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Socha P, Jańczyk W, Zanetto A, Burra P, Czlonkowska A, Debray D, Ferenci P, Merle U, Nicastro E, Poujois A, Schmidt H, Tsochatzis E. EASL-ERN Clinical Practice Guidelines on Wilson's disease. J Hepatol 2025; 82:S0168-8278(24)02706-5. [PMID: 40089450 DOI: 10.1016/j.jhep.2024.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 11/08/2024] [Indexed: 03/17/2025]
Abstract
Wilson's disease is an autosomal recessive disorder of copper metabolism which affects the liver, brain and other organs. Diagnosis is based on: clinical features; biochemical tests, including plasma ceruloplasmin concentration, 24-h urinary copper excretion, copper content in the liver; and molecular analysis. Leipzig score and additionally relative exchangeable copper determination are recommended for diagnosis. Pharmacological therapy comprises chelating agents (penicillamine, trientine) and zinc salts, while only chelators are recommended for significant liver disease. Monitoring is based on clinical symptoms, liver tests and copper metabolism (urinary copper excretion, exchangeable copper) to detect poor compliance and over/under-treatment. Acute liver failure is challenging as making a diagnosis is difficult and pharmacological therapy may not be sufficient to save life. Liver transplantation has a well-defined role in Wilsonian acute hepatic failure but may also be considered in neurological disease.
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Brown AN, Lange MM, Aliasi-Sinai L, Zhang X, Kogan S, Martin L, Kushner T. Adverse pregnancy outcomes and effect of treatment in Wilson disease during pregnancy: Systematic review and meta-analysis. Liver Int 2024; 44:3020-3030. [PMID: 39206599 DOI: 10.1111/liv.16072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 07/16/2024] [Accepted: 08/06/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND AND AIMS Wilson disease (WD) is a rare disorder of copper metabolism, leading to liver and neurological disease. Existing literature on WD in pregnancy is scarce, limiting preconception and obstetrical counselling. In this systematic review with meta-analysis, we determine the prevalence of various adverse pregnancy and neonatal outcomes in WD, as well as evaluate the impact of WD treatment on these outcomes. METHODS Scopus, MEDLINE and EMBASE were searched until 12 May 2023, for studies of pregnant individuals with WD and at least one pregnancy or neonatal outcome of interest. Meta-analysis of single proportions was conducted to pool prevalence data for each outcome. Outcome rates were compared between treated and untreated groups in a meta-analysis of dichotomous events. RESULTS Sixteen studies, published from 1975 to 2022, were included in the systematic review. Thirty-seven percent of pregnancies reported at least one adverse pregnancy outcome. Spontaneous abortions (20%), liver diseases of pregnancy (4.5%) and preterm births (2%) were the most frequent adverse pregnancy outcomes in patients with WD. The prevalence of spontaneous abortions was significantly lower in pregnant individuals with WD who received treatment during pregnancy (OR: .47, 95% CI: 35%-63%). The prevalence of any adverse pregnancy outcome was also significantly lower with treatment (OR: .53, 95% CI: .37-.76), which appears to be mostly driven by the reduction of spontaneous abortions. CONCLUSIONS There is low to moderate quality evidence to suggest that preconception and obstetrical counselling for patients with WD should include a discussion on the potentially high frequency of adverse pregnancy outcomes in this population, as well as the importance of continuing WD treatment during pregnancy to ensure satisfactory pregnancy course and potentially minimize the risk of spontaneous abortions.
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Affiliation(s)
- Ashley N Brown
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - M Marcia Lange
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Lital Aliasi-Sinai
- Department of Medicine, Icahn School of Medicine at Mount Sinai Morningside/West, New York, USA
| | - Xiaotao Zhang
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Sasha Kogan
- Jacob's School of Medicine at the University of Buffalo, Buffalo, New York, USA
| | - Lily Martin
- Levy Library, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Tatyana Kushner
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Romero-Gutiérrez M, Alonso P, Berenguer M, Olveira A, González-Diéguez ML, Iruzubieta P, Masnou H, Delgado M, Hernández-Guerra M, Lorente S, Lázaro M, Moreno-Planas JM, González C, Fernández-Álvarez P, Cuenca F, Gómez J, García-Villareal L, Rodríguez O, Mariño Z. Reproductive and pregnancy control in Wilson disease patients in Spain. Eur J Gastroenterol Hepatol 2024; 36:1340-1345. [PMID: 39166415 DOI: 10.1097/meg.0000000000002831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/22/2024]
Abstract
BACKGROUND AND AIM Recommendations on pregnancy, lactation, and contraception in women with Wilson disease are briefly stated in international guidelines but are not entirely homogeneous. Data regarding the management of these special events among patients with Wilson disease in Spain are lacking. We used the Wilson Registry platform of the Spanish Association for the Study of the Liver to question patients on their reproductive and gestational lives. METHODS This was a multicentre ambispective study including adult women with Wilson disease in the Spanish Wilson Registry interviewed about their contraception, childbearing, pregnancy, and lactation experiences. Clinical and analytical data were extracted from the registry. RESULTS The study included 92 women from 17 centres in Spain. Most (63%) reported having a previous pregnancy history. The rate of spontaneous miscarriages was 21.6%, mainly occurring in the first trimester and up to one third among undiagnosed patients. Most pregnant women received chelator therapy during pregnancy, but dose reduction was recommended in less than 10%. After delivery, artificial lactation predominated (60.3%) and its use was mainly based on physician's recommendations (68%). Up to 40% of the women included reported some concerns about their reproductive lives, mainly related to the potential drug toxicity to their children. Most of the patients considered the information given by specialists to be sufficient. CONCLUSION Gestational management among women with Wilson disease in Spain was found to be highly heterogeneous and frequently different from what is described in international guidelines. Education on rare liver diseases should be a priority for scientific societies in order to homogenize patient follow-up and recommendations.
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Affiliation(s)
- Marta Romero-Gutiérrez
- Complejo Hospitalario Universitario de Toledo, Gastroenterology and Hepatology Department, Toledo
| | - Pablo Alonso
- Universidad Las Palmas Gran Canaria (ULPGC), Complejo Hospitalario Universitario Insular Materno Infantil, Gastroenterology and Hepatology Department, Las Palmas de Gran Canaria
| | - Marina Berenguer
- Hospital Universitari i Politècnic La Fe, Gastroenterology and Hepatology Department, IISLaFe, Ciberehd, Valencia
| | - Antonio Olveira
- Hospital Universitario La Paz, Gastroenterology and Hepatology Department, Madrid
| | | | - Paula Iruzubieta
- Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Hospital Universitario Marqués de Valdecilla, Gastroenterology and Hepatology Department, Santander
| | - Helena Masnou
- Hospital Universitario Germans Trias i Pujol, Gastroenterology and Hepatology Department, Badalona
| | - Manuel Delgado
- Hospital Universitario A Coruña, Gastroenterology and Hepatology Department, La Coruña
| | - Manuel Hernández-Guerra
- Hospital Universitario de Canarias, Gastroenterology and Hepatology Department, Santa Cruz Tenerife
| | - Sara Lorente
- Hospital Clínico Lozano Blesa de Zaragoza, Gastroenterology and Hepatology Department, IISS Aragón
| | - María Lázaro
- Hospital Universitario Miguel Servet, Gastroenterology and Hepatology Department, Zaragoza
| | - José María Moreno-Planas
- Complejo Hospitalario Universitario de Albacete, Gastroenterology and Hepatology Department, Albacete
| | - Concepción González
- Complejo Hospitalario Universitario de Toledo, Gastroenterology and Hepatology Department, Toledo
| | | | - Francisca Cuenca
- Hospital Clínico San Carlos, Gastroenterology and Hepatology Department, Madrid
| | - Judith Gómez
- Hospital Universitario de Burgos, Gastroenterology and Hepatology Department, Burgos
| | - Luis García-Villareal
- Complejo Hospitalario Universitario Insular Materno Infantil, Gastroenterology and Hepatology Department, IUIBS ULPGC, Las Palmas de Gran Canaria
| | - Olga Rodríguez
- Complejo Hospitalario Universitario de Toledo, Obstetrics and Gynaecology Department, Toledo
| | - Zoe Mariño
- Liver Unit, Hospital Clínic Barcelona, IDIBAPS, CIBERehd, ERN-RARE Liver, Universitat de Barcelona, Barcelona, Spain
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Rao R, Yu XE, Zhou ZH, Shu S, Du YG, Han YZ, Han YS. Outcomes of pregnancy in Wilson's disease: a population-based study from multiple centres of the Han population in China. Front Med (Lausanne) 2024; 11:1436828. [PMID: 39247638 PMCID: PMC11377272 DOI: 10.3389/fmed.2024.1436828] [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: 05/23/2024] [Accepted: 08/05/2024] [Indexed: 09/10/2024] Open
Abstract
Objectives Wilson's disease is an autosomal recessive disorder related to copper metabolism which mostly patients occurs in adolescents, fertility has become a problem that WD needs to face. Methods A 21 years retrospective follow up study was conducted and a total of 220 female patients were included to identify patients with outcomes of pregnancy. Results Untreated female patients with WD had a spontaneous abortion rate of 44%. During the study period, 146 female patients with WD from multicenter, 75 patients (51.4%) had successful outcomes of pregnancy. Notably, urinary copper levels below 616 μg/24 h were strongly associated with successful pregnancy. The nomogram built on these variables were age, urinary copper, haemoglobin and Child-Pugh classification, internally validated and showed good performance. Conclusion The spontaneous abortion rate was 44% in untreated females with WD and developed a four-variable risk prediction model to accurately predict the likelihood of a successful pregnancy.
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Affiliation(s)
- Rao Rao
- Institute of Neurology, Anhui University of Chinese Medicine, Hefei, China
- Department of Neurology, Affiliated Hospital of Neurology Research Institute of Anhui University of Chinese Medicine, Hefei, China
| | - Xu-En Yu
- Institute of Neurology, Anhui University of Chinese Medicine, Hefei, China
- Department of Neurology, Affiliated Hospital of Neurology Research Institute of Anhui University of Chinese Medicine, Hefei, China
| | - Zhi-Hua Zhou
- Department of Neurology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Shan Shu
- Institute of Neurology, Anhui University of Chinese Medicine, Hefei, China
- Department of Neurology, Affiliated Hospital of Neurology Research Institute of Anhui University of Chinese Medicine, Hefei, China
| | - Yi-Gang Du
- Department of Neurology, Anhui Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Hefei, China
| | - Yong-Zhu Han
- Institute of Neurology, Anhui University of Chinese Medicine, Hefei, China
- Department of Neurology, Affiliated Hospital of Neurology Research Institute of Anhui University of Chinese Medicine, Hefei, China
| | - Yong-Sheng Han
- Institute of Neurology, Anhui University of Chinese Medicine, Hefei, China
- Wannan Medical College, Wuhu, China
- Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM, Anhui University of Chinese Medicine, Hefei, China
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Weinstein D, Shah DA. Wilson disease and pregnancy. Clin Liver Dis (Hoboken) 2024; 23:e0110. [PMID: 38312994 PMCID: PMC10833626 DOI: 10.1097/cld.0000000000000110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 10/22/2023] [Indexed: 02/06/2024] Open
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Affiliation(s)
- Eve A Roberts
- From the Departments of Paediatrics, Medicine, and Pharmacology and Toxicology, University of Toronto, and the Hospital for Sick Children Research Institute - both in Toronto; and the History of Science and Technology Programme, University of King's College, Halifax, NS, Canada (E.A.R.); and the Departments of Medicine and Surgery, Yale University School of Medicine, New Haven, CT (M.L.S.)
| | - Michael L Schilsky
- From the Departments of Paediatrics, Medicine, and Pharmacology and Toxicology, University of Toronto, and the Hospital for Sick Children Research Institute - both in Toronto; and the History of Science and Technology Programme, University of King's College, Halifax, NS, Canada (E.A.R.); and the Departments of Medicine and Surgery, Yale University School of Medicine, New Haven, CT (M.L.S.)
