospholipid-associated cholelithiasis (LPAC) syndrome is a form of cholelithiasis associated with the ABCB4 gene mutation. The defects of the protein ABCB4 encoded by this gene promote the formation of biliary cholesterol microcalculations. ABCB4 screening is negative in a significant proportion of patients. PATIENTS AND METHODS An analytical study of the epidemiological, clinical, biological, and radiological characteristics of 19 patients was conducted, followed by Sanger-type sequencing of the 27 exons encoding the ABCB4 gene. RESULTS Our results showed a female predominance, symptomatic vesicular lithiasis predominance, and a high frequency of biliary complications in patients carrying an ABCB4 mutation. Normal liver enzyme values were found in 84.2% of the cases. Intrahepatic hyperechoic foci were present in 68.4%. Molecular analysis detected a pathogenic mutation of the ABCB4 gene in 31.57% of patients. The mutations found were a nonsense mutation and three missense mutations, including two new mutations. CONCLUSION Our epidemiological, clinical, and genetic results concord with previous studies of LPAC syndrome. Two of the mutations we found have never been detected in patients with LPAC. The low percentage of ABCB4 gene mutations can be explained by the absence of studies of other genes involved in bile acid homeostasis besides the ABCB4 gene and by the inclusion criteria used in this study.
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Affiliation(s)
- Yosra Halleb
- Laboratory of Cytogenetics, Molecular Genetics and Biology of Human Reproduction, University Hospital Farhat Hached, Sousse, Tunisia; Faculty of Medicine of Sousse, University of Sousse.
| | - Elhem Ben Jazia
- Faculty of Medicine of Sousse, University of Sousse; Gastroenterology Department, University Hospital Farhat Hached, Sousse, Tunisia
| | - Imen Akkari
- Faculty of Medicine of Sousse, University of Sousse; Gastroenterology Department, University Hospital Farhat Hached, Sousse, Tunisia
| | - Houneida Zaghouani
- Faculty of Medicine of Sousse, University of Sousse; Medical Imaging Department, University Hospital Farhat Hached , Sousse, Tunisia
| | - Fahmi Hmila
- Faculty of Medicine of Sousse, University of Sousse; Department of General Surgery, University Hospital Farhat Hached, Sousse, Tunisia
| | - Rafik Ghrissi
- Faculty of Medicine of Sousse, University of Sousse; Department of General Surgery, University Hospital Farhat Hached, Sousse, Tunisia
| | - Ali Saad
- Laboratory of Cytogenetics, Molecular Genetics and Biology of Human Reproduction, University Hospital Farhat Hached, Sousse, Tunisia; Faculty of Medicine of Sousse, University of Sousse
| | - Moez Gribaa
- Laboratory of Cytogenetics, Molecular Genetics and Biology of Human Reproduction, University Hospital Farhat Hached, Sousse, Tunisia; Faculty of Medicine of Sousse, University of Sousse
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12
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Wang HH, Portincasa P, Liu M, Wang DQH. Genetic Analysis of ABCB4 Mutations and Variants Related to the Pathogenesis and Pathophysiology of Low Phospholipid-Associated Cholelithiasis. Genes (Basel) 2022; 13:1047. [PMID: 35741809 PMCID: PMC9222727 DOI: 10.3390/genes13061047] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 06/08/2022] [Indexed: 12/28/2022] Open
Abstract
Clinical studies have revealed that the ABCB4 gene encodes the phospholipid transporter on the canalicular membrane of hepatocytes, and its mutations and variants are the genetic basis of low phospholipid-associated cholelithiasis (LPAC), a rare type of gallstone disease caused by a single-gene mutation or variation. The main features of LPAC include a reduction or deficiency of phospholipids in bile, symptomatic cholelithiasis at <40 years of age, intrahepatic sludge and microlithiasis, mild chronic cholestasis, a high cholesterol/phospholipid ratio in bile, and recurrence of biliary symptoms after cholecystectomy. Needle-like cholesterol crystals, putatively “anhydrous” cholesterol crystallization at low phospholipid concentrations in model and native bile, are characterized in ABCB4 knockout mice, a unique animal model for LPAC. Gallbladder bile with only trace amounts of phospholipids in these mice is supersaturated with cholesterol, with lipid composition plotting in the left two-phase zone of the ternary phase diagram, consistent with “anhydrous” cholesterol crystallization. In this review, we summarize the molecular biology and physiological functions of ABCB4 and comprehensively discuss the latest advances in the genetic analysis of ABCB4 mutations and variations and their roles in the pathogenesis and pathophysiology of LPAC in humans, based on the results from clinical studies and mouse experiments. To date, approximately 158 distinct LPAC-causing ABCB4 mutations and variants in humans have been reported in the literature, indicating that it is a monogenic risk factor for LPAC. The elucidation of the ABCB4 function in the liver, the identification of ABCB4 mutations and variants in LPAC patients, and the exploration of gene therapy for ABCB4 deficiency in animal models can help us to better understand the cellular, molecular, and genetic mechanisms underlying the onset of the disease, and will pave the way for early diagnosis and prevention of susceptible subjects and effective intervention for LPAC in patients.
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Affiliation(s)
- Helen H. Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA;
| | - Piero Portincasa
- Department of Biomedical Sciences and Human Oncology, Clinica Medica “A. Murri”, University of Bari Medical School, 70124 Bari, Italy;
| | - Min Liu
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA;
| | - David Q.-H. Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA;
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13
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Falcão D, Pedroto I, Moreira T. The wide phenotypic and genetic spectrum of ABCB4 gene deficiency: A case series. Dig Liver Dis 2022; 54:221-227. [PMID: 34376370 DOI: 10.1016/j.dld.2021.07.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 07/06/2021] [Accepted: 07/07/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND ABCB4-gene mutations are responsible for several cholestatic diseases with a heterogeneous clinical spectrum. AIMS To analyse phenotype/genotype relationships in ABCB4-mutations. METHODS Retrospective characterization of adult patients with ABCB4-variations diagnosed between 2015 and 2020. Genotype-phenotype correlations were analysed and compared with previously reported data. RESULTS Twenty patients from 12 families were included. Thirteen patients presented recurrent elevated liver tests, eight fulfilled Low-Phospholipid-Associated-Cholelithiasis syndrome criteria, five had Intrahepatic Cholestasis of Pregnancy and three patients developed Drug-Induced-Liver-Injury. ABCB4 screening identified eight different mutations. Five patients were homozygotes to the variant c.504T > C. Ten patients had one mutation in heterozygote-state and five patients had two mutations in compound-heterozygosity. Portal fibrosis occurred in two patients. One of these patients presented progressive fibrosis and progression of cholestasis despite ursodeoxycholic-acid treatment, this patient also harbours a ABCB11 polymorphism. CONCLUSION Although, phenotype-genotype relationships have not been clearly defined, an early diagnosis of ABCB4-variants may have an important role in management decisions and patient outcomes. To our knowledge, we describe a not previously reported deletion (c.1181delT) in ABCB4. The c.504T > C polymorphism, although a silent mutation at the protein level, seems to be associated to different cholestatic diseases. The role of other genes variants, namely ABCB11, as co-factor for progression, needs to be clarified.
