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1
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Al-Judaibi B, Alzahrani H, Alahmari A, Almohareb F, Albenmousa A, Al-Hamoudi W, Alghamdi S, Alrajhi I, Alotaibi S, AlMozain N, Saner F, Duvoux C. Emerging need for a hepato-hematology program for patients with sickle cell disease in Saudi Arabia. Saudi J Gastroenterol 2025; 31:53-58. [PMID: 40051245 DOI: 10.4103/sjg.sjg_419_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Accepted: 02/10/2025] [Indexed: 03/22/2025] Open
Abstract
ABSTRACT There is an increasing recognition of the need for a specialized hepatohematology program in countries with a high prevalence of sickle cell disease. This program would be tailored specifically for patients with sickle cell disease, addressing the unique challenges they face, including the management of liver and biliary complications, and hematological issues associated with their condition. By integrating hepatology and hematology expertise, we can improve knowledge of liver SCD-related diseases, and patient outcomes, enhance care coordination, and provide comprehensive management strategies for this vulnerable population. While the primary focus of this program is on SCD-related liver disease, there may be opportunities shortly to expand its scope to include patients with various hematological liver diseases.
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Affiliation(s)
- Bandar Al-Judaibi
- Department of Liver and Health Small Bowel Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Hazzaa Alzahrani
- Hematology Department, Adult Transplant Intensive Care Unit, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Ali Alahmari
- Hematology Department, Adult Transplant Intensive Care Unit, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Fahad Almohareb
- Hematology Department, Adult Transplant Intensive Care Unit, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Ali Albenmousa
- Department of Liver and Health Small Bowel Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Waleed Al-Hamoudi
- Department of Liver and Health Small Bowel Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Saad Alghamdi
- Department of Liver and Health Small Bowel Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Ibrahim Alrajhi
- Department of Liver and Health Small Bowel Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Shaykhah Alotaibi
- Hematology Department, Adult Transplant Intensive Care Unit, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Nour AlMozain
- Pathology and Laboratory Medicine, Adult Transplant Intensive Care Unit, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Fuat Saner
- Orgran Transplant Centre of Excellence, Adult Transplant Intensive Care Unit, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Christophe Duvoux
- Department of Hepatology and Medical Liver Transplant Unit, Henri Mondor Hospital-APHP, University Paris Est Creteil, France
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2
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Haroun E, Lim SH, Dutta D. GBT1118, a Voxelotor Analog, Ameliorates Hepatopathy in Sickle Cell Disease. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:1581. [PMID: 39459368 PMCID: PMC11509622 DOI: 10.3390/medicina60101581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 09/20/2024] [Accepted: 09/23/2024] [Indexed: 10/28/2024]
Abstract
Background and Objectives: In sickle cell disease (SCD), hepatopathy is a cumulative consequence of ischemia/reperfusion (I/R) injury from a vaso-occlusive crisis, tissue inflammation, and iron overload due to blood transfusion. Hepatopathy is a major contributing factor of shortened life span in SCD patients. We hypothesized that the voxelotor, a hemoglobin allosteric modifier, ameliorates sickle hepatopathy. Materials and Methods: Townes SCD mice and their controls were treated with either chow containing GBT1118, a voxelotor analog, or normal chow. We evaluated inflammation, fibrosis, apoptosis and ferroptosis in their livers using qPCR, ELISA, histology, and immunohistochemistry. Results: GBT1118 treatment resulted in reduced hemolysis, iron overload and inflammation in the liver of SCD mice. There were significant reductions in the liver enzyme levels and bile acids. Furthermore, GBT1118-treated mice exhibited reduced apoptosis, necrosis, and fibrosis. Increased ferroptosis as evident from elevated 4-hydroxynonenal (4-HNE) staining, malondialdehyde (MDA) levels, and expression of Ptgs2 and Slc7a11 mRNAs, were also significantly reduced after GBT1118 treatment. To explain the increased ferroptosis, we evaluated iron homeostasis markers in livers. SCD mice showed decreased expression of heme oxygenase-1, ferritin, hepcidin, and ferroportin mRNA levels. GBT1118 treatment significantly increased expressions of these genes. Conclusions: Our results suggest GBT1118 treatment in SCD confers the amelioration of sickle hepatopathy by reducing inflammation, fibrosis, apoptosis, iron overload and ferroptosis.
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Affiliation(s)
| | | | - Dibyendu Dutta
- Division of Hematology and Oncology, Department of Medicine, State University of New York Upstate Medical University, Syracuse, NY 13210, USA; (E.H.); (S.H.L.)
