1
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Cadnapaphornchai MA, Dell KM, Gimpel C, Guay-Woodford LM, Gulati A, Hartung EA, Liebau MC, Mallett AJ, Marlais M, Mekahli D, Piccirilli A, Seeman T, Tindal K, Winyard PJD. Polycystic Kidney Disease in Children: The Current Status and the Next Horizon. Am J Kidney Dis 2025:S0272-6386(25)00772-3. [PMID: 40113156 DOI: 10.1053/j.ajkd.2025.01.022] [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: 09/28/2024] [Revised: 01/17/2025] [Accepted: 01/24/2025] [Indexed: 03/22/2025]
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are inherited disorders that share many features such as kidney cysts, hypertension, urinary concentrating defects, and progressive chronic kidney disease. Underlying pathogenic mechanisms for both include cilia dysfunction and dysregulated intracellular signaling. ADPKD has been traditionally regarded as an adult-onset disease, whereas ARPKD has been classically described as an infantile or childhood condition. However, clinicians must recognize that both disorders can present across all age groups ranging from fetal life and infancy to childhood and adolescence, as well as adulthood. Here we highlight the points of overlap and distinct features for these disorders with respect to pathogenesis, diagnostic modalities (radiological and genetic), clinical assessment, and early therapeutic management. In particular, we consider key issues at two critical points for transition of care, i.e., fetal life to infancy and adolescence to adulthood. These timepoints are poorly covered in the extant literature. Therefore, we recommend guiding principles for transitions of clinical care at these critical junctures in the lifespan. While there is no cure for polycystic kidney disease (PKD), recent insights into pathogenic mechanisms have identified promising therapeutic targets that are currently being evaluated in a growing portfolio of clinical trials. We summarize the key findings from these largely adult-based trials and discuss the implications for designing child-focused studies. Finally, we look forward to the next horizon for childhood PKD, highlighting gaps in our current knowledge, and discussing future directions and strategies to attenuate the full burden of disease for children affected with PKD.
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Affiliation(s)
| | - Katherine M Dell
- Cleveland Clinic Children's Institute and Case Western Reserve University, Cleveland, USA
| | | | - Lisa M Guay-Woodford
- Children's Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, USA.
| | - Ashima Gulati
- Children's National Hospital and the George Washington University, Washington, DC, USA
| | - Erum A Hartung
- Children's Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, USA
| | - Max C Liebau
- University Hospital Cologne and the University of Cologne, Cologne, Germany
| | - Andrew J Mallett
- Townsville University Hospital and James Cook University , Queensland, Australia
| | - Matko Marlais
- Great Ormond Street Hospital for Children and UCL Great Ormond Street Institute of Child Health, London, UK
| | - Djalila Mekahli
- KU Leuven University and UZ Leuven Hospital, Leuven, Belgium
| | | | - Tomas Seeman
- Charles University and Ostrava University, Prague and Ostrava, Czech Republic
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2
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Tidwell J, Wu GY. Heritable Chronic Cholestatic Liver Diseases: A Review. J Clin Transl Hepatol 2024; 12:726-738. [PMID: 39130622 PMCID: PMC11310751 DOI: 10.14218/jcth.2024.00119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 05/14/2024] [Accepted: 05/28/2024] [Indexed: 08/13/2024] Open
Abstract
Chronic cholestasis due to heritable causes is usually diagnosed in childhood. However, many cases can present and survive into adulthood. The time course varies considerably depending on the underlying etiology. Laboratory data usually reveal elevated conjugated hyperbilirubinemia, alkaline phosphatase, and gamma-glutamyl transpeptidase. Patients may be asymptomatic; however, when present, the typical symptoms are pruritus, jaundice, fatigue, and alcoholic stools. The diagnostic methods and management required depend on the underlying etiology. The development of genome-wide associated studies has allowed the identification of specific genetic mutations related to the pathophysiology of cholestatic liver diseases. The aim of this review was to highlight the genetics, clinical pathophysiology, presentation, diagnosis, and treatment of heritable etiologies of chronic cholestatic liver disease.
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Affiliation(s)
- Jasmine Tidwell
- Department of Medicine, University of Connecticut Health Center, Farmington, CT, USA
| | - George Y. Wu
- Department of Medicine, University of Connecticut Health Center, Farmington, CT, USA
- Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
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3
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Zhao J, Yue P, Mi N, Li M, Fu W, Zhang X, Gao L, Bai M, Tian L, Jiang N, Lu Y, Ma H, Dong C, Zhang Y, Zhang H, Zhang J, Ren Y, Suzuki A, Wong PF, Tanaka K, Rerknimitr R, Junger HH, Cheung TT, Melloul E, Demartines N, Leung JW, Yao J, Yuan J, Lin Y, Schlitt HJ, Meng W. Biliary fibrosis is an important but neglected pathological feature in hepatobiliary disorders: from molecular mechanisms to clinical implications. MEDICAL REVIEW (2021) 2024; 4:326-365. [PMID: 39135601 PMCID: PMC11317084 DOI: 10.1515/mr-2024-0029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 06/06/2024] [Indexed: 08/15/2024]
Abstract
Fibrosis resulting from pathological repair secondary to recurrent or persistent tissue damage often leads to organ failure and mortality. Biliary fibrosis is a crucial but easily neglected pathological feature in hepatobiliary disorders, which may promote the development and progression of benign and malignant biliary diseases through pathological healing mechanisms secondary to biliary tract injuries. Elucidating the etiology and pathogenesis of biliary fibrosis is beneficial to the prevention and treatment of biliary diseases. In this review, we emphasized the importance of biliary fibrosis in cholangiopathies and summarized the clinical manifestations, epidemiology, and aberrant cellular composition involving the biliary ductules, cholangiocytes, immune system, fibroblasts, and the microbiome. We also focused on pivotal signaling pathways and offered insights into ongoing clinical trials and proposing a strategic approach for managing biliary fibrosis-related cholangiopathies. This review will offer a comprehensive perspective on biliary fibrosis and provide an important reference for future mechanism research and innovative therapy to prevent or reverse fibrosis.