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Affiliation(s)
- Daniela Falcão
- Largo do Prof. Abel Salazar, Centro Hospitalar Universitário do Porto, Praça D. Filipa de Lencastre n° 189, 2° frente, Porto 4050-189, Portugal.
| | - Isabel Pedroto
- Largo do Prof. Abel Salazar, Centro Hospitalar Universitário do Porto, Praça D. Filipa de Lencastre n° 189, 2° frente, Porto 4050-189, Portugal
| | - Teresa Moreira
- Largo do Prof. Abel Salazar, Centro Hospitalar Universitário do Porto, Praça D. Filipa de Lencastre n° 189, 2° frente, Porto 4050-189, Portugal
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Kinsenoside Alleviates 17α-Ethinylestradiol-Induced Cholestatic Liver Injury in Rats by Inhibiting Inflammatory Responses and Regulating FXR-Mediated Bile Acid Homeostasis. Pharmaceuticals (Basel) 2021; 14:ph14050452. [PMID: 34064649 PMCID: PMC8151897 DOI: 10.3390/ph14050452] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 04/27/2021] [Accepted: 05/06/2021] [Indexed: 12/13/2022] Open
Abstract
Cholestasis is an important predisposing factor of liver diseases, such as hepatocyte necrosis, liver fibrosis and primary biliary cirrhosis. In this study, we aimed to investigate the effects of Kinsenoside (KD), a natural active ingredient of Anoectochilus roxburghii, on estrogen-induced cholestatic liver injury in Sprague-Dawley rats and the underlying mechanism. The rats were randomly divided into six groups: control group, model group, low-dose KD group (50 mg/kg body weight, KD-L), medium-dose KD group (100 mg/kg body weight, KD-M), high-dose KD group (200 mg/kg body weight, KD-H) and ursodeoxycholic acid group (40 mg/kg body weight, UDCA). 17α-Ethinylestradiol (EE) was used to establish an experimental animal model of estrogen-induced cholestasis (EIC). The results demonstrated that KD alleviated liver pathologic damage, serum biochemical status and inhibited hepatocellular microstructure disorder and bile duct hyperplasia in EE-induced cholestatic rats. Mechanically, KD alleviated EE-induced cholestatic liver injury by inhibiting inflammatory responses and regulating bile acid homeostasis. Concretely, KD reduced the expression of IL-1β and IL-6 by inhibiting NF-κB p65 to suppress EE-mediated inflammation in rat liver. KD enhanced the expression of FXR and inhibited EE-mediated reduction of FXR in vitro and in vivo. It was the potential mechanism that KD mitigates cholestasis by increasing efflux and inhibiting uptake of bile acids via FXR-mediated induction of bile salt export pump (BSEP) and reduction of Na+-dependent taurocholate cotransport peptide (NTCP) to maintain bile acid homeostasis. Moreover, KD repressed the bile acid synthesis through reducing the expression of synthetic enzyme (CYP7A1), thereby normalizing the expression of metabolic enzyme (SULT2A1) of bile acid. In conclusion, our results revealed that KD may be an effective drug candidate for the treatment of cholestasis.
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15
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Bull LN, Ellmers R, Foskett P, Strautnieks S, Sambrotta M, Czubkowski P, Jankowska I, Wagner B, Deheragoda M, Thompson RJ. Cholestasis Due to USP53 Deficiency. J Pediatr Gastroenterol Nutr 2021; 72:667-673. [PMID: 33075013 PMCID: PMC8549450 DOI: 10.1097/mpg.0000000000002926] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 08/17/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Although a number of genetic forms of cholestasis have been identified, the genetic etiology of disease remains unidentified in a subset of cholestasis patients. METHODS Whole exome sequencing (WES) was performed in DNA from patients diagnosed with cholestasis, at different points on the continuum from progressive familial intrahepatic cholestasis to benign recurrent intrahepatic cholestasis, in whom no disease mutations in known cholestasis genes had been identified. Candidate genes were then assessed in a larger patient sample, by targeted next-generation sequencing (NGS). Disease features at presentation and follow-up were collected from available medical records. RESULTS By WES, we identified 3 patients with homozygous mutations in USP53. Screening of USP53 in a larger set of patients identified 4 additional patients with homozygous mutations in USP53. Six of the 7 patients had deletion mutations, and 1 had a missense mutation; 3 of the patients were siblings, all bearing a deletion that also disrupted neighboring MYOZ2. Age of onset ranged from early infancy to adolescence. Cholestasis tended to be biochemically mild and intermittent, and responsive to medication. Liver fibrosis was, however, present in all 4 patients who were biopsied, and splenomegaly was apparent in 5 of 7 at last ultrasound. CONCLUSIONS Two groups recently identified patients with liver disease and mutation in USP53. We have now identified biallelic mutation in USP53 in 7 further patients with cholestasis, from 5 families. Most individuals had evidence of chronic liver disease, and long-term follow-up is recommended.
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Affiliation(s)
- Laura N. Bull
- Liver Center Laboratory, Department of Medicine and Institute for Human Genetics, University of California San Francisco, San Francisco, CA
| | | | | | | | | | - Piotr Czubkowski
- Department of Gastroenterology, Hepatology, Nutritional Disturbances and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Irena Jankowska
- Department of Gastroenterology, Hepatology, Nutritional Disturbances and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Bart Wagner
- Histopathology Department, Royal Hallamshire Hospital, Sheffield, UK
| | | | - Richard J. Thompson
- Institute of Liver Studies, King's College Hospital
- Institute of Liver Studies, King's College London, London, UK
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16
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Use of a Comprehensive 66-Gene Cholestasis Sequencing Panel in 2171 Cholestatic Infants, Children, and Young Adults. J Pediatr Gastroenterol Nutr 2021; 72:654-660. [PMID: 33720099 DOI: 10.1097/mpg.0000000000003094] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
OBJECTIVES Cholestasis is caused by a wide variety of etiologies, often genetic in origin. Broad overlap in clinical presentations, particularly in newborns, renders prioritizing diagnostic investigations challenging. In this setting, a timely, comprehensive assessment using a multigene panel by a clinical diagnostic laboratory would likely prove useful. We summarize initial findings from a testing program designed to discover genetic causes of cholestasis. METHODS A neonatal/adult sequencing panel containing 66 genes (originally 57; nine added March 2017) relevant to cholestasis was used. A broad range of eligible patients were enrolled with current/history of cholestasis without an identified cause, or unexplained chronic liver disease. DNA sequencing utilized a custom-designed capture library, and variants were classified and reported as benign, likely benign, variant of unknown significance (VOUS), likely pathogenic (LP), or pathogenic (P), according to the clinical interpretation workflow at EGL Genetics (Tucker, GA). RESULTS A total of 2433 samples were submitted between February 2016 and December 2017; 2171 results were reported. Median turnaround time was 21 days. Results from the 2171 subjects (57% <1 year old) included 583 P variants, 79 LP variants, and 3117 VOUS; 166 P/LP variants and 415 VOUS were novel. The panel's overall diagnostic yield was 12% (n = 265/2171) representing 32 genes. The top five genetic diagnoses for the group, in order: JAG1 + NOTCH2 (Alagille syndrome), ABCB11, SERPINA1, ABCB4, and POLG. CONCLUSIONS These findings support the utility of comprehensive rapid multigene testing in diagnosing cholestasis and highlight the evolving understanding of genetic variants contributing to the pathogenesis of cholestasis.
