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Samreen S, Khan E, Ahmad IZ. Molecular docking and molecular dynamics simulation analysis of bioactive compounds of Cichorium intybus L. seed against hepatocellular carcinoma. J Biomol Struct Dyn 2024; 42:9133-9144. [PMID: 37621217 DOI: 10.1080/07391102.2023.2250465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 08/12/2023] [Indexed: 08/26/2023]
Abstract
In this article, bioactive compounds present in Cichorium intybus L. seeds were collected from literature review and analyzed for probable remedy for hepatocellular carcinoma. Cichorium intybus L. is a traditional plant used all over the world mainly in hepatic disorders and renal diseases. This therapeutic plant has many bioactive compounds like chicoric acid, chlorogenic acid, sesquiterpne lactones, stigmasterols etc are found in seeds. Here, the target protein p53 (PDB ID: 2OCJ) which is involved in many cancerous pathways, is chosen. The preADMET study filtered out some compounds which were then subjected to molecular docking studies by Autodock tool 4.2. Afterwards, two best compounds (Esculetin and Isochlorogenic acid) were screened out on the basis of binding energy as compared to the standard compound (Doxorubicin). All these complexes were then analyzed for stability by molecular dynamics using online GROMACS tool. In the comparative simulation study, the compound Esculetin shows a stable interaction with the p53 over the 100 ns trajectory. Hepatocellular carcinoma accounts for high mortality of cancer related death worldwide. These findings suggest that these compound can be used to treat the hepatocellular carcinoma.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Sadiyah Samreen
- Natural Products Laboratory, Department of Bioengineering, Integral University, Lucknow, India
| | - Elhan Khan
- Natural Products Laboratory, Department of Bioengineering, Integral University, Lucknow, India
| | - Iffat Zareen Ahmad
- Natural Products Laboratory, Department of Bioengineering, Integral University, Lucknow, India
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Heumann P, Albert A, Gülow K, Tümen D, Müller M, Kandulski A. Insights in Molecular Therapies for Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:1831. [PMID: 38791911 PMCID: PMC11120383 DOI: 10.3390/cancers16101831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 05/03/2024] [Accepted: 05/06/2024] [Indexed: 05/26/2024] Open
Abstract
We conducted a comprehensive review of the current literature of published data and clinical trials (MEDLINE), as well as published congress contributions and active recruiting clinical trials on targeted therapies in hepatocellular carcinoma. Combinations of different agents and medical therapy along with radiological interventions were analyzed for the setting of advanced HCC. Those settings were also analyzed in combination with adjuvant situations after resection or radiological treatments. We summarized the current knowledge for each therapeutic setting and combination that currently is or has been under clinical evaluation. We further discuss the results in the background of current treatment guidelines. In addition, we review the pathophysiological mechanisms and pathways for each of these investigated targets and drugs to further elucidate the molecular background and underlying mechanisms of action. Established and recommended targeted treatment options that already exist for patients are considered for systemic treatment: atezolizumab/bevacizumab, durvalumab/tremelimumab, sorafenib, lenvatinib, cabozantinib, regorafenib, and ramucirumab. Combination treatment for systemic treatment and local ablative treatment or transarterial chemoembolization and adjuvant and neoadjuvant treatment strategies are under clinical investigation.
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Affiliation(s)
- Philipp Heumann
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany (K.G.); (D.T.)
| | | | | | | | | | - Arne Kandulski
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany (K.G.); (D.T.)
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Meng L, Treem W, Heap GA, Chen J. A stacking ensemble machine learning model to predict alpha-1 antitrypsin deficiency-associated liver disease clinical outcomes based on UK Biobank data. Sci Rep 2022; 12:17001. [PMID: 36220873 PMCID: PMC9554039 DOI: 10.1038/s41598-022-21389-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Accepted: 09/27/2022] [Indexed: 12/29/2022] Open
Abstract
Alpha-1 antitrypsin deficiency associated liver disease (AATD-LD) is a rare genetic disorder and not well-recognized. Predicting the clinical outcomes of AATD-LD and defining patients more likely to progress to advanced liver disease are crucial for better understanding AATD-LD progression and promoting timely medical intervention. We aimed to develop a tailored machine learning (ML) model to predict the disease progression of AATD-LD. This analysis was conducted through a stacking ensemble learning model by combining five different ML algorithms with 58 predictor variables using nested five-fold cross-validation with repetitions based on the UK Biobank data. Performance of the model was assessed through prediction accuracy, area under the receiver operating characteristic (AUROC), and area under the precision-recall curve (AUPRC). The importance of predictor contributions was evaluated through a feature importance permutation method. The proposed stacking ensemble ML model showed clinically meaningful accuracy and appeared superior to any single ML algorithms in the ensemble, e.g., the AUROC for AATD-LD was 68.1%, 75.9%, 91.2%, and 67.7% for all-cause mortality, liver-related death, liver transplant, and all-cause mortality or liver transplant, respectively. This work supports the use of ML to address the unanswered clinical questions with clinically meaningful accuracy using real-world data.
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Affiliation(s)
- Linxi Meng
- Florida State University, Tallahassee, USA
| | - Will Treem
- Takeda Development Center Americas, Inc., Cambridge, MA, USA
| | - Graham A Heap
- Takeda Development Center Americas, Inc., Cambridge, MA, USA
| | - Jingjing Chen
- Takeda Development Center Americas, Inc., Cambridge, MA, USA.
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Mornex JF, Balduyck M, Bouchecareilh M, Cuvelier A, Epaud R, Kerjouan M, Le Rouzic O, Pison C, Plantier L, Pujazon MC, Reynaud-Gaubert M, Toutain A, Trumbic B, Willemin MC, Zysman M, Brun O, Campana M, Chabot F, Chamouard V, Dechomet M, Fauve J, Girerd B, Gnakamene C, Lefrançois S, Lombard JN, Maitre B, Maynié-François C, Moerman A, Payancé A, Reix P, Revel D, Revel MP, Schuers M, Terrioux P, Theron D, Willersinn F, Cottin V, Mal H. [French clinical practice guidelines for the diagnosis and management of lung disease with alpha 1-antitrypsin deficiency]. Rev Mal Respir 2022; 39:633-656. [PMID: 35906149 DOI: 10.1016/j.rmr.2022.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 05/31/2022] [Indexed: 11/18/2022]
Affiliation(s)
- J-F Mornex
- Université de Lyon, université Lyon 1, INRAE, EPHE, UMR754, IVPC, 69007 Lyon, France; Centre de référence coordonnateur des maladies pulmonaires rares, hospices civils de Lyon, hôpital Louis-Pradel, service de pneumologie, 69500 Bron, France.
| | - M Balduyck
- CHU de Lille, centre de biologie pathologie, laboratoire de biochimie et biologie moléculaire HMNO, faculté de pharmacie, EA 7364 RADEME, université de Lille, service de biochimie et biologie moléculaire, Lille, France
| | - M Bouchecareilh
- Université de Bordeaux, CNRS, Inserm U1053 BaRITon, Bordeaux, France
| | - A Cuvelier
- Service de pneumologie, oncologie thoracique et soins intensifs respiratoires, CHU de Rouen, Rouen, France; Groupe de recherche sur le handicap ventilatoire et neurologique (GRHVN), université Normandie Rouen, Rouen, France
| | - R Epaud
- Centre de références des maladies respiratoires rares, site de Créteil, Créteil, France
| | - M Kerjouan
- Service de pneumologie, CHU Pontchaillou, Rennes, France
| | - O Le Rouzic
- CHU Lille, service de pneumologie et immuno-allergologie, Lille, France; Université de Lille, CNRS, Inserm, institut Pasteur de Lille, U1019, UMR 9017, CIIL, OpInfIELD team, Lille, France
| | - C Pison
- Service de pneumologie physiologie, pôle thorax et vaisseaux, CHU de Grenoble, Grenoble, France; Université Grenoble Alpes, Saint-Martin-d'Hères, France
| | - L Plantier
- Service de pneumologie et explorations fonctionnelles respiratoires, CHRU de Tours, Tours, France; Université de Tours, CEPR, Inserm UMR1100, Tours, France
| | - M-C Pujazon
- Service de pneumologie et allergologie, pôle clinique des voies respiratoires, hôpital Larrey, Toulouse, France
| | - M Reynaud-Gaubert
- Service de pneumologie, centre de compétence pour les maladies pulmonaires rares, AP-HM, CHU Nord, Marseille, France; Aix-Marseille université, IHU-Méditerranée infection, Marseille, France
| | - A Toutain
- Service de génétique, CHU de Tours, Tours, France; UMR 1253, iBrain, université de Tours, Inserm, Tours, France
| | | | - M-C Willemin
- Service de pneumologie et oncologie thoracique, CHU d'Angers, hôpital Larrey, Angers, France
| | - M Zysman
- Service de pneumologie, CHU Haut-Lévèque, Bordeaux, France; Université de Bordeaux, centre de recherche cardiothoracique, Inserm U1045, CIC 1401, Pessac, France
| | - O Brun
- Centre de pneumologie et d'allergologie respiratoire, Perpignan, France
| | - M Campana
- Service de pneumologie, CHR d'Orléans, Orléans, France
| | - F Chabot
- Département de pneumologie, CHRU de Nancy, Vandœuvre-lès-Nancy, France; Inserm U1116, université de Lorraine, Vandœuvre-lès-Nancy, France
| | - V Chamouard
- Service pharmaceutique, hôpital cardiologique, GHE, HCL, Bron, France
| | - M Dechomet
- Service d'immunologie biologique, centre de biologie sud, centre hospitalier Lyon Sud, HCL, Pierre-Bénite, France
| | - J Fauve
- Cabinet médical, Bollène, France
| | - B Girerd
- Université Paris-Saclay, faculté de médecine, Le Kremlin-Bicêtre, France; AP-HP, centre de référence de l'hypertension pulmonaire, service de pneumologie et soins intensifs respiratoires, hôpital Bicêtre, Le Kremlin-Bicêtre, France; Inserm UMR_S 999, hôpital Marie-Lannelongue, Le Plessis-Robinson, France
| | - C Gnakamene
- Service de pneumologie, CH de Montélimar, GH Portes de Provence, Montélimar, France
| | | | | | - B Maitre
- Service de pneumologie, centre hospitalier intercommunal, Créteil, France; Inserm U952, UFR de santé, université Paris-Est Créteil, Créteil, France
| | - C Maynié-François
- Université de Lyon, collège universitaire de médecine générale, Lyon, France; Université Claude-Bernard Lyon 1, laboratoire de biométrie et biologie évolutive, UMR5558, Villeurbanne, France
| | - A Moerman
- CHRU de Lille, hôpital Jeanne-de-Flandre, Lille, France; Cabinet de médecine générale, Lille, France
| | - A Payancé
- Service d'hépatologie, CHU Beaujon, AP-HP, Clichy, France; Filière de santé maladies rares du foie de l'adulte et de l'enfant (FilFoie), CHU Saint-Antoine, Paris, France
| | - P Reix
- Service de pneumologie pédiatrique, allergologie, mucoviscidose, hôpital Femme-Mère-Enfant, HCL, Bron, France; UMR 5558 CNRS équipe EMET, université Claude-Bernard Lyon 1, Villeurbanne, France
| | - D Revel
- Université Claude-Bernard Lyon 1, Lyon, France; Hospices civils de Lyon, Lyon, France
| | - M-P Revel
- Université Paris Descartes, Paris, France; Service de radiologie, hôpital Cochin, AP-HP, Paris, France
| | - M Schuers
- Université de Rouen Normandie, département de médecine générale, Rouen, France; Sorbonne université, LIMICS U1142, Paris, France
| | | | - D Theron
- Asten santé, Isneauville, France
| | | | - V Cottin
- Université de Lyon, université Lyon 1, INRAE, EPHE, UMR754, IVPC, 69007 Lyon, France; Centre de référence coordonnateur des maladies pulmonaires rares, hospices civils de Lyon, hôpital Louis-Pradel, service de pneumologie, 69500 Bron, France
| | - H Mal
- Service de pneumologie B, hôpital Bichat-Claude-Bernard, AP-HP, Paris, France; Inserm U1152, université Paris Diderot, site Xavier Bichat, Paris, France
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Strnad P, Mandorfer M, Choudhury G, Griffiths W, Trautwein C, Loomba R, Schluep T, Chang T, Yi M, Given BD, Hamilton JC, San Martin J, Teckman JH. Fazirsiran for Liver Disease Associated with Alpha 1-Antitrypsin Deficiency. N Engl J Med 2022; 387:514-524. [PMID: 35748699 DOI: 10.1056/nejmoa2205416] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Alpha1-antitrypsin (AAT) deficiency results from carriage of a homozygous SERPINA1 "Z" mutation (proteinase inhibitor [PI] ZZ). The Z allele produces a mutant AAT protein called Z-AAT, which accumulates in hepatocytes and can lead to progressive liver disease and fibrosis. This open-label, phase 2 trial investigated the safety and efficacy of fazirsiran, an RNA interference therapeutic, in patients with liver disease associated with AAT deficiency. METHODS We assigned adults with the PI ZZ genotype and liver fibrosis to receive fazirsiran at a dose of 200 mg (cohorts 1 [4 patients] and 2 [8 patients]) or 100 mg (cohort 1b [4 patients]) subcutaneously on day 1 and week 4 and then every 12 weeks. The primary end point was the change from baseline to week 24 (cohorts 1 and 1b) or week 48 (cohort 2) in liver Z-AAT concentrations, which were measured by means of liquid chromatography-mass spectrometry. RESULTS All the patients had reduced accumulation of Z-AAT in the liver (median reduction, 83% at week 24 or 48). The nadir in serum was a reduction of approximately 90%, and treatment was also associated with a reduction in histologic globule burden (from a mean score of 7.4 [scores range from 0 to 9, with higher scores indicating a greater globule burden] at baseline to 2.3 at week 24 or 48). All cohorts had reductions in liver enzyme concentrations. Fibrosis regression was observed in 7 of 15 patients and fibrosis progression in 2 of 15 patients after 24 or 48 weeks. There were no adverse events leading to trial or drug discontinuation. Four serious adverse events (viral myocarditis, diverticulitis, dyspnea, and vestibular neuronitis) resolved. CONCLUSIONS In this small trial, fazirsiran was associated with a strong reduction of Z-AAT concentrations in the serum and liver and concurrent improvements in liver enzyme concentrations. (Funded by Arrowhead Pharmaceuticals; AROAAT-2002 ClinicalTrials.gov number, NCT03946449.).