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Williamson C, Nana M, Poon L, Kupcinskas L, Painter R, Taliani G, Heneghan M, Marschall HU, Beuers U. EASL Clinical Practice Guidelines on the management of liver diseases in pregnancy. J Hepatol 2023; 79:768-828. [PMID: 37394016 DOI: 10.1016/j.jhep.2023.03.006] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 03/10/2023] [Indexed: 07/04/2023]
Abstract
Liver diseases in pregnancy comprise both gestational liver disorders and acute and chronic hepatic disorders occurring coincidentally in pregnancy. Whether related to pregnancy or pre-existing, liver diseases in pregnancy are associated with a significant risk of maternal and fetal morbidity and mortality. Thus, the European Association for the Study of Liver Disease invited a panel of experts to develop clinical practice guidelines aimed at providing recommendations, based on the best available evidence, for the management of liver disease in pregnancy for hepatologists, gastroenterologists, obstetric physicians, general physicians, obstetricians, specialists in training and other healthcare professionals who provide care for this patient population.
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Bailey KM, Sahota N, To U, Hedera P. "Because it is a rare disease…it needs to be brought to attention that there are things out of the norm": a qualitative study of patient and physician experiences of Wilson disease diagnosis and management in the US. Orphanet J Rare Dis 2023; 18:158. [PMID: 37349760 PMCID: PMC10288732 DOI: 10.1186/s13023-023-02778-3] [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: 11/07/2022] [Accepted: 06/18/2023] [Indexed: 06/24/2023] Open
Abstract
BACKGROUND Wilson disease (WD) is a genetic disorder of copper metabolism that leads to copper accumulation in various organs, primarily the liver and brain, resulting in heterogenous hepatic, neurologic, and psychiatric symptoms. Diagnosis can occur at any age, requiring lifelong treatment, which can involve liver transplantation. This qualitative study aims to understand the wider patient and physician experience of the diagnosis and management of WD in the US. METHODS Primary data were collected from 1:1 semi structured interviews with US-based patients and physicians and thematically analyzed with NVivo. RESULTS Twelve WD patients and 7 specialist WD physicians (hepatologists and neurologists) were interviewed. Analysis of the interviews revealed 18 themes, which were organized into 5 overarching categories: (1) Diagnosis journey, (2) Multidisciplinary approach, (3) Medication, (4) The role of insurance, and (5) Education, awareness, and support. Patients who presented with psychiatric or neurological symptoms reported longer diagnostic journeys (range 1 to 16 years) than those presenting with hepatic symptoms or through genetic screening (range 2 weeks to 3 years). All were also affected by geographical proximity to WD specialists and access to comprehensive insurance. Exploratory testing was often burdensome for patients, but receipt of a definitive diagnosis led to relief for some. Physicians emphasized the importance of multidisciplinary teams beyond hepatology, neurology, and psychiatry and recommended a combination of chelation, zinc, and a low-copper diet; however, only half the patients in this sample were on a chelator, and some struggled to access prescription zinc due to insurance issues. Caregivers often advocated for and supported adolescents with their medication and dietary regimen. Patients and physicians recommended more education and awareness for the healthcare community. CONCLUSIONS WD requires the coordination of care and medication among several specialists due to its complex nature, but many patients do not have access to multiple specialties due to geographical or insurance barriers. Because some patients cannot be treated in Centers of Excellence, easy access to reliable and up-to-date information is important to empower physicians, patients, and their caregivers in managing the condition, along with general community outreach programs.
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Affiliation(s)
| | | | - Uyen To
- Yale University, New Haven, Connecticut, United States
| | - Peter Hedera
- University of Louisville, Louisville, KY, USA.
- Department of Neurology Institution, University of Louisville, 220 Abraham Flexner Way, Suite 606, Louisville, KY, 40202, USA.
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Alkhouri N, Gonzalez-Peralta RP, Medici V. Wilson disease: a summary of the updated AASLD Practice Guidance. Hepatol Commun 2023; 7:02009842-202306010-00006. [PMID: 37184530 DOI: 10.1097/hc9.0000000000000150] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 03/15/2023] [Indexed: 05/16/2023] Open
Abstract
Wilson disease (WD) is caused by autosomal variants affecting the ATP7B gene on chromosome 13, resulting in alterations in physiological copper homeostasis and copper accumulation. Excess copper clinically manifests in many organs, most often in the central nervous system and liver, ultimately causing cirrhosis and death. Often considered a pediatric or young adult disease, WD actually affects patients of all ages, and aging patients need to be regularly managed with long-term follow-up. Despite over a century of advances in diagnosis and treatment, WD is still associated with diagnostic challenges and considerable disability and death, in part due to delays in diagnosis and limitations in treatment. Standard-of-care treatments are considered generally effective when the diagnosis is timely but are also limited by efficacy, safety concerns, multiple daily dosing, and adherence. This expert perspective review seeks to facilitate improvements in the awareness, understanding, diagnosis, and management of WD. The objectives are to provide a full overview of WD and streamline updated diagnosis and treatment guidance, as recently published by the American Association for the Study of Liver Diseases, in a practical way for clinical use.
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Affiliation(s)
| | | | - Valentina Medici
- Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, California, USA
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Schilsky ML, Roberts EA, Bronstein JM, Dhawan A, Hamilton JP, Rivard AM, Washington MK, Weiss KH, Zimbrean PC. A multidisciplinary approach to the diagnosis and management of Wilson disease: Executive summary of the 2022 Practice Guidance on Wilson disease from the American Association for the Study of Liver Diseases. Hepatology 2023; 77:1428-1455. [PMID: 36152019 DOI: 10.1002/hep.32805] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 09/13/2022] [Indexed: 12/08/2022]
Affiliation(s)
- Michael L Schilsky
- Medicine and Surgery , Yale University School of Medicine , New Haven , Connecticut , USA
| | - Eve A Roberts
- Paediatrics, Medicine, Pharmacology and Toxicology , University of Toronto , Toronto , Ontario , Canada
| | - Jeff M Bronstein
- Neurology , University of California Los Angeles , Los Angeles , California , USA
| | - Anil Dhawan
- Paediatric Liver, GI and Nutrition Centre and MowatLabs , King's College Hospital , London , UK
| | - James P Hamilton
- Medicine , Johns Hopkins University School of Medicine , Baltimore , Maryland , USA
| | - Anne Marie Rivard
- Food and Nutrition Services , Yale New Haven Hospital , New Haven , Connecticut , USA
| | - Mary Kay Washington
- Pathology, Immunology and Microbiology , Vanderbilt University Medical Center , Nashville , Tennessee , USA
| | | | - Paula C Zimbrean
- Psychiatry , Yale University School of Medicine , New Haven , Connecticut , USA
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Xiong X, Wei H, Zhu Y, Zhou X, Zhao Z, Chen Q. Wilson disease in pregnancy: A case series. Medicine (Baltimore) 2023; 102:e32968. [PMID: 36800617 PMCID: PMC9936009 DOI: 10.1097/md.0000000000032968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/19/2023] Open
Abstract
RATIONALE Hepatolenticular degeneration, also known as Wilson disease (WD), is an autosomal recessive inherited disease characterized by copper metabolism, which has complex clinical manifestations, and mainly including liver and nervous system lesions. Pregnancy combined with WD is extremely harmful to mothers and children, with high miscarriage rates, and premature birth rates and perinatal mortality. PATIENT CONCERNS Here we introduced the basic information of 4 pregnant women with WD. The first pregnant woman had a 16-year history of WD, stopped taking penicillamine 1 year before pregnancy. The second woman had a 3-year history of WD and was taking penicillamine regularly, unintended pregnancy occurred 1 month after stopping the drug. The third woman had a history of WD for 5 years with penicillamine treatment. The 4th woman was found to have WD due to repeated missed miscarriage with abnormal liver function, after which penicillamine was regularly taken. Fortunately, she was pregnant again a year later. DIAGNOSES The pregnant women in case 1 and case 2 were diagnosed with decompensated cirrhosis with coagulation dysfunction during pregnancy. The pregnant woman in case 3 was found to have liver cirrhosis by ultrasound, and the pregnant woman in case 4 did not have liver abnormalities during pregnancy. INTERVENTIONS The pregnant woman in case 1 began to take copper-removing drugs and take a low-copper diet after finding the aggravation of the disease in the early stage of pregnancy, and had good compliance during pregnancy. The pregnant woman in case 2 had poor compliance during pregnancy and did not receive any treatment. The pregnant woman in case 3 refused to use copper elimination drugs during pregnancy, but took a low copper diet. The pregnant woman in case 4 had good compliance during pregnancy, and she was treated with drugs and low copper diet during the whole pregnancy. OUTCOMES Three of the four pregnant women got a healthy baby but premature, and only the pregnant woman in case 2 had spontaneous abortion at 25 weeks. LESSONS After comprehensive monitoring and multidisciplinary management of professional medical staff before and after pregnancy, WD pregnant women still have the opportunity to obtain a better pregnancy outcome and improve quality of life.
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Affiliation(s)
- Xiali Xiong
- Department of Obstetrics, Beijing You’An Hospital, Capital Medical University, Beijing, China
| | - Hong Wei
- Department of Obstetrics, Beijing You’An Hospital, Capital Medical University, Beijing, China
| | - Yunxia Zhu
- Department of Obstetrics, Beijing You’An Hospital, Capital Medical University, Beijing, China
| | - Xin Zhou
- Department of Obstetrics, Beijing You’An Hospital, Capital Medical University, Beijing, China
| | - Zhiqiang Zhao
- Department of Obstetrics, Beijing You’An Hospital, Capital Medical University, Beijing, China
| | - Qiang Chen
- China Academy of Chinese Medical Sciences Eye Hospital, Beijing, China
- * Correspondence: Qiang Chen, China Academy of Chinese Medical Sciences Eye Hospital, No. 33 Lu Gu Road, Shi Jing Shan District, Beijing 100040, China (e-mail: )
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Maternal and perinatal outcome in pregnancies complicated with portal hypertension: a systematic review and meta-analysis. Hepatol Int 2023; 17:170-179. [PMID: 35802227 DOI: 10.1007/s12072-022-10385-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 06/15/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND Portal hypertension is secondary to either cirrhotic or non-cirrhotic causes, and complicating pregnancy poses a challenge to the treating team. A systematic review was performed to determine maternal and perinatal outcomes in women with portal hypertension. Outcomes were compared among those with cirrhotic (CPH) with non-cirrhotic portal hypertension (NCPH) as well as non-cirrhotic portal fibrosis (NCPF) with extra-hepatic portal vein obstruction (EHPVO). METHODS Medline and EMBASE databases were searched for studies reporting outcomes among pregnant women with portal hypertension. Reference lists from relevant papers and reviews were hand-searched for appropriate citations. Data were extracted to describe maternal complications, obstetric and neonatal outcomes. A random-effects model was used to derive pooled estimates of various outcomes, and final estimates were reported as percentages with a 95% confidence interval (CI). Cumulative, sequential and sensitivity analysis was studied to assess the temporal trends of outcomes over the period. RESULTS Information on 895 pregnancies among 581 patients with portal hypertension was included from 26 studies. Portal hypertension was diagnosed during pregnancy in 10% (95% CI 4-24%). There were 22 maternal deaths (0%, 95% CI 0-1%), mostly following complications from variceal bleeding or hepatic decompensation. Variceal bleeding complicated in 14% (95% CI 9-20%), and endoscopic interventions were performed in 12% (95% CI 8-17%) during pregnancy. Decompensation of liver function occurred in 7% (95% CI 3-12%). Thrombocytopenia was the most common complication (41%, 95% CI 23-60%). Miscarriages occurred in 14% (95% CI 8-20%), preterm birth in 27% (95% CI 19-37%), and low birth weights in 22% (95% CI 15-30%). Risk of postpartum hemorrhage was higher (RR 5.09, 95% CI 1.84-14.12), and variceal bleeding was lower (RR 0.51, 95% CI 0.30-0.86) among those with CPH compared to NCPH. Risk of various outcomes was comparable between NCPF and EHPVO. CONCLUSION One in ten pregnancies complicated with portal hypertension is diagnosed during pregnancy, and thrombocytopenia is the most common complication. Hepatic decompensation and variceal bleeding remain the most common cause of maternal deaths, with reduced rates of bleeding and its complications reported following the introduction of endoscopic procedures during pregnancy. CPH increases the risk of postpartum hemorrhage, whereas variceal bleeding is higher among NCPH.