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17
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ABCB4 variants in adult patients with cholestatic disease are frequent and underdiagnosed. Dig Liver Dis 2021; 53:329-344. [PMID: 33390354 DOI: 10.1016/j.dld.2020.12.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 12/01/2020] [Accepted: 12/05/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Heterozygous ABCB4 variants are not routinely tested in adults with cholestasis because of their supposed rarity and high costs. METHODS Nineteen adult patients presenting with unexplained cholestasis, and/or recurrent gallstones were included; genotyping was not done in five due to lack of health insurance approval. RESULTS heterozygous ABCB4 variants were identified in seven patients, followed by cascade testing of 12 family members: one patient underwent liver transplantation at age 40 for end-stage liver disease; one had compensated cirrhosis; all symptomatic adults had gallstones, including four with low phospholipid-associated cholelithiasis; four had intrahepatic cholestasis of pregnancy; all children and one 54-year old female were asymptomatic. Genotype: Families A and C: c.2211G>A (p.Ala737=) combined with c.959C>T (p.Ser320Phe) in one subject; Family B: c.1130T>C (p.Ile377Thr); Family D: large deletion removing ABCB4 exons 1-4 plus ABCB1, RUNDC3B, SLC25A40, DBF4, ADAM22 exons 1-3; Family E: c.1565T>C (p.Phe522Ser) ; Family F: c.1356+2T>C combined with c.217C>G (p.Leu73Val). All patients responded to ursodeoxycholic acid. CONCLUSIONS We found ABCB4 variants in half of the adults with unexplained cholestasis and/or recurrent gallstones presenting at our center, suggesting that this condition is underdiagnosed and undertreated, with serious consequences not only for the patients and their families, but also in terms of healthcare costs.
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18
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Dong C, Condat B, Picon-Coste M, Chrétien Y, Potier P, Noblinski B, Arrivé L, Hauuy MP, Barbu V, Maftouh A, Gaouar F, Ben Belkacem K, Housset C, Poupon R, Zanditenas D, Chazouillères O, Corpechot C. Low-phospholipid-associated cholelithiasis syndrome: Prevalence, clinical features, and comorbidities. JHEP Rep 2020; 3:100201. [PMID: 33554096 PMCID: PMC7848766 DOI: 10.1016/j.jhepr.2020.100201] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 10/18/2020] [Accepted: 10/26/2020] [Indexed: 01/02/2023] Open
Abstract
Background & Aims Low-phospholipid-associated cholelithiasis (LPAC) syndrome, a rare genetic form of intrahepatic cholelithiasis in adults, is still poorly understood. We report the results of the largest-ever case-control study of patients with LPAC syndrome aiming to assess the prevalence, clinical features, and comorbidities of the disease. Methods We included all LPAC cases diagnosed between 2001 and 2016 in 11 French centres. Controls consisted of all patients who underwent a cholecystectomy for common gallstone disease in a single non-academic centre over 1 year. A logistic regression analysis was used to identify the clinical features associated with LPAC syndrome across several patient strata with increasing levels of diagnostic confidence. The ratio between the incident cases of LPAC syndrome and the total number of cholecystectomies for gallstones was used to assess the relative prevalence of the disease. Results In this study, 308 cases and 206 controls were included. LPAC syndrome accounted for 0.5–1.9% of all patients admitted with symptomatic gallstone disease. Age at first symptoms <40 years, absence of overweight, persistence of symptoms after cholecystectomy, intrahepatic micro- or macrolithiasis, common bile duct (CBD) lithiasis, and no history of cholecystitis were independently associated with LPAC diagnosis. ATP-binding cassette subfamily B member 4 (ABCB4) variants, present in 46% of cases, were associated with CBD lithiasis, chronic elevation of gamma-glutamyltransferase (GGT), and personal or family history of hepato-biliary cancer. Conclusions In this case-control study, LPAC syndrome accounted for approximately 1% of symptomatic cholelithiasis in adults. In addition to pre-established diagnostic criteria, normal weight, CBD lithiasis, and no history of cholecystitis were significantly associated with the syndrome. ABCB4 gene variations in patients with LPAC were associated with CBD lithiasis, chronic cholestasis, and a personal or family history of hepato-biliary cancer. Lay summary In the largest case-control study ever conducted in patients with LPAC syndrome, a rare genetic form of intrahepatic cholelithiasis in young adults, LPAC syndrome was found in approximately 1% of all patients admitted to the hospital for symptomatic gallstones and, in addition to the pre-established characteristics of the syndrome (age at first symptoms <40 years, recurrence of symptoms after cholecystectomy, and/or imaging evidence of intrahepatic microlithiasis), was associated with lower BMI, higher prevalence of common bile duct stones, and lower incidence of acute cholecystitis. ABCB4 gene variants, which were detected in about half of cases, were associated with common bile duct stones and a personal or family history of hepato-biliary cancer.
Low-phospholipid-associated cholelithiasis (LPAC) syndrome affects approximately 1% of adults with symptomatic cholelithiasis. Normal weight, common bile duct stones, and lack of cholecystitis are clinical features significantly associated with this syndrome. ABCB4 variants in patients with LPAC may be associated with an increased personal or family risk of hepato-biliary cancer.
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Affiliation(s)
- Catherine Dong
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN RARE-LIVER, Saint-Antoine Hospital, Assistance Publique–Hôpitaux de Paris, Sorbonne University, Paris, France
| | - Bertrand Condat
- Division of Gastroenterology and Hepatology, French Polynesia Hospital, Pirae, French Polynesia
- Association Nationale des Hépato-Gastroentérologues des Hôpitaux Généraux de France (ANGH), Montfermeil, France
- French National Cohort of Patients with LPAC syndrome (RaDiCo-COLPAC), RaDiCo, Inserm U933, Armand Trousseau Hospital, Paris, France
| | - Magalie Picon-Coste
- Association Nationale des Hépato-Gastroentérologues des Hôpitaux Généraux de France (ANGH), Montfermeil, France
- French National Cohort of Patients with LPAC syndrome (RaDiCo-COLPAC), RaDiCo, Inserm U933, Armand Trousseau Hospital, Paris, France
- Division of Gastroenterology and Hepatology, Aix-en-Provence Hospital, Aix-en-Provence, France
| | - Yves Chrétien
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN RARE-LIVER, Saint-Antoine Hospital, Assistance Publique–Hôpitaux de Paris, Sorbonne University, Paris, France
- Sorbonne University, INSERM, Centre de Recherche Saint-Antoine, Paris, France
| | - Pascal Potier
- Association Nationale des Hépato-Gastroentérologues des Hôpitaux Généraux de France (ANGH), Montfermeil, France
- French National Cohort of Patients with LPAC syndrome (RaDiCo-COLPAC), RaDiCo, Inserm U933, Armand Trousseau Hospital, Paris, France
- Division of Gastroenterology and Hepatology, Orléans Hospital, Orléans, France