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Affiliation(s)
- Pavel Strnad
- From the Department of Internal Medicine III, University Hospital, RWTH (Rheinisch-Westfälische Technische Hochschule) Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE-LIVER), Aachen, Germany (P.S., C.T.); the Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, ERN RARE-LIVER, Vienna (M.M.); the Department of Respiratory Medicine, Royal Infirmary of Edinburgh University Hospital, University of Edinburgh, Edinburgh (G.C.), and the Department of Hepatology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge (W.G.) - both in the United Kingdom; the Division of Gastroenterology, University of California San Diego School of Medicine, La Jolla (R.L.), and Arrowhead Pharmaceuticals, Pasadena (T.S., T.C., M.Y., B.D.G., J.C.H., J.S.M.) - both in California; and the Departments of Pediatrics and Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis (J.H.T.)
| | - Mattias Mandorfer
- From the Department of Internal Medicine III, University Hospital, RWTH (Rheinisch-Westfälische Technische Hochschule) Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE-LIVER), Aachen, Germany (P.S., C.T.); the Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, ERN RARE-LIVER, Vienna (M.M.); the Department of Respiratory Medicine, Royal Infirmary of Edinburgh University Hospital, University of Edinburgh, Edinburgh (G.C.), and the Department of Hepatology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge (W.G.) - both in the United Kingdom; the Division of Gastroenterology, University of California San Diego School of Medicine, La Jolla (R.L.), and Arrowhead Pharmaceuticals, Pasadena (T.S., T.C., M.Y., B.D.G., J.C.H., J.S.M.) - both in California; and the Departments of Pediatrics and Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis (J.H.T.)
| | - Gourab Choudhury
- From the Department of Internal Medicine III, University Hospital, RWTH (Rheinisch-Westfälische Technische Hochschule) Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE-LIVER), Aachen, Germany (P.S., C.T.); the Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, ERN RARE-LIVER, Vienna (M.M.); the Department of Respiratory Medicine, Royal Infirmary of Edinburgh University Hospital, University of Edinburgh, Edinburgh (G.C.), and the Department of Hepatology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge (W.G.) - both in the United Kingdom; the Division of Gastroenterology, University of California San Diego School of Medicine, La Jolla (R.L.), and Arrowhead Pharmaceuticals, Pasadena (T.S., T.C., M.Y., B.D.G., J.C.H., J.S.M.) - both in California; and the Departments of Pediatrics and Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis (J.H.T.)
| | - William Griffiths
- From the Department of Internal Medicine III, University Hospital, RWTH (Rheinisch-Westfälische Technische Hochschule) Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE-LIVER), Aachen, Germany (P.S., C.T.); the Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, ERN RARE-LIVER, Vienna (M.M.); the Department of Respiratory Medicine, Royal Infirmary of Edinburgh University Hospital, University of Edinburgh, Edinburgh (G.C.), and the Department of Hepatology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge (W.G.) - both in the United Kingdom; the Division of Gastroenterology, University of California San Diego School of Medicine, La Jolla (R.L.), and Arrowhead Pharmaceuticals, Pasadena (T.S., T.C., M.Y., B.D.G., J.C.H., J.S.M.) - both in California; and the Departments of Pediatrics and Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis (J.H.T.)
| | - Christian Trautwein
- From the Department of Internal Medicine III, University Hospital, RWTH (Rheinisch-Westfälische Technische Hochschule) Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE-LIVER), Aachen, Germany (P.S., C.T.); the Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, ERN RARE-LIVER, Vienna (M.M.); the Department of Respiratory Medicine, Royal Infirmary of Edinburgh University Hospital, University of Edinburgh, Edinburgh (G.C.), and the Department of Hepatology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge (W.G.) - both in the United Kingdom; the Division of Gastroenterology, University of California San Diego School of Medicine, La Jolla (R.L.), and Arrowhead Pharmaceuticals, Pasadena (T.S., T.C., M.Y., B.D.G., J.C.H., J.S.M.) - both in California; and the Departments of Pediatrics and Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis (J.H.T.)
| | - Rohit Loomba
- From the Department of Internal Medicine III, University Hospital, RWTH (Rheinisch-Westfälische Technische Hochschule) Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE-LIVER), Aachen, Germany (P.S., C.T.); the Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, ERN RARE-LIVER, Vienna (M.M.); the Department of Respiratory Medicine, Royal Infirmary of Edinburgh University Hospital, University of Edinburgh, Edinburgh (G.C.), and the Department of Hepatology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge (W.G.) - both in the United Kingdom; the Division of Gastroenterology, University of California San Diego School of Medicine, La Jolla (R.L.), and Arrowhead Pharmaceuticals, Pasadena (T.S., T.C., M.Y., B.D.G., J.C.H., J.S.M.) - both in California; and the Departments of Pediatrics and Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis (J.H.T.)
| | - Thomas Schluep
- From the Department of Internal Medicine III, University Hospital, RWTH (Rheinisch-Westfälische Technische Hochschule) Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE-LIVER), Aachen, Germany (P.S., C.T.); the Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, ERN RARE-LIVER, Vienna (M.M.); the Department of Respiratory Medicine, Royal Infirmary of Edinburgh University Hospital, University of Edinburgh, Edinburgh (G.C.), and the Department of Hepatology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge (W.G.) - both in the United Kingdom; the Division of Gastroenterology, University of California San Diego School of Medicine, La Jolla (R.L.), and Arrowhead Pharmaceuticals, Pasadena (T.S., T.C., M.Y., B.D.G., J.C.H., J.S.M.) - both in California; and the Departments of Pediatrics and Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis (J.H.T.)
| | - Ting Chang
- From the Department of Internal Medicine III, University Hospital, RWTH (Rheinisch-Westfälische Technische Hochschule) Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE-LIVER), Aachen, Germany (P.S., C.T.); the Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, ERN RARE-LIVER, Vienna (M.M.); the Department of Respiratory Medicine, Royal Infirmary of Edinburgh University Hospital, University of Edinburgh, Edinburgh (G.C.), and the Department of Hepatology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge (W.G.) - both in the United Kingdom; the Division of Gastroenterology, University of California San Diego School of Medicine, La Jolla (R.L.), and Arrowhead Pharmaceuticals, Pasadena (T.S., T.C., M.Y., B.D.G., J.C.H., J.S.M.) - both in California; and the Departments of Pediatrics and Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis (J.H.T.)
| | - Min Yi
- From the Department of Internal Medicine III, University Hospital, RWTH (Rheinisch-Westfälische Technische Hochschule) Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE-LIVER), Aachen, Germany (P.S., C.T.); the Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, ERN RARE-LIVER, Vienna (M.M.); the Department of Respiratory Medicine, Royal Infirmary of Edinburgh University Hospital, University of Edinburgh, Edinburgh (G.C.), and the Department of Hepatology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge (W.G.) - both in the United Kingdom; the Division of Gastroenterology, University of California San Diego School of Medicine, La Jolla (R.L.), and Arrowhead Pharmaceuticals, Pasadena (T.S., T.C., M.Y., B.D.G., J.C.H., J.S.M.) - both in California; and the Departments of Pediatrics and Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis (J.H.T.)
| | - Bruce D Given
- From the Department of Internal Medicine III, University Hospital, RWTH (Rheinisch-Westfälische Technische Hochschule) Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE-LIVER), Aachen, Germany (P.S., C.T.); the Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, ERN RARE-LIVER, Vienna (M.M.); the Department of Respiratory Medicine, Royal Infirmary of Edinburgh University Hospital, University of Edinburgh, Edinburgh (G.C.), and the Department of Hepatology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge (W.G.) - both in the United Kingdom; the Division of Gastroenterology, University of California San Diego School of Medicine, La Jolla (R.L.), and Arrowhead Pharmaceuticals, Pasadena (T.S., T.C., M.Y., B.D.G., J.C.H., J.S.M.) - both in California; and the Departments of Pediatrics and Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis (J.H.T.)
| | - James C Hamilton
- From the Department of Internal Medicine III, University Hospital, RWTH (Rheinisch-Westfälische Technische Hochschule) Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE-LIVER), Aachen, Germany (P.S., C.T.); the Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, ERN RARE-LIVER, Vienna (M.M.); the Department of Respiratory Medicine, Royal Infirmary of Edinburgh University Hospital, University of Edinburgh, Edinburgh (G.C.), and the Department of Hepatology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge (W.G.) - both in the United Kingdom; the Division of Gastroenterology, University of California San Diego School of Medicine, La Jolla (R.L.), and Arrowhead Pharmaceuticals, Pasadena (T.S., T.C., M.Y., B.D.G., J.C.H., J.S.M.) - both in California; and the Departments of Pediatrics and Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis (J.H.T.)
| | - Javier San Martin
- From the Department of Internal Medicine III, University Hospital, RWTH (Rheinisch-Westfälische Technische Hochschule) Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE-LIVER), Aachen, Germany (P.S., C.T.); the Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, ERN RARE-LIVER, Vienna (M.M.); the Department of Respiratory Medicine, Royal Infirmary of Edinburgh University Hospital, University of Edinburgh, Edinburgh (G.C.), and the Department of Hepatology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge (W.G.) - both in the United Kingdom; the Division of Gastroenterology, University of California San Diego School of Medicine, La Jolla (R.L.), and Arrowhead Pharmaceuticals, Pasadena (T.S., T.C., M.Y., B.D.G., J.C.H., J.S.M.) - both in California; and the Departments of Pediatrics and Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis (J.H.T.)
| | - Jeffery H Teckman
- From the Department of Internal Medicine III, University Hospital, RWTH (Rheinisch-Westfälische Technische Hochschule) Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE-LIVER), Aachen, Germany (P.S., C.T.); the Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, ERN RARE-LIVER, Vienna (M.M.); the Department of Respiratory Medicine, Royal Infirmary of Edinburgh University Hospital, University of Edinburgh, Edinburgh (G.C.), and the Department of Hepatology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge (W.G.) - both in the United Kingdom; the Division of Gastroenterology, University of California San Diego School of Medicine, La Jolla (R.L.), and Arrowhead Pharmaceuticals, Pasadena (T.S., T.C., M.Y., B.D.G., J.C.H., J.S.M.) - both in California; and the Departments of Pediatrics and Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis (J.H.T.)