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Schilsky ML, Roberts EA, Bronstein JM, Dhawan A, Hamilton JP, Rivard AM, Washington MK, Weiss KH, Zimbrean PC. A multidisciplinary approach to the diagnosis and management of Wilson disease: 2022 Practice Guidance on Wilson disease from the American Association for the Study of Liver Diseases. Hepatology 2022:01515467-990000000-00207. [PMID: 36151586 DOI: 10.1002/hep.32801] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 09/13/2022] [Indexed: 01/18/2023]
Affiliation(s)
- Michael L Schilsky
- Medicine and Surgery , Yale University School of Medicine , New Haven , Connecticut , USA
| | - Eve A Roberts
- Paediatrics, Medicine, Pharmacology and Toxicology , University of Toronto , Toronto , Ontario , Canada
| | - Jeff M Bronstein
- Neurology , University of California Los Angeles , Los Angeles , California , USA
| | - Anil Dhawan
- Paediatric Liver, GI and Nutrition Centre and MowatLabs , King's College Hospital , London , UK
| | - James P Hamilton
- Medicine , Johns Hopkins University School of Medicine , Baltimore , Maryland , USA
| | - Anne Marie Rivard
- Food and Nutrition Services , Yale New Haven Hospital , New Haven , Connecticut , USA
| | - Mary Kay Washington
- Pathology, Immunology and Microbiology , Vanderbilt University Medical Center , Nashville , Tennessee , USA
| | | | - Paula C Zimbrean
- Psychiatry , Yale University School of Medicine , New Haven , Connecticut , USA
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Mussi MCL, Nardelli MJ, Santos BC, Abreu ESD, Osório FMF, Cançado GGL, Ferrari TCA, Faria LC, Couto CA. Pregnancy Outcomes in Wilson's Disease Women: Single-Center Case Series. Fetal Pediatr Pathol 2022; 41:741-748. [PMID: 34350816 DOI: 10.1080/15513815.2021.1960940] [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: 10/20/2022]
Abstract
OBJECTIVES To evaluate and compare pregnancy outcomes in women with Wilson's disease (WD) undergoing different therapies during pregnancy. MATERIAL AND METHODS Retrospective review of medication in WD patients during pregnancy and the outcomes. RESULTS Of 26 pregnancies, zinc was used in 14 (53.8%), D-penicillamine in 4 (15.4%) patients, and 8 (30.8%) were untreated. Spontaneous abortion was observed in 8 (30.8%) pregnancies - untreated patients (4/8 pregnancies), zinc (2/14 pregnancies) and D-penicillamine (2/4 pregnancies) -, healthy outcome in 12 (46.1%) and birth defects in 6 (23.1%). All cases of birth defects occurred in patients using zinc therapy (6/14 pregnancies). CONCLUSIONS A remarkably high frequency of fetal complications shed lights on the potentially harmful effect of WD drugs during childbearing age. Zinc's safety profile may have to be better evaluated during pregnancy, as all of birth defects occurred with zinc therapy.
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Affiliation(s)
| | | | - Bruno Campos Santos
- Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | | | - Fernanda Maria Farage Osório
- Instituto Alfa de Gastroenterologia, Hospital das Clínicas da Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Guilherme Grossi Lopes Cançado
- Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.,Instituto Alfa de Gastroenterologia, Hospital das Clínicas da Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Teresa Cristina Abreu Ferrari
- Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.,Instituto Alfa de Gastroenterologia, Hospital das Clínicas da Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Luciana Costa Faria
- Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.,Instituto Alfa de Gastroenterologia, Hospital das Clínicas da Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Claudia Alves Couto
- Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.,Instituto Alfa de Gastroenterologia, Hospital das Clínicas da Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
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15
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Litwin T, Bembenek J, Antos A, Kurkowska-Jastrzębska I, Przybyłkowski A, Skowrońska M, Smoliński Ł, Członkowska A. The Maternal and Fetal Outcomes of Pregnancy in Wilson’s Disease: A Systematic Literature Review and Meta-Analysis. Biomedicines 2022; 10:biomedicines10092072. [PMID: 36140172 PMCID: PMC9495510 DOI: 10.3390/biomedicines10092072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Revised: 08/17/2022] [Accepted: 08/22/2022] [Indexed: 11/16/2022] Open
Abstract
Wilson’s disease (WD) is a rare, treatable genetic disorder with multi-organ symptoms related mainly to copper accumulation. Most patients become aware of the disease as young adults, thus knowledge on fertility, pregnancy course and outcome is very important both for patients and physicians. The aim of this study was to perform a systematic review and meta-analysis of pregnancy outcomes in women with WD. This systematic literature review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies were identified by searching the PubMed database (up to 12 January 2022) and by screening reference lists. We found 49 publications, including 13 retrospective studies and 36 series and case reports on pregnancy outcomes in WD patients. In total, descriptions of 449 pregnant women with 822 pregnancies were retrieved. Successful deliveries were achieved in 78.3% (644/822) of all pregnancies. Spontaneous abortions were observed in 21.7% (178/822) of pregnancies, more frequently in patients who were untreated 68.6% (96/140). Analyzing maternal outcome, 2.2% (18/822) of pregnancies were associated with the aggravation of neurological symptoms. Symptoms of hepatic deterioration were observed in 4.6% (38/822) of cases. These were usually transient and recovered after pregnancy; however, death due to liver failure was observed in 0.2% (2/822) of cases. Birth defects occurred in 4.7% (39/822) of pregnancies. The available meta-analysis showed statistically significant positive associations between anti-copper treatment and pregnancy outcome. Our results document the significance of anti-copper treatment as the main factor leading to successful pregnancy, as well as positive outcomes for women with WD.
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Affiliation(s)
- Tomasz Litwin
- Second Department of Neurology, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957 Warsaw, Poland
- Correspondence: ; Tel.: +48-22-4582537; Fax: +48-22-8424023
| | - Jan Bembenek
- Department of Clinical Neurophysiology, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957 Warsaw, Poland
| | - Agnieszka Antos
- Second Department of Neurology, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957 Warsaw, Poland
| | | | - Adam Przybyłkowski
- Department of Gastroenterology and Internal Medicine, Medical University of Warsaw, Banacha 1a, 02-097 Warsaw, Poland
| | - Marta Skowrońska
- Second Department of Neurology, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957 Warsaw, Poland
| | - Łukasz Smoliński
- Second Department of Neurology, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957 Warsaw, Poland
| | - Anna Członkowska
- Second Department of Neurology, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957 Warsaw, Poland
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16
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Li LB, Fan YG, Wu WX, Bai CY, Jia MY, Hu JP, Gao HL, Wang T, Zhong ML, Huang XS, Guo C. Novel melatonin-trientine conjugate as potential therapeutic agents for Alzheimer's disease. Bioorg Chem 2022; 128:106100. [PMID: 35988518 DOI: 10.1016/j.bioorg.2022.106100] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 08/09/2022] [Accepted: 08/11/2022] [Indexed: 12/17/2022]
Abstract
Researchers continue to explore drug targets to treat the characteristic pathologies of Alzheimer's disease (AD). Some drugs relieve the pathological processes of AD to some extent, but the failed clinical trials indicate that multifunctional agents seem more likely to achieve the therapy goals for this neurodegenerative disease. Herein, a novel compound named melatonin-trientine (TM) has been covalently synthesized with the natural antioxidant compounds melatonin and the metal ion chelator trientine. After toxicological and pharmacokinetic verification, we elucidated the effects of intraperitoneal administration of TM on AD-like pathology in 6-month-old mice that express both the β-amyloid (Aβ) precursor protein and presenilin-1 (APP/PS1). We found that TM significantly decreased Aβ deposition and neuronal degeneration in the brains of the APP/PS1 double transgenic mice. This result may be due to the upregulation of iron regulatory protein-2 (IRP2), insulin degrading enzyme (IDE), and low density lipoprotein receptor related protein 1 (LRP1), which leads to decreases in APP and Aβ levels. Additionally, TM may promote APP non-amyloidogenic processing by activating the melatonin receptor-2 (MT2)-dependent signaling pathways, but not MT1. In addition, TM plays an important role in blocking γ-secretase, tau hyperphosphorylation, neuroinflammation, oxidative stress, and metal ion dyshomeostasis. Our results suggest that TM may effectively maximize the therapeutic efficacy of targeting multiple mechanisms associated with AD pathology.
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Affiliation(s)
- Lin-Bo Li
- College of Life and Health Sciences, Northeastern University, Shenyang 110819, China
| | - Yong-Gang Fan
- Institute of Health Sciences, Key Laboratory of Medical Cell Biology of Ministry of Education, China Medical University, Shenyang 110122, China
| | - Wen-Xi Wu
- College of Life and Health Sciences, Northeastern University, Shenyang 110819, China
| | - Chen-Yang Bai
- College of Life and Health Sciences, Northeastern University, Shenyang 110819, China
| | - Meng-Yu Jia
- College of Life and Health Sciences, Northeastern University, Shenyang 110819, China
| | - Jiang-Ping Hu
- Department of Histology and Embryology, Mudanjiang Medical University, Mudanjiang 157011, China
| | - Hui-Ling Gao
- College of Life and Health Sciences, Northeastern University, Shenyang 110819, China
| | - Tao Wang
- College of Life and Health Sciences, Northeastern University, Shenyang 110819, China
| | - Man-Li Zhong
- College of Life and Health Sciences, Northeastern University, Shenyang 110819, China
| | - Xue-Shi Huang
- College of Life and Health Sciences, Northeastern University, Shenyang 110819, China.
| | - Chuang Guo
- College of Life and Health Sciences, Northeastern University, Shenyang 110819, China.
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17
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Shribman S, Marjot T, Sharif A, Vimalesvaran S, Ala A, Alexander G, Dhawan A, Dooley J, Gillett GT, Kelly D, McNeill A, Warner TT, Wheater V, Griffiths W, Bandmann O. Investigation and management of Wilson's disease: a practical guide from the British Association for the Study of the Liver. Lancet Gastroenterol Hepatol 2022; 7:560-575. [PMID: 35429442 DOI: 10.1016/s2468-1253(22)00004-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 01/04/2022] [Accepted: 01/05/2022] [Indexed: 02/07/2023]
Abstract
Wilson's disease is an autosomal-recessive disorder of copper metabolism with hepatic, neurological, psychiatric, ophthalmological, haematological, renal, and rheumatological manifestations. Making a diagnosis can be challenging given that no single test can confirm or exclude the disease, and diagnostic delays are common. Treatment protocols vary and adverse effects, including paradoxical neurological worsening, can occur. In this Review, we provide a practical guide to the diagnosis of Wilson's disease. We include recommendations on indications for testing, how to interpret results, and when additional investigations are required. We also cover treatment initiation, ideally under the guidance of a specialist centre for Wilson's disease, and the principles behind long-term management. This guidance was developed by a multidisciplinary group of Wilson's disease experts formed through the British Association for the Study of the Liver. The guidance has been endorsed by the British Society of Gastroenterology and approved by the Association of British Neurologists.
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Affiliation(s)
- Samuel Shribman
- Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK
| | - Thomas Marjot
- Oxford Liver Unit, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Abubakar Sharif
- Liver Unit, Birmingham Women and Children's Hospital, Birmingham, UK
| | - Sunitha Vimalesvaran
- Paediatric Liver, GI and Nutrition Centre and Mowat Labs, King's College Hospital, Denmark Hill, London, UK
| | - Aftab Ala
- Department of Gastroenterology and Hepatology, Royal Surrey NHS Foundation Trust, Guildford; Institute of Liver Studies, King's College Hospital, London, UK
| | - Graeme Alexander
- University College London Institute of Liver and Digestive Health, London, UK
| | - Anil Dhawan
- Paediatric Liver, GI and Nutrition Centre and Mowat Labs, King's College Hospital, Denmark Hill, London, UK
| | - James Dooley
- University College London Institute of Liver and Digestive Health, London, UK
| | - Godfrey T Gillett
- Laboratory Medicine, Northern General Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Deirdre Kelly
- Liver Unit, Birmingham Women and Children's Hospital, Birmingham, UK
| | | | - Thomas T Warner
- Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK
| | | | | | - Oliver Bandmann
- Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience, University of Sheffield, UK.