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Affiliation(s)
- Jinyu Zhao
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Ping Yue
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Ningning Mi
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Matu Li
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Wenkang Fu
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Xianzhuo Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Long Gao
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Mingzhen Bai
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Liang Tian
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Ningzu Jiang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yawen Lu
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Haidong Ma
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Chunlu Dong
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yong Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Hengwei Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Jinduo Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yanxian Ren
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Azumi Suzuki
- Department of Gastroenterology, Hamamatsu Medical Center, Hamamatsu, Japan
| | - Peng F. Wong
- Department of Vascular Surgery, The James Cook University Hospital, Middlesbrough, UK
| | - Kiyohito Tanaka
- Department of Gastroenterology, Kyoto Second Red Cross Hospital, Kyoto, Japan
| | - Rungsun Rerknimitr
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn, Bangkok, Thailand
- Excellence Center for Gastrointestinal Endoscopy, King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Henrik H. Junger
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Tan T. Cheung
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Emmanuel Melloul
- Department of Visceral Surgery, Lausanne University Hospital CHUV, University of Lausanne (UNIL), Lausanne, Switzerland
| | - Nicolas Demartines
- Department of Visceral Surgery, Lausanne University Hospital CHUV, University of Lausanne (UNIL), Lausanne, Switzerland
| | - Joseph W. Leung
- Division of Gastroenterology and Hepatology, UC Davis Medical Center and Sacramento VA Medical Center, Sacramento, CA, USA
| | - Jia Yao
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China
| | - Jinqiu Yuan
- Clinical Research Center, Big Data Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Yanyan Lin
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Hans J. Schlitt
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Wenbo Meng
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
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4
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Ravindranath A, Yachha SK. An Approach to Investigations of Chronic Liver Disease. Indian J Pediatr 2024; 91:262-269. [PMID: 37702974 DOI: 10.1007/s12098-023-04751-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Accepted: 06/23/2023] [Indexed: 09/14/2023]
Abstract
Chronic liver disease (CLD) in children is more diverse compared to adults with respect to the etiology, progression and response to therapy. After history and clinical examination, the first step is to confirm the presence of CLD with basic blood investigations and ultrasonography. Markers of portal hypertension are splenomegaly, increased portal vein diameter, thrombocytopenia and presence of varices on endoscopy. The next step is to evaluate the etiology of CLD which will depend on the age of the child and needs targeted investigations as metabolic and inherited causes predominate in early childhood. CLD progression ought to be monitored regularly and several non-invasive markers are available but they have to be evaluated further in children. Since CLD progresses, complications have to be detected early not only to initiate appropriate treatment but also to prognosticate.
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Affiliation(s)
- Aathira Ravindranath
- Department of Pediatric Gastroenterology, Institute of Gastrointestinal Sciences, Apollo BGS Hospitals, Kuvempunagar, Mysore, Karnataka, 570023, India
| | - Surender Kumar Yachha
- Department of Pediatric Gastroenterology, Hepatology and Liver Transplantation, Sakra World Hospital, Bengaluru, Karnataka, 560103, India.
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5
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Zhou T, Liu K, Wei H, Zhong Q, Luo D, Yang W, Zhang P, Xiao Y. Histopathology and molecular pathology confirmed a diagnosis of atypical Caroli's syndrome: a case report. Diagn Pathol 2024; 19:36. [PMID: 38388441 PMCID: PMC10882844 DOI: 10.1186/s13000-024-01462-9] [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: 03/07/2023] [Accepted: 02/07/2024] [Indexed: 02/24/2024] Open
Abstract
Caroli's syndrome is a congenital disease characterized by dilation of intrahepatic bile ducts and congenital hepatic fibrosis. It is a rare condition in clinical work. Typically, the diagnosis of this disease is confirmed through medical imaging. Here, we report a case of atypical Caroli's syndrome in a patient who presented with recurrent upper gastrointestinal tract bleeding. The patient underwent imaging examinations, liver biopsy and whole exome sequencing. The results of the imaging examination were non-specific. However, with the aid of pathological examination, the patient was diagnosed with Caroli's syndrome. In conclusion, for cases where the imaging presentation of Caroli's syndrome is inconclusive, an accurate diagnosis should rely on pathology. By discussing this specific case, our aim is to enhance readers' understanding of this disease, provide valuable information that can aid in the early detection and appropriate management of Caroli's syndrome, ultimately improving patient outcomes.