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Balbi B, Benini F, Corda L, Corsico A, Ferrarotti I, Gatta N. An Italian expert consensus on the management of alpha1-antitrypsin deficiency: a comprehensive set of algorithms. Panminerva Med 2022; 64:215-227. [PMID: 35146988 DOI: 10.23736/s0031-0808.22.04592-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Alpha1-antitrypin deficiency (AATD) is a genetic-based risk condition, mainly affecting the lungs and liver. Despite its wide distribution, it is largely underdiagnosed, thus being considered a rare disease, and is consequently managed in ad hoc reference centers. Unfortunately, an easy-to-use algorithm for managing such a complex disease is still lacking. METHODS An expert consensus meeting was conducted among experts in the management of AATD to build a comprehensive algorithm, including diagnosis, monitoring, AAT therapy, rehabilitation and lung transplantation, and liver disease, that could serve as a guide for physicians and treating centers. A panel of AATD specialists evaluated the results of their work. RESULTS Diagnosis is the most delicate phase, and awareness about this condition should be raised among GPs. A set of recommendations has been written about the most suitable follow-up visits. Augmentation therapy with AAT may be useful to reduce the progression of emphysema and lung function decline in selected patients. Exercise capacity may be improved by pulmonary rehabilitation and, in selected cases, by lung volume reduction or lung transplantation. Support therapies are needed for those who develop liver disease, and, in selected cases, liver transplantation may be considered. Patients should be carefully educated about their lifestyle, including smoking cessation, body weight control, and reduced alcohol intake. CONCLUSIONS The proposed algorithm obtained the endorsement of the Italian Society of Pneumology (SIP). However, further studies and additional clinical data are required to confirm the validity of these recommendations.
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Affiliation(s)
- Bruno Balbi
- Pulmonary Rehabilitation of the Institute of Veruno, Istituti Clinici Scientifici Maugeri IRCCS, Novara, Italy -
| | - Federica Benini
- Center for diagnosis, monitoring and therapy of alpha1-antitrypsin deficiency, Gastroenterology Unit, Department of Medicine, Spedali Civili, Brescia, Italy
| | - Luciano Corda
- Center for diagnosis, monitoring and therapy of alpha1-antitrypsin deficiency. Respiratory, Medicine Unit, Department of Internal Medicine, Spedali Civili, Brescia, Italy
| | - Angelo Corsico
- Center for diagnosis of alpha1-antitrypsin hereditary deficiency, Chest Medicine Unit. I.R.C.C.S. Policlinico San Matteo Foundation, University of Pavia, Pavia, Italy
| | - Ilaria Ferrarotti
- Center for diagnosis of alpha1-antitrypsin hereditary deficiency, Chest Medicine Unit. I.R.C.C.S. Policlinico San Matteo Foundation, University of Pavia, Pavia, Italy
| | - Nuccia Gatta
- Patients' association Associazione Nazionale Alfa1-At per la tutela dei pazienti con Deficit di Alfa1-antitripsina, Sarezzo, Brescia, Italy
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Guillaud O, Jacquemin E, Couchonnal E, Vanlemmens C, Francoz C, Chouik Y, Conti F, Duvoux C, Hilleret MN, Kamar N, Houssel-Debry P, Neau-Cransac M, Pageaux GP, Gonzales E, Ackermann O, Gugenheim J, Lachaux A, Ruiz M, Radenne S, Debray D, Lacaille F, McLin V, Duclos-Vallée JC, Samuel D, Coilly A, Dumortier J. Long term results of liver transplantation for alpha-1 antitrypsin deficiency. Dig Liver Dis 2021; 53:606-611. [PMID: 33139195 DOI: 10.1016/j.dld.2020.10.016] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 10/13/2020] [Accepted: 10/13/2020] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Liver transplantation (LT) is the therapeutic option for end-stage liver disease associated with alpha1 antitrypsin (A1AT) deficiency. The aim of the present retrospective study was to report on long-term outcomes following LT for A1AT deficiency. METHODS The medical records of 90 pediatric and adult patients transplanted between 1982 and 2017 in France and Geneva (Switzerland) were reviewed. RESULTS The study population consisted of 32 adults and 58 children; median age at transplant was 13.0 years (range: 0.2-65.1), and 65 were male (72.2%). Eighty-two patients (94.8% of children and 84.4% of adults) had the PI*ZZ genotype/phenotype and eight patients (8.9%) had the Pi*SZ genotype/phenotype. Eighty-four patients (93.3%) were transplanted for end-stage liver disease and six (all Pi*ZZ adults) for HCC. Median follow-up after LT was 13.6 years (0.1-31.7). The overall cumulative patient survival rates post-transplant were 97.8% at 1 year, and 95.5%, 95.5%, 92.0%, 89.1% at 5, 10, 15, 20 years respectively. The overall cumulative graft survival rates were 92.2% at 1 year, and 89.9%, 89.9%, 84.4%, 81.5% at 5, 10, 15 and 20 years, respectively. CONCLUSIONS In a representative cohort of patients having presented with end-stage-liver disease or HCC secondary to A1AT, liver transplantation offered very good patient and graft survival rates.
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Affiliation(s)
- Olivier Guillaud
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Fédération des spécialités digestives, Lyon, France; Ramsay Générale de Santé, Clinique de la Sauvegarde, Lyon, France
| | - Emmanuel Jacquemin
- Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Hépatologie et Transplantation Hépatique Pédiatriques, Centre National de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques, Université Paris Saclay, Le Kremlin-Bicêtre, France; Inserm U1193, Hepatinov, Université Paris Saclay, Orsay, France
| | - Eduardo Couchonnal
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Service d'Hépato-gastroentérologie et Nutrition Pédiatrique, Bron, France
| | | | - Claire Francoz
- Assistance Publique-Hôpitaux de Paris, Hôpital Beaujon, Service d'Hépatologie, Clichy, France
| | - Yasmina Chouik
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Fédération des spécialités digestives, Lyon, France
| | - Filomena Conti
- Assistance Publique-Hôpitaux de Paris, Hôpital La Pitié-Salpétrière, Service d'Hépato-gastroentérolgie, Paris, France
| | - Christophe Duvoux
- Assistance Publique-Hôpitaux de Paris, Hôpital Henri Mondor, Service d'Hépatologie, Créteil, France
| | - Marie-Noëlle Hilleret
- CHU de Grenoble, Hôpital Michalon, Service d'Hépato-Gastroentérologie, La Tronche, France
| | - Nassim Kamar
- CHU de Toulouse, Hôpital Rangueil, Service de Néphrologie-Hypertension artérielle-Dialyse-Transplantation, Toulouse, France
| | | | - Martine Neau-Cransac
- CHU de Bordeaux, Hôpital Haut Lévêque, Service de Chirurgie Hépatobiliaire et de Transplantation Hépatique, Bordeaux, France
| | - Georges-Philippe Pageaux
- CHU de Montpellier, Hôpital Saint-Eloi, Fédération Médico-Chirurgicale des Maladies de l'Appareil Digestif, Montpellier, France
| | - Emmanuel Gonzales
- Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Hépatologie et Transplantation Hépatique Pédiatriques, Centre National de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques, Université Paris Saclay, Le Kremlin-Bicêtre, France; Inserm U1193, Hepatinov, Université Paris Saclay, Orsay, France
| | - Oanez Ackermann
- Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Hépatologie et Transplantation Hépatique Pédiatriques, Centre National de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques, Université Paris Saclay, Le Kremlin-Bicêtre, France; Inserm U1193, Hepatinov, Université Paris Saclay, Orsay, France
| | - Jean Gugenheim
- CHU de Nice, Hôpital L'Archet 2, Service de Chirurgie Digestive, Nice, France
| | - Alain Lachaux
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Service d'Hépato-gastroentérologie et Nutrition Pédiatrique, Bron, France; Université de Lyon, Lyon, France
| | - Mathias Ruiz
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Service d'Hépato-gastroentérologie et Nutrition Pédiatrique, Bron, France
| | - Sylvie Radenne
- Hospices Civils de Lyon, Hôpital de la Croix-Rousse, Service d'Hépatologie, Lyon, France
| | - Dominique Debray
- Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants malades, Unité d'Hépatologie pédiatrique, Centre de référence de l'Atrèsie des voies biliaires et cholestases génétiques, filière de santé Filfoie, Paris, France
| | - Florence Lacaille
- Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants malades, Unité d'Hépatologie pédiatrique, Centre de référence de l'Atrèsie des voies biliaires et cholestases génétiques, filière de santé Filfoie, Paris, France
| | - Valérie McLin
- Centre Suisse du Foie de l'Enfant, Hôpitaux Universitaires de Genève, Département de Pédiatrie, Gynécologie et Obstétrique, Genève, Suisse
| | - Jean-Charles Duclos-Vallée
- Inserm U1193, Hepatinov, Université Paris Saclay, Orsay, France; Assistance Publique-Hôpitaux de Paris, Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France
| | - Didier Samuel
- Inserm U1193, Hepatinov, Université Paris Saclay, Orsay, France; Assistance Publique-Hôpitaux de Paris, Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France
| | - Audrey Coilly
- Inserm U1193, Hepatinov, Université Paris Saclay, Orsay, France; Assistance Publique-Hôpitaux de Paris, Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France
| | - Jérôme Dumortier
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Fédération des spécialités digestives, Lyon, France; Université de Lyon, Lyon, France.
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Finotti M, Auricchio P, Vitale A, Gringeri E, Cillo U. Liver transplantation for rare liver diseases and rare indications for liver transplant. Transl Gastroenterol Hepatol 2021; 6:27. [PMID: 33824931 DOI: 10.21037/tgh-19-282] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 06/12/2020] [Indexed: 12/13/2022] Open
Abstract
Liver transplantation (LT) is currently considered the gold standard treatment for end-stage liver failure. Compared to the first decades of its use, LT is associated with lower comorbidity and mortality, with a 5-year survival over 70%. Worldwide, liver cirrhosis and hepatocellular carcinoma represent the major indications to LT. However, almost 1% of LT is performed for rare diseases or rare indications, which include non-hepatocellular malignancy, vascular disorders, metabolic and congenital liver disorders. These diseases can lead to hepatocellular necrosis, biliary tree abnormality and/or hepatomegaly. Most of these diseases are not associated with liver failure but in highly selected patients, LT represent an effective therapy improving the overall survival and quality of life. Rare indications for LT often overlap with rare diseases. However, rare LT indications for non-rare diseases are rising in the last decades, especially for benign primary liver tumor, colon rectal liver metastasis, neuroendocrine liver metastasis, and cholangiocarcinoma (CCA). Non-rare diseases with rare indication for LT and rare adult disease with an indication for LT are categorized and discussed in detail, focusing on some disorders for which the literature provides a more definitive evidence base. Early referral to a transplant center is encouraged to provide an effective therapeutic option in these non-standard indications for LT.
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Affiliation(s)
- Michele Finotti
- Department of Surgery, Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation Unit, Padova University Hospital, Padova, Italy
| | - Pasquale Auricchio
- Department of Surgery, Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation Unit, Padova University Hospital, Padova, Italy
| | - Alessandro Vitale
- Department of Surgery, Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation Unit, Padova University Hospital, Padova, Italy
| | - Enrico Gringeri
- Department of Surgery, Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation Unit, Padova University Hospital, Padova, Italy
| | - Umberto Cillo
- Department of Surgery, Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation Unit, Padova University Hospital, Padova, Italy
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Chidambaranathan-Reghupaty S, Fisher PB, Sarkar D. Hepatocellular carcinoma (HCC): Epidemiology, etiology and molecular classification. Adv Cancer Res 2020; 149:1-61. [PMID: 33579421 PMCID: PMC8796122 DOI: 10.1016/bs.acr.2020.10.001] [Citation(s) in RCA: 484] [Impact Index Per Article: 96.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC), the primary malignancy of hepatocytes, is a diagnosis with bleak outcome. According to National Cancer Institute's SEER database, the average five-year survival rate of HCC patients in the US is 19.6% but can be as low as 2.5% for advanced, metastatic disease. When diagnosed at early stages, it is treatable with locoregional treatments including surgical resection, Radio-Frequency Ablation, Trans-Arterial Chemoembolization or liver transplantation. However, HCC is usually diagnosed at advanced stages when the tumor is unresectable, making these treatments ineffective. In such instances, systemic therapy with tyrosine kinase inhibitors (TKIs) becomes the only viable option, even though it benefits only 30% of patients, provides only a modest (~3months) increase in overall survival and causes drug resistance within 6months. HCC, like many other cancers, is highly heterogeneous making a one-size fits all option problematic. The selection of liver transplantation, locoregional treatment, TKIs or immune checkpoint inhibitors as a treatment strategy depends on the disease stage and underlying condition(s). Additionally, patients with similar disease phenotype can have different molecular etiology making treatment responses different. Stratification of patients at the molecular level would facilitate development of the most effective treatment option. With the increase in efficiency and affordability of "omics"-level analysis, considerable effort has been expended in classifying HCC at the molecular, metabolic and immunologic levels. This review examines the results of these efforts and the ways they can be leveraged to develop targeted treatment options for HCC.