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18
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Lynch EN, Campani C, Innocenti T, Dragoni G, Forte P, Galli A. Practical insights into chronic management of hepatic Wilson’s disease. World J Clin Cases 2022; 10:4334-4347. [PMID: 35663095 PMCID: PMC9125272 DOI: 10.12998/wjcc.v10.i14.4334] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 10/07/2021] [Accepted: 03/26/2022] [Indexed: 02/06/2023] Open
Abstract
Wilson’s disease (WD) is a rare inherited disorder of human copper metabolism, with an estimated prevalence of 1:30000-1:50000 and a broad spectrum of hepatic and neuropsychiatric manifestations. In healthy individuals, the bile is the main route of elimination of copper. In WD patients, copper accumulates in the liver, it is released into the bloodstream, and is excreted in urine. Copper can also be accumulated in the brain, kidneys, heart, and osseous matter and causes damage due to direct toxicity or oxidative stress. Hepatic WD is commonly but not exclusively diagnosed in childhood or young adulthood. Adherent, non-cirrhotic WD patients seem to have a normal life expectancy. Nevertheless, chronic management of patients with Wilson’s disease is challenging, as available biochemical tests have many limitations and do not allow a clear identification of non-compliance, overtreatment, or treatment goals. To provide optimal care, clinicians should have a complete understanding of these limitations and counterbalance them with a thorough clinical assessment. The aim of this review is to provide clinicians with practical tools and suggestions which may answer doubts that can arise during chronic management of patients with hepatic WD. In particular, it summarises current knowledge on Wilson’s disease clinical and biochemical monitoring and treatment. It also analyses available evidence on pregnancy and the role of low-copper diet in WD. Future research should focus on trying to provide new copper metabolism tests which could help to guide treatment adjustments.
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Affiliation(s)
- Erica Nicola Lynch
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Claudia Campani
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Tommaso Innocenti
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Gabriele Dragoni
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
- Department of Medical Biotechnologies, University of Siena, Siena 53100, Italy
| | - Paolo Forte
- Division of Gastroenterology, University Hospital “Careggi”, Florence 50134, Italy
| | - Andrea Galli
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
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19
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Garrido I, Marques M, Liberal R, Cardoso H, Lopes S, Macedo G. Wilson disease in Northern Portugal: a long-term follow-up study. Orphanet J Rare Dis 2022; 17:82. [PMID: 35197085 PMCID: PMC8867740 DOI: 10.1186/s13023-022-02245-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 02/13/2022] [Indexed: 12/02/2022] Open
Abstract
Introduction Wilson disease is an autosomal recessive disease of liver copper metabolism with predominant hepatic and neurological manifestations. Long-term data on the clinical follow-up and treatment efficacy are limited due to the low frequency of the disease. We evaluated a large cohort of Wilson disease patients from Northern Portugal during a 20-year follow-up period. Methods Twenty-four patients, diagnosed from 1975 to 2020 in a tertiary care center in Portugal, were retrospectively evaluated according to their clinical presentation, therapies and outcomes. Results Most of the patients were males (54%), with a median age at diagnosis of 19 years old (interquartile range 15–25). The main manifestations of Wilson disease were hepatic (71%) and neurological (25%). Family history was positive in 5 (21%) patients. Four patients (17%) presented with acute liver failure and fifteen (63%) individuals had cirrhosis at diagnosis. Penicillamine therapy was used by 11 (46%) patients, while trientine and zinc were given to 8 (33%) and 1 (4%) patient, respectively. Ten (42%) individuals underwent liver transplantation. The majority of patients (83%) had stable disease or improved outcomes during follow-up. Conclusion This is the largest cohort of adult patients with Wilson disease reported in Northern Portugal. We show that Wilson disease has favorable outcomes with long overall survival, assuming adherence to therapy and lack of other insults to their liver.
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Affiliation(s)
- Isabel Garrido
- Gastroenterology and Hepatology Department, Centro Hospitalar Universitário de São João, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal. .,World Gastroenterology Organization (WGO) Porto Training Center, Porto, Portugal.
| | - Margarida Marques
- Gastroenterology and Hepatology Department, Centro Hospitalar Universitário de São João, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal.,World Gastroenterology Organization (WGO) Porto Training Center, Porto, Portugal
| | - Rodrigo Liberal
- Gastroenterology and Hepatology Department, Centro Hospitalar Universitário de São João, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal.,World Gastroenterology Organization (WGO) Porto Training Center, Porto, Portugal
| | - Hélder Cardoso
- Gastroenterology and Hepatology Department, Centro Hospitalar Universitário de São João, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal.,World Gastroenterology Organization (WGO) Porto Training Center, Porto, Portugal
| | - Susana Lopes
- Gastroenterology and Hepatology Department, Centro Hospitalar Universitário de São João, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal.,World Gastroenterology Organization (WGO) Porto Training Center, Porto, Portugal
| | - Guilherme Macedo
- Gastroenterology and Hepatology Department, Centro Hospitalar Universitário de São João, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal.,World Gastroenterology Organization (WGO) Porto Training Center, Porto, Portugal
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20
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Abstract
Wilson disease (WD) is an autosomal recessive disorder caused by mutations of the ATP7B gene, with a reported prevalence of 1:30,000-50,000. ATP7B encodes an enzyme called transmembrane copper-transporting ATPase, which is essential for copper incorporation into ceruloplasmin and for copper excretion into the bile. A lack or dysfunction of this enzyme results in a progressive accumulation of copper in several organs, especially in the liver, the nervous system, corneas, kidneys, and heart. Children with WD can present with asymptomatic liver disease, cirrhosis, or acute liver failure, with or without neurological and psychiatric symptoms. Approximately 20%-30% of WD patients present with ALF, while most of the other patients have chronic progressive hepatitis or cirrhosis if untreated. Although genetic testing has become a more important diagnostic tool for WD, the diagnosis remains based on both clinical features and laboratory investigations. The aims of treatment are to reduce copper levels and prevent its accumulation in the liver and other organs, especially in the central nervous system. Liver transplantation in WD is a life-saving option for patients presenting with liver failure and encephalopathy. For WD patients treated with chelating agents, adherence to the therapy is essential for long-term success. In this review, we also address specific issues in young adults as compared to children.
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Affiliation(s)
- Atchariya Chanpong
- Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, Denmark Hill, London, United Kingdom,Division of Gastroenterology and Hepatology, Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
| | - Anil Dhawan
- Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, Denmark Hill, London, United Kingdom,Address for correspondence: Prof. Anil Dhawan, Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, Denmark Hill, London SE5 9RH, United Kingdom. E-mail:
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21
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Li C, Ma L, Qi T, Pan W, Huang Y, Luo J, Ye X, Lan Y, Liu J, Zhou W, Ruan F, Zhou J. Urinary trace elements in association with premature ovarian insufficiency and reproductive hormones in a Chinese population. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 225:112731. [PMID: 34488147 DOI: 10.1016/j.ecoenv.2021.112731] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 08/26/2021] [Accepted: 08/27/2021] [Indexed: 06/13/2023]
Abstract
Homeostasis disturbance of trace elements has been linked to adverse reproductive consequences, including premature ovarian insufficiency (POI) in women, but limited evidence has been reported so far. This case-control study evaluated the associations between 5 common urinary trace elements [copper (Cu), manganese (Mn), Iron (Fe), Selenium (Se), and zinc (Zn)] and the odds for POI. Urinary concentrations of these 5 metals and serum levels of POI-related reproductive hormones of 169 cases and 209 healthy controls were measured. The urinary levels of Cu and Se in women with POI were significantly higher than those in the controls. The positive associations were observed between Cu levels and the odds of POI [for the medium tertile: odds ratio (OR) = 3.79, 95% CI: 1.98-7.27, p < 0.001; for the highest tertile: OR = 3.85, 95% CI: 2.00-7.41, p < 0.001]. The highest tertile of urinary Se levels was associated with increasing POI risk (for the highest tertile: OR = 2.54, 95% CI: 1.38-4.70, compared with the lowest tertile, p for trend = 0.001). In POI patients, urinary concentrations of Zn and Fe were negatively associated with serum levels of follicle-stimulating hormone (FSH). Our findings suggested that higher exposure levels of Cu and Se might lead to an increased risk of POI.
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Affiliation(s)
- Chunming Li
- Women's Reproductive Health Key Laboratory of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
| | - LinJuan Ma
- Women's Reproductive Health Key Laboratory of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
| | - Tongyun Qi
- Women's Reproductive Health Key Laboratory of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
| | - Wuye Pan
- MOE Key Laboratory of Environmental Remediation and Ecosystem Health, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China
| | - Yizhou Huang
- Women's Reproductive Health Key Laboratory of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
| | - Jie Luo
- Women's Reproductive Health Key Laboratory of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
| | - Xiaoqing Ye
- College of Medical Technology, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Yibing Lan
- Women's Reproductive Health Key Laboratory of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
| | - Jing Liu
- MOE Key Laboratory of Environmental Remediation and Ecosystem Health, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China
| | - Wenchao Zhou
- Women's Reproductive Health Key Laboratory of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China; Cixi People's Hospital Medical and Health Group, China
| | - Fei Ruan
- Women's Reproductive Health Key Laboratory of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
| | - Jianhong Zhou
- Women's Reproductive Health Key Laboratory of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
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22
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Kasztelan-Szczerbinska B, Cichoz-Lach H. Wilson's Disease: An Update on the Diagnostic Workup and Management. J Clin Med 2021; 10:5097. [PMID: 34768617 PMCID: PMC8584493 DOI: 10.3390/jcm10215097] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 10/18/2021] [Accepted: 10/27/2021] [Indexed: 02/08/2023] Open
Abstract
Wilson's disease (WD) is a rare autosomal recessive disorder of hepatocellular copper deposition. The diagnostic approach to patients with WD may be challenging and is based on a complex set of clinical findings that derive from patient history, physical examination, as well as laboratory and imaging testing. No single examination can unequivocally confirm or exclude the disease. Timely identification of signs and symptoms using novel biomarkers and modern diagnostic tools may help to reduce treatment delays and improve patient prognosis. The proper way of approaching WD management includes, firstly, early diagnosis and prompt treatment introduction; secondly, careful and lifelong monitoring of patient compliance and strict adherence to the treatment; and, last but not least, screening for adverse effects and evaluation of treatment efficacy. Liver transplantation is performed in about 5% of WD patients who present with acute liver failure at first disease presentation or with signs of decompensation in the course of liver cirrhosis. Increasing awareness of this rare inherited disease among health professionals, emphasizing their training to consider early signs and symptoms of the illness, and strict monitoring are vital strategies for the patient safety and efficacy of WD therapy.
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Affiliation(s)
- Beata Kasztelan-Szczerbinska
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, 8 Jaczewski Street, 20-954 Lublin, Poland;
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23
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Abstract
Liver disease in pregnancy can be related to a pre-existing condition (such as autoimmune liver disease) or arise as a consequence of pregnancy. In women with pre-existing disease, pre-pregnancy counselling is important to discuss the potential complications that may occur during pregnancy and how best to manage these. Acute fatty liver of pregnancy and HELLP (haemolysis, elevated liver enzymes and low platelets) syndrome are pregnancy-related liver diseases and are considered obstetric emergencies. Women with liver dysfunction need appropriate investigations, including blood tests and imaging. They should be managed as part of a multidisciplinary team with obstetricians, obstetric anaesthetists, specialist midwives, gastroenterologists and obstetric physicians.
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Affiliation(s)
- Elvyna Lim
- Luton and Dunstable University Hospital, Luton, UK.,joint first authors
| | - Maria Mouyis
- Luton and Dunstable University Hospital, Luton, UK .,joint first authors
| | - Lucy MacKillop
- Oxford University Hospitals NHS Foundation Trust, Oxford, UK and honorary senior clinical lecturer, University of Oxford, Oxford, UK
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24
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Abstract
Chronic liver disease in pregnancy is rare. Historically, many chronic liver diseases were considered contraindications to pregnancy; however, with current monitoring and treatment strategies, pregnancy may be considered in many cases. Preconception and initial antepartum consultation should focus on disease activity, medication safety, risks of pregnancy, as well as the need for additional monitoring during pregnancy. In most cases, a multidisciplinary approach is necessary to ensure optimal maternal and fetal outcomes. Despite improving outcomes, pregnancy in women with the chronic liver disease remains high risk.