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3
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Kaminski TW, Sivanantham A, Mozhenkova A, Smith A, Ungalara R, Dubey RK, Shrestha B, Hanway C, Katoch O, Tejero J, Sundd P, Novelli EM, Kato GJ, Pradhan-Sundd T. Hemoglobin scavenger receptor CD163 as a potential biomarker of hemolysis-induced hepatobiliary injury in sickle cell disease. Am J Physiol Cell Physiol 2024; 327:C423-C437. [PMID: 38682236 PMCID: PMC11427010 DOI: 10.1152/ajpcell.00386.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 04/05/2024] [Accepted: 04/05/2024] [Indexed: 05/01/2024]
Abstract
Sickle cell disease (SCD)-associated chronic hemolysis promotes oxidative stress, inflammation, and thrombosis leading to organ damage, including liver damage. Hemoglobin scavenger receptor CD163 plays a protective role in SCD by scavenging both hemoglobin-haptoglobin complexes and cell-free hemoglobin. A limited number of studies in the past have shown a positive correlation of CD163 expression with poor disease outcomes in patients with SCD. However, the role and regulation of CD163 in SCD-related hepatobiliary injury have not been fully elucidated yet. Here we show that chronic liver injury in SCD patients is associated with elevated levels of hepatic membrane-bound CD163. Hemolysis and increase in hepatic heme, hemoglobin, and iron levels elevate CD163 expression in the SCD mouse liver. Mechanistically we show that heme oxygenase-1 (HO-1) positively regulates membrane-bound CD163 expression independent of nuclear factor erythroid 2-related factor 2 (NRF2) signaling in SCD liver. We further demonstrate that the interaction between CD163 and HO-1 is not dependent on CD163-hemoglobin binding. These findings indicate that CD163 is a potential biomarker of SCD-associated hepatobiliary injury. Understanding the role of HO-1 in membrane-bound CD163 regulation may help identify novel therapeutic targets for hemolysis-induced chronic liver injury.
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MESH Headings
- Antigens, Differentiation, Myelomonocytic/metabolism
- Antigens, Differentiation, Myelomonocytic/genetics
- Anemia, Sickle Cell/metabolism
- Anemia, Sickle Cell/blood
- Anemia, Sickle Cell/complications
- Antigens, CD/metabolism
- Antigens, CD/genetics
- Animals
- Hemolysis
- Receptors, Cell Surface/metabolism
- Receptors, Cell Surface/genetics
- Humans
- Biomarkers/metabolism
- Biomarkers/blood
- Heme Oxygenase-1/metabolism
- Hemoglobins/metabolism
- Mice
- Male
- Liver/metabolism
- Liver/pathology
- Female
- Mice, Inbred C57BL
- Adult
- NF-E2-Related Factor 2/metabolism
- Heme/metabolism
- Liver Diseases/metabolism
- Liver Diseases/pathology
- Signal Transduction
- Haptoglobins/metabolism
- Membrane Proteins
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Affiliation(s)
- Tomasz W Kaminski
- Thrombosis and Hemostasis Program, Versiti Blood Research Institute, Milwaukee, Wisconsin, United States
| | - Ayyanar Sivanantham
- Thrombosis and Hemostasis Program, Versiti Blood Research Institute, Milwaukee, Wisconsin, United States
| | - Anna Mozhenkova
- Transfusion Medicine, Vascular Biology and Cell Therapy Program, Versiti Blood Research Institute, Milwaukee, Wisconsin, United States
| | - Ashley Smith
- Transfusion Medicine, Vascular Biology and Cell Therapy Program, Versiti Blood Research Institute, Milwaukee, Wisconsin, United States
| | - Ramakrishna Ungalara
- Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
| | - Rikesh K Dubey
- Thrombosis and Hemostasis Program, Versiti Blood Research Institute, Milwaukee, Wisconsin, United States
| | - Bibhav Shrestha
- Transfusion Medicine, Vascular Biology and Cell Therapy Program, Versiti Blood Research Institute, Milwaukee, Wisconsin, United States
| | - Corrine Hanway
- Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
| | - Omika Katoch
- Transfusion Medicine, Vascular Biology and Cell Therapy Program, Versiti Blood Research Institute, Milwaukee, Wisconsin, United States
| | - Jesús Tejero
- Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
| | - Prithu Sundd
- Thrombosis and Hemostasis Program, Versiti Blood Research Institute, Milwaukee, Wisconsin, United States
- Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
| | - Enrico M Novelli
- Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
- Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
| | - Gregory J Kato
- Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
- Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
| | - Tirthadipa Pradhan-Sundd
- Transfusion Medicine, Vascular Biology and Cell Therapy Program, Versiti Blood Research Institute, Milwaukee, Wisconsin, United States
- Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
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4
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Han J, Zhang X, Shah BN, Saraf SL, Gordeuk VR. Alkaline phosphatase as a marker for painful vaso-occlusive events and other acute complications in sickle cell disease. Br J Haematol 2024; 205:716-718. [PMID: 38772687 DOI: 10.1111/bjh.19554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 05/13/2024] [Indexed: 05/23/2024]
Affiliation(s)
- Jin Han
- Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA
- Division of Hematology & Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Xu Zhang
- Division of Hematology & Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Binal N Shah