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Affiliation(s)
- Saranya Chidambaranathan-Reghupaty
- C. Kenneth and Dianne Wright Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA, United States
| | - Paul B Fisher
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States
| | - Devanand Sarkar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States.
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10
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Rashed WM, Kandeil MAM, Mahmoud MO, Ezzat S. Hepatocellular Carcinoma (HCC) in Egypt: A comprehensive overview. J Egypt Natl Canc Inst 2020; 32:5. [PMID: 32372179 DOI: 10.1186/s43046-020-0016-x] [Citation(s) in RCA: 108] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 01/02/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Worldwide, hepatocellular carcinoma (HCC) is a universal problem and its epidemiological data showed variation from place to place. Hepatocellular carcinoma (HCC) is the sixth and fourth common cancer in worldwide and Egypt, respectively. Egypt ranks the third and 15th most populous country in Africa and worldwide, respectively. The aim of this review is to compare the status of HCC in Egypt to that in the worldwide from different issues; risk factors, screening and surveillance, diagnosis and treatment, prevention, as well as research strategy. MAIN BODY The risk factors for HCC in Egypt are of great importance to be reported. The risk factor for HCC are either environmental- or host/genetic-related risk factors. In the last years, there is a tangible improvement of both screening and surveillance strategies of HCC in Egypt. The unprecedented national screening campaign launched by the end of 2018 is a mirror image of this improvement. While the improvement of the HCC prevention requires the governmental health administration to implement health policies. Although the diagnosis of Egyptian HCC patients follows the international guidelines but HCC treatment options are limited in terms of cost. In addition, there are limited Egyptian reports about HCC survival and relapse. Both basic and clinical HCC research in Egypt are still limited compared to worldwide. SHORT CONCLUSION Deep analysis and understanding of factors affecting HCC burden variation worldwide help in customization of efforts exerted to face HCC in different countries especially large country like Egypt. Overall, the presence of a research strategy to fight HCC in Egyptian patients will help in the optimum allocation of available resources to reduce the numbers of HCC cases and deaths and to improve the quality of life.
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Affiliation(s)
- Wafaa M Rashed
- Department of Research, Children's Cancer Hospital-57357, Cairo, Egypt.
| | | | - Mohamed O Mahmoud
- Department of Biochemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Sameera Ezzat
- Department of Epidemiology and Prevention Medicine, National Liver Institute, Menoufia University, Menoufia, Egypt
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11
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Mela M, Smeeton W, Davies SE, Miranda E, Scarpini C, Coleman N, Alexander GJM. The Alpha-1 Antitrypsin Polymer Load Correlates With Hepatocyte Senescence, Fibrosis Stage and Liver-Related Mortality. CHRONIC OBSTRUCTIVE PULMONARY DISEASES-JOURNAL OF THE COPD FOUNDATION 2020; 7:151-162. [PMID: 32726073 DOI: 10.15326/jcopdf.7.3.2019.0158] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Background Alpha-1 antitrypsin deficiency (AATD) is an important, inherited cause of chronic liver disease. Marked variation in fibrosis stages in patients with homozygous deficiency and those factors that determine whether heterozygous carriers develop liver fibrosis, remain unexplained. Murine studies implicate polymerized alpha-1 antitrypsin (AAT) within hepatocytes as pathogenic. Aims and Methods The relationship between the quantity of polymerized AAT within hepatocytes (polymer load), stage of hepatic fibrosis and liver-related clinical outcomes (death, evolution to hepatocellular carcinoma, or need for liver transplantation) were investigated using liver tissue from 92 patients at first presentation with either homozygous or heterozygous AATD. Further tissue-based studies were undertaken to determine if polymerized AAT was associated with failure of cell cycle progression, accelerated aging or hepatocyte senescence by immunohistochemical analysis. Results The AAT polymer load correlated closely with hepatic fibrosis stage and long-term clinical outcome, independent of homozygous or heterozygous status. AAT polymers within hepatocytes correlated closely with failure of cell cycle progression assessed using cell cycle phase markers, accelerated aging manifest as shortened telomeres and other markers consistent with hepatocyte senescence manifest as the presence of nuclear p21 expression and enlarged nuclei. The proportion of p21 positive hepatocytes or hepatocytes with enlarged nuclei correlated with hepatic fibrosis stage and the long-term clinical outcome. Conclusion These data suggest that accumulation of AAT polymers within hepatocytes drives senescence. Quantitation of both the AAT polymer load or hepatocyte senescence markers correlated with hepatic fibrosis stage and the long-term clinical outcome. Either or both could be considered markers of disease severity and treatment response in clinical trials.
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Affiliation(s)
- Marianna Mela
- Division of Gastroenterology and Hepatology, University Department of Medicine, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Wendy Smeeton
- Division of Gastroenterology and Hepatology, University Department of Medicine, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Susan E Davies
- Department of Histopathology, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Elena Miranda
- Department of Biology and Biotechnologies, Charles Darwin and Pasteur Institute Cenci-Bolognetti Foundation, Sapienza University of Rome, Rome, Italy
| | - Cinzia Scarpini
- Department of Pathology, Cambridge University, Cambridge, United Kingdom
| | - Nick Coleman
- Department of Pathology, Cambridge University, Cambridge, United Kingdom
| | - Graeme J M Alexander
- UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, United Kingdom
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Hamesch K, Mandorfer M, Pereira VM, Moeller LS, Pons M, Dolman GE, Reichert MC, Schneider CV, Woditsch V, Voss J, Lindhauer C, Fromme M, Spivak I, Guldiken N, Zhou B, Arslanow A, Schaefer B, Zoller H, Aigner E, Reiberger T, Wetzel M, Siegmund B, Simões C, Gaspar R, Maia L, Costa D, Bento-Miranda M, van Helden J, Yagmur E, Bzdok D, Stolk J, Gleiber W, Knipel V, Windisch W, Mahadeva R, Bals R, Koczulla R, Barrecheguren M, Miravitlles M, Janciauskiene S, Stickel F, Lammert F, Liberal R, Genesca J, Griffiths WJ, Trauner M, Krag A, Trautwein C, Strnad P. Liver Fibrosis and Metabolic Alterations in Adults With alpha-1-antitrypsin Deficiency Caused by the Pi*ZZ Mutation. Gastroenterology 2019; 157:705-719.e18. [PMID: 31121167 DOI: 10.1053/j.gastro.2019.05.013] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2018] [Revised: 05/07/2019] [Accepted: 05/09/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Alpha-1 antitrypsin deficiency (AATD) is among the most common genetic disorders. Severe AATD is caused by a homozygous mutation in the SERPINA1 gene that encodes the Glu342Lys substitution (called the Pi*Z mutation, Pi*ZZ genotype). Pi*ZZ carriers may develop lung and liver diseases. Mutation-associated lung disorders have been well studied, but less is known about the effects in liver. We assessed the liver disease burden and associated features in adults with this form of AATD. METHODS We collected data from 554 Pi*ZZ adults (403 in an exploratory cohort, 151 in a confirmatory cohort), in 9 European countries, with AATD who were homozygous for the Pi*Z mutation, and 234 adults without the Pi*Z mutation (controls), all without pre-existing liver disease. We collected data on demographic parameters, comorbidities, lung- and liver-related health, and blood samples for laboratory analysis. Liver fibrosis was assessed non-invasively via the serum tests Aspartate Aminotransferase to Platelet Ratio Index and HepaScore and via transient elastography. Liver steatosis was determined via transient elastography-based controlled attenuation parameter. We performed histologic analyses of livers from transgenic mice that overexpress the AATD-associated Pi*Z variant. RESULTS Serum levels of liver enzymes were significantly higher in Pi*ZZ carriers vs controls. Based on non-invasive tests for liver fibrosis, significant fibrosis was suspected in 20%-36% of Pi*ZZ carriers, whereas signs of advanced fibrosis were 9- to 20-fold more common in Pi*ZZ carriers compared to non-carriers. Male sex; age older than 50 years; increased levels of alanine aminotransferase, aspartate aminotransferase, or γ-glutamyl transferase; and low numbers of platelets were associated with higher liver fibrosis burden. We did not find evidence for a relationship between lung function and liver fibrosis. Controlled attenuation parameter ≥280 dB/m, suggesting severe steatosis, was detected in 39% of Pi*ZZ carriers vs 31% of controls. Carriers of Pi*ZZ had lower serum concentrations of triglyceride and low- and very-low-density lipoprotein cholesterol than controls, suggesting impaired hepatic secretion of lipid. Livers from Pi*Z-overexpressing mice had steatosis and down-regulation of genes involved in lipid secretion. CONCLUSIONS In studies of AATD adults with the Pi*ZZ mutation, and of Pi*Z-overexpressing mice, we found evidence of liver steatosis and impaired lipid secretion. We identified factors associated with significant liver fibrosis in patients, which could facilitate hepatologic assessment and counseling of individuals who carry the Pi*ZZ mutation. ClinicalTrials.gov Number NCT02929940.
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Affiliation(s)
- Karim Hamesch
- Coordinating Center for Alpha1-Antitrypsin Deficiency-Related Liver Disease of the European Reference Network "Rare Liver" and the European Association for the Study of the Liver Registry Group "Alpha1-Liver," University Hospital Aachen, Aachen, Germany; Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University Vienna, Vienna, Austria
| | - Vítor M Pereira
- Department of Gastroenterology, Centro Hospitalar do Funchal, Madeira, Portugal
| | - Linda S Moeller
- Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Monica Pons
- Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute, Universitat Autonoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain
| | - Grace E Dolman
- Department of Hepatology, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, UK
| | - Matthias C Reichert
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Carolin V Schneider
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany
| | - Vivien Woditsch
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany
| | - Jessica Voss
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany
| | - Cecilia Lindhauer
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany
| | - Malin Fromme
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany
| | - Igor Spivak
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany
| | - Nurdan Guldiken
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany
| | - Biaohuan Zhou
- Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany
| | - Anita Arslanow
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany; Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Benedikt Schaefer
- Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria
| | - Heinz Zoller
- Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria
| | - Elmar Aigner
- Department of Internal Medicine I, Paracelsus Medical University, Salzburg, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University Vienna, Vienna, Austria
| | - Martin Wetzel
- Department of Medicine I, Charité-Universitaetsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Britta Siegmund
- Department of Medicine I, Charité-Universitaetsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Carolina Simões
- Gastroenterology Department, Centro Hospitalar Lisboa Norte, Lisbon, Portugal
| | - Rui Gaspar
- Gastroenterology Department, Centro Hospitalar de São João, Faculty of Medicine of Porto University, Porto, Portugal
| | - Luís Maia
- Gastroenterology Department, Centro Hospitalar do Porto, Porto, Portugal
| | - Dalila Costa
- Gastroenterology Department, Hospital de Braga, Braga, Portugal
| | - Mário Bento-Miranda
- Gastroenterology Department, Hospital Universitário de Coimbra, Coimbra, Portugal
| | - Josef van Helden
- Medical Care Centre, Dr Stein and Colleagues, Moenchengladbach, Germany
| | - Eray Yagmur
- Medical Care Centre, Dr Stein and Colleagues, Moenchengladbach, Germany
| | - Danilo Bzdok
- Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany; Jülich Aachen Research Alliance-Brain, Aachen, Germany
| | - Jan Stolk
- Clinic for Pulmonology, Leiden University Medical Center, Leiden, The Netherlands
| | - Wolfgang Gleiber
- Clinic for Pulmonology, University Hospital Frankfurt, Frankfurt, Germany
| | - Verena Knipel
- Department of Pneumology, Cologne Merheim Hospital, Kliniken der Stadt Köln gGmbH, Witten/Herdecke University, Faculty of Health/School of Medicine, Cologne, Germany
| | - Wolfram Windisch
- Department of Pneumology, Cologne Merheim Hospital, Kliniken der Stadt Köln gGmbH, Witten/Herdecke University, Faculty of Health/School of Medicine, Cologne, Germany
| | - Ravi Mahadeva
- Department of Respiratory Medicine, Cambridge National Institute for Health Research, Biomedical Research Centre, University of Cambridge, Cambridge, UK
| | - Robert Bals
- Department of Medicine V, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Rembert Koczulla
- Clinic for Pneumology, Marburg University Hospital, Marburg, Germany; Institute for Pulmonary Rehabilitation Research, Schoen Clinic Berchtesgadener Land, Member of the Deutsches Zentrum für Lungenforschung, Schönau am Königssee, Germany
| | - Miriam Barrecheguren
- Department of Pneumology, Vall d'Hebron University Hospital, Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Barcelona, Spain
| | - Marc Miravitlles
- Department of Pneumology, Vall d'Hebron University Hospital, Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Barcelona, Spain
| | - Sabina Janciauskiene
- Clinic for Pneumology, German Center for Lung Research, Medical University Hannover, Hannover, Germany
| | - Felix Stickel
- Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Rodrigo Liberal
- Gastroenterology Department, Centro Hospitalar de São João, Faculty of Medicine of Porto University, Porto, Portugal
| | - Joan Genesca
- Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute, Universitat Autonoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain
| | - William J Griffiths
- Department of Hepatology, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, UK
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University Vienna, Vienna, Austria
| | - Aleksander Krag
- Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Christian Trautwein
- Coordinating Center for Alpha1-Antitrypsin Deficiency-Related Liver Disease of the European Reference Network "Rare Liver" and the European Association for the Study of the Liver Registry Group "Alpha1-Liver," University Hospital Aachen, Aachen, Germany; Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany
| | - Pavel Strnad
- Coordinating Center for Alpha1-Antitrypsin Deficiency-Related Liver Disease of the European Reference Network "Rare Liver" and the European Association for the Study of the Liver Registry Group "Alpha1-Liver," University Hospital Aachen, Aachen, Germany; Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany.