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25
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Gao X, Zhu Y, Liu H, Yu H, Wang M. Maternal and fetal outcomes of patients with liver cirrhosis: a case-control study. BMC Pregnancy Childbirth 2021; 21:280. [PMID: 33832453 PMCID: PMC8033723 DOI: 10.1186/s12884-021-03756-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 03/24/2021] [Indexed: 12/27/2022] Open
Abstract
Background We aimed to describe the characteristics and outcomes in pregnant women with liver cirrhosis, and identify the predictors of adverse events of mother and fetus. Methods Retrospectively collected mothers with liver cirrhosis in our center from 6/2010 to 6/2019. Women without liver cirrhosis were selected as a control in a 1:2 ratio. The primary assessment was the frequency of maternal and fetal adverse events. The secondary assessment was the adverse events in patients continuing pregnancy or not and the factors to predict the severe adverse events. Results Of 126 pregnancies enrolled, 29 pregnancies were terminated for worrying disease progression and 97 pregnancies continued. One hundred ninety-four pregnancies without liver cirrhosis were selected as control. At baseline, patients with liver cirrhosis have a lower level of platelet, hemoglobin, prothrombin activity, and a higher level of ALT, total Bilirubin, creatinine. Compared to control, patients with liver cirrhosis had a higher frequency of adverse events, including bleeding gums (7.2%vs. 1.0%), TBA elevation (18.6%vs.3.1%), infection (10.3%vs.0.5%), cesarean section (73.6%vs.49.5%), postpartum hemorrhage (13.8% vs 2.1%), blood transfusion (28.9% vs 2.1%), new ascites or aggravating ascites (6.2% vs.0%), MODS (7.2% vs.0.5%) and intensive care unit admissions (24.1% vs 1.1%). The incidence of severe maternal adverse events was also higher (32.0% vs 1.5%). Women who chose to terminated the pregnancy had less severe adverse events (3.4% vs.32.0%). A higher frequency of fetal/infants’ complications was observed in liver cirrhosis population than control, including newborn asphyxia (10.2% vs1.1%), low birth weight infant (13.6% vs. 2.6%). In patients who progressed into the third trimester, multivariable regression analysis demonstrated that severe adverse events were associated with a higher CTP score (OR 2.128, 95% CI [1.002, 4.521], p = 0.049). Wilson’s disease related liver cirrhosis has a better prognosis (OR = 0.009, 95% CI [0, 0.763], p = 0.038). Conclusions The incidence of the adverse events was significantly increased in pregnancies complicated by cirrhosis. The predictor of severe adverse events is higher CTP score. Wilson’s disease induced liver cirrhosis have a better prognosis. Timely termination of pregnancy during the first trimester may avoid the incidence of severe adverse events. Supplementary Information The online version contains supplementary material available at 10.1186/s12884-021-03756-y.
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Affiliation(s)
- Xiang Gao
- Department of Obstetrics and Gynecology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Yunxia Zhu
- Department of Obstetrics and Gynecology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Haixia Liu
- Department of Clinical Care Medicine of Liver Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Hongwei Yu
- Department of Clinical Care Medicine of Liver Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Ming Wang
- Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Qihelou street No.17, Dongcheng District, Beijing, 100006, China.
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Iorio GG, Conforti A, Vallone R, Carbone L, Matarazzo M, De Rosa A, De Rosa P, Picarelli S, Fedele F, Perruolo G, Formisano P, Iorio R, Alviggi C, Di Dato F. Reproductive function of long-term treated patients with hepatic onset of Wilson's disease: a prospective study. Reprod Biomed Online 2021; 42:835-841. [PMID: 33549482 DOI: 10.1016/j.rbmo.2020.12.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 11/09/2020] [Accepted: 12/22/2020] [Indexed: 12/12/2022]
Abstract
RESEARCH QUESTION Wilson's disease (WD) is a disorder of copper metabolism that can cause hormonal alterations. The impact of WD and its therapies on fertility is not well defined. The aim of this study was to evaluate ovarian reserve and sperm parameters in long-term treated WD patients with hepatic onset. DESIGN WD patients with hepatic onset treated for at least 5 years were compared with healthy controls. Men underwent spermiogram and sperm DNA fragmentation (SDF) analysis. Women were tested for serum FSH, anti-Müllerian hormone (AMH) and sonographic antral follicle count (AFC) in the early follicular phase. Ovulation was monitored with ultrasound and progesterone serum concentrations in the luteal phase. RESULTS The WD group included 26 patients (12 males), the control group 19 subjects (9 males). All patients apart from four (one male) were responders to WD treatment. Sperm count and morphology were comparable between cases and controls. Sperm motility (total and after 1 h) was significantly lower in cases (44.78 ± 21.65%; 47.85 ± 21.52%) than controls (61.88 ± 11.03; 69.44 ± 11.02%, P = 0.03 and 0.01, respectively). The only non-responder had severe oligo-astheno-teratozoospermia. SDF values were normal in cases and controls. AMH, AFC and FSH did not differ between cases and controls. LH was significantly lower in cases (3.36 ± 1.65 mIU/ml) than controls (6.25 ± 1.03 mIU/ml, P < 0.0001). A non-responder woman who developed neurological signs had a 7-year history of infertility. CONCLUSIONS WD patients with hepatic onset, diagnosed early and treated, have no impairment in fertility potential even if males show reduced sperm motility and females lower LH values. Only patients with poor disease control have some evidence of impaired fertility.
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Affiliation(s)
- Giuseppe Gabriele Iorio
- Department of Neuroscience, Reproductive Science and Odontostomatology, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy.
| | - Alessandro Conforti
- Department of Neuroscience, Reproductive Science and Odontostomatology, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Roberta Vallone
- Department of Neuroscience, Reproductive Science and Odontostomatology, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Luigi Carbone
- Department of Neuroscience, Reproductive Science and Odontostomatology, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Margherita Matarazzo
- Department di Translational Medical Science, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Anna De Rosa
- Department of Neuroscience, Reproductive Science and Odontostomatology, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Pasquale De Rosa
- Department of Neuroscience, Reproductive Science and Odontostomatology, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Silvia Picarelli
- Department of Neuroscience, Reproductive Science and Odontostomatology, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Flora Fedele
- Department di Translational Medical Science, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Giuseppe Perruolo
- Department di Translational Medical Science, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Pietro Formisano
- Department di Translational Medical Science, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Raffaele Iorio
- Department di Translational Medical Science, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Carlo Alviggi
- Department of Neuroscience, Reproductive Science and Odontostomatology, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Fabiola Di Dato
- Department di Translational Medical Science, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
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Rahim MN, Pirani T, Williamson C, Heneghan MA. Management of pregnancy in women with cirrhosis. United European Gastroenterol J 2021; 9:110-119. [PMID: 33259738 PMCID: PMC8259114 DOI: 10.1177/2050640620977034] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 10/08/2020] [Indexed: 12/26/2022] Open
Abstract
Although pregnancy is rare in women with cirrhosis, it is increasingly prevalent in an era of modern assisted conception techniques and improved awareness, monitoring and management of underlying liver disease. After overcoming the difficulties of subfertility and becoming pregnant, women undergo a 'high-risk' pregnancy which can be complicated by variceal haemorrhage (≤50%) and hepatic decompensation (≤25%). Management of these complications are similar to non-pregnant individuals. However, there are a few caveats to consider. These pregnancies are associated with adverse maternal and foetal outcomes, such as mortality (0%-8%) and prematurity (19%-67%) in the newborn, and mortality (0%-14%), pregnancy-induced hypertension (5%-22%) and post-partum haemorrhage (5%-45%) in the mother. Pre-pregnancy counselling, use of predictive scores and appropriate variceal screening during pregnancy can stratify patients and improve outcomes. This review focusses on the complications that can occur during pregnancy in women with cirrhosis.
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Affiliation(s)
| | - Tasneem Pirani
- Institute of Liver Studies, King's College Hospital, London, UK
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28
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Roseira J, Lopes R, Silva MJ, Vieira AM, Sampaio M, Calinas F. Gynecological history up to diagnosis and pregnancy outcomes in diagnosed Wilson's disease under therapy - a bicentric matched control cohort study. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2021; 114:198-203. [PMID: 33393331 DOI: 10.17235/reed.2020.7444/2020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Introduction Most studies narrowly focus on pregnancy outcomes comparisons between Wilson Disease (WD) patients on and off treatment. We aimed to identify menses irregularities in untreated WD and evaluate pregnancy outcomes in treated WD compared with matched controls (with and without liver disease). Methods Women with WD, women with Hepatitis C (liver disease controls), and women with other gastrointestinal conditions (controls without liver disease), were identified from two tertiary hospital gastroenterology departments. Gynecological and obstetric data was retrospectively collected. Comparison of gynecological and obstetric outcomes between groups was performed, and regression models were used to further assess obstetric outcomes. Results We identified 18 women with WD, comprising 19 pregnancies under treatment in 11 patients, and 20 women for each control group. Age and liver disease stage between groups was adjusted. The incidence of menses irregularities was higher for WD (late menarche, 83% vs. 10% vs. 10%, p<0.01; irregular cycles, 100% vs. 20% vs. 20%, p<0.01; amenorrhea, 67% vs. 10% vs. 5%, p<0.01). Logistic regression models identified WD as a predictor of miscarriage and low birth weight (OR 6.0; IC 1.1-33.3; p<0.05), but not of birth defects. Neither therapies (D-Pencillamine 300mg or zinc acetate 150mg) nor disease presentation (hepatic or/and neurological) were associated with obstetric complications in WD. Conclusion There was a higher incidence of menses irregularities in untreated women with WD. Additionally, our data suggests that treated WD still carries a higher risk of spontaneous abortion and low birth weight, compared to matched control groups with and without liver disease.
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Affiliation(s)
- Joana Roseira
- Gastroenterology, Algarve Universitary Hospital Center, Portugal
| | - Rita Lopes
- Medicine Faculty - University of the Algarve, Portugal, Portugal
| | - Mário Jorge Silva
- Gastroenterology , Central Lisbon Universitary Hospital Center, Portugal - Capuchos Hospital, Portugal
| | | | | | - Filipe Calinas
- Gastroenterology, Central Lisbon Universitary Hospital Center, Portugal - Capuchos Hospital, Portugal
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29
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Sarkar M, Brady CW, Fleckenstein J, Forde KA, Khungar V, Molleston JP, Afshar Y, Terrault NA. Reproductive Health and Liver Disease: Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology 2021; 73:318-365. [PMID: 32946672 DOI: 10.1002/hep.31559] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 09/08/2020] [Indexed: 12/11/2022]
Affiliation(s)
- Monika Sarkar
- University of California, San Francisco, San Francisco, CA
| | | | | | | | | | - Jean P Molleston
- Indiana University and Riley Hospital for Children, Indianapolis, IN
| | - Yalda Afshar
- University of California, Los Angeles, Los Angeles, CA
| | - Norah A Terrault
- Keck School of Medicine, University of Southern California, Los Angeles, CA
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30
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Grzeszczak K, Kwiatkowski S, Kosik-Bogacka D. The Role of Fe, Zn, and Cu in Pregnancy. Biomolecules 2020; 10:E1176. [PMID: 32806787 PMCID: PMC7463674 DOI: 10.3390/biom10081176] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 08/05/2020] [Accepted: 08/05/2020] [Indexed: 12/15/2022] Open
Abstract
Iron (Fe), copper (Cu), and zinc (Zn) are microelements essential for the proper functioning of living organisms. These elements participatein many processes, including cellular metabolism and antioxidant and anti-inflammatory defenses, and also influence enzyme activity, regulate gene expression, and take part in protein synthesis. Fe, Cu, and Zn have a significant impact on the health of pregnant women and in the development of the fetus, as well as on the health of the newborn. A proper concentration of these elements in the body of women during pregnancy reduces the risk of complications such as anemia, induced hypertension, low birth weight, preeclampsia, and postnatal complications. The interactions between Fe, Cu, and Zn influence their availability due to their similar physicochemical properties. This most often occurs during intestinal absorption, where metal ions compete for binding sites with transport compounds. Additionally, the relationships between these ions have a great influence on the course of reactions in the tissues, as well as on their excretion, which can be stimulated or delayed. This review aims to summarize reports on the influence of Fe, Cu, and Zn on the course of single and multiple pregnancies, and to discuss the interdependencies and mechanisms occurring between Fe, Cu, and Zn.