| | - Béatrice Noblinski
- Radiology Department, Saint-Antoine Hospital, Assistance Publique–Hôpitaux de Paris, Paris, France
| | - Lionel Arrivé
- Sorbonne University, INSERM, Centre de Recherche Saint-Antoine, Paris, France
- Radiology Department, Saint-Antoine Hospital, Assistance Publique–Hôpitaux de Paris, Paris, France
| | | | - Véronique Barbu
- Sorbonne University, INSERM, Centre de Recherche Saint-Antoine, Paris, France
- Molecular Biology and Genetics Laboratory, Saint-Antoine Hospital, Assistance Publique–Hôpitaux de Paris, Paris, France
| | - Anware Maftouh
- Visceral Surgery Department, Saint-Camille Hospital, Bry-sur-Marne, France
| | - Farid Gaouar
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN RARE-LIVER, Saint-Antoine Hospital, Assistance Publique–Hôpitaux de Paris, Sorbonne University, Paris, France
| | - Karima Ben Belkacem
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN RARE-LIVER, Saint-Antoine Hospital, Assistance Publique–Hôpitaux de Paris, Sorbonne University, Paris, France
- French National Cohort of Patients with LPAC syndrome (RaDiCo-COLPAC), RaDiCo, Inserm U933, Armand Trousseau Hospital, Paris, France
| | - Chantal Housset
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN RARE-LIVER, Saint-Antoine Hospital, Assistance Publique–Hôpitaux de Paris, Sorbonne University, Paris, France
- Sorbonne University, INSERM, Centre de Recherche Saint-Antoine, Paris, France
| | - Raoul Poupon
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN RARE-LIVER, Saint-Antoine Hospital, Assistance Publique–Hôpitaux de Paris, Sorbonne University, Paris, France
| | - David Zanditenas
- Association Nationale des Hépato-Gastroentérologues des Hôpitaux Généraux de France (ANGH), Montfermeil, France
- French National Cohort of Patients with LPAC syndrome (RaDiCo-COLPAC), RaDiCo, Inserm U933, Armand Trousseau Hospital, Paris, France
- Division of Gastroenterology and Hepatology, Saint-Camille Hospital, Bry-sur-Marne, France
| | - Olivier Chazouillères
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN RARE-LIVER, Saint-Antoine Hospital, Assistance Publique–Hôpitaux de Paris, Sorbonne University, Paris, France
- French National Cohort of Patients with LPAC syndrome (RaDiCo-COLPAC), RaDiCo, Inserm U933, Armand Trousseau Hospital, Paris, France
- Sorbonne University, INSERM, Centre de Recherche Saint-Antoine, Paris, France
| | - Christophe Corpechot
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN RARE-LIVER, Saint-Antoine Hospital, Assistance Publique–Hôpitaux de Paris, Sorbonne University, Paris, France
- French National Cohort of Patients with LPAC syndrome (RaDiCo-COLPAC), RaDiCo, Inserm U933, Armand Trousseau Hospital, Paris, France
- Sorbonne University, INSERM, Centre de Recherche Saint-Antoine, Paris, France
- Corresponding author. Address: Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN RARE-LIVER, Saint-Antoine Hospital, Assistance Publique–Hôpitaux de Paris, 184 Rue du Faubourg Saint-Antoine, 75571, Paris Cedex 12, France. Tel.: +33149282836, Fax: +33149282107.
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Mirza N, Malhotra S, Sibal A. A Novel Compound Heterozygous Mutation in ABCB4 Gene Leading to Cholelithiasis, Progressive Familial Intrahepatic Cholestasis (Type 3), and Cirrhosis in a Child. JOURNAL OF CHILD SCIENCE 2020. [DOI: 10.1055/s-0040-1717106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
AbstractProgressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal recessive disorders of childhood which presents with intermittent or progressive episodes of cholestasis, with jaundice and pruritus as most common presenting symptoms. PFIC type 3 occurs due to mutations in the ABCB4 gene, mutation in this gene has wide spectrum of features which include intrahepatic stones, cholelithiasis, PFIC type 3, and intrahepatic cholestasis of pregnancy. Here, we are reporting a peculiar case of young male adolescent with novel variant compound heterozygote missense mutation in ABCB4 gene who had gall stone as initial symptom, followed by symptoms of PFIC and eventually decompensated chronic liver disease.
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Affiliation(s)
- Nida Mirza
- Indraprastha Apollo Hospital, New Delhi, India
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20
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Terziroli Beretta-Piccoli B, Thompson R, Foskett P, Cerny A, Merlo E, Vergani D, Rougemont AL, Moix I, Mieli-Vergani G, Morris M. A Heterozygous ABCB4, RUNDC3B, and ABCB1 Deletion Associated With Severe Cholestatic Liver Disease in Adulthood. Hepatology 2019; 70:1484-1487. [PMID: 31127640 DOI: 10.1002/hep.30783] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 05/15/2019] [Indexed: 12/07/2022]
Affiliation(s)
- Benedetta Terziroli Beretta-Piccoli
- Epatocentro Ticino, Lugano, Switzerland.,Institute of Liver Studies, MowatLabs, King's College Hospital, Denmark Hill, London, United Kingdom
| | - Richard Thompson
- Institute of Liver Studies, King's College London, London, United Kingdom
| | - Pierre Foskett
- Institute of Liver Studies, MowatLabs, King's College Hospital, Denmark Hill, London, United Kingdom
| | | | | | - Diego Vergani
- Institute of Liver Studies, MowatLabs, King's College Hospital, Denmark Hill, London, United Kingdom
| | - Anne-Laure Rougemont
- Division of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland
| | | | - Giorgina Mieli-Vergani
- Pediatric Liver, GI and Nutrition Center, MowatLabs, King's College Hospital, Denmark Hill, London, United Kingdom
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Goubault P, Brunel T, Rode A, Bancel B, Mohkam K, Mabrut JY. Low-Phospholipid Associated Cholelithiasis (LPAC) syndrome: A synthetic review. J Visc Surg 2019; 156:319-328. [PMID: 30922600 DOI: 10.1016/j.jviscsurg.2019.02.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Low-Phospholipid Associated Cholelithiasis (LPAC) is a genetic disease responsible for the development of intrahepatic lithiasis. It is associated with a mutation of the ABCB4 gene which codes for protein MDR3, a biliary carrier. As a nosological entity, it is defined by presence of two of the three following criteria: age less than 40 years at onset of biliary symptoms, recurrence of biliary symptoms after cholecystectomy, and intrahepatic hyperechogenic foci detected by ultrasound. While the majority of clinical forms are simple, there also exist complicated forms, involving extended intrahepatic lithiasis and its consequences: lithiasis migration, acute cholangitis, intrahepatic abscess. Chronic evolution can lead to secondary sclerosing cholangitis or secondary biliary cirrhosis. In unusual cases, degeneration into cholangiocarcinoma may occur. Treatment is built around ursodeoxycholic acid, which yields dissolution of biliary calculi. Complicated forms may call for interventional, radiological, endoscopic or surgical treatment. This synthetic review illustrates and summarizes the different aspects of this entity, from simple gallbladder lithiasis to cholangiocarcinoma, as well as secondary biliary cirrhosis requiring liver transplant, on the basis of clinical cases and the iconography of patients treated in our ward.