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Lopes AP, Mineiro MA, Costa F, Gomes J, Santos C, Antunes C, Maia D, Melo R, Canotilho M, Magalhães E, Vicente I, Valente C, Gonçalves BG, Conde B, Guimarães C, Sousa C, Amado J, Brandão ME, Sucena M, Oliveira MJ, Seixas S, Teixeira V, Telo L. Portuguese consensus document for the management of alpha-1-antitrypsin deficiency. Pulmonology 2019; 24 Suppl 1:1-21. [PMID: 30473034 DOI: 10.1016/j.pulmoe.2018.09.004] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 09/12/2018] [Accepted: 09/14/2018] [Indexed: 01/08/2023] Open
Abstract
Alpha-1-antitrypsin deficiency (AATD) is a genetic autosomal codominant disorder caused by mutations in SERPINA1 gene. It is one of the most prevalent genetic disorders, although it remains underdiagnosed. Whereas at international level there are several areas of consensus on this disorder, in Portugal, inter-hospital heterogeneity in clinical practice and resources available have been adding difficulties in reaching a diagnosis and in making therapeutic decisions in this group of patients. This raised a need to draft a document expressing a national consensus for AATD. To this end, a group of experts in this field was created within the Portuguese Pulmonology Society - Study group on AATD, in order to elaborate the current manuscript. The authors reviewed the existing literature and provide here general guidance and extensive recommendations for the diagnosis and management of AATD that can be adopted by Portuguese clinicians from different areas of Medicine. This article is part of a supplement entitled "Portuguese consensus document for the management of alpha-1-antitrypsin deficiency" which is sponsored by Sociedade Portuguesa de Pneumologia.
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Affiliation(s)
- A P Lopes
- Centro Hospitalar e Universitário de Coimbra (HUC); Alpha-1-antitrypsin deficiency study group coordinator.
| | | | - F Costa
- Centro Hospitalar e Universitário de Coimbra (HG)
| | | | | | | | - D Maia
- Centro Hospital Lisboa Central
| | - R Melo
- Hospital Prof. Doutor Fernando da Fonseca
| | | | | | | | | | | | - B Conde
- Centro Hospitalar de Trás os Montes e Alto Douro
| | | | - C Sousa
- Centro Hospitalar de São João
| | - J Amado
- Unidade Local de Saúde de Matosinhos
| | - M E Brandão
- Centro Hospitalar de Trás os Montes e Alto Douro
| | | | | | - S Seixas
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto (I3S); Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)
| | - V Teixeira
- Serviço de Saúde da Região Autónoma da Madeira (SESARAM)
| | - L Telo
- Centro Hospitalar Lisboa Norte
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14
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Hung MH, Wang XW. Molecular Alterations and Heterogeneity in Hepatocellular Carcinoma. MOLECULAR AND TRANSLATIONAL MEDICINE 2019. [DOI: 10.1007/978-3-030-21540-8_14] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Clark VC, Marek G, Liu C, Collinsworth A, Shuster J, Kurtz T, Nolte J, Brantly M. Clinical and histologic features of adults with alpha-1 antitrypsin deficiency in a non-cirrhotic cohort. J Hepatol 2018; 69:1357-1364. [PMID: 30138687 DOI: 10.1016/j.jhep.2018.08.005] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 07/30/2018] [Accepted: 08/13/2018] [Indexed: 01/14/2023]
Abstract
BACKGROUND & AIMS Alpha-1 antitrypsin deficiency (AATD) is an uncommonly recognized cause of liver disease in adults, with descriptions of its natural history limited to case series and patient-reported data from disease registries. Liver pathology is limited to selected patients or unavailable. Therefore, we aimed to determine the prevalence and severity of liver fibrosis in an adult AATD population who were not known to have cirrhosis, while defining risk factors for fibrosis and testing non-invasive markers of disease. METHODS A total of 94 adults with classic genotype 'PI*ZZ' AATD were recruited from North America and prospectively enrolled in the study. Liver aminotransferases and markers of synthetic function, transient elastography, and liver biopsy were performed. RESULTS The prevalence of clinically significant liver fibrosis (F ≥ 2) was 35.1%. Alanine aminotransferase, aspartate aminotransferase and gamma-glutamyltransferase values were higher in the F ≥ 2 group. Metabolic syndrome was associated with the presence of clinically significant fibrosis (OR 14.2; 95% CI 3.7-55; p <0.001). Additionally, the presence of accumulated abnormal AAT in hepatocytes, portal inflammation, and hepatocellular degeneration were associated with clinically significant fibrosis. The accuracy of transient elastography to detect F ≥ 2 fibrosis was fair, with an AUC of 0.70 (95% CI 0.58-0.82). CONCLUSIONS Over one-third of asymptomatic and lung affected adults with 'PI*ZZ' AATD have significant underlying liver fibrosis. Liver biopsies demonstrated variable amounts of accumulated Z AAT. The risk of liver fibrosis increases in the presence of metabolic syndrome, accumulation of AAT in hepatocytes, and portal inflammation on baseline biopsy. The results support the hypothesis that liver disease in this genetic condition may be related to a "toxic gain of function" from accumulation of AAT in hepatocytes. LAY SUMMARY Individuals diagnosed with classic alpha-1 antitrypsin deficiency (ZZ) are at risk of liver injury and scarring, because of the accumulation of abnormal alpha-1 antitrypsin in the liver. A liver biopsy in ZZ individuals can demonstrate the accumulation of alpha-1 antitrypsin within the liver and identify if any associated liver scarring is present. Indviduals with large amounts of alpha-1 antitrypsin on biopsy may be at risk of liver injury and fibrosis. Additional common medical conditions of diabetes, obesity, high cholesterol, and hypertension (known as metabolic syndrome) are associated with a greater degree of liver injury. CLINICAL TRIAL NUMBER: clinicaltrials.gov NCT01810458.
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Affiliation(s)
- Virginia C Clark
- Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, United States.
| | - George Marek
- Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida, United States
| | - Chen Liu
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, United States; Department of Pathology and Laboratory Medicine, Rutgers New Jersey Medical School, United States
| | - Amy Collinsworth
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, United States
| | - Jonathan Shuster
- Department of Health Outcomes and Policy, University of Florida, United States
| | - Tracie Kurtz
- Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida, United States
| | - Joanna Nolte
- Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida, United States
| | - Mark Brantly
- Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida, United States
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Update in global trends and aetiology of hepatocellular carcinoma. Contemp Oncol (Pozn) 2018; 22:141-150. [PMID: 30455585 PMCID: PMC6238087 DOI: 10.5114/wo.2018.78941] [Citation(s) in RCA: 148] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Accepted: 08/25/2018] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver responsible for an increasing number of cancer-related deaths, especially in developing economies of Asia and Africa. A plethora of risk factors have been described in the literature. Some of the important ones include chronic viral hepatitis, liver cirrhosis, environmental toxins such as aflatoxin, non-alcoholic fatty liver disease, lifestyle factors like alcohol consumption, smoking, and dietary factors, metabolic diseases like diabetes mellitus and obesity, and genetic and hereditary disorders. The development of HCC is complex involving sustained inflammatory damage leading to hepatocyte necrosis, regeneration, and fibrotic deposition. It also poses multiple challenges in diagnosis and treatment despite advances in diagnostic, surgical, and other therapeutic advancements. This is a narrative review of findings of multiple studies that were retrieved from electronic databases like PubMed, MEDLINE, Embase, Google Scholar, Scopus, and Cochrane. We summarise the current knowledge regarding the epidemiology and various risk factors for the development of HCC with a brief note on various prevention strategies.
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Khanna R, Verma SK. Pediatric hepatocellular carcinoma. World J Gastroenterol 2018; 24:3980-3999. [PMID: 30254403 PMCID: PMC6148423 DOI: 10.3748/wjg.v24.i35.3980] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2018] [Revised: 07/11/2018] [Accepted: 08/01/2018] [Indexed: 02/06/2023] Open
Abstract
Pediatric hepatocellular carcinoma (HCC) is the second common malignant liver tumor in children after hepatoblastoma. It differs from the adult HCC in the etiological predisposition, biological behavior and lower frequency of cirrhosis. Perinatally acquired hepatitis-B virus, hepatorenal tyrosinemia, progressive familial intrahepatic cholestasis, glycogen storage disease, Alagille’s syndrome and congenital portosystemic shunts are important predisposing factors. Majority of children (87%) are older than 5 years of age. Following mass immunization against hepatitis-B, there has been a drastic fall in the incidence of new cases of pediatric HCC in the Asia-Pacific region. Management is targeted on complete surgical removal either by resection or liver transplantation. There is a trend towards improving survival of children transplanted for HCC beyond Milan criteria. Chemotherapeutic regimens do not offer good results but may be helpful for down-staging of advanced HCC. Surveillance of children with chronic liver diseases with ultrasound and alpha-fetoprotein may be helpful in timely detection, intervention and overall improvement in outcome of HCC.
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Affiliation(s)
- Rajeev Khanna
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi 110070, India
| | - Sanjeev Kumar Verma
- Department of Pediatrics, King George Medical University, Uttar Pradesh 226003, India
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18
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Hepatic-targeted RNA interference provides robust and persistent knockdown of alpha-1 antitrypsin levels in ZZ patients. J Hepatol 2018; 69:378-384. [PMID: 29572094 DOI: 10.1016/j.jhep.2018.03.012] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 02/19/2018] [Accepted: 03/08/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder causing pulmonary and liver disease. The PiZ mutation in AAT (SERPINA1) results in mis-folded AAT protein (Z-AAT) accumulating in hepatocytes, leading to fibrosis and cirrhosis. RNAi-based therapeutics silencing production of hepatic Z-AAT might benefit patients with AATD-associated liver disease. This study evaluated an RNAi therapeutic to silence production of AAT. METHODS Part A of this double-blind first-in-human study randomized 54 healthy volunteers (HVs) into single dose cohorts (two placebo: four active), receiving escalating doses of the investigational agent ARC-AAT from 0.38 to 8.0 mg/kg or placebo. Part B randomized 11 patients with PiZZ (homozygous for Z-AAT) genotype AATD, who received up to 4.0 mg/kg of ARC-AAT or placebo. Patients with baseline FibroScan® >11 kPa or forced expiratory volume in one second (FEV1) <60% were excluded. Assessments included safety, pharmacokinetics, and change in serum AAT concentrations. RESULTS A total of 36 HVs received ARC-AAT and 18 received placebo (part A). Seven PiZZ individuals received ARC-AAT and four received placebo (part B). A dose response in serum AAT reduction was observed at doses ≥4 mg/kg with similar relative reductions in PiZZ patients and HVs at 4 mg/kg and a maximum reduction of 76.1% (HVs) vs. 78.8% (PiZZ) at this dose. The time it took for serum AAT to return to baseline was similar for HV and PiZZ. There were no notable differences between HV and PiZZ safety parameters. The study was terminated early because of toxicity findings related to the delivery vehicle (ARC-EX1) seen in a non-human primate study. CONCLUSION PiZZ patients and HVs responded similarly to ARC-AAT. Deep and durable knockdown of hepatic AAT production based on observed reduction in serum AAT concentrations was demonstrated. LAY SUMMARY Accumulation of abnormal proteins in the livers of patients with alpha-1 antitrypsin deficiency may lead to decreased liver function and potentially liver failure. Therapeutics targeting the production of these abnormal proteins may be used to prevent or treat liver disease in patients with alpha-1 antitrypsin deficiency. CLINICAL TRIAL REGISTRATION NUMBER NCT02363946.