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Affiliation(s)
- Tianmin Zhou
- Department of Pathology, Infectious Diseases Hospital of Nanchang University, Nanchang, 330001, Jiangxi, China
| | - Keyu Liu
- Queen Mary School, Nanchang University, Nanchang, 330006, China
| | - Hao Wei
- The First Clinical Department, Nanchang University, Nanchang, 330006, China
| | - Qingmei Zhong
- Department of Pathology, Infectious Diseases Hospital of Nanchang University, Nanchang, 330001, Jiangxi, China
| | - Daya Luo
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University, Nanchang, 330006, China
| | - Wenjuan Yang
- Infectious Diseases Hospital of Nanchang University, Nanchang, 330001, Jiangxi, China
| | - Ping Zhang
- Department of Pathology, Infectious Diseases Hospital of Nanchang University, Nanchang, 330001, Jiangxi, China
| | - Yingqun Xiao
- Department of Pathology, Infectious Diseases Hospital of Nanchang University, Nanchang, 330001, Jiangxi, China.
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6
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Cabel T, Pascu CM, Ghenea CS, Dumbrava BF, Gunsahin D, Andrunache A, Negoita LM, Panaitescu A, Rinja EM, Pavel C, Plotogea OM, Stan-Ilie M, Sandru V, Mihaila M. Exceptional Liver Transplant Indications: Unveiling the Uncommon Landscape. Diagnostics (Basel) 2024; 14:226. [PMID: 38275473 PMCID: PMC10813978 DOI: 10.3390/diagnostics14020226] [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: 12/06/2023] [Revised: 01/14/2024] [Accepted: 01/18/2024] [Indexed: 01/27/2024] Open
Abstract
Liver transplantation represents the definitive intervention for various etiologies of liver failure and encompasses a spectrum of rare indications crucial to understanding the diverse landscape of end-stage liver disease, with significantly improved survival rates over the past three decades. Apart from commonly encountered liver transplant indications such as decompensated cirrhosis and liver cancer, several rare diseases can lead to transplantation. Recognition of these rare indications is essential, providing a lifeline to individuals facing complex liver disorders where conventional treatments fail. Collaborative efforts among healthcare experts lead not only to timely interventions but also to the continuous refinement of transplant protocols. This continued evolution in transplant medicine promises hope for those facing diverse and rare liver diseases, marking a paradigm shift in the landscape of liver disease management.
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Affiliation(s)
- Teodor Cabel
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania; (T.C.); (D.G.); (L.-M.N.); (E.M.R.)
| | - Cristina Madalina Pascu
- Department of Internal Medicine, Fundeni Clinical Institute, 022328 Bucharest, Romania (M.M.)
| | - Catalin Stefan Ghenea
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania; (T.C.); (D.G.); (L.-M.N.); (E.M.R.)
| | - Bogdan Florin Dumbrava
- Department of Gastroenterology, “Sf. Ioan” Emergency Hospital, 014461 Bucharest, Romania
| | - Deniz Gunsahin
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania; (T.C.); (D.G.); (L.-M.N.); (E.M.R.)
| | - Andreea Andrunache
- Department of Internal Medicine, Fundeni Clinical Institute, 022328 Bucharest, Romania (M.M.)
| | - Livia-Marieta Negoita
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania; (T.C.); (D.G.); (L.-M.N.); (E.M.R.)
| | - Afrodita Panaitescu
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania; (T.C.); (D.G.); (L.-M.N.); (E.M.R.)
| | - Ecaterina Mihaela Rinja
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania; (T.C.); (D.G.); (L.-M.N.); (E.M.R.)
| | - Christopher Pavel
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania; (T.C.); (D.G.); (L.-M.N.); (E.M.R.)
- Department 5, “Carol Davila” University of Medicine and Pharmacy, 050447 Bucharest, Romania
| | - Oana-Mihaela Plotogea
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania; (T.C.); (D.G.); (L.-M.N.); (E.M.R.)
- Department 5, “Carol Davila” University of Medicine and Pharmacy, 050447 Bucharest, Romania
| | - Madalina Stan-Ilie
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania; (T.C.); (D.G.); (L.-M.N.); (E.M.R.)
- Department 5, “Carol Davila” University of Medicine and Pharmacy, 050447 Bucharest, Romania
| | - Vasile Sandru
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania; (T.C.); (D.G.); (L.-M.N.); (E.M.R.)
- Department 5, “Carol Davila” University of Medicine and Pharmacy, 050447 Bucharest, Romania
| | - Mariana Mihaila
- Department of Internal Medicine, Fundeni Clinical Institute, 022328 Bucharest, Romania (M.M.)
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Sun J, Mi X, Ye X, ShenTu Y, Liu C, Tang D, Yang W, Yang J, Ye X, Ma X, Shi J, Chen G, Gong L. Biliary sepsis complication with congenital hepatic fibrosis: an unexpected outcome. BMC Infect Dis 2023; 23:715. [PMID: 37872485 PMCID: PMC10591346 DOI: 10.1186/s12879-023-08681-3] [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: 05/30/2023] [Accepted: 10/07/2023] [Indexed: 10/25/2023] Open
Abstract
BACKGROUND CHF (Congenital hepatic fibrosis) is a rare hereditary disease characterized by periportal fibrosis and ductal plate malformation. Little is known about the clinical presentations and outcome in CHF patients with an extraordinary complication with biliary sepsis. Our case described a 23-year-old female diagnosed as CHF combined with biliary sepsis. Her blood culture was positive for KP (Klebsiella pneumoniae), and with a high level of CA19-9 (> 1200.00 U/ml, ref: <37.00 U/ml). Meanwhile, her imaging examinations showed intrahepatic bile duct dilatation, portal hypertension, splenomegaly, and renal cysts. Liver pathology revealed periportal fibrosis and irregularly shaped proliferating bile ducts. Whole-exome sequencing identified two heterozygous missense variants c.3860T > G (p. V1287G) and c.9059T > C (p. L3020P) in PKHD1 gene. After biliary sepsis relieved, her liver function test was normal, and imaging examination results showed no significant difference with the results harvested during her biliary sepsis occurred. CONCLUSION The diagnosis of CHF complicated with biliary sepsis in the patient was made. Severely biliary sepsis due to KP infection may not inevitably aggravate congential liver abnormality in young patients. Our case provides a good reference for timely treatment of CHF patients with biliary sepsis.