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Affiliation(s)
- Konrad Grzeszczak
- Department of Biology and Medical Parasitology, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland;
| | - Sebastian Kwiatkowski
- Department of Obstetrics and Gynecology, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland;
| | - Danuta Kosik-Bogacka
- Independent Laboratory of Pharmaceutical Botany, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland
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31
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García-Romero CS, Guzman C, Cervantes A, Cerbón M. Liver disease in pregnancy: Medical aspects and their implications for mother and child. Ann Hepatol 2020; 18:553-562. [PMID: 31126882 DOI: 10.1016/j.aohep.2019.04.009] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 04/15/2019] [Indexed: 02/04/2023]
Abstract
Liver disease during pregnancy is more common than expected and may require specialized intervention. It is important to determine if changes in liver physiology may develop into liver disease, to assure early diagnosis. For adequate surveillance of mother-fetus health outcome, liver disease during pregnancy might require intervention from a hepatologist. Liver diseases have a prevalence of at least 3% of all pregnancies in developed countries, and they are classified into two main categories: related to pregnancy; and those non- related that are present de novo or are preexisting chronic liver diseases. In this review we describe and discuss the main characteristics of those liver diseases associated with pregnancy and only some frequent pre-existing and co-incidental in pregnancy are considered. In addition to the literature review, we compiled the data of liver disease occurring during pregnancies attended at the National Institute of Perinatology in Mexico City in a three-year period. In our tertiary referral women hospital, liver disease was present in 11.24 % of all pregnancies. Associated liver disease was found in 10.8% of all pregnancies, mainly those related to pre-eclampsia (9.9% of pregnancies). Only 0.56% was due to liver disease that was co-incidental or preexisting; the acute or chronic hepatitis C virus was the most frequent in this group (0.12%). When managing pregnancy in referral hospitals in Latin America, it is important to discard liver alterations early for adequate follow up of the disease and to prevent adverse consequences for the mother and child.
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Affiliation(s)
| | - Carolina Guzman
- Laboratorio de Hígado, Páncreas y Motilidad, Unidad de Medicina Experimental, Facultad de Medicina, Universidad Nacional Autonoma de Mexico (UNAM)/Hospital General de México Dr. Eduardo Liceaga, Mexico City, Mexico
| | - Alicia Cervantes
- Servicio de Genética, Hospital General de México Dr. Eduardo Liceaga/Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico.
| | - Marco Cerbón
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología-Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
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32
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Faulkes RE, Chauhan A, Knox E, Johnston T, Thompson F, Ferguson J. Review article: chronic liver disease and pregnancy. Aliment Pharmacol Ther 2020; 52:420-429. [PMID: 32598048 DOI: 10.1111/apt.15908] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 02/02/2020] [Accepted: 06/01/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND The prevalence of chronic liver disease in women of child bearing age is increasing, leading to a higher incidence of pregnancy in this cohort. Chronic medical conditions have a significant adverse effect on maternal morbidity and mortality. To date, reviews on this topic have been written either from a hepatology or obstetrics viewpoint, and no specific guidelines are available solely for the management of chronic liver disease in pregnancy. AIMS To produce a comprehensive review on the clinical management of women with chronic liver disease during pregnancy, addressing the risks of pregnancy to mother and child, how these risks can be ameliorated, and what additional considerations are required for management of chronic liver disease in pregnancy. METHODS Data were collected up to May 2020 from the biomedical database PubMed, national and international guidelines in gastroenterology and hepatology. RESULTS During pregnancy, women with cirrhosis are more likely to develop decompensated disease, worsening of portal hypertension, and to deliver premature infants. CONCLUSIONS The risks associated with pregnancy can be ameliorated by advanced planning, assessing risk using the model for end stage liver disease score and risk reduction through varices screening. A multidisciplinary approach is paramount in order to minimise complications and maximise the chance of a safe pregnancy and birth for mother and baby.
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Affiliation(s)
| | - Abhishek Chauhan
- Liver Unit, Queen Elizabeth Hospital, Birmingham, UK.,Centre for Liver Research, Institute of Immunology and Inflammation, and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, The Medical School, University of Birmingham, Birmingham, UK
| | - Ellen Knox
- Birmingham Womens' Hospital, Birmingham, UK
| | | | | | - James Ferguson
- Liver Unit, Queen Elizabeth Hospital, Birmingham, UK.,Centre for Liver Research, Institute of Immunology and Inflammation, and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, The Medical School, University of Birmingham, Birmingham, UK
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33
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Abstract
PURPOSE OF REVIEW The aim of this article is to review recent developments in the areas of the disease features and treatment of Wilson disease, and survey disorders that share its pathophysiology or clinical symptoms. RECENT FINDINGS Knowledge of the clinical spectrum of Wilson disease has expanded with recognition of patients who present in atypical age groups - patients with very early onset (<5 years) and those in whom symptoms present in mid-to-late adulthood. A disease phenotype with dominant psychiatric features and increased risk of cardiac problems and various sleep disorders have been identified.In addition to a better understanding of the phenotype of Wilson disease itself, features of some related disorders ('Wilson disease-mimics') have been described leading to a better understanding of copper homeostasis in humans. These disorders include diseases of copper disposition, such as mental retardation, enteropathy, deafness, neuropathy, ichthyosis, keratoderma syndrome, Niemann-Pick type C, and certain congenital disorders of glycosylation, as well as analogous disorders of iron and manganese metabolism.Outcomes for existing treatments, including in certain patient subpopulations of interest, are better known. Novel treatment strategies being studied include testing of bis-choline tetrathiomolybdate in phase 2 clinical trial as well as various preclinical explorations of new copper chelators and ways to restore ATP7B function or repair the causative gene. SUMMARY Recent studies have expanded the phenotype of Wilson disease, identified rare inherited metal-related disorders that resemble Wilson disease, and studied long-term outcomes of existing treatments. These developments can be expected to have an immediate as well as a long-term impact on the clinical management of the disease, and point to promising avenues for future research.
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Affiliation(s)
- Annu Aggarwal
- Wilson Disease Clinic, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute (KDAH)
- Memory Clinic, KDAH
| | - Mohit Bhatt
- Wilson Disease Clinic, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute (KDAH)
- Movement Disorder Clinic, KDAH, Mumbai, Maharashtra, India
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Abstract
Movement disorders in women during pregnancy are uncommon. Therefore, high quality studies are limited, and guidelines are lacking for the treatment of movement disorders in pregnancy, thus posing a significant therapeutic challenge for the treating physicians. In this chapter, we discuss movement disorders that arise during pregnancy and the preexisting movement disorders during pregnancy. Common conditions encountered in pregnancy include but are not limited to restless legs syndrome, chorea gravidarum, Parkinson disease, essential tremor, and Huntington disease as well as more rare movement disorders (Wilson's disease, dystonia, etc.). This chapter summarizes the published literature on movement disorders and pharmacologic and surgical considerations for neurologists and physicians in other specialties caring for patients who are pregnant or considering pregnancy.
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Affiliation(s)
- Fang Ba
- Division of Neurology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Janis M Miyasaki
- Division of Neurology, Department of Medicine, University of Alberta, Edmonton, AB, Canada.
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35
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Pfaff AR, Beltz J, King E, Ercal N. Medicinal Thiols: Current Status and New Perspectives. Mini Rev Med Chem 2020; 20:513-529. [PMID: 31746294 PMCID: PMC7286615 DOI: 10.2174/1389557519666191119144100] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 10/29/2019] [Accepted: 10/31/2019] [Indexed: 02/08/2023]
Abstract
The thiol (-SH) functional group is found in a number of drug compounds and confers a unique combination of useful properties. Thiol-containing drugs can reduce radicals and other toxic electrophiles, restore cellular thiol pools, and form stable complexes with heavy metals such as lead, arsenic, and copper. Thus, thiols can treat a variety of conditions by serving as radical scavengers, GSH prodrugs, or metal chelators. Many of the compounds discussed here have been in use for decades, yet continued exploration of their properties has yielded new understanding in recent years, which can be used to optimize their clinical application and provide insights into the development of new treatments. The purpose of this narrative review is to highlight the biochemistry of currently used thiol drugs within the context of developments reported in the last five years. More specifically, this review focuses on thiol drugs that represent the standard of care for their associated conditions, including N-acetylcysteine, 2,3-meso-dimercaptosuccinic acid, British anti-Lewisite, D-penicillamine, amifostine, and others. Reports of novel dosing regimens, delivery strategies, and clinical applications for these compounds were examined with an eye toward emerging approaches to address a wide range of medical conditions in the future.
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Affiliation(s)
- Annalise R. Pfaff
- Department of Chemistry, Missouri University of Science and Technology, Rolla, Missouri, U.S.A
| | - Justin Beltz
- Department of Chemistry, Missouri University of Science and Technology, Rolla, Missouri, U.S.A
| | - Emily King
- Department of Chemistry, Missouri University of Science and Technology, Rolla, Missouri, U.S.A
| | - Nuran Ercal
- Department of Chemistry, Missouri University of Science and Technology, Rolla, Missouri, U.S.A
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36
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Yu XE, Pan M, Han YZ, Yang RM, Wang J, Gao S. The study of Wilson disease in pregnancy management. BMC Pregnancy Childbirth 2019; 19:522. [PMID: 31878905 PMCID: PMC6933618 DOI: 10.1186/s12884-019-2641-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2019] [Accepted: 11/27/2019] [Indexed: 12/22/2022] Open
Abstract
Introduction Pregnancy management in women with Wilson disease (WD) remains an important clinical problem. This research was conducted to investigate how to avoid worsening of WD symptoms during pregnancy and increase pregnancy success in women with WD by identifying the best pregnancy management approaches in these patients. Patients and methods The clinical data of 117 pregnancies among 75 women with WD were retrospectively analyzed. Related information of the fetus was also recorded and analyzed. At the same time, regression analysis was performed for data of 22 pregnant women without WD, as normal controls. Results Of a total of 117 pregnancies among the 75 women with WD and 31 pregnancies among the 22 control womenincluded in this study, there were 108 successful pregnancies and 9 spontaneous abortions. Among the 108 successful pregnancies, 97 women a history of copper chelation therapy before pregnancy; all 97 women stopped anti-copper therapy during pregnancy. The nine women with spontaneous abortion had no pre-pregnancy history of copper displacement therapy. The incidence of lower limb edema was higher in the WD group than in normal controls (P = 0.036). Compared with the control group, there was a higher proportion in the WD group of male infants (P = 0.022) and lower average infant birth weight (t = 3.514, P = 0.001). Conclusion It is relatively safe for women with WD patients to become pregnant. The best management method for pregnancy in women with WD may be intensive pre-pregnancy copper chelation therapy and no anti-copper treatment during pregnancy.
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Affiliation(s)
- Xu-En Yu
- Department of Pharmacology, Basic Medical College, Anhui Medical University, Hefei, 230032, China.,Affiliated Hospital of the Institute of Neurology, Anhui University of Chinese Medicine, Hefei, 230061, China
| | - Min Pan
- Department of Pharmacology, Basic Medical College, Anhui Medical University, Hefei, 230032, China
| | - Yong-Zhu Han
- Affiliated Hospital of the Institute of Neurology, Anhui University of Chinese Medicine, Hefei, 230061, China
| | - Ren-Min Yang
- Affiliated Hospital of the Institute of Neurology, Anhui University of Chinese Medicine, Hefei, 230061, China.
| | - Juan Wang
- Department of Neurology, Hefei Second People's Hospital, Hefei, 230001, China.
| | - Shan Gao
- Department of Pharmacology, Basic Medical College, Anhui Medical University, Hefei, 230032, China.
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Saito K, Onishi E, Itagaki J, Toda N, Haitani A, Yamauchi M. Perioperative anesthetic management for cesarean delivery of severe Wilson’s disease with liver failure: a case report. JA Clin Rep 2019; 5:75. [PMID: 32026097 PMCID: PMC6966748 DOI: 10.1186/s40981-019-0294-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Accepted: 10/15/2019] [Indexed: 01/11/2023] Open
Abstract
Background Wilson’s disease is a rare autosomal recessive disorder affecting copper metabolism, which presents liver and brain dysfunction caused by abnormal copper accumulation. We report a patient who showed exacerbation of liver failure during pregnancy. Case presentation A 24-year-old woman with Wilson’s disease was scheduled for emergency cesarean delivery at 30 weeks of gestation. The patient exhibited severe coagulopathy and prominent body weight gain (+ 30 kg) caused by systemic edema and ascites. We decided to perform emergency cesarean delivery under general anesthesia. We used platelet concentrates, cryoprecipitate, and fibrinogen concentrate. Intraoperative hemorrhage was well controlled. On the 15th postpartum day, weight was reduced by 20 kg and liver function had improved. She and her baby were discharged without complications. Conclusions The appropriate continued treatment of Wilson’s disease and supplementation of coagulation factors and/or platelets when indicated greatly increase the likelihood of a successful pregnancy, even in patients with liver failure exacerbation.