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Shiani A, Narayanan S, Pena L, Friedman M. The Role of Diagnosis and Treatment of Underlying Liver Disease for the Prognosis of Primary Liver Cancer. Cancer Control 2018; 24:1073274817729240. [PMID: 28975833 PMCID: PMC5937237 DOI: 10.1177/1073274817729240] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related
deaths worldwide. Underlying chronic liver disease has been associated with an
increased risk of developing HCC. This study is a review of the current
literature regarding the diagnosis, prognostic significance, and role of
treating underlying liver disease in patients who are at risk of primary liver
cancer. Relevant peer review of the English literature between 1980 and 2017
within PubMed and the Cochrane library was conducted for scientific content on
current advances in managing chronic liver diseases and the development of
hepatocellular carcinoma. Hepatitis C virus, hepatitis B virus (HBV),
nonalcoholic steatohepatitis, autoimmune hepatitis, hereditary hemochromatosis,
Wilson disease, primary biliary cirrhosis, α 1-antitrypsin deficiency, and
certain drugs lead to an increased risk of developing HCC. Patients with
underlying liver disease have an increased incidence of HCC. Hepatitis C virus,
HBV, and hemochromatosis can directly lead to HCC without the presence of
cirrhosis, while HCC related to other underlying liver diseases occurs in
patients with cirrhosis. Treating the underlying liver disease and reducing the
progression to cirrhosis should lead to a decreased incidence of HCC.
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Affiliation(s)
- Ashok Shiani
- 1 Department of Internal Medicine, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Shreya Narayanan
- 1 Department of Internal Medicine, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Luis Pena
- 2 Department of Gastroenterology, Gastrointestinal Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Mark Friedman
- 2 Department of Gastroenterology, Gastrointestinal Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
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Abstract
Liver cancer remains one of the most common human cancers with a high mortality rate. Therapies for hepatocellular carcinoma (HCC) remain ineffective, due to the heterogeneity of HCC with regard to both the etiology and mutation spectrum, as well as its chemotherapy resistant nature; thus surgical resection and liver transplantation remain the gold standard of patient care. The most common etiologies of HCC are extrinsic factors. Humans have multiple defense mechanisms against extrinsic factor-induced carcinogenesis, of which tumor suppressors play crucial roles in preventing normal cells from becoming cancerous. The tumor suppressor p53 is one of the most frequently mutated genes in liver cancer. p53 regulates expression of genes involved in cell cycle progression, cell death, and cellular metabolism to avert tumor development due to carcinogens. This review article mainly summarizes extrinsic factors that induce liver cancer and potentially have etiological association with p53, including aflatoxin B1, vinyl chloride, non-alcoholic fatty liver disease, iron overload, and infection of hepatitis viruses.
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Affiliation(s)
- Tim Link
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Tomoo Iwakuma
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
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21
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Stoller JK. Alpha-1-Antitrypsin Deficiency: Epidemiological Studies and Other AATD Associated Diseases. ALPHA-1-ANTITRYPSIN DEFICIENCY 2017:133-158. [DOI: 10.1016/b978-0-12-803942-7.00009-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Cummings EE, O’Reilly LP, King DE, Silverman RM, Miedel MT, Luke CJ, Perlmutter DH, Silverman GA, Pak SC. Deficient and Null Variants of SERPINA1 Are Proteotoxic in a Caenorhabditis elegans Model of α1-Antitrypsin Deficiency. PLoS One 2015; 10:e0141542. [PMID: 26512890 PMCID: PMC4626213 DOI: 10.1371/journal.pone.0141542] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Accepted: 10/10/2015] [Indexed: 12/24/2022] Open
Abstract
α1-antitrypsin deficiency (ATD) predisposes patients to both loss-of-function (emphysema) and gain-of-function (liver cirrhosis) phenotypes depending on the type of mutation. Although the Z mutation (ATZ) is the most prevalent cause of ATD, >120 mutant alleles have been identified. In general, these mutations are classified as deficient (<20% normal plasma levels) or null (<1% normal levels) alleles. The deficient alleles, like ATZ, misfold in the ER where they accumulate as toxic monomers, oligomers and aggregates. Thus, deficient alleles may predispose to both gain- and loss-of-function phenotypes. Null variants, if translated, typically yield truncated proteins that are efficiently degraded after being transiently retained in the ER. Clinically, null alleles are only associated with the loss-of-function phenotype. We recently developed a C. elegans model of ATD in order to further elucidate the mechanisms of proteotoxicity (gain-of-function phenotype) induced by the aggregation-prone deficient allele, ATZ. The goal of this study was to use this C. elegans model to determine whether different types of deficient and null alleles, which differentially affect polymerization and secretion rates, correlated to any extent with proteotoxicity. Animals expressing the deficient alleles, Mmalton, Siiyama and S (ATS), showed overall toxicity comparable to that observed in patients. Interestingly, Siiyama expressing animals had smaller intracellular inclusions than ATZ yet appeared to have a greater negative effect on animal fitness. Surprisingly, the null mutants, although efficiently degraded, showed a relatively mild gain-of-function proteotoxic phenotype. However, since null variant proteins are degraded differently and do not appear to accumulate, their mechanism of proteotoxicity is likely to be different to that of polymerizing, deficient mutants. Taken together, these studies showed that C. elegans is an inexpensive tool to assess the proteotoxicity of different AT variants using a transgenic approach.
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Affiliation(s)
- Erin E. Cummings
- Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, United States of America
| | - Linda P. O’Reilly
- Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, United States of America
| | - Dale E. King
- Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, United States of America
| | - Richard M. Silverman
- Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, United States of America
| | - Mark T. Miedel
- Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, United States of America
| | - Cliff J. Luke
- Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, United States of America
| | - David H. Perlmutter
- Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, United States of America
- Department of Cell Biology and Molecular Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
| | - Gary A. Silverman
- Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, United States of America
- Department of Cell Biology and Molecular Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
- * E-mail: (SCP); (GAS)
| | - Stephen C. Pak
- Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, United States of America
- * E-mail: (SCP); (GAS)
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Abstract
Hepatic neoplasia is a rare but serious complication of metabolic diseases in children. The risk of developing neoplasia, the age at onset, and the measures to prevent it differ in the various diseases. We review the most common metabolic disorders that are associated with a heightened risk of developing hepatocellular neoplasms, with a special emphasis on reviewing recent advances in the molecular pathogenesis of the disorders and pre-clinical therapeutic options. The cellular and genetic pathways driving carcinogenesis are poorly understood, but best understood in tyrosinemia.
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Affiliation(s)
- Deborah A Schady
- Department of Pathology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030, USA
| | - Angshumoy Roy
- Department of Pathology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030, USA
| | - Milton J Finegold
- Department of Pathology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030, USA
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Antoury C, Lopez R, Zein N, Stoller JK, Alkhouri N. Alpha-1 antitrypsin deficiency and the risk of hepatocellular carcinoma in end-stage liver disease. World J Hepatol 2015; 7:1427-1432. [PMID: 26052388 PMCID: PMC4450206 DOI: 10.4254/wjh.v7.i10.1427] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2014] [Revised: 03/05/2015] [Accepted: 04/14/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the association between alpha-1 antitrypsin deficiency (A1ATD) and hepatocellular carcinoma (HCC) in patients with end-stage liver disease (ESLD).
METHODS: Patients with cirrhosis and ESLD referred to the Cleveland Clinic Foundation for liver transplantation between 2003 and 2014 were included in the study (N = 675). ESLD was defined as having histological features of cirrhosis and/or radiological evidence of cirrhosis in the context of portal hypertension (ascites, variceal bleeding, thrombocytopenia, or hepatic encephalopathy). A1ATD was diagnosed using phenotype characterization (MZ or ZZ), liver biopsy detection of PAS-positive diastase-resistant (PAS+) globules, or both. Patients with other causes of liver diseases such as hepatitis C virus (HCV), alcoholic liver disease and non-alcoholic steatohepatitis (NASH) or NASH were also included in the study. HCC was diagnosed by using imaging modalities, biopsy findings, or explanted liver inspection. Follow-up time was defined as the number of years from the diagnosis of cirrhosis to the diagnosis of hepatocellular carcinoma, or from the diagnosis of cirrhosis to the last follow up visit. The rate of HCC was assessed using time-to-interval analysis for interval censored data.
RESULTS: This study included 675 patients. 7% of subjects had A1ATD (n = 47). Out of all subjects who did not have A1ATD, 46% had HCV, 17% had alcoholic liver disease, 19% had NASH and 18% had another primary diagnosis. Of the 47 subjects with A1ATD, 15 had a primary diagnosis of A1ATD (PI*ZZ phenotype and PAS+ globules), 8 had a PI*MZ phenotype alone, 14 had PAS+ alone, and 10 had both the PI*MZ phenotype and PAS+. Median follow-up time was 3.4 (25th, 75th percentiles: 1, 5.2) years. The overall rate of hepatocellular carcinoma in all subjects was 29% (n = 199). In the A1ATD group, the incidence rate of HCC was 8.5% compared to 31% in the group of patients with other causes of cirrhosis (P = 0.001). Patients with ESLD due to A1ATD had the lowest yearly cumulative rate of hepatocellular carcinoma at 0.88% per year compared to 2.7% for those with HCV cirrhosis, 1.5% in patients with NASH and 0.9% in alcohol-induced liver disease (P < 0.001).
CONCLUSION: Within this group of patients with ESLD, there was no significant association between A1ATD and increased risk of HCC.
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Wallace MC, Preen D, Jeffrey GP, Adams LA. The evolving epidemiology of hepatocellular carcinoma: a global perspective. Expert Rev Gastroenterol Hepatol 2015; 9:765-79. [PMID: 25827821 DOI: 10.1586/17474124.2015.1028363] [Citation(s) in RCA: 273] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Primary liver cancer, the majority of which are hepatocellular carcinomas, is now the second leading cause of cancer death worldwide. Hepatocellular carcinoma is a unique cancer that typically arises in the setting of chronic liver disease at a rate dependent upon the complex interplay between the host, disease and environmental factors. Infection with chronic hepatitis B or C virus is currently the dominant risk factor worldwide. However, changing lifestyle and environmental factors in western countries plus rising neonatal hepatitis B vaccination rates and decreasing exposure to dietary aflatoxins in developing countries are driving an evolution of the epidemiology of this cancer. An understanding of this change is crucial in combating the rising incidence currently being seen in western regions and will underpin the efforts to reduce the mortality rates associated with this cancer.
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Affiliation(s)
- Michael C Wallace
- University of Western Australia, School of Medicine and Pharmacology, 35 Stirling Highway, Crawley, Perth, Western Australia, Australia
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Martin P, DiMartini A, Feng S, Brown R, Fallon M. Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Hepatology 2014; 59:1144-65. [PMID: 24716201 DOI: 10.1002/hep.26972] [Citation(s) in RCA: 670] [Impact Index Per Article: 60.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Abstract
Our understanding of the patho-physiology of hepatocellular carcinoma (HCC) is still much fragmented making difficult the improvement of the clinical outcome for the majority of HCC patients. Discovery of single nucleotide polymorphisms (SNPs) associated with individual susceptibility to HCC may enable the persons at risk to adapt their lifestyle and legitimate implementation by their doctors of surveillance programs facilitating early detection and subsequent management of the disease. To shed light on the influence of human genetic variation on HCC, we conducted a review of the meta-analyses of candidate SNPs and genome wide association studies (GWAS) performed for HCC by search of PubMed and Google Scholar databases. Genetic variations occurring in pathways historically considered as instrumental for liver tumorigenesis (TP53/MDM2, HLA, glutathione-S-transferases/cytochrome P540, TNFα/TGFβ, etc…) are discussed. An immense majority of the data has been produced in Eastern Asia (China, Japan, Korea). These meta-analyses indicate that the TP53, the MDM2 SNP309 G and the GSTT1 null genotype contribute to an increased risk of HCC both in Asians and Caucasians. Significant differences of odds ratios are, however, commonly observed between Eastern-Asians and other populations. Amazingly, GWAS studies performed so far exclusively with HCC patients from Eastern Asia produced drastically different outcomes pointing at unrelated biological pathways. The small magnitude of the risk associated with the genetic variants raises the question of their future utility as markers in clinical practice. An assessment of their impact on tumor progression (vascular invasion, metastases) remains, however, to be done and may prove to be more useful for clinicians. Finally, the evaluation of these variants is not available for various populations of the world and particularly for Subsaharan Africans who are especially affected by HCC.