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Affiliation(s)
- P Goubault
- Service de chirurgie générale, digestive et transplantation hépatique et intestinale (general, digestive, liver transplant and intestinal surgery department), hôpital de la Croix Rousse, hospices civils de Lyon, 103, grande rue de la Croix-Rousse, 69317 Lyon cedex 04, France.
| | - T Brunel
- Service de radiologie (radiology department), hôpital de la Croix Rousse, hospices civils de Lyon, 103, grande rue de la Croix-Rousse, 69317 Lyon cedex 04, France
| | - A Rode
- Service de radiologie (radiology department), hôpital de la Croix Rousse, hospices civils de Lyon, 103, grande rue de la Croix-Rousse, 69317 Lyon cedex 04, France
| | - B Bancel
- Service d'anatomie et de cytologie pathologiques (pathological anatomy and cytology department), hôpital de la Croix Rousse, hospices civils de Lyon, 103, grande rue de la Croix-Rousse, 69317 Lyon cedex 04, France
| | - K Mohkam
- Service de chirurgie générale, digestive et transplantation hépatique et intestinale (general, digestive, liver transplant and intestinal surgery department), hôpital de la Croix Rousse, hospices civils de Lyon, 103, grande rue de la Croix-Rousse, 69317 Lyon cedex 04, France
| | - J-Y Mabrut
- Service de chirurgie générale, digestive et transplantation hépatique et intestinale (general, digestive, liver transplant and intestinal surgery department), hôpital de la Croix Rousse, hospices civils de Lyon, 103, grande rue de la Croix-Rousse, 69317 Lyon cedex 04, France
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22
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Chlorpromazine toxicity is associated with disruption of cell membrane integrity and initiation of a pro-inflammatory response in the HepaRG hepatic cell line. Biomed Pharmacother 2019; 111:1408-1416. [DOI: 10.1016/j.biopha.2019.01.020] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 01/04/2019] [Accepted: 01/06/2019] [Indexed: 12/26/2022] Open
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23
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Kulecka M, Habior A, Paziewska A, Goryca K, Dąbrowska M, Ambrozkiewicz F, Walewska-Zielecka B, Gabriel A, Mikula M, Ostrowski J. Clinical Applicability of Whole-Exome Sequencing Exemplified by a Study in Young Adults with the Advanced Cryptogenic Cholestatic Liver Diseases. Gastroenterol Res Pract 2017; 2017:4761962. [PMID: 28626473 PMCID: PMC5463139 DOI: 10.1155/2017/4761962] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 04/11/2017] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The proper use of new medical tests in clinical practice requires the establishment of their value and range of diagnostic usefulness. While whole-exome sequencing (WES) has already entered the medical practice, recognizing its diagnostic usefulness in multifactorial diseases has not yet been achieved. AIMS The objective of this study was to establish usability of WES in determining genetic background of chronic cholestatic liver disease (CLD) in young patients. METHODS WES was performed on six young patients (between 17 and 22 years old) with advanced fibrosis or cirrhosis due to CLD and their immediate families. Sequencing was performed on an Ion Proton sequencer. RESULTS On average, 19,673 variants were identified, of which from 7 to 14 variants of an individual were nonsynonymous, homozygous, recessively inherited, and considered in silico as pathogenic. Although monogenic cause of CLD has not been determined, several heterozygous rare variants and polymorphisms were uncovered in genes previously known to be associated with CLD, including ATP8B1, ABCB11, RXRA, and ABCC4, indicative of multifactorial genetic background. CONCLUSIONS WES is a potentially useful diagnostic tool in determining genetic background of multifactorial diseases, but its main limitation results from the lack of opportunities for direct linkage between the uncovered genetic variants and molecular mechanisms of disease.
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Affiliation(s)
- Maria Kulecka
- Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Center for Postgraduate Education, Roentgena 5, 02-781 Warsaw, Poland
| | - Andrzej Habior
- Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Center for Postgraduate Education, Roentgena 5, 02-781 Warsaw, Poland
| | - Agnieszka Paziewska
- Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Center for Postgraduate Education, Roentgena 5, 02-781 Warsaw, Poland
| | - Krzysztof Goryca
- Department of Genetics, Cancer Center-Institute, Roentgena 5, 02-781 Warsaw, Poland
| | - Michalina Dąbrowska
- Department of Genetics, Cancer Center-Institute, Roentgena 5, 02-781 Warsaw, Poland
| | - Filip Ambrozkiewicz
- Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Center for Postgraduate Education, Roentgena 5, 02-781 Warsaw, Poland
| | - Bożena Walewska-Zielecka
- Department of Public Health, Faculty of Health Sciences, Medical University of Warsaw, Żwirki i Wigury 61, 02-091 Warsaw, Poland
| | - Andrzej Gabriel
- Department of Pathomorphology, Medical University of Silesia, Medyków 18, 40-752 Katowice, Poland
| | - Michal Mikula
- Department of Genetics, Cancer Center-Institute, Roentgena 5, 02-781 Warsaw, Poland
| | - Jerzy Ostrowski
- Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Center for Postgraduate Education, Roentgena 5, 02-781 Warsaw, Poland
- Department of Genetics, Cancer Center-Institute, Roentgena 5, 02-781 Warsaw, Poland
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Mhatre S, Wang Z, Nagrani R, Badwe R, Chiplunkar S, Mittal B, Yadav S, Zhang H, Chung CC, Patil P, Chanock S, Dikshit R, Chatterjee N, Rajaraman P. Common genetic variation and risk of gallbladder cancer in India: a case-control genome-wide association study. Lancet Oncol 2017; 18:535-544. [PMID: 28274756 DOI: 10.1016/s1470-2045(17)30167-5] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Revised: 01/17/2017] [Accepted: 01/26/2017] [Indexed: 02/03/2023]
Abstract
BACKGROUND Gallbladder cancer is highly lethal, with notable differences in incidence by geography and ethnic background. The aim of this study was to identify common genetic susceptibility alleles for gallbladder cancer. METHODS In this case-control genome-wide association study (GWAS), we did a genome-wide scan of gallbladder cancer cases and hospital visitor controls, both of Indian descent, followed by imputation across the genome. Cases were patients aged 20-80 years with microscopically confirmed primary gallbladder cancer diagnosed or treated at Tata Memorial Hospital, Mumbai, India, and enrolled in the study between Sept 12, 2010, and June 8, 2015. We only included patients who had been diagnosed less than 1 year before the date of enrolment and excluded patients with any other malignancies. We recruited visitor controls aged 20-80 years with no history of cancer visiting all departments or units of Tata Memorial Hospital during the same time period and frequency matched them to cases on the basis of age, sex, and current region of residence. We estimated association using logistic regression, adjusting for age, sex, and five eigenvectors. We recruited samples for a replication cohort from patients visiting Tata Memorial Hospital between Aug 4, 2015, and May 17, 2016, and patients visiting the Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India, between July, 2010, and May, 2015. We used the same inclusion and exclusion criteria for the replication set. We examined three of the most significant single-nucleotide polymorphisms (SNPs) in the replication cohort and did a meta-analysis of the GWAS discovery and replication sets to get combined estimates of association. FINDINGS The discovery cohort comprised 1042 gallbladder cancer cases and 1709 controls and the replication cohort contained 428 gallbladder cancer cases and 420 controls. We observed genome-wide significant associations for several markers in the chromosomal region 7q21.12 harbouring both the ABCB1 and ABCB4 genes, with the most notable SNPs after replication and meta-analysis being rs1558375 (GWAS p=3·8 × 10-9; replication p=0·01; combined p=2·3 × 10-10); rs17209837 (GWAS p=2·0 × 10-8; replication p=0·02; combined p=2·3 × 10-9), and rs4148808 (GWAS p=2·4 × 10-8; replication p=0·008; combined p=2·7 × 10-9). Combined estimates of per-allele trend odds ratios were 1·47 (95% CI 1·30-1·66; p=2·31 × 10-10) for rs1558375, 1·61 (1·38-1·89; p=2·26 × 10-9) for rs17209837, and 1·57 (1·35-1·82; p=2·71 × 10-9) for rs4148808. GWAS heritability analysis suggested that common variants are associated with substantial variation in risk of gallbladder cancer (sibling relative risk 3·15 [95% CI 1·80-5·49]). INTERPRETATION To our knowledge, this study is the first report of common genetic variation conferring gallbladder cancer risk at genome-wide significance. This finding, along with in-silico and biological evidence indicating the potential functional significance of ABCB1 and ABCB4, underlines the likely importance of these hepatobiliary phospholipid transporter genes in the pathology of gallbladder cancer. FUNDING The Tata Memorial Centre and Department of Biotechnology.