- Division of Hematology & Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Santosh L Saraf
- Division of Hematology & Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Victor R Gordeuk
- Division of Hematology & Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
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5
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Kamimura S, Smith M, Vogel S, Almeida LEF, Thein SL, Quezado ZMN. Mouse models of sickle cell disease: Imperfect and yet very informative. Blood Cells Mol Dis 2024; 104:102776. [PMID: 37391346 PMCID: PMC10725515 DOI: 10.1016/j.bcmd.2023.102776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 06/16/2023] [Indexed: 07/02/2023]
Abstract
The root cause of sickle cell disease (SCD) has been known for nearly a century, however, few therapies to treat the disease are available. Over several decades of work, with advances in gene editing technology and after several iterations of mice with differing genotype/phenotype relationships, researchers have developed humanized SCD mouse models. However, while a large body of preclinical studies has led to huge gains in basic science knowledge about SCD in mice, this knowledge has not led to the development of effective therapies to treat SCD-related complications in humans, thus leading to frustration with the paucity of translational progress in the SCD field. The use of mouse models to study human diseases is based on the genetic and phenotypic similarities between mouse and humans (face validity). The Berkeley and Townes SCD mice express only human globin chains and no mouse hemoglobin. With this genetic composition, these models present many phenotypic similarities, but also significant discrepancies that should be considered when interpreting preclinical studies results. Reviewing genetic and phenotypic similarities and discrepancies and examining studies that have translated to humans and those that have not, offer a better perspective of construct, face, and predictive validities of humanized SCD mouse models.
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Affiliation(s)
- Sayuri Kamimura
- Department of Perioperative Medicine, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
| | - Meghann Smith
- Department of Perioperative Medicine, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
| | - Sebastian Vogel
- Department of Perioperative Medicine, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
| | - Luis E F Almeida
- Department of Perioperative Medicine, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
| | - Swee Lay Thein
- Sickle Cell Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Zenaide M N Quezado
- Department of Perioperative Medicine, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA; Sickle Cell Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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6
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Jafari P, Evaristo G, Du XA, Sharma AE, Marcus V, Liu X, Zhao L, Westerhoff M, Hart J. Portosinusoidal Vascular Disorder: A Heretofore Unrecognized Manifestation of Sickle Cell Disease? Mod Pathol 2024; 37:100351. [PMID: 37820763 DOI: 10.1016/j.modpat.2023.100351] [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: 07/09/2023] [Revised: 09/10/2023] [Accepted: 10/04/2023] [Indexed: 10/13/2023]
Abstract
Portosinusoidal vascular disorder (PSVD) is a recently proposed histopathologic entity that encompasses a spectrum of often subtle hepatic microvascular lesions and related microarchitectural abnormalities. Clinical manifestations may arise years after histologic diagnosis and include extrahepatic portal vein thrombosis and portal hypertension. While the histopathologic features of PSVD have been associated with numerous clinical conditions, most notably prothrombotic/vasculopathic disorders, PSVD has not yet been described in sickle cell disease. This gap is striking given the central role of microvascular dysfunction in sickle cell disease and well-described patterns of hepatic injury and dysfunction in this population. This case series is the first to explore the prevalence and pathogenesis of PSVD in sickle cell disease. Forty-one diagnostically adequate liver biopsies from patients with sickle cell disease were identified across the archives of 5 tertiary medical centers. All biopsies exhibited at least 1 histopathologic feature associated with PSVD (mean 3.8 features/case). Overall, 90.2% of patients met the criteria for a diagnosis of PSVD based on the presence of specific histopathologic and/or clinical findings. Immunohistochemical stains for von Willebrand factor, CD34, and glutamine synthetase were performed on 36 cases (87.8%). Aberrant (centrilobular sinusoidal) CD34 and von Willebrand factor staining was present in 97.2% and 86.1% of cases, respectively. Glutamine synthetase reactivity was at least mildly decreased in zone 3 hepatocytes in 52.8% of cases. We posit that chronic erythrocyte sickling results in dysfunction and remodeling of the portal microvasculature, culminating in regression of zone 3 hepatocytes. The presence of PSVD may explain, at least in part, the hepatic dysfunction observed in this patient population. These patients may also benefit from extended clinical surveillance for portal hypertension and other complications. While subtle and prone to overdiagnosis, the features of PSVD should be carefully considered when interpreting liver biopsies from patients with sickle cell disease.