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Affiliation(s)
- Jiawei Sun
- Hangzhou Normal University, Zhejiang, China
| | - Xiaoxiao Mi
- Institute of Translational Medicine, The Affiliated Hospital of Hangzhou Normal University, Zhejiang, China
| | | | - Yiling ShenTu
- Department of Respiratory Medicine, Fuyang First People's Hospital, Hangzhou, China
| | - Chun Liu
- Hangzhou Normal University, Zhejiang, China
| | - Dong Tang
- Department of Medical Imaging (Radiology), The Affiliated Hospital of Hangzhou Normal University, Zhejiang, China
| | - WenJun Yang
- Department of Pathology, The Affiliated Hospital of Hangzhou Normal University, Zhejiang, China
| | - Jie Yang
- Department of Infectious Disease (Liver Diseases), Lishui Municipal Central Hospital, Zhejiang, China
| | - Xiaoping Ye
- Department of Infectious Disease (Liver Diseases), The Affiliated Hospital of Hangzhou Normal University, Zhejiang, 310015, China
| | - Xiaojie Ma
- Department of Infectious Disease (Liver Diseases), The Affiliated Hospital of Hangzhou Normal University, Zhejiang, 310015, China
| | - Junping Shi
- Department of Infectious Disease (Liver Diseases), The Affiliated Hospital of Hangzhou Normal University, Zhejiang, 310015, China
| | - Gongying Chen
- Department of Infectious Disease (Liver Diseases), The Affiliated Hospital of Hangzhou Normal University, Zhejiang, 310015, China
| | - Ling Gong
- Department of Infectious Disease (Liver Diseases), The Affiliated Hospital of Hangzhou Normal University, Zhejiang, 310015, China.
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Drenth J, Barten T, Hartog H, Nevens F, Taubert R, Torra Balcells R, Vilgrain V, Böttler T. EASL Clinical Practice Guidelines on the management of cystic liver diseases. J Hepatol 2022; 77:1083-1108. [PMID: 35728731 DOI: 10.1016/j.jhep.2022.06.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 06/01/2022] [Indexed: 02/07/2023]
Abstract
The advent of enhanced radiological imaging techniques has facilitated the diagnosis of cystic liver lesions. Concomitantly, the evidence base supporting the management of these diseases has matured over the last decades. As a result, comprehensive clinical guidance on the subject matter is warranted. These Clinical Practice Guidelines cover the diagnosis and management of hepatic cysts, mucinous cystic neoplasms of the liver, biliary hamartomas, polycystic liver disease, Caroli disease, Caroli syndrome, biliary hamartomas and peribiliary cysts. On the basis of in-depth review of the relevant literature we provide recommendations to navigate clinical dilemmas followed by supporting text. The recommendations are graded according to the Oxford Centre for Evidence-Based Medicine system and categorised as 'weak' or 'strong'. We aim to provide the best available evidence to aid the clinical decision-making process in the management of patients with cystic liver disease.
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9
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Sharbidre K, Zahid M, Venkatesh SK, Bhati C, Lalwani N. Imaging of fibropolycystic liver disease. Abdom Radiol (NY) 2022; 47:2356-2370. [PMID: 35670875 DOI: 10.1007/s00261-022-03565-7] [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: 03/22/2022] [Revised: 05/14/2022] [Accepted: 05/17/2022] [Indexed: 11/01/2022]
Abstract
Fibropolycystic liver diseases (FLDs) make up a rare spectrum of heritable hepatobiliary diseases resulting from congenital ductal plate malformations (DPMs) due to the dysfunction of proteins expressed on the primary cilia of cholangiocytes. The embryonic development of the ductal plate is key to understanding this spectrum of diseases. In particular, DPMs can result in various degrees of intrahepatic duct involvement and a wide spectrum of cholangiopathies, including congenital hepatic fibrosis, Caroli disease, polycystic liver disease, and Von Meyenberg complexes. The most common clinical manifestations of FLDs are portal hypertension, cholestasis, cholangitis, and (in rare cases) cholangiocarcinoma. This article reviews recent updates in the pathophysiology, imaging, and clinical management of FLDs.