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Affiliation(s)
- Sharayu Mhatre
- Centre for Cancer Epidemiology, Tata Memorial Centre, Kharghar, Navi Mumbai, India
| | - Zhaoming Wang
- Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN, USA
| | - Rajini Nagrani
- Centre for Cancer Epidemiology, Tata Memorial Centre, Kharghar, Navi Mumbai, India
| | - Rajendra Badwe
- Department of Surgical Oncology, Tata Memorial Hospital, Parel, Mumbai, India
| | - Shubhada Chiplunkar
- Advanced Center for Treatment, Research and Education in Cancer, Tata Memorial Hospital, Parel, Mumbai, India
| | - Balraj Mittal
- Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Saurabh Yadav
- Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Haoyu Zhang
- Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | - Charles C Chung
- Cancer Genomics Research Laboratory, Leidos Biomedical Research, Gaithersburg, MD, USA; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
| | - Prachi Patil
- Department of Digestive Diseases and Clinical Nutrition, Tata Memorial Hospital, Parel, Mumbai, India
| | - Stephen Chanock
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
| | - Rajesh Dikshit
- Centre for Cancer Epidemiology, Tata Memorial Centre, Kharghar, Navi Mumbai, India.
| | - Nilanjan Chatterjee
- Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA; Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Preetha Rajaraman
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA; Centre for Global Health, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
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Mehl A, Bohorquez H, Serrano MS, Galliano G, Reichman TW. Liver transplantation and the management of progressive familial intrahepatic cholestasis in children. World J Transplant 2016; 6:278-290. [PMID: 27358773 PMCID: PMC4919732 DOI: 10.5500/wjt.v6.i2.278] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Revised: 02/24/2016] [Accepted: 03/14/2016] [Indexed: 02/05/2023] Open
Abstract
Progressive familial intrahepatic cholestasis (PFIC) is a constellation of inherited disorders that result in the impairment of bile flow through the liver that predominantly affects children. The accumulation of bile results in progressive liver damage, and if left untreated leads to end stage liver disease and death. Patients often present with worsening jaundice and pruritis within the first few years of life. Many of these patients will progress to end stage liver disease and require liver transplantation. The role and timing of liver transplantation still remains debated especially in the management of PFIC1. In those patients who are appropriately selected, liver transplantation offers an excellent survival benefit. Appropriate timing and selection of patients for liver transplantation will be discussed, and the short and long term management of patients post liver transplantation will also be described.
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Dixon PH, Williamson C. The pathophysiology of intrahepatic cholestasis of pregnancy. Clin Res Hepatol Gastroenterol 2016; 40:141-53. [PMID: 26823041 DOI: 10.1016/j.clinre.2015.12.008] [Citation(s) in RCA: 121] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Revised: 12/02/2015] [Accepted: 12/10/2015] [Indexed: 02/06/2023]
Abstract
A number of liver disorders are specific to pregnancy. Amongst these, intrahepatic cholestasis of pregnancy (ICP), also known as obstetric cholestasis (OC), is the commonest, affecting approximately 1 in 140 UK pregnancies. Patients commonly present in the third trimester with severe pruritus and deranged serum liver tests; bile acids are elevated, in severe cases >40 μmol/L. Although the disease is considered relatively benign for the mother, increased rates of adverse fetal outcomes, including stillbirth, are associated with ICP. As our knowledge of the mechanisms underlying bile acid homeostasis has advanced in the last 15 years our understanding of ICP has grown, in particular with respect to genetic influences on susceptibility to the disease, the role of reproductive hormones and their metabolites and the possible identity of the pruritic agents. In this review, we will describe recent advances in the understanding of this condition with a particular emphasis on how aspects of genetic and reproductive hormone involvement in pathophysiology have been elucidated. We also review recent developments regarding our knowledge of placental and fetal pathophysiology and the long-term health consequences for the mother and child.
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Affiliation(s)
- Peter H Dixon
- Division of Women's Health, 2.30W Hodgkin Building, King's College London, Guy's Campus, SE1 1UL London, United Kingdom
| | - Catherine Williamson
- Division of Women's Health, 2.30W Hodgkin Building, King's College London, Guy's Campus, SE1 1UL London, United Kingdom.
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Zhou M, Learned RM, Rossi SJ, DePaoli AM, Tian H, Ling L. Engineered fibroblast growth factor 19 reduces liver injury and resolves sclerosing cholangitis in Mdr2-deficient mice. Hepatology 2016; 63:914-29. [PMID: 26418580 PMCID: PMC5063176 DOI: 10.1002/hep.28257] [Citation(s) in RCA: 106] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 09/25/2015] [Indexed: 12/12/2022]
Abstract
UNLABELLED Defects in multidrug resistance 3 gene (MDR3), which encodes the canalicular phospholipid flippase, cause a wide spectrum of cholangiopathy phenotypes in humans. Mice deficient in Mdr2 (murine ortholog of MDR3) develop liver diseases that closely reproduce the biochemical, histological, and clinical features of human cholangiopathies such as progressive familial intrahepatic cholestasis and primary sclerosing cholangitis. We hypothesized that modulating bile acid metabolism by the gut hormone fibroblast growth factor 19 (FGF19) may represent a novel approach for treating cholangiopathy and comorbidities. We introduced adeno-associated virus carrying the gene for either the endocrine hormone FGF19 or engineered FGF19 variant M70 to 12-week old Mdr2-deficient mice with fully established disease. Effects on serum levels of liver enzymes, liver histology, and bile acid homeostasis were evaluated. FGF19 and M70 rapidly and effectively reversed liver injury, decreased hepatic inflammation, attenuated biliary fibrosis, and reduced cholecystolithiasis in Mdr2-deficient mice. Mechanistically, FGF19 and M70 significantly inhibited hepatic expression of Cyp7a1 and Cyp27a1, which encode enzymes responsible for the rate-limiting steps in the classic and alternate bile acid synthetic pathways, thereby reducing the hepatic bile acid pool and blood levels of bile acids. Importantly, prolonged exposure to FGF19, but not M70, led to the formation of hepatocellular carcinomas in the Mdr2-deficient mice. Furthermore, M70 ameliorated the hepatosplenomegaly and ductular proliferation that are associated with cholangiopathy. CONCLUSION These results demonstrate the potential for treating cholangiopathy by safely harnessing FGF19 biology to suppress bile acid synthesis.