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Affiliation(s)
- Pari Jafari
- Department of Pathology, University of Chicago Medicine, The University of Chicago, Chicago, Illinois.
| | - Gertruda Evaristo
- Department of Pathology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Xiaotang Alison Du
- Department of Pathology, David Geffen School of Medicine, University of California, Los Angeles, California
| | - Aarti E Sharma
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Victoria Marcus
- Department of Pathology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Xiuli Liu
- Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, Missouri
| | - Lei Zhao
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Maria Westerhoff
- Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan
| | - John Hart
- Department of Pathology, University of Chicago Medicine, The University of Chicago, Chicago, Illinois
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7
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Duvoux C, Blaise L, Matimbo JJ, Mubenga F, Ngongang N, Hurtova M, Laurent A, Augustin J, Calderaro J, Reizine E, Luciani A, Habibi A, Bachir D, Vole G, Gellen-Dautremer J, Leroy V, Levesque E, Bartolucci P. The liver in sickle cell disease. Presse Med 2023; 52:104212. [PMID: 37981193 DOI: 10.1016/j.lpm.2023.104212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/21/2023] Open
Abstract
Liver involvement in SCD patients is frequent but often misdiagnosed or underestimated, except in case of advanced liver diseases. Because of so far poorly recognized forms of chronic SCD-related vascular injury that can silently evolved towards end stages or facilitate ACLF, any persisting liver function tests abnormalities should be carefully investigated, following the above proposed algorithm. Work up and management must be considered multidisciplinary in relationship with a Hepatologist. Early SCD hepatopathy should prompt revision of SCD management to prevent further liver injury and decompensation, discussing transfusion exchanges and hydro urea when not yet initiated, and control for any cofactor of liver injury. The role of HSCT in early SCD hepatopathies also deserves evaluation. In advanced SCD hepatopathies, liver transplantation, which has been rarely performed so far, is the only therapeutic option associated with improved survival. It should definitely be discussed- either electively in case of decompensation in SCD cirrhosis or jaundice/recurrent cholangitis in cholestatic diseases, with excellent outcome, - or emergently in case of ALF or ACLF with more mitigate results. To improve knowledge and management of SCD liver diseases, creation of national and international registries, as well as longitudinal observational cohorts are encouraged.
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Affiliation(s)
- Christophe Duvoux
- Department of Hepatology and Medical Liver Transplant Unit, Henri Mondor Hospital-APHP, University Paris Est Créteil, France.
| | - Lorraine Blaise
- Department of Hepatology and Liver Oncology, Avicenne Hospital-APHP, Bobigny, France
| | - Jean-Jacques Matimbo
- Department of Hepatology and Medical Liver Transplant Unit, Henri Mondor Hospital-APHP, University Paris Est Créteil, France; Department of Hepatology and Liver Oncology, Avicenne Hospital-APHP, Bobigny, France; Department of Hepatology and Gastroenterology, Clinique Universitaire Kinshasa, Democratic Republic of Congo
| | | | - Norbert Ngongang
- Department of Hepatology and Medical Liver Transplant Unit, Henri Mondor Hospital-APHP, University Paris Est Créteil, France
| | - Monika Hurtova
- Department of Hepatology and Medical Liver Transplant Unit, Henri Mondor Hospital-APHP, University Paris Est Créteil, France
| | - Alexis Laurent
- Department of Digestive & HPB Surgery, Henri Mondor Hospital-APHP, University Paris Est Créteil, France
| | - Jérémy Augustin
- Department of Pathology, Henri Mondor Hospital-APHP, University Paris Est Créteil, France
| | - Julien Calderaro
- Department of Pathology, Henri Mondor Hospital-APHP, University Paris Est Créteil, France
| | - Edouard Reizine
- Department of Radiology, Henri Mondor Hospital-APHP, University Paris Est Créteil, France
| | - Alain Luciani
- Department of Radiology, Henri Mondor Hospital-APHP, University Paris Est Créteil, France
| | - Anoosha Habibi
- UMGGR, Department of Internal Medicine, Sickle Cell National Referral Center, Henri Mondor-Hospital APHP, University Paris Est Créteil, France; IMRB, UPEC, INSERM, EFS, Team Pirenne. University Paris Est Créteil, France