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Affiliation(s)
- Sayeh Ezzikouri
- Viral Hepatitis Laboratory, Pasteur Institute of Morocco, Casablanca, Morocco. .,Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc 1, Place Louis Pasteur, 20360, Casablanca, Morocco.
| | - Soumaya Benjelloun
- Viral Hepatitis Laboratory, Pasteur Institute of Morocco, Casablanca, Morocco
| | - Pascal Pineau
- Unité Organisation Nucléaire et Oncogenèse, INSERM U993, Institut Pasteur, Paris, France
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Dawwas MF, Davies SE, Griffiths WJH, Lomas DA, Alexander GJ. Prevalence and Risk Factors for Liver Involvement in Individuals with PiZZ-related Lung Disease. Am J Respir Crit Care Med 2013; 187:502-8. [DOI: 10.1164/rccm.201204-0739oc] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
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Topic A, Ljujic M, Radojkovic D. Alpha-1-antitrypsin in pathogenesis of hepatocellular carcinoma. HEPATITIS MONTHLY 2012; 12:e7042. [PMID: 23162602 PMCID: PMC3496874 DOI: 10.5812/hepatmon.7042] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2012] [Revised: 05/29/2012] [Accepted: 06/30/2012] [Indexed: 12/11/2022]
Abstract
CONTEXT Alpha-1-antitrypsin (A1AT) is the most abundant liver-derived, highly polymorphic, glycoprotein in plasma. Hereditary deficiency of alpha-1-antitrypsin in plasma (A1ATD) is a consequence of accumulation of polymers of A1AT mutants in endoplasmic reticulum of hepatocytes and other A1AT-producing cells. One of the clinical manifestations of A1ATD is liver disease in childhood and cirrhosis and/or hepatocellular carcinoma (HCC) in adulthood. Epidemiology and pathophysiology of liver failure in early childhood caused by A1ATD are well known, but the association with hepatocellular carcinoma is not clarified. The aim of this article is to review different aspects of association between A1AT variants and hepatocellular carcinoma, with emphasis on the epidemiology and molecular pathogenesis. The significance of A1AT as a biomarker in the diagnosis of HCC is also discussed. EVIDENCE ACQUISITIONS Search for relevant articles were performed through Pub Med, HighWire, and Science Direct using the keywords "alpha-1-antitrypsin", "liver diseases", "hepatocellular carcinoma", "SERPINA1". Articles published until 2011 were reviewed. RESULTS Epidemiology studies revealed that severe A1ATD is a significant risk factor for cirrhosis and HCC unrelated to the presence of HBV or HCV infections. However, predisposition to HCC in moderate A1ATD is rare, and probably happens in combination with HBV and/or HCV infections or other unknown risk factors. It is assumed that accumulation of polymers of A1ATD variants in endoplasmic reticulum of hepatocytes leads to damage of hepatocytes by gain-of-function mechanism. Also, increased level of A1AT was recognized as diagnostic and prognostic marker of HCC. CONCLUSIONS Clarification of a carcinogenic role for A1ATD and identification of proinflammatory or some still unknown factors that lead to increased susceptibility to HCC associated with A1ATD may contribute to a better understanding of hepatic carcinogenesis and to the development of new drugs.
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Affiliation(s)
- Aleksandra Topic
- University of Belgrade, Faculty of Pharmacy, Department of Medical Biochemistry, Belgrade, Serbia
- Corresponding author: Aleksandra Topic, University of Belgrade, Faculty of Pharmacy, Department of Medical Biochemistry, Vojvode Stepe, 45011221, Belgrade, Serbia. Tel.: +38-1113951283, Fax: +38-1113972840, E-mail:
| | - Mila Ljujic
- University of Belgrade, Institute of Molecular Genetics and Genetic Engineering, Belgrade, Serbia
| | - Dragica Radojkovic
- University of Belgrade, Institute of Molecular Genetics and Genetic Engineering, Belgrade, Serbia
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Abstract
The only hope for a cure from hepatocellular carcinoma (HCC) rests on early diagnosis as it can be attained through semiannual surveillance with abdominal ultrasound (US) of patients at risk. While the strategy of semiannual screening rests on the growth rate of the tumor that in cirrhotic patients takes 6 months to double its volume, on average, the noninvasive radiological diagnosis of HCC is possible in cirrhotic patients with a de novo HCC and patients with chronic hepatitis B. More recently, metabolic diseases related to insulin resistance, including diabetes and obesity, have been recognized to be causally related to HCC as well, in most patients bridging HCC to the histopathological diagnosis of non-alcoholic steatohepatitis (NASH). While the endpoint of an early diagnosis is achieved quite easily in most patients with >1 cm HCC by computed tomography (CT) or magnetic resonance imaging (MRI) demonstrating the specific pattern of an intense contrast uptake during the arterial phase (wash-in) and contrast wash-out during the venous/delayed phase, nodules <1 cm in size are more difficult to diagnose, almost invariably requiring an enhanced follow up with three monthly examinations with US until they grow in size or change their echo pattern. Owing to the lack of robust controlled evidence demonstrating a clinical benefit of surveillance, the real support for screening for liver cancer comes from the striking differences in response to therapy between screened populations in whom HCC is diagnosed and treated at early stages and patients with more advanced, incidentally detected tumors. This notwithstanding, numerous barriers work against screening effectiveness, including limited or outdated knowledge, lack of financial incentives, and limited access to appropriate testing and treatment. Though strengthening prediction in individual patients is expected to improve the cost-effectiveness ratio of screening, the benefits of approaches like pretreatment patient stratification by clinical, histologic, and genetic scores remain uncertain, while the worthiness of excluding patients with severe comorbidities and aged individuals is still debated.
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Affiliation(s)
- Cristina Della Corte
- Department of Medicine, First Division of Gastroenterology, Centro AM e A Migliavacca for the Study of Liver Disease, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and Università degli Studi di Milano, Milan, Italy
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31
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Nelson D, Teckman J, Di Bisceglie A, Brenner DA. Diagnosis and management of patients with α1-antitrypsin (A1AT) deficiency. Clin Gastroenterol Hepatol 2012; 10:575-80. [PMID: 22200689 PMCID: PMC3360829 DOI: 10.1016/j.cgh.2011.12.028] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2011] [Revised: 12/08/2011] [Accepted: 12/12/2011] [Indexed: 02/07/2023]
Abstract
Alpha(1)-antitrypsin (A1AT) deficiency is an autosomal codominant disease that can cause chronic liver disease, cirrhosis, and hepatocellular carcinoma in children and adults and increases risk for emphysema in adults. The development of symptomatic disease varies; some patients have life-threatening symptoms in childhood, whereas others remain asymptomatic and healthy into old age. As a result of this variability, patients present across multiple disciplines, including pediatrics, adult medicine, hepatology, genetics, and pulmonology. This can give physicians the mistaken impression that the condition is less common than it actually is and can lead to fragmented care that omits critical interventions commonly performed by other specialists. We sought to present a rational approach for hepatologists to manage adult patients with A1AT deficiency.
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Affiliation(s)
- David Nelson
- Department of Medicine, University of Florida, Gainesville, FL, 32611
| | - Jeffrey Teckman
- Department of Pediatrics, Saint Louis University, St. Louis, MO, 63104
| | - Adrian Di Bisceglie
- Department of Internal Medicine, Saint Louis University, St Louis, MO, 63104
| | - David A. Brenner
- Department of Medicine, University of California, San Diego, La Jolla, CA, 92093
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Czaja AJ. Cryptogenic chronic hepatitis and its changing guise in adults. Dig Dis Sci 2011; 56:3421-38. [PMID: 21647651 DOI: 10.1007/s10620-011-1769-9] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2011] [Accepted: 05/20/2011] [Indexed: 12/11/2022]
Abstract
Cryptogenic chronic hepatitis is a disease that is unexplained by conventional clinical, laboratory and histological findings, and it can progress to cirrhosis, develop hepatocellular carcinoma, and require liver transplantation. The goals of this review are to describe the changing phenotype of cryptogenic chronic hepatitis in adults, develop a diagnostic algorithm appropriate to current practice, and suggest treatment options. The frequency of cryptogenic hepatitis is estimated at 5.4%. Cryptogenic cirrhosis is diagnosed in 5-30% of patients with cirrhosis, and it is present in 3-14% of adults awaiting liver transplantation. Nonalcoholic fatty liver disease has been implicated in 21-63% of patients, and autoimmune hepatitis is a likely diagnosis in 10-54% of individuals. Viral infections, hereditary liver diseases, celiac disease, and unsuspected alcohol or drug-induced liver injury are recognized infrequently in the current cryptogenic population. Manifestations of the metabolic syndrome heighten the suspicion of nonalcoholic fatty liver disease, and the absence of hepatic steatosis does not discount this possibility. The diagnostic scoring system of the International Autoimmune Hepatitis Group can support the diagnosis of autoimmune hepatitis in some patients. Certain genetic mutations may have disease-specificity, and they suggest that some patients may have an independent and uncharacterized disease. Corticosteroid therapy is effective in patients with autoimmune features, and life-style changes and specific therapies for manifestations of the metabolic syndrome are appropriate for all obese patients. The 1- and 5-year survivals after liver transplantation have ranged from 72-85% to 58-73%, respectively.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street S.W., Rochester, MN 55905, USA.
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33
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Hereditary pancreatic and hepatobiliary cancers. Int J Surg Oncol 2011; 2011:154673. [PMID: 22312493 PMCID: PMC3265279 DOI: 10.1155/2011/154673] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2011] [Accepted: 04/28/2011] [Indexed: 02/08/2023] Open
Abstract
Hereditary etiologies of pancreatic and hepatobiliary cancers are increasingly recognized. An estimated >10% of pancreatic and increasing number of hepatobiliary cancers are hereditary. The cumulative risk of hereditary pancreatic cancer ranges from measurable but negligible in cystic fibrosis to a sobering 70% in cases of hereditary pancreatitis. Candidates for pancreatic cancer surveillance are those with a risk pancreatic cancer estimated to be >10-fold that of the normal population. Screening for pancreatic cancer in high-risk individuals is typically performed by endoscopic ultrasound and should begin at least 10 years prior to the age of the youngest affected relative. Disease states known to be associated with increased risk of hepatocellular cancer include hereditary hemochromatosis, autoimmune hepatitis, porphyria, and α1-antitrypsin deficiency, with relative risks as high as 36-fold. Although much less is known about hereditary bile-duct cancers, Muir-Torre syndrome and bile salt export pump deficiency are diseases whose association with hereditary carcinogenesis is under investigation.
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34
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Abstract
Hepatic neoplasia is a rare but serious complication of metabolic diseases in children. The risk of developing neoplasia, the age at onset, and the measures to prevent it differ in various diseases. This article reviews the most common metabolic disorders in humans that are associated with neoplasms, with a special emphasis on the molecular etiopathogenesis of this process. The cellular pathways driving carcinogenesis are poorly understood, but best known in tyrosinemia.
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Affiliation(s)
- Angshumoy Roy
- Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
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35
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Abstract
Hepatocellular carcinoma (HCC) is a common form of cancer that arises from hepatocytes and whose risk may be affected by several known environmental factors, including hepatitis viruses, alcohol, cigarette smoking, and others. Rare monogenic syndromes, such as alpha1-antitrypsin deficiency, glycogen storage disease type I, hemochromatosis, acute intermittent and cutanea tarda porphyria, as well as hereditary tyrosinemia type I are associated with a high risk of HCC. Several common conditions or diseases inherited as polygenic traits e.g. autoimmune hepatitis, type 2 diabetes, a family history of HCC, hypothyroidism, and non-alcoholic steatohepatitis also show an increased risk of HCC compared to the general population. Overall, the genetic susceptibility to HCC is characterized by a genetic heterogeneity; a high individual risk of HCC may thus be caused by several unlinked single gene defects, whose carriers are rare in the general population, or by more common conditions inherited by complex genetics.
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Affiliation(s)
- Tommaso A Dragani
- Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Via G. Venezian 1, Milan, Italy.