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Affiliation(s)
- Mei Zhou
- NGM Biopharmaceuticals, Inc.South San FranciscoCA
| | | | | | | | - Hui Tian
- NGM Biopharmaceuticals, Inc.South San FranciscoCA
| | - Lei Ling
- NGM Biopharmaceuticals, Inc.South San FranciscoCA
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28
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Zhan L, Pan YZ, Chen L, Zhang H, Zhang H, Song J, Tzeng CM, Sun CY. Prevalence of ABCB4 polymorphisms in gallstone disease in han-Chinese population. Am J Transl Res 2016; 8:1218-1227. [PMID: 27158408 PMCID: PMC4846965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 02/05/2016] [Indexed: 06/05/2023]
Abstract
ATP Binding Cassette Transporter A4 (ABCB4) is a sterol export pump that regulates excretion of biliary cholesterol. We tested association between ABCB4 polymorphisms and gallstone disease using meta-analysis. In a cross-sectional study, 296 subjects were recruited from a hospital-based population. Total of 171 subjects were diagnosed as gallstone disease by abdominal ultrasonography from three cohort studies. We evaluated prevalence of ABCG8 rs11887534 (D19H) as a positive control, and the ABCB4 rs1202283 and rs2230028 polymorphisms on Chinese population were screened by meta-analysis and genotyped using TaqMan® SNP assay. Stata/SE 11.0 software and random-effects model were used in meta-analyzing 3 cohort between study heterogeneity. Four studies including three cohorts were used for final meta-analysis. In allelic model, minor alleles of ABCB4 rs1202283 (OR = 0.41, 95% CI: 0.25-0.67, P<0.001) and of ABCB4 rs2230028 (OR = 0.12, 95% CI: 0.06-0.22, P = 0.001) were associated with an increased risk for gallstone disease in Europeans. Funnel plot and Egger's test suggested absence of publication bias. Concentration of total cholesterol, low-density lipoprotein cholesterol (LDLC) (P = 0.015) and high-density lipoprotein cholesterol (HDLC) (P = 0.028) were significantly higher in subjects with gallstones disease than controls. ABCB4 rs1202283 (heterozygote AG) (P<0.0001), rs2230028 (heterozygote CT) (P = 0.023) and ABCG8 rs11887534 (heterozygote CG) (P = 0.006) were significantly associated with gallstone disease in Chinese population. Genetic risk associated with ABCB4 rs2230028 (homozygote GG) polymorphism was dominated in asymptomatic gallstone disease (95% C.I.: 0.219-0.768; P = 0.005). In conclusion, carriers of ABCB4 rs1202283, rs2230028 are at an increased risk for gallstone disease, while ABCB4 rs2230028 is associated with asymptomatic gallstone disease.
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Affiliation(s)
- Lei Zhan
- Department of Biliary-Hepatic Surgery, The Affiliated Hospital of Guizhou Medical UniversityGuiyang, Guizhou, China
| | - Yao-Zhen Pan
- Department of Biliary-Hepatic Surgery, The Affiliated Hospital of Guizhou Medical UniversityGuiyang, Guizhou, China
| | - Ling Chen
- Department of Biliary-Hepatic Surgery, The Affiliated Hospital of Guizhou Medical UniversityGuiyang, Guizhou, China
| | - Hao Zhang
- Department of Biliary-Hepatic Surgery, The Affiliated Hospital of Guizhou Medical UniversityGuiyang, Guizhou, China
| | - Hong Zhang
- Department of Biliary-Hepatic Surgery, The Affiliated Hospital of Guizhou Medical UniversityGuiyang, Guizhou, China
| | - Jian Song
- Department of Biliary-Hepatic Surgery, The Affiliated Hospital of Guizhou Medical UniversityGuiyang, Guizhou, China
| | - Chi-Meng Tzeng
- Translational Medicine Research Center, School of Pharmaceutical Sciences, Xiamen UniversityXiamen, Fujian, China
| | - Cheng-Yi Sun
- Department of Biliary-Hepatic Surgery, The Affiliated Hospital of Guizhou Medical UniversityGuiyang, Guizhou, China
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Abstract
Intrahepatic cholestasis of pregnancy (ICP) is characterized by maternal pruritus, and elevated serum transaminases and bile acids. Genetic defects in at least 6 canalicular transporters have been found. Association studies stress the variability of genotypes, different penetrance, and influence of environmental factors. Serum autotaxin is a sensitive, specific, and robust diagnostic marker. Elevated maternal bile acids correlate with fetal complications. Long-term sequelae for mothers include the gallstone risk and chronic liver disease. There is an association between ICP and hepatitis C. Current treatment is ursodeoxycholic acid, owing to benefits on pruritus, liver function, safety, and decreased rates of adverse effects.
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Affiliation(s)
- Annarosa Floreani
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Via Giustiniani, 2, Padova 35128, Italy.
| | - Maria Teresa Gervasi
- Department of Obstetrics and Gynecology, Azienda Ospedaliera, Via Giustiniani, 2, Padova 35128, Italy
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Yang XF, Liu GS, Li MX. Analysis of mutations of MDR3 exons 9 and 23 in infants with parenteral nutrition-associated cholestasis. Exp Ther Med 2015; 10:2361-2365. [PMID: 26668642 DOI: 10.3892/etm.2015.2800] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Accepted: 01/08/2015] [Indexed: 02/07/2023] Open
Abstract
The aim of this study was to investigate mutations of multidrug resistance 3 (MDR3) exons 9 and 23 in infants with parenteral nutrition-associated cholestasis (PNAC). A total of 41 infants with PNAC were enrolled in the study. Genomic DNA was extracted from the peripheral venous blood leukocytes of each patient and MDR3 exons 9 and 23 were amplified by polymerase chain reaction. One patient was identified who carried a frameshift mutation in MDR3 exon 23 (C.2793) that was caused by the insertion of a single adenine residue, while mutations were not found in MDR3 exon 23 in the other 40 patients. The clinical features of the patient with the MDR3 exon 23 frameshift mutation included high serum γ-glutamyl transferase levels, the absence of biliary dilatation and deformity in magnetic resonance cholangiopancreatography, and abnormal electrical capacitance tomography imaging of the liver. No mutations in MDR3 exon 9 were identified in any of the patients. All 41 PNAC patients recovered following oral ursodeoxycholic acid treatment. The C.2793 frameshift mutation in MDR3 exon 23 is potentially associated with the development of PNAC in infants.
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Affiliation(s)
- Xiu-Fang Yang
- Department of Neonatology, Zhongshan People's Hospital Affiliated to Sun Yat-sen University, Zhongshan, Guangdong 528403, P.R. China
| | - Guo-Sheng Liu
- Department of Neonatology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China
| | - Min-Xu Li
- Dongguan Maternal and Child Health Center, Dongguan, Guangdong 523000, P.R. China
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31
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Abu-Hayyeh S, Williamson C. Estradiol, farnesoid X receptor, and altered metabolism in pregnancy. Hepatology 2014; 60:1815-7. [PMID: 24975680 DOI: 10.1002/hep.27280] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Accepted: 06/24/2014] [Indexed: 12/19/2022]
Affiliation(s)
- Shadi Abu-Hayyeh
- Women's Health Academic Centre, Kings College London, Guy's Campus, London, UK
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32
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Yang XF, Liu GS, Yi B. Correlation between mutation of MDR3 gene exon 6 and parenteral nutrition-associated cholestasis of preterm infants. Exp Ther Med 2014; 8:1655-1659. [PMID: 25289076 PMCID: PMC4186371 DOI: 10.3892/etm.2014.1980] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Accepted: 08/21/2014] [Indexed: 01/12/2023] Open
Abstract
The aim of this study was to investigate the association between the mutation of multidrug resistance 3 (MDR3) exon 6 and parenteral nutrition-associated cholestasis (PNAC) in preterm infants. A total of 41 preterm infants with PNAC formed the experimental group, and 56 preterm infants receiving total parenteral nutrition (TPN) for >14 days but without cholestasis formed the control group. Genomic DNA was extracted from peripheral venous blood leukocytes. Polymerase chain reaction was used to amplify exon 6 of the MDR3 gene. The target band of MDR3 gene exon 6 was identified in all blood samples from all cases. We identified five cases with C. 504 C>T heterozygous mutations of exon 6 of the MDR3 gene and 14 cases with C. 504 C>T homozygous mutations in the experimental group. In the control group, we identified seven cases with the C. 504 C>T homozygous mutation and six cases with the C. 504 C>T heterozygous mutation. The distribution of the T/C allele frequency of C. 504 in exon 6 of the MDR3 gene between the experimental group and control group was statistically significant (P<0.05). Further analysis revealed the odds ratio of the T/C allele frequency of the C. 504 mutation in exon 6 of the MDR3 gene between the experimental group and control group to be 0.316. Point mutation C. 485 T>A was detected in one case in the experimental group. The C. 504 C>T and C. 485 T>A MDR3 mutations in exon 6 are possibly responsible for the development of PNAC in infants. C. 504 C>T may not be the only risk factor of neonatal PNAC. In order to further confirm the association between exon 6 of the MDR3 gene and PNAC, a large-sample multicenter study should be carried out.