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Affiliation(s)
- Kedar Sharbidre
- Department of Abdominal Imaging, University of Alabama at Birmingham, Birmingham, AB, USA.
| | - Mohd Zahid
- Department of Abdominal Imaging, University of Alabama at Birmingham, Birmingham, AB, USA
| | | | - Chandra Bhati
- Department of Transplant Surgery, University of Maryland Medical Center, Baltimore, ML, USA
| | - Neeraj Lalwani
- Department of Abdominal Imaging, Virginia Commonwealth University, Richmond, VA, USA
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10
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Hepatic manifestations of systemic disease: an imaging-based review. Pediatr Radiol 2022; 52:852-864. [PMID: 34797394 DOI: 10.1007/s00247-021-05222-5] [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: 06/20/2021] [Revised: 08/28/2021] [Accepted: 10/05/2021] [Indexed: 10/19/2022]
Abstract
The liver is responsible for many processes that maintain human metabolic homeostasis and can be affected by several pediatric systemic diseases. In this manuscript, we explore key pathological findings and imaging features across multiple modalities of a spectrum of congenital, metabolic and autoimmune disorders. Strengthening the radiologists' knowledge regarding potential hepatic manifestations of these systemic diseases will ultimately lead to improved care for pediatric patients.
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11
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Gan W, Liao B, Li X. A Rare Cause of Liver Fibrosis in Adulthood. Gastroenterology 2022; 162:e1-e3. [PMID: 34464631 DOI: 10.1053/j.gastro.2021.08.048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 08/24/2021] [Accepted: 08/26/2021] [Indexed: 02/07/2023]
Affiliation(s)
- Weiqiang Gan
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China; Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China
| | - Bing Liao
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Xinhua Li
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China; Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China.
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12
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Cadamuro M, Strazzabosco M. Inflammatory pathways and cholangiocarcinoma risk mechanisms and prevention. Adv Cancer Res 2022; 156:39-73. [PMID: 35961707 PMCID: PMC10916841 DOI: 10.1016/bs.acr.2022.02.001] [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] [Indexed: 11/19/2022]
Abstract
Cholangiocarcinoma (CCA), a neoplasm burdened by a poor prognosis and currently lacking adequate therapeutic treatments, can originate at different levels of the biliary tree, in the intrahepatic, hilar, or extrahepatic area. The main risk factors for the development of CCA are the presence of chronic cholangiopathies of various etiology. To date, the most studied prodromal diseases of CCA are primary sclerosing cholangitis, Caroli's disease and fluke infestations, but other conditions, such as metabolic syndrome, nonalcoholic fatty liver disease and obesity, are emerging as associated with an increased risk of CCA development. In this review, we focused on the analysis of the pro-inflammatory mechanisms that induce the development of CCA and on the role of cells of the immune response in cholangiocarcinogenesis. In very recent times, these cellular mechanisms have been the subject of emerging studies aimed at verifying how the modulation of the inflammatory and immunological responses can have a therapeutic significance and how these can be used as therapeutic targets.
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Affiliation(s)
| | - Mario Strazzabosco
- Liver Center, Department of Internal Medicine, Yale University, New Haven, CT, United States.
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Sergi CM. Vitamin D supplementation for autoimmune hepatitis: A need for further investigation. World J Hepatol 2022; 14:295-299. [PMID: 35126856 PMCID: PMC8790399 DOI: 10.4254/wjh.v14.i1.295] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 10/25/2021] [Accepted: 12/23/2021] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis is a chronic liver disease harboring an autoimmune basis and progressive character. Despite still obscurity in etiology and pathogenesis, some evidence supports the importance of sustaining the immune system. Vitamin D is a lipo-soluble vitamin, which has been identified as decreased in our body. It is often due to the daily habit change and decrease of individual sun exposure due to the increase of the ultraviolet-induced potential melanocytic transformation. Here, we emphasize the importance of vitamin D supplementation in patients affected with liver disease.
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Affiliation(s)
- Consolato M Sergi
- Anatomic Pathology Division, Children’s Hospital of Eastern Ontario (CHEO), University of Ottawa, Ottawa K1H 8L1, ON, Canada
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton T6G 2B7, AB, Canada.
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14
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Sugita K, Onishi S, Muto M, Nishida N, Nagano A, Murakami M, Harumatsu T, Yamada K, Yamada W, Kawano T, Ieiri S. Case report: Severe hepatic fibrosis induced by chronic cholestasis of congenital biliary dilation treated by laparoscopic surgery after immunonutrition support- An infantile case. Front Pediatr 2022; 10:1101000. [PMID: 36714635 PMCID: PMC9878591 DOI: 10.3389/fped.2022.1101000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 12/29/2022] [Indexed: 01/13/2023] Open
Abstract
INTRODUCTION In some patients with congenital biliary dilation (CBD), biliary cirrhosis has been reported to rapidly progress from the neonatal period to the infantile period. We herein report an infantile case of CBD that showed severe biliary cirrhosis at the diagnosis, which was treated by laparoscopic surgery. CASE PRESENTATION A 16-month-old girl underwent conservative therapy for liver dysfunction and cholangitis on a remote island of our prefecture. She was transferred to our hospital after the detection of a huge dilated common bile duct on imaging at the previous hospital. Contrast-enhanced computed tomography showed a dilated common bile duct (maximum diameter: 5 cm), thus suggesting CBD. However, her laboratory data on admission showed a poor nutritional status and severe liver dysfunction (Alb, 2.5 mg/dl; AST, 79 IU/L; ALT, 43 IU/L; γ-GTP, 491 mg/dl; D-bil, 0.3 mg/dl; CHE, 90 IU/L; NH3, 123 μg/dl). We initially performed laparoscopic exploration and bile drainage via the gallbladder, noting severe hepatic fibrosis resembling end-stage liver cirrhosis. After placing a drainage tube in the gallbladder, cholangiography was performed. Cholangiography showed Todani type IVa CBD with pancreaticobiliary maljunction. Contrast agent flowing into the duodenum could not be confirmed. The patient received liver-supporting therapy and nutritional support for 7 weeks before definitive surgery. Following the improvement of the hepatic synthetic capacity (Alb, 4.0 mg/dl; AST, 82 IU/L; ALT, 78 IU/L; γ-GTP, 157 mg/dl; D-bil, 0.2 mg/dl; CHE, 232 IU/L; NH3, 75 μg/dl), we performed extrahepatic bile duct excision and hepaticojejunostomy laparoscopically. Laparoscopic surgery was successfully performed along with liver biopsy. Histopathologically, the liver specimen showed chronic hepatitis and fibrosis (F3A2). Biliary scintigraphy showed good bile excretion at postoperative day 15. The postoperative course uneventful, and the patient was discharged on the 23rd day after surgery. A needle liver biopsy six months later showed mild improvement of chronic hepatitis and fibrosis (F2-3A1). The patient was regularly followed at the outpatient clinic. CONCLUSIONS Severe liver fibrosis was suspected to be continuous cholestasis of CBD after birth. CBD with severe liver fibrosis may avoid liver transplantation by two-stage surgery with hepatoprotection therapy and immunonutritional support.