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Arora A, Kumar A, Anand AC, Puri P, Dhiman RK, Acharya SK, Aggarwal K, Aggarwal N, Aggarwal R, Chawla YK, Dixit VK, Duseja A, Eapen CE, Goswami B, Gujral K, Gupta A, Jindal A, Kar P, Kumari K, Madan K, Malhotra J, Malhotra N, Pandey G, Pandey U, Puri RD, Rai RR, Rao PN, Sarin SK, Sharma A, Sharma P, Shenoy KT, Singh KR, Singh SP, Suri V, Trehanpati N, Wadhawan M. Indian National Association for the Study of the Liver-Federation of Obstetric and Gynaecological Societies of India Position Statement on Management of Liver Diseases in Pregnancy. J Clin Exp Hepatol 2019; 9:383-406. [PMID: 31360030 PMCID: PMC6637074 DOI: 10.1016/j.jceh.2019.02.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 02/25/2019] [Indexed: 12/12/2022] Open
Abstract
Liver diseases occurring during pregnancy can be serious and can progress rapidly, affecting outcomes for both the mother and fetus. They are a common cause of concern to an obstetrician and an important reason for referral to a hepatologist, gastroenterologist, or physician. Liver diseases during pregnancy can be divided into disorders unique to pregnancy, those coincidental with pregnancy, and preexisting liver diseases exacerbated by pregnancy. A rapid differential diagnosis between liver diseases related or unrelated to pregnancy is required so that specialist and urgent management of these conditions can be carried out. Specific Indian guidelines for the management of these patients are lacking. The Indian National Association for the Study of the Liver (INASL) in association with the Federation of Obstetric and Gynaecological Societies of India (FOGSI) had set up a taskforce for development of consensus guidelines for management of patients with liver diseases during pregnancy, relevant to India. For development of these guidelines, a two-day roundtable meeting was held on 26-27 May 2018 in New Delhi, to discuss, debate, and finalize the consensus statements. Only those statements that were unanimously approved by most members of the taskforce were accepted. The primary objective of this review is to present the consensus statements approved jointly by the INASL and FOGSI for diagnosing and managing pregnant women with liver diseases. This article provides an overview of liver diseases occurring in pregnancy, an update on the key mechanisms involved in its pathogenesis, and the recommended treatment options.
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Key Words
- ABCB4, ATP-binding cassette subfamily B member 4
- AFLP, Acute fatty liver of pregnancy
- ALF, Acute liver failure
- ALP, Alkaline phosphatase
- ALT, Alanine transferase
- ART, Antiretroviral therapy
- AST, Aspartate aminotransferase
- BCS, Budd-Chiari syndrome
- CT, Computerized tomography
- DIC, Disseminated intravascular coagulation
- DNA, Deoxyribonucleic acid
- DPTA, Diethylenetriamine pentaacetic acid
- ERCP, Endoscopic retrograde cholangiopancreatography
- FDA, Food and Drug Administration
- FOGSI, Federation of Obstetric and Gynaecological Societies of India
- GGT, Gamma-glutamyl transpeptidase
- GI, Gastrointestinal
- GRADE, Grading of Recommendations Assessment Development and Evaluation
- HBIG, Hepatitis B immune globulin
- HBV, Hepatitis B virus
- HBeAg, Hepatitis B envelope antigen
- HBsAg, Hepatitis B surface antigen
- HCV, Hepatitis C virus
- HELLP syndrome
- HELLP, Hemolysis, elevated liver enzymes, low platelet count
- HG, Hyperemesis gravidarum
- HIV, Human immunodeficiency virus
- HV, Hepatic vein
- ICP, Intrahepatic cholestasis of pregnancy
- INASL, Indian National Association for the Study of Liver
- IVF, In vitro fertilization
- LFT, Liver function test
- MDR, Multidrug resistance
- MRI, Magnetic resonance imaging
- MTCT, Mother-to-child transmission
- NA, Nucleos(t)ide analog
- PIH, Pregnancy-induced hypertension
- PT, Prothrombin time
- PUQE, Pregnancy-Unique Quantification of Emesis
- PegIFN, Pegylated interferon
- RNA, Ribonucleic acid
- TAF, Tenofovir alafenamide
- TDF, Tenofovir disoproxil fumarate
- TIPS, Transjugular intrahepatic portosystemic shunt
- UDCA, Ursodeoxycholic acid
- UGI, Upper gastrointestinal
- ULN, Upper limit of normal
- acute fatty liver of pregnancy
- hyperemesis gravidarum
- intrahepatic cholestasis of pregnancy
- liver diseases in pregnancy
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Affiliation(s)
- Anil Arora
- Institute of Liver, Gastroenterology, and Pancreatico-Biliary Sciences, Sir Ganga Ram Hospital, New Delhi, India
| | - Ashish Kumar
- Institute of Liver, Gastroenterology, and Pancreatico-Biliary Sciences, Sir Ganga Ram Hospital, New Delhi, India
| | - Anil C. Anand
- Kalinga Institute of Medical Sciences, KIIT University, Bubaneswar, India
| | - Pankaj Puri
- Institute of Liver, Gastroenterology, and Pancreatico-Biliary Sciences, Sir Ganga Ram Hospital, New Delhi, India
| | - Radha K. Dhiman
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Subrat K. Acharya
- Kalinga Institute of Medical Sciences, KIIT University, Bubaneswar, India
| | - Kiran Aggarwal
- Department of Obstetrics and Gynecology, LHMC & Associated Hospitals, New Delhi, India
| | - Neelam Aggarwal
- Department of Obstetrics and Gynecology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Rakesh Aggarwal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Yogesh K. Chawla
- Kalinga Institute of Medical Sciences, KIIT University, Bubaneswar, India
| | - Vinod K. Dixit
- Department of Gastroenterology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | | | - Bhabadev Goswami
- Department of Gastroenterology, Guwahati Medical College, Assam, India
| | - Kanwal Gujral
- Institute of Obstetrics and Gynecology, Sir Ganga Ram Hospital, New Delhi, India
| | - Anoop Gupta
- Delhi IVF and Fertility Research Centre, New Delhi, India
| | - Ankur Jindal
- Institute of Liver and Biliary Sciences, New Delhi, India
| | - Premashish Kar
- Department of Gastroenterology and Hepatology, Max Super Speciality Hospital, Vaishali, Patparganj, New Delhi
| | - Krishna Kumari
- Max Cure Suyosha Woman & Child Hospital, Hyderabad, India
| | - Kaushal Madan
- Max Smart Super Speciality Hospital, Saket, New Delhi, India
| | | | | | - Gaurav Pandey
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Uma Pandey
- Dept of Obstetrics & Gynecology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Ratna D. Puri
- Institute of Liver, Gastroenterology, and Pancreatico-Biliary Sciences, Sir Ganga Ram Hospital, New Delhi, India
| | - Ramesh R. Rai
- Department of Gastroenterology, NIMS Medical College and Hospital, Jaipur, India
| | - Padaki N. Rao
- Department of Hepatology, Asian Institute of Gastroenterology Hospitals, Hyderabad, India
| | - Shiv K. Sarin
- Institute of Liver and Biliary Sciences, New Delhi, India
| | - Aparna Sharma
- Department of Obstetrics and Gynecology, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Praveen Sharma
- Institute of Liver, Gastroenterology, and Pancreatico-Biliary Sciences, Sir Ganga Ram Hospital, New Delhi, India
| | - Koticherry T. Shenoy
- Sree Gokulam Medical College and Research Foundation, Venjaramoodu, Thiruvananthapuram, India
| | - Karam R. Singh
- Regional Institute of Medical Sciences (RIMS), Imphal, Manipur, India
| | | | - Vanita Suri
- Department of Obstetrics and Gynecology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Abstract
Liver diseases during pregnancy pose a unique clinical challenge because they can affect the lives of both the mother and unborn child. Although severe liver disease is rare, pregnancy-related liver disease affects approximately 3% of pregnancies and can be fatal. Timely recognition and diagnosis are essential in order to institute appropriate management strategies. This article provides an overview of liver diseases during pregnancy and is divided into 2 sections: (1) liver diseases specific to pregnancy, and (2) preexisting or coincident liver diseases during pregnancy.
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Affiliation(s)
- Karen Ma
- Section of Gastroenterology, Division of Digestive Diseases, Department of Internal Medicine, Rush University Medical Center, 1725 West Harrison Street, Suite 207, Chicago, IL 60612, USA
| | - Daniel Berger
- Section of Gastroenterology, Division of Digestive Diseases, Department of Internal Medicine, Rush University Medical Center, 1725 West Harrison Street, Suite 207, Chicago, IL 60612, USA
| | - Nancy Reau
- Section of Hepatology, Division of Digestive Diseases, Department of Internal Medicine, Rush University Medical Center, 1725 West Harrison Street, Suite 319, Chicago, IL 60612, USA.
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Reuner U, Dinger J. Pregnancy and Wilson disease: management and outcome of mother and newborns-experiences of a perinatal centre. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:S56. [PMID: 31179293 DOI: 10.21037/atm.2019.04.40] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Background Wilson disease is an autosomal recessive genetic disorder affecting copper transport leading to hepatic and/or neuropsychiatric manifestation. Untreated Wilson disease in females may cause sub fertility or spontaneous miscarriage. Although the literature shows an increasing number of successful outcomes after treatment, pregnant patients with Wilson disease still need close monitoring and interdisciplinary management. Methods In a retrospective study patient charts of 32 pregnancies in 22 women with Wilson disease were reviewed retrospectively for the initial clinical manifestation, medical treatment prior and during pregnancy, maternal and fetal course and outcome. Results A total of 32 pregnancies in 22 patients were analyzed. The majority of our patients did not have any deterioration of symptoms of Wilson disease prior to and during pregnancy. One pregnant patient decided to stop her anticopper medications while pregnant with fatal outcome for both, mother and foetus. None of our newborns showed major birth defects or side effects in this cohort after maternal chelation treatment. Conclusions Reproductive status and pregnancies of women with Wilson disease may be problematic. Pregnant women need close monitoring and multidisciplinary management. Anticopper therapy during pregnancy and breast feeding are safe. Treatment should be maintained during pregnancy and the pregnant women should be treated by a multi-disciplinary team. With adequate medical treatment and close monitoring before and during pregnancy, a successful outcome of mother and newborn can be achieved.
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Affiliation(s)
- Ulrike Reuner
- Clinic of Neurology, Faculty of Medicine Carl Gustav Carus, Technical University of Dresden, Dresden, Germany
| | - Juergen Dinger
- Department of Neonatology and Paediatric Intensive Care, Faculty of Medicine Carl Gustav Carus, Technical University of Dresden, Dresden, Germany
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Sun Y, Wang W, Guo Y, Zheng B, Li H, Chen J, Zhang W. High copper levels in follicular fluid affect follicle development in polycystic ovary syndrome patients: Population-based and in vitro studies. Toxicol Appl Pharmacol 2019; 365:101-111. [PMID: 30641075 DOI: 10.1016/j.taap.2019.01.008] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 01/09/2019] [Accepted: 01/10/2019] [Indexed: 01/01/2023]
Abstract
Although the adverse effects of copper overexposure on the liver, kidney, spleen and intestinal organs are well known, information about the impact of copper toxicity on human reproduction is limited. A total of 348 infertile patients were enrolled in our present study, including 89 with polycystic ovary syndrome (PCOS), 145 with fallopian tube obstruction and 114 controls. The follicular fluid concentrations of 22 trace elements were measured by inductively coupled plasma mass spectrometry (ICP-MS). Principal component analysis was used to identify trace element profile alterations in different groups. The mRNA levels of steroidogenesis-related genes were measured by real-time PCR. Our results showed that the trace element profile in follicular fluid was obviously altered in PCOS patients. Copper concentrations were significantly (p < .05) higher in the PCOS group than in the other two groups. Increased copper levels in follicular fluid were associated with a higher number of retrievable oocytes in the PCOS group (B = 1.785, p = .001) but a lower rate of high-quality embryos (B = -6.360, p = .050). Moreover, follicular fluid copper levels were positively correlated with follicular fluid progesterone levels (r = 0.275, p = .010) and testosterone levels (r = 0.250, p = .022). Cultured human granulosa cells overexposed to copper showed significantly (p < .05) increased estradiol secretion and decreased testosterone levels. Real-time quantitative PCR revealed a significant (p < .05) increase in CYP19A1 and HSD3b mRNA expression. Our results indicate that increased copper levels in follicular fluid could affect follicle development in PCOS patients, and the mechanism may be related to copper-induced abnormalities in steroidogenesis.