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α1-Antitrypsin deficiency, chronic obstructive pulmonary disease and the serpinopathies. Clin Sci (Lond) 2009; 116:837-50. [DOI: 10.1042/cs20080484] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
α1-Antitrypsin is the prototypical member of the serine proteinase inhibitor or serpin superfamily of proteins. The family includes α1-antichymotrypsin, C1 inhibitor, antithrombin and neuroserpin, which are all linked by a common molecular structure and the same suicidal mechanism for inhibiting their target enzymes. Point mutations result in an aberrant conformational transition and the formation of polymers that are retained within the cell of synthesis. The intracellular accumulation of polymers of mutant α1-antitrypsin and neuroserpin results in a toxic gain-of-function phenotype associated with cirrhosis and dementia respectively. The lack of important inhibitors results in overactivity of proteolytic cascades and diseases such as COPD (chronic obstructive pulmonary disease) (α1-antitrypsin and α1-antichymotrypsin), thrombosis (antithrombin) and angio-oedema (C1 inhibitor). We have grouped these conditions that share the same underlying disease mechanism together as the serpinopathies. In the present review, the molecular and pathophysiological basis of α1-antitrypsin deficiency and other serpinopathies are considered, and we show how understanding this unusual mechanism of disease has resulted in the development of novel therapeutic strategies.
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Abstract
Alpha-1-antitrypsin (AAT) is an important serine protease inhibitor in humans. Hereditary alpha-1-antitrypsin deficiency (AATD) affects lungs and liver. Liver disease caused by AATD in paediatric patients has been previously well documented. However, the association of liver disease with alpha-1-antitrypsin gene polymorphisms in adults is less clear. Therefore, we aimed to study AAT polymorphisms in adults with liver disease. We performed a case-control study. AAT polymorphisms were investigated by isoelectric focusing in 61 patients with liver cirrhosis and 9 patients with hepatocellular carcinoma. The control group consisted of 218 healthy blood donors. A significant deviation of observed and expected frequency of AAT phenotypes from Hardy-Weinberg equilibrium (chi-square = 34.77, df 11, P = 0.000) in the patient group was caused by a higher than expected frequency of Pi ZZ homozygotes (f = 0.0143 and f = 0.0005, respectively, P = 0.000). In addition, Pi M homozygotes were more frequent in patients than in controls (63% and 46%, respectively, P = 0.025). Our study results show that Pi ZZ homozygosity in adults could be associated with severe liver disease. Presence of Pi M homozygosity could be associated with liver disease via some mechanism different from Z allele-induced liver damage through accumulation of AAT polymers.
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Affiliation(s)
- Aleksandra Topic
- Institute of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.
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Abstract
Chronic liver failure is an important cause of morbidity and mortality and is the long-term consequence of many chronic liver diseases. In addition to determining the specific cause of the chronic liver disease, which may be amenable to targeted therapy, it is important to treat the sequelae of chronic liver failure effectively to improve quality of life, to prolong survival, and to provide a bridge to liver transplantation. Once a patient who has chronic liver failure develops hepatic decompensation, liver transplantation is the definitive treatment for those who qualify. Management of chronic liver failure is the focus of this article.
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Affiliation(s)
- Gaurav Arora
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Room M211, Stanford, CA 94305-5187, USA
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40
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Chappell S, Hadzic N, Stockley R, Guetta-Baranes T, Morgan K, Kalsheker N. A polymorphism of the alpha1-antitrypsin gene represents a risk factor for liver disease. Hepatology 2008; 47:127-32. [PMID: 17972336 DOI: 10.1002/hep.21979] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Abstract
UNLABELLED Alpha(1)-antitrypsin deficiency (AATD) due to homozygosity of the protease inhibitor (Pi) Z variant predisposes to childhood liver disease and pulmonary emphysema. About 10% of all neonates with AATD develop liver disease, and about 3% overall progress to severe disease. AATD is a principal genetic indication for liver transplantation in children. The liver pathology is associated with accumulation of abnormally folded protein in hepatocytes, the principal producers of circulating alpha(1)-antitrypsin (AAT). It is currently unknown why only a small proportion of Pi ZZ individuals progress to clinically significant cirrhosis. The AAT gene shows significant variation, and we hypothesized that cryptic genetic variants within the AAT gene may contribute to susceptibility to liver disease. In a case-control study consisting of 42 patients with established moderate-to-severe liver disease and 335 homozygous Pi ZZ patients who mostly presented with chronic obstructive pulmonary disease (n = 322: 242 index cases and 80 unaffected sibs) or were asymptomatic (n = 13) with no evidence of liver disease, we identified a single nucleotide polymorphism (SNP) that conferred a significant risk for liver disease (P = 0.007). The frequency of the SNP was no different in 242 Pi ZZ cases with chronic obstructive pulmonary disease compared with 80 nonindex cases. The SNP therefore appears to confer susceptibility to liver disease, although reporter gene assays failed to show any functional differences between alleles. CONCLUSION This is the first description of a genetic modifier of liver disease in homozygous ZZ children and has potential implications for screening and possible therapies that are currently being developed.
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Affiliation(s)
- Sally Chappell
- Institute of Genetics, University of Nottingham, Nottingham, United Kingdom
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41
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Abstract
Good management of patients at risk for the development of hepatocellular carcinoma includes regular ultrasound surveillance, and aggressive management of lesions detected at ultrasound. Good radiology and good pathology are essential to the appropriate management of these small lesions. With good quality testing it is possible to cure the majority of HCCs using minimally invasive techniques such as radiofrequency ablation. Such an approach has the potential to convert HCC from a disease in which incidence more or less equaled mortality to one in which cure is frequently possible.
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American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med 2007; 168:818-900. [PMID: 14522813 DOI: 10.1164/rccm.168.7.818] [Citation(s) in RCA: 649] [Impact Index Per Article: 36.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
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Abstract
This article reviews methodological issues around screening for hepatocellular carcinoma, and discusses selection of the at-risk group, which screening test to use, and how frequently it should be applied. Screening of patients at risk for hepatocellular carcinoma should be undertaken using ultrasonography applied at six-month intervals. Patients at risk include all those with cirrhosis, and certain non-cirrhotic patients withchronic hepatitis B. In this population, screening has been shown to reduce disease-specific mortality. Although data do not exist for other populations, screening is nonetheless advised because small cancers can be cured with appreciable frequency.
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44
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Parikh S, Hyman D. Hepatocellular cancer: a guide for the internist. Am J Med 2007; 120:194-202. [PMID: 17349437 DOI: 10.1016/j.amjmed.2006.11.020] [Citation(s) in RCA: 125] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2006] [Revised: 11/14/2006] [Accepted: 11/20/2006] [Indexed: 12/18/2022]
Abstract
Hepatocellular cancer is the third leading cause of cancer-related deaths worldwide. Its incidence has increased dramatically in the United States because of the spread of hepatitis C virus infection and is expected to increase for the next 2 decades. Hepatitis B virus, hepatitis C virus, and chronic heavy alcohol use leading to cirrhosis of the liver remain the most important causes. The diagnosis of hepatocellular cancer rests on a combination of radiologic, serologic, and histopathologic criteria. Liver transplantation is the only definitive treatment. Resection of the tumor and other percutaneous therapies are more commonly used in practice, because most hepatocellular cancers are detected at an advanced stage. Patients who are at high risk for the development of hepatocellular cancer should be screened with an ultrasound of the liver every 6 months. The prognosis is dependent on both the underlying liver function and the stage at which the tumor is diagnosed. The aim of this review is to familiarize internists in screening, diagnosis, and referral of patients with hepatocellular cancer in an appropriate and timely fashion.
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Affiliation(s)
- Sameer Parikh
- Department of Medicine, Baylor College of Medicine, Houston, Tex, USA.
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45
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Piitulainen E, Carlson J, Ohlsson K, Sveger T. Alpha1-antitrypsin deficiency in 26-year-old subjects: lung, liver, and protease/protease inhibitor studies. Chest 2005; 128:2076-81. [PMID: 16236857 DOI: 10.1378/chest.128.4.2076] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
Abstract
BACKGROUND Clinical and biochemical signs of lung and liver disease have been followed prospectively in a birth cohort of individuals with alpha1-antitrypsin (AAT) deficiency. OBJECTIVE At age 26 years, the focus was on clinical health, lung and liver function tests, and plasma markers of the protease/antiprotease balance. The effect of early childhood environment and symptoms was also studied. METHODS Eligible individuals were 26-year-old subjects with AAT deficiency (PiZ, n = 122; PiZ -, n = 2; PiSZ/S-, n = 53) and control subjects (PiMM, n = 44). Of the original AAT-deficient subjects, 119 completed the clinical examination and 134 answered the questionnaire. RESULTS The prevalence of respiratory symptoms did not differ between the PiZ and SZ groups. Sixteen percent of PiZ and 14% of PiSZ subjects had asthma. Four current smokers (67%) and 22% of ex-smokers/never-smokers reported recurrent wheezing (p = 0.03). No difference in FEV1 or FEV1/FVC ratio was found between the PiZ, SZ (5% being smokers), and MM individuals (all nonsmokers). A decreased FEV1/FVC ratio was found in PiZ subjects with neonatal cholestasis, compared to remaining PiZ subjects (p = 0.02). Recurrent wheezers at age 2 years with AAT deficiency had decreased FEV1/FVC ratio (p = 0.025) at age 26 years. None had clinical symptoms of liver disease. Six percent of PiZ and 9% of PiSZ subjects had a marginal increase of serum alanine aminotransferase; 7% of PiZ and 4% of PiSZ had abnormal gamma-glutamyl transferase test results. The PiZ and SZ individuals had decreased plasma albumin (p = 0.0002). Secretory leukocyte protease inhibitor (SLPI) was increased in PiZ and SZ subjects compared to PiMM subjects (p = 0.0001). Neutrophil lipocalin was decreased in PiZ subjects (p = 0.0004) and PiSZ subjects (p = 0.001) compared to PiMM individuals. The elastase/AAT complex concentration was lower in AAT-deficient subjects (p = 0.0001). CONCLUSION Twenty-six-year-old PiZ and SZ individuals (5% smokers) had normal lung function test results, and 4 to 9% had marginal deviations in liver test results. Analyses of SLPI and neutrophil lipocalin, a marker of neutrophil activity, indicate compensatory changes in the AAT-deficiency state.
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Affiliation(s)
- Eeva Piitulainen
- Department of Respiratory Medicine, Lund University, University Hospital, SE-20502 Malmö, Sweden
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46
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Affiliation(s)
- Jordi Bruix
- BCLC Group. Liver Unit. Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
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Murray KF, Carithers RL. AASLD practice guidelines: Evaluation of the patient for liver transplantation. Hepatology 2005; 41:1407-32. [PMID: 15880505 DOI: 10.1002/hep.20704] [Citation(s) in RCA: 508] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Karen F Murray
- Division of Gastroenterology, University of Washington School of Medicine, Seattle, WA 98195-6174, USA
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Abstract
There is currently no evidence that screening patients at risk for hepatocellular carcinoma reduces mortality from the disease. Nonetheless, screening is widely practiced. Screening is a process that includes selecting patients, applying screening tests, deciding on recall policies, and subsequently proving or disproving the presence of cancer. The literature on screening for hepatocellular carcinoma is confusing at best, and does not adequately consider the many biases that result from uncontrolled and retrospective studies. Nonetheless, screening can be justified because it is likely that mortality is decreased by adequate treatment of small cancers, particularly in the era of liver transplantation. False-positive screening test results are common. Once an abnormal screening result is obtained there is little guidance from the literature as to how patients should be investigated further, nor about how to determine whether the screening test result was a false-positive. This should at minimum include short interval follow-up with CT scans and MRI's.
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Affiliation(s)
- Morris Sherman
- University of Toronto and Toronto General Hospital, 200 Elizabeth Street, Toronto, Ont., Canada M5G 2C4.
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Abstract
A review of the clinical manifestations of alpha(1)-antitrypsin (AAT) deficiency, including lung disease and liver disease, and risk factors affecting the rate of decline in lung function in AAT deficient patients.
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Affiliation(s)
- M Needham
- Department of Respiratory Medicine, Queen Elizabeth Hospital, Birmingham, UK
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Abstract
Hepatocellular carcinoma is an increasingly common clinical problem. Investigators have begun to understand aspects of the pathogenesis of the tumor, mainly from a morphologic point of view. Preneoplastic lesions and early cancer may be difficult to distinguish radiologically. Nonetheless, programs for surveillance of liver cancer have been developed. Little uniformity exists in methods of surveillance, and even less in methods of investigation and follow-up after an abnormal result is obtained. This article attempts to bring some rigor to the understanding of hepatocellular carcinoma.
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