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Affiliation(s)
- Xiu Fang Yang
- Department of Neonatology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China ; Department of Neonatology, Zhongshan People's Hospital Affiliated to Sun Yat-sen University, Zhongshan, Guangdong 528403, P.R. China
| | - Guo Sheng Liu
- Department of Neonatology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China
| | - Bing Yi
- Zhongshan Cancer Institute, Zhongshan People's Hospital Affiliated to Sun Yat-sen University, Zhongshan, Guangdong 528403, P.R. China
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Cuperus FJC, Claudel T, Gautherot J, Halilbasic E, Trauner M. The role of canalicular ABC transporters in cholestasis. Drug Metab Dispos 2014; 42:546-60. [PMID: 24474736 DOI: 10.1124/dmd.113.056358] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Cholestasis, a hallmark feature of hepatobiliary disease, is characterized by the retention of biliary constituents. Some of these constituents, such as bile acids, inflict damage to hepatocytes and bile duct cells. This damage may lead to inflammation, fibrosis, cirrhosis, and eventually carcinogenesis, sequelae that aggravate the underlying disease and deteriorate clinical outcome. Canalicular ATP-binding cassette (ABC) transporters, which mediate the excretion of individual bile constituents, play a key role in bile formation and cholestasis. The study of these transporters and their regulatory nuclear receptors has revolutionized our understanding of cholestatic disease. This knowledge has served as a template to develop novel treatment strategies, some of which are currently already undergoing phase III clinical trials. In this review we aim to provide an overview of the structure, function, and regulation of canalicular ABC transporters. In addition, we will focus on the role of these transporters in the pathogenesis and treatment of cholestatic bile duct and liver diseases.
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Affiliation(s)
- Frans J C Cuperus
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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Condat B, Zanditenas D, Barbu V, Hauuy MP, Parfait B, El Naggar A, Collot V, Bonnet J, Ngo Y, Maftouh A, Dugué L, Balian C, Charlier A, Blazquez M, Rosmorduc O. Prevalence of low phospholipid-associated cholelithiasis in young female patients. Dig Liver Dis 2013; 45:915-9. [PMID: 23684896 DOI: 10.1016/j.dld.2013.04.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2012] [Revised: 03/07/2013] [Accepted: 04/03/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS We evaluated the prevalence of low phospholipid-associated cholelithiasis, a specific form of cholelithiasis associated with at least 2 of the 3 following criteria: first symptoms before the age of 40; intrahepatic comet tail artefacts, sludge or microlithiasis on ultrasound imaging; and recurrence of symptoms after cholecystectomy. METHODS We prospectively studied the cases of 60 consecutive female patients under 30 with symptomatic cholelithiasis. RESULTS A diagnosis of low phospholipid-associated cholelithiasis was made in 14/60 patients (23%). The molecular analysis showed ABCB4 (n=4) and ABCB11 (n=4) gene mutations. Low phospholipid-associated cholelithiasis was frequently observed in non-overweight patients [13/27 (48%)], was present in most patients whose biliary symptoms occurred before the age of 18 [7/10 (70%)] and was often associated with cholangitis or acute pancreatitis [9/14 (64%), p<0.05] while "common" cholelithiasis was mainly associated with cholecystitis [16/46 (35%), p<0.05]. CONCLUSION Nearly one quarter of the female patients under the age of 30 admitted for symptomatic cholelithiasis had low phospholipid-associated cholelithiasis; particularly if body weight was normal, the symptoms began before the age of 18 or in the presence of severe biliary complications.
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Affiliation(s)
- Bertrand Condat
- Services d'hépato-gastro-entérologie, de radiologie et de chirurgie viscérale, Hôpital Saint-Camille, Bry-sur-Marne, France.
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Clinical utility gene card for: progressive familial intrahepatic cholestasis type 3. Eur J Hum Genet 2013; 22:ejhg2013188. [PMID: 24002166 DOI: 10.1038/ejhg.2013.188] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
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Poupon R, Rosmorduc O, Boëlle PY, Chrétien Y, Corpechot C, Chazouillères O, Housset C, Barbu V. Genotype-phenotype relationships in the low-phospholipid-associated cholelithiasis syndrome: a study of 156 consecutive patients. Hepatology 2013; 58:1105-10. [PMID: 23533021 DOI: 10.1002/hep.26424] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Accepted: 03/21/2013] [Indexed: 12/26/2022]
Abstract
UNLABELLED The low-phospholipid-associated cholelithiasis syndrome (LPAC; OMIM 171060) is a peculiar form of intrahepatic cholelithiasis occurring in young adults, associated with ABCB4/MDR3 gene sequence variations. Our aim was to determine the genotype-phenotype relationships in 156 consecutive patients with the criteria of LPAC syndrome. A variant was detected in 79 (61 missense and 18 truncating sequence variants), 63 being monoallelic. The clinical features (age at onset, high prevalence in women, frequency and severity of acute and chronic complications, intrahepatic cholestasis of pregnancy [ICP]) were similar in the patients with or without ABCB4 gene sequence variation. Truncating variations were associated with an earlier onset of symptoms both in women and men. Acute and chronic biliary complications were variant-independent. Half of the women who had pregnancy developed ICP. The frequency of ICP and fetal complications were similar in patients with missense and truncating variants. CONCLUSION The LPAC syndrome is more frequent in women and highly associated with ICP. Half of the patients harbored missense or truncating variants of the ABCB4 gene. The characteristics of the patients without detectable variant are similar to those with variant, indicating that yet unexplored regions of the ABCB4 and other genes may be involved.
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Affiliation(s)
- Raoul Poupon
- UPMC Univ Paris 06, INSERM, UMR_S 938, Paris, France; INSERM, U938, Centre de Recherche Saint-Antoine, Paris, France.
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Abstract
Cholestasis is an overarching term applied for conditions whereby biliary constituents are found in the circulation because of impairment to bile flow. A variety of processes can lead to cholestasis, be they acute or chronic injuries to hepatocytes, cholangiocytes, or the broader biliary tree itself. Such injuries may be driven by rare but highly informative primary genetic abnormalities, or may be seen in individuals with a prior genetic predisposition when confronted by specific environmental challenges such as drug exposure. This review provides a broad outline of some fundamental primary genetic cholestatic syndromes and an update on varying genetic predisposition underlying several acquired cholestatic processes.
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