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Affiliation(s)
- Koshiro Sugita
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
| | - Shun Onishi
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
| | - Mitsuru Muto
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
| | - Nanako Nishida
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
| | - Ayaka Nagano
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
| | - Masakazu Murakami
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
| | - Toshio Harumatsu
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
| | - Koji Yamada
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
| | - Waka Yamada
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
| | - Takafumi Kawano
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
| | - Satoshi Ieiri
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
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15
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Chen C, Wu H, Ye H, Tortajada A, Rodríguez-Perales S, Torres-Ruiz R, Vidal A, Peligros MI, Reissing J, Bruns T, Mohamed MR, Zheng K, Lujambio A, Iraburu MJ, Colyn L, Latasa MU, Arechederra M, Fernández-Barrena MG, Berasain C, Vaquero J, Bañares R, Nelson LJ, Trautwein C, Davis RJ, Martinez-Naves E, Nevzorova YA, Villanueva A, Avila MA, Cubero FJ. Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease. Cancers (Basel) 2021; 14:78. [PMID: 35008241 PMCID: PMC8750579 DOI: 10.3390/cancers14010078] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 12/18/2021] [Accepted: 12/21/2021] [Indexed: 12/19/2022] Open
Abstract
Fibropolycystic liver disease is characterized by hyperproliferation of the biliary epithelium and the formation of multiple dilated cysts, a process associated with unfolded protein response (UPR). In the present study, we aimed to understand the mechanisms of cyst formation and UPR activation in hepatocytic c-Jun N-terminal kinase 1/2 (Jnk1/2) knockout mice. Floxed JNK1/2 (Jnkf/f) and Jnk∆hepa animals were sacrificed at different time points during progression of liver disease. Histological examination of specimens evidenced the presence of collagen fiber deposition, increased α-smooth muscle actin (αSMA), infiltration of CD45, CD11b and F4/80 cells and proinflammatory cytokines (Tnf, Tgfβ1) and liver injury (e.g., ALT, apoptosis and Ki67-positive cells) in Jnk∆hepa compared with Jnkf/f livers from 32 weeks of age. This was associated with activation of effectors of the UPR, including BiP/GRP78, CHOP and spliced XBP1. Tunicamycin (TM) challenge strongly induced ER stress and fibrosis in Jnk∆hepa animals compared with Jnkf/f littermates. Finally, thioacetamide (TAA) administration to Jnk∆hepa mice induced UPR activation, peribiliary fibrosis, liver injury and markers of biliary proliferation and cholangiocarcinoma (CCA). Orthoallografts of DEN/CCl4-treated Jnk∆hepa liver tissue triggered malignant CCA. Altogether, these results suggest that activation of the UPR in conjunction with fibrogenesis might trigger hepatic cystogenesis and early stages of CCA.
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Affiliation(s)
- Chaobo Chen
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, Spain; (C.C.); (H.W.); (H.Y.); (A.T.); (K.Z.); (E.M.-N.); (Y.A.N.)
- 12 de Octubre Health Research Institute (imas12), 28041 Madrid, Spain
- Department of General Surgery, Wuxi Branch of Zhongda Hospital, Southeast University, Wuxi 214105, China
- Department of Hepatic-Biliary-Pancreatic Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
| | - Hanghang Wu
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, Spain; (C.C.); (H.W.); (H.Y.); (A.T.); (K.Z.); (E.M.-N.); (Y.A.N.)
| | - Hui Ye
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, Spain; (C.C.); (H.W.); (H.Y.); (A.T.); (K.Z.); (E.M.-N.); (Y.A.N.)
- Department of Anesthesia, Zhongda Hospital, Southeast University, Nanjing 210008, China
| | - Agustín Tortajada
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, Spain; (C.C.); (H.W.); (H.Y.); (A.T.); (K.Z.); (E.M.-N.); (Y.A.N.)