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Affiliation(s)
- Yan Sun
- Reproductive Medicine Center, Fujian Provincial Maternity and Children's Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China; Fujian Province Key Laboratory of Environment and Health, School of Public Health, Fujian Medical University, Fuzhou, Fujian, China
| | - Wenxiang Wang
- Fujian Province Key Laboratory of Environment and Health, School of Public Health, Fujian Medical University, Fuzhou, Fujian, China; Department of Health Inspection and Quarantine, School of Public Health, Fujian Medical University, Fuzhou, Fujian, China.
| | - Yiwei Guo
- Department of Health Inspection and Quarantine, School of Public Health, Fujian Medical University, Fuzhou, Fujian, China
| | - Beihong Zheng
- Reproductive Medicine Center, Fujian Provincial Maternity and Children's Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Hong Li
- Department of Pharmaceuticals, Fujian Health College, Fuzhou, Fujian, China
| | - Jinfa Chen
- Department of Health Inspection and Quarantine, School of Public Health, Fujian Medical University, Fuzhou, Fujian, China
| | - Wenchang Zhang
- Fujian Province Key Laboratory of Environment and Health, School of Public Health, Fujian Medical University, Fuzhou, Fujian, China; Fujian Province Key Laboratory of Environment and Cancer, School of Public Health, Fujian Medical University, Fuzhou, Fujian, China
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Nagral A, Sarma MS, Matthai J, Kukkle PL, Devarbhavi H, Sinha S, Alam S, Bavdekar A, Dhiman RK, Eapen CE, Goyal V, Mohan N, Kandadai RM, Sathiyasekaran M, Poddar U, Sibal A, Sankaranarayanan S, Srivastava A, Thapa BR, Wadia PM, Yachha SK, Dhawan A. Wilson's Disease: Clinical Practice Guidelines of the Indian National Association for Study of the Liver, the Indian Society of Pediatric Gastroenterology, Hepatology and Nutrition, and the Movement Disorders Society of India. J Clin Exp Hepatol 2019; 9:74-98. [PMID: 30765941 PMCID: PMC6363961 DOI: 10.1016/j.jceh.2018.08.009] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Accepted: 08/25/2018] [Indexed: 12/12/2022] Open
Abstract
Clinical practice guidelines for Wilson's disease (WD) have been published by the American Association for the Study of Liver Diseases and European Association for the Study of the Liver in 2008 and 2012, respectively. Their focus was on the hepatic aspects of the disease. Recently, a position paper on pediatric WD was published by the European Society of Pediatric Gastroenterology Hepatology and Nutrition. A need was felt to harmonize guidelines for the hepatic, pediatric, and neurological aspects of the disease and contextualize them to the resource-constrained settings. Therefore, experts from national societies from India representing 3 disciplines, hepatology (Indian National Association for Study of the Liver), pediatric hepatology (Indian Society of Pediatric Gastroenterology, Hepatology and Nutrition), and neurology (Movement Disorders Society of India) got together to evolve fresh guidelines. A literature search on retrospective and prospective studies of WD using MEDLINE (PubMed) was performed. Members voted on each recommendation, using the nominal voting technique. The Grades of Recommendation, Assessment, Development and Evaluation system was used to determine the quality of evidence. Questions related to diagnostic tests, scoring system, and its modification to a version suitable for resource-constrained settings were posed. While ceruloplasmin and 24-h urine copper continue to be important, there is little role of serum copper and penicillamine challenge test in the diagnostic algorithm. A new scoring system - Modified Leipzig score has been suggested with extra points being added for family history and serum ceruloplasmin lower than 5 mg/dl. Liver dry copper estimation and penicillamine challenge test have been removed from the scoring system. Differences in pharmacological approach to neurological and hepatic disease and global monitoring scales have been included. Rising bilirubin and worsening encephalopathy are suggested as indicators predicting need for liver transplant but need to be validated. The clinical practice guidelines provide recommendations for a comprehensive management of WD which will be of value to all specialties.
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Key Words
- AASLD, American Association for the Study of Liver Diseases
- ACLF, Acute on Chronic Liver Failure
- ALF, Acute Liver Failure
- ALT, Alanine Transaminase
- AST, Aspartate Transaminase
- Cu, Copper
- DP, D-Penicillamine
- EASL, European Association for the Study of the Liver
- GAS for WD, Global Assessment Scale for Wilson's Disease
- HCC, Hepatocellular Carcinoma
- INR, International Normalized Ratio
- KF, Kayser-Fleischer
- LT, Liver Transplantation
- MARS, Molecular Absorption Recirculating System
- MELD, Model for End-Stage Liver Disease
- MRI, Magnetic Resonance Imaging
- NGS, Next-Generation Sequencing
- NWI, New Wilson's Index
- PELD, Pediatric end stage liver disease
- TPE, Total Plasma Exchange
- TTM, Tetrathiomolybdate
- WD, Wilson's Disease
- Wilson's disease scoring
- genetic disorder
- modified Leipzig scoring
- rare disease
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Affiliation(s)
- Aabha Nagral
- Department of Gastroenterology, Jaslok Hospital and Research Centre, Mumbai, India
- Department of Gastroenterology, Apollo Hospitals, Navi Mumbai, India
| | - Moinak S. Sarma
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - John Matthai
- Department of Paediatric Gastroenterology, Masonic Medical Centre for Children, Coimbatore, India
| | | | - Harshad Devarbhavi
- Department of Gastroenterology and Hepatology, St. John's Medical College Hospital, Bangalore, India
| | - Sanjib Sinha
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Seema Alam
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | | | - Radha K. Dhiman
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | | | - Vinay Goyal
- Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
| | - Neelam Mohan
- Department of Pediatric Gastroenterology, Hepatology & Liver Transplantation, Medanta – The Medicity Hospital, Gurgaon, India
| | - Rukmini M. Kandadai
- Department of Neurology, Nizam's Institute of Medical Sciences, Hyderabad, India
| | - Malathi Sathiyasekaran
- Department of Pediatric Gastroenterology, Kanchi Kamakoti Childs Trust Hospital Chennai, India
| | - Ujjal Poddar
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Anupam Sibal
- Department of Pediatric Gastroenterology and Hepatology, Indraprastha Apollo Hospitals, New Delhi, India
| | | | - Anshu Srivastava
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Baburam R. Thapa
- Department of Gastroenterology & Pediatric Gastroenterology, MM Medical Institute of Medical Sciences and Research, Mullana, Ambala, India
| | - Pettarusp M. Wadia
- Department of Neurology, Jaslok Hospital and Research Centre, Mumbai, India
| | - Surendra K. Yachha
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Anil Dhawan
- Department of Pediatrics and Pediatric Liver GI and Nutrition Center and Mowat Labs, King's College Hospital, London, UK
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Abstract
PURPOSE OF REVIEW Exciting developments relating to Wilson disease (WD) have taken place with respect to both basic biological and clinical research. This review critically examines some of these findings and considers their implications for current thinking about WD. It is not a comprehensive review of WD as a clinical disorder. RECENT FINDINGS The structure of the gene product of ATP7B, abnormal in WD, is being worked out in detail, along with a broader description of how the protein ATP7B (Wilson ATPase) functions in cells including enterocytes, not only in relation to copper disposition but also to lipid synthesis. Recent population studies raise the possibility that WD displays incomplete penetrance. Innovative screening techniques may increase ascertainment. New strategies for diagnosing and treating WD are being developed. Several disorders have been identified which might qualify as WD-mimics. WD can be difficult to diagnose and treat. Insights from its pathobiology are providing new options for managing WD.
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Woimant F, Djebrani-Oussedik N, Collet C, Girardot N, Poujois A. The hidden face of Wilson's disease. Rev Neurol (Paris) 2018; 174:589-596. [DOI: 10.1016/j.neurol.2018.08.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 08/20/2018] [Accepted: 08/20/2018] [Indexed: 02/07/2023]
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Członkowska A, Litwin T, Dusek P, Ferenci P, Lutsenko S, Medici V, Rybakowski JK, Weiss KH, Schilsky ML. Wilson disease. Nat Rev Dis Primers 2018; 4:21. [PMID: 30190489 PMCID: PMC6416051 DOI: 10.1038/s41572-018-0018-3] [Citation(s) in RCA: 518] [Impact Index Per Article: 74.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Wilson disease (WD) is a potentially treatable, inherited disorder of copper metabolism that is characterized by the pathological accumulation of copper. WD is caused by mutations in ATP7B, which encodes a transmembrane copper-transporting ATPase, leading to impaired copper homeostasis and copper overload in the liver, brain and other organs. The clinical course of WD can vary in the type and severity of symptoms, but progressive liver disease is a common feature. Patients can also present with neurological disorders and psychiatric symptoms. WD is diagnosed using diagnostic algorithms that incorporate clinical symptoms and signs, measures of copper metabolism and DNA analysis of ATP7B. Available treatments include chelation therapy and zinc salts, which reverse copper overload by different mechanisms. Additionally, liver transplantation is indicated in selected cases. New agents, such as tetrathiomolybdate salts, are currently being investigated in clinical trials, and genetic therapies are being tested in animal models. With early diagnosis and treatment, the prognosis is good; however, an important issue is diagnosing patients before the onset of serious symptoms. Advances in screening for WD may therefore bring earlier diagnosis and improvements for patients with WD.
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Affiliation(s)
- Anna Członkowska
- 2nd Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland.
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland.
| | - Tomasz Litwin
- 2nd Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Petr Dusek
- Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Peter Ferenci
- Internal Medicine 3, Department of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Svetlana Lutsenko
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Valentina Medici
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of California, Davis, Sacramento, CA, USA
| | - Janusz K Rybakowski
- Department of Adult Psychiatry, Poznań University of Medical Sciences, Poznań, Poland
| | - Karl Heinz Weiss
- Department of Gastroenterology and Hepatology, University Hospital Heidelberg, Heidelberg, Germany
| | - Michael L Schilsky
- Section of Digestive Diseases and Transplantation and Immunology, Department of Medicine and Surgery, Yale University School of Medicine, New Haven, CT, USA
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The Health Care Transition of Youth With Liver Disease Into the Adult Health System: Position Paper From ESPGHAN and EASL. J Pediatr Gastroenterol Nutr 2018; 66:976-990. [PMID: 29570559 DOI: 10.1097/mpg.0000000000001965] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Medical advances have dramatically improved the long-term prognosis of children and adolescents with once-fatal hepatobiliary diseases. However, there is no generally accepted optimal pathway of care for the transition from paediatric care to the adult health system. AIM The purpose of this position paper is to propose a transition process for young people with paediatric onset hepatobiliary diseases from child-centred to adult-centred healthcare services. METHODS Seventeen ESPGHAN/EASL physicians from 13 countries (Austria, Belgium, France, Germany, Hungary, Italy, the Netherlands, Norway, Poland, Spain, Sweden, Switzerland, and United Kingdom) formulated and answered questions after examining the currently published literature on transition from childhood to adulthood. PubMed and Google Scholar were systematically searched between 1980 and January 2018. Quality of evidence was assessed by the Grading of Recommendation Assessment, Development and Evaluation (GRADE) system. Expert opinions were used to support recommendations whenever the evidence was graded weak. All authors voted on each recommendation, using the nominal voting technique. RESULTS We reviewed the literature regarding the optimal timing for the initiation of the transition process and the transfer of the patient to adult services, principal documents, transition multi-professional team components, main barriers, and goals of the general transition process. A transition plan based on available evidence was agreed focusing on the individual young people's readiness and on coordinated teamwork, with transition monitoring continuing until the first year of adult services.We further agreed on selected features of transitioning processes inherent to the most frequent paediatric-onset hepatobiliary diseases. The discussion highlights specific clinical issues that will probably present to adult gastrointestinal specialists and that should be considered, according to published evidence, in the long-term tracking of patients. CONCLUSIONS Transfer of medical care of individuals with paediatric onset hepatobiliary chronic diseases to adult facilities is a complex task requiring multiple involvements of patients and both paediatric and adult care providers.
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Rabiee A, Hamilton JPA. Pregnancy in Wilson disease. Hepatology 2018; 67:1201-1203. [PMID: 29077220 DOI: 10.1002/hep.29619] [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: 10/05/2017] [Revised: 10/17/2017] [Accepted: 10/25/2017] [Indexed: 12/07/2022]
Affiliation(s)
- Atoosa Rabiee
- Johns Hopkins University School of Medicine, Baltimore, MD
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