- 12 de Octubre Health Research Institute (imas12), 28041 Madrid, Spain
| | - Sandra Rodríguez-Perales
- Molecular Cytogenetics and Genome Editing Unit, Human Cancer Genetics Program, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain; (S.R.-P.); (R.T.-R.)
| | - Raúl Torres-Ruiz
- Molecular Cytogenetics and Genome Editing Unit, Human Cancer Genetics Program, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain; (S.R.-P.); (R.T.-R.)
| | - August Vidal
- Laboratorio de Investigación Traslacional (LRT1)-ProCURE, Institut Català d’Oncologia (ICO)-IDIBELL, L’Hospitalet de Llobregat, 08908 Barcelona, Spain; (A.V.); (A.V.)
| | - Maria Isabel Peligros
- Institute of Pathology, Hospital Universitario Gregorio Marañon, 28007 Madrid, Spain;
| | - Johanna Reissing
- Department of Internal Medicine III, University Hospital RWTH, 52074 Aachen, Germany; (J.R.); (T.B.); (M.R.M.); (C.T.)
| | - Tony Bruns
- Department of Internal Medicine III, University Hospital RWTH, 52074 Aachen, Germany; (J.R.); (T.B.); (M.R.M.); (C.T.)
| | - Mohamed Ramadan Mohamed
- Department of Internal Medicine III, University Hospital RWTH, 52074 Aachen, Germany; (J.R.); (T.B.); (M.R.M.); (C.T.)
| | - Kang Zheng
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, Spain; (C.C.); (H.W.); (H.Y.); (A.T.); (K.Z.); (E.M.-N.); (Y.A.N.)
| | - Amaia Lujambio
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Maria J. Iraburu
- Department of Biochemistry and Genetics, University of Navarra, 31008 Pamplona, Spain;
| | - Leticia Colyn
- Hepatology Program, Cima, University of Navarra, 31008 Pamplona, Spain; (L.C.); (M.U.L.); (M.A.); (M.G.F.-B.); (C.B.)
| | - Maria Ujue Latasa
- Hepatology Program, Cima, University of Navarra, 31008 Pamplona, Spain; (L.C.); (M.U.L.); (M.A.); (M.G.F.-B.); (C.B.)
| | - María Arechederra
- Hepatology Program, Cima, University of Navarra, 31008 Pamplona, Spain; (L.C.); (M.U.L.); (M.A.); (M.G.F.-B.); (C.B.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain; (J.V.); (R.B.)
- Instituto de Investigaciones Sanitarias de Navarra-IdiSNA, 31008 Pamplona, Spain
| | - Maite G. Fernández-Barrena
- Hepatology Program, Cima, University of Navarra, 31008 Pamplona, Spain; (L.C.); (M.U.L.); (M.A.); (M.G.F.-B.); (C.B.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain; (J.V.); (R.B.)
- Instituto de Investigaciones Sanitarias de Navarra-IdiSNA, 31008 Pamplona, Spain
| | - Carmen Berasain
- Hepatology Program, Cima, University of Navarra, 31008 Pamplona, Spain; (L.C.); (M.U.L.); (M.A.); (M.G.F.-B.); (C.B.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain; (J.V.); (R.B.)
- Instituto de Investigaciones Sanitarias de Navarra-IdiSNA, 31008 Pamplona, Spain
| | - Javier Vaquero
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain; (J.V.); (R.B.)
- Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), 28007 Madrid, Spain
- Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain
| | - Rafael Bañares
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain; (J.V.); (R.B.)
- Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), 28007 Madrid, Spain
- Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain
| | - Leonard J. Nelson
- Institute for Bioengineering (IBioE), Faraday Building, The University of Edinburgh, Edinburgh EH8 9AB, UK;
| | - Christian Trautwein
- Department of Internal Medicine III, University Hospital RWTH, 52074 Aachen, Germany; (J.R.); (T.B.); (M.R.M.); (C.T.)
| | - Roger J. Davis
- Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01655, USA;
| | - Eduardo Martinez-Naves
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, Spain; (C.C.); (H.W.); (H.Y.); (A.T.); (K.Z.); (E.M.-N.); (Y.A.N.)
- 12 de Octubre Health Research Institute (imas12), 28041 Madrid, Spain
| | - Yulia A. Nevzorova
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, Spain; (C.C.); (H.W.); (H.Y.); (A.T.); (K.Z.); (E.M.-N.); (Y.A.N.)
- Department of Internal Medicine III, University Hospital RWTH, 52074 Aachen, Germany; (J.R.); (T.B.); (M.R.M.); (C.T.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain; (J.V.); (R.B.)
- Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), 28007 Madrid, Spain
| | - Alberto Villanueva
- Laboratorio de Investigación Traslacional (LRT1)-ProCURE, Institut Català d’Oncologia (ICO)-IDIBELL, L’Hospitalet de Llobregat, 08908 Barcelona, Spain; (A.V.); (A.V.)
| | - Matias A. Avila
- Hepatology Program, Cima, University of Navarra, 31008 Pamplona, Spain; (L.C.); (M.U.L.); (M.A.); (M.G.F.-B.); (C.B.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain; (J.V.); (R.B.)
- Instituto de Investigaciones Sanitarias de Navarra-IdiSNA, 31008 Pamplona, Spain
| | - Francisco Javier Cubero
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, Spain; (C.C.); (H.W.); (H.Y.); (A.T.); (K.Z.); (E.M.-N.); (Y.A.N.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain; (J.V.); (R.B.)
- Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), 28007 Madrid, Spain
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16
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Wu Y, Wu Y, Liu K, Liu H, Wang S, Huang J, Ding H. Identification of Genetic Predisposition in Noncirrhotic Portal Hypertension Patients With Multiple Renal Cysts by Integrated Analysis of Whole-Genome and Single-Cell RNA Sequencing. Front Genet 2021; 12:775470. [PMID: 34868264 PMCID: PMC8633307 DOI: 10.3389/fgene.2021.775470] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 10/26/2021] [Indexed: 01/16/2023] Open
Abstract
Background and Aims: The multiple renal cysts (MRC) occur in some patients with noncirrhotic portal hypertension (NCPH) could be a subset of ciliopathy. However, the potential genetic influencers and/or determinants in NCPH with MRC are largely unknown. The aim of this study was to explore the potential candidate variants/genes associated with those patients. Methods: 8,295 cirrhotic patients with portal hypertension were enrolled in cohort 1 and 267 patients affected with NCPH were included in cohort 2. MRC was defined as at least two cysts in both kidneys within a patient detected by ultrasonography or computed tomography. Whole-genome sequencing (WGS) was performed in nine patients (four from cohort 1 and five from cohort 2). Then we integrated WGS and publicly available single-cell RNA sequencing (scRNA-seq) to prioritize potential candidate genes. Genes co-expressed with known pathogenic genes within same cell types were likely associated NCPH with MRC. Results: The prevalence of MRC in NCPH patients (19.5%, 52/267) was significantly higher than cirrhotic patients (6.2%, 513/8,295). Further, the clinical characteristics of NCPH patients with MRC were distinguishable from cirrhotic patients, including late-onset, more prominent portal hypertension however having preserved liver functions. In the nine whole genome sequenced patients, we identified three patients with early onset harboring compound rare putative pathogenic variants in the known disease gene PKHD1. For the remaining patients, by assessing cilia genes profile in kidney and liver scRNA-seq data, we identified CRB3 was the most co-expressed gene with PKHD1 that highly expressed in ureteric bud cell, kidney stromal cell and hepatoblasts. Moreover, we found a homozygous variant, CRB3 p.P114L, that caused conformational changes in the evolutional conserved domain, which may associate with NCPH with MRC. Conclusion: ScRNA-seq enables unravelling cell heterogeneity with cell specific gene expression across multiple tissues. With the boosting public accessible scRNA-seq data, we believe our proposed analytical strategy would effectively help disease risk gene identification.
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Affiliation(s)
- Yanjing Wu
- Department of Gastroenterology and Hepatology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, China
| | - Yongle Wu
- Department of Gastroenterology and Hepatology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, China
| | - Kun Liu
- Department of General Surgery, Beijing Friendship Hospital, Affiliated with Capital Medical University, Beijing, China
| | - Hui Liu
- Department of Pathology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, China
| | - Shanshan Wang
- Beijing Institute of Hepatology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, China
| | - Jian Huang
- Experimental Center, Beijing Friendship Hospital, Affiliated with Capital Medical University, Beijing, China
| | - Huiguo Ding
- Department of Gastroenterology and Hepatology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, China
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17
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Masyuk TV, Masyuk AI, LaRusso NF. Polycystic Liver Disease: Advances in Understanding and Treatment. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2021; 17:251-269. [PMID: 34724412 DOI: 10.1146/annurev-pathol-042320-121247] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Polycystic liver disease (PLD) is a group of genetic disorders characterized by progressive development of cholangiocyte-derived fluid-filled hepatic cysts. PLD is the most common manifestation of autosomal dominant and autosomal recessive polycystic kidney diseases and rarely occurs as autosomal dominant PLD. The mechanisms of PLD are a sequence of the primary (mutations in PLD-causative genes), secondary (initiation of cyst formation), and tertiary (progression of hepatic cystogenesis) interconnected molecular and cellular events in cholangiocytes. Nonsurgical, surgical, and limited pharmacological treatment options are currently available for clinical management of PLD. Substantial evidence suggests that pharmacological targeting of the signaling pathways and intracellular processes involved in the progression of hepatic cystogenesis is beneficial for PLD. Many of these targets have been evaluated in preclinical and clinical trials. In this review, we discuss the genetic, molecular, and cellular mechanisms of PLD and clinical and preclinical treatment strategies. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Tatyana V Masyuk
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota 55905, USA;
| | - Anatoliy I Masyuk
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota 55905, USA;
| | - Nicholas F LaRusso
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota 55905, USA;
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18
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Abstract
Rare liver diseases caused by ductal plate malformation, such as congenital hepatic fibrosis (CHF), Caroli syndrome, and polycystic liver disease, can have clinical manifestations such as recurrent cholangitis—frequently involving multidrug-resistant microorganisms—leading to difficulties in selecting the optimal antimicrobial treatment. Without prompt recognition, these infections severely hamper the patient’s quality of life and can develop into life-threatening complications. We report here the case of a 50-year-old woman with a history of recurring cholangitis with occasional systemic involvement leading to bloodstream infection, who ultimately received a diagnosis of CHF and was put on chronic suppressive antibiotic therapy while on the waiting list for a liver transplant. We also reviewed the literature collecting cases of recurrent infections occurring in patients with ductal plate malformation.
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