| | - Dora Bachir
- UMGGR, Department of Internal Medicine, Sickle Cell National Referral Center, Henri Mondor-Hospital APHP, University Paris Est Créteil, France
| | - Geoffroy Vole
- UMGGR, Department of Internal Medicine, Sickle Cell National Referral Center, Henri Mondor-Hospital APHP, University Paris Est Créteil, France; IMRB, UPEC, INSERM, EFS, Team Pirenne. University Paris Est Créteil, France
| | | | - Vincent Leroy
- Department of Hepatology and Medical Liver Transplant Unit, Henri Mondor Hospital-APHP, University Paris Est Créteil, France
| | - Eric Levesque
- Department of Anesthesia and Surgical Intensive Care-liver ICU, Henri Mondor Hospital-APHP, University Paris Est Créteil, France
| | - Pablo Bartolucci
- UMGGR, Department of Internal Medicine, Sickle Cell National Referral Center, Henri Mondor-Hospital APHP, University Paris Est Créteil, France; IMRB, UPEC, INSERM, EFS, Team Pirenne. University Paris Est Créteil, France
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8
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Katoch O, Ungalara R, Kaminski T, Li Z, Dubey RK, Burholt I, Gudapati S, Pradhan-Sundd T. Long-Term L-Glutamine Treatment Reduces Hemolysis without Ameliorating Hepatic Vaso-Occlusion and Liver Fibrosis in a Mouse Model of Sickle Cell Disease. Biomedicines 2023; 11:2412. [PMID: 37760853 PMCID: PMC10526062 DOI: 10.3390/biomedicines11092412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 08/21/2023] [Accepted: 08/24/2023] [Indexed: 09/29/2023] Open
Abstract
Sickle cell disease (SCD) is an autosomal recessive monogenic disorder caused by a homozygous mutation in the β-globin gene, which leads to erythrocyte sickling, hemolysis, vaso-occlusion, and sterile inflammation. The administration of oral L-glutamine has been shown to reduce the frequency of pain in SCD patients; however, the long-term effect of L-glutamine in SCD remains to be determined. To understand the long-term effect of L-glutamine administration in the liver we used quantitative liver intravital microscopy and biochemical analysis in humanized SCD mice. We here show that chronic L-glutamine administration reduces hepatic hemoglobin-heme-iron levels but fails to ameliorate ischemic liver injury. Remarkably, we found that this failure in the resolution of hepatobiliary injury and persistent liver fibrosis is associated with the reduced expression of hepatic Kupffer cells post-L-glutamine treatment. These findings establish the importance of investigating the long-term effects of L-glutamine therapy on liver pathophysiology in SCD patients.
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Affiliation(s)
- Omika Katoch
- Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Ramakrishna Ungalara
- Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Tomasz Kaminski
- Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Ziming Li
- Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Rikesh K. Dubey
- Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Isabella Burholt
- Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Shweta Gudapati
- Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Tirthadipa Pradhan-Sundd
- Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
- Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
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Ali Hadi Z, Odda AH, Jawad AF, Al-Tu’ma FJ. Design and Development of Fe3O4@Prussian Blue Nanocomposite: Potential Application in the Detoxification of Bilirubin. Asian Pac J Cancer Prev 2023; 24:2809-2815. [PMID: 37642068 PMCID: PMC10685236 DOI: 10.31557/apjcp.2023.24.8.2809] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Accepted: 08/16/2023] [Indexed: 08/31/2023] Open
Abstract
BACKGROUND Prussian blue nanoparticles (PBNPs) due to their high solubility, stability, flexible molecular structure, tunable size, easy synthesis, and surface modification have attracted the attention of researchers as high-efficiency therapeutic agents. Recently, it has been reported that magnetic nanoparticles can be to bind pathogenic substances on their surface, followed by a recollection by magnetic separation. Considering the potential application of PB and magnetic nanoparticles, in the current study we aimed to strategically design and synthesize a highly efficient nano-magnetic bilirubin scavenger system based on iron oxides@prussian blue nanocomposites (Fe3O4@PB) NCs. MATERIALS AND METHODS The Fe3O4@PB NCs were synthesized by an improved shell-growing procedure and identified using advanced characteristic techniques TEM, SEM, XRD, DLS, and Zeta potential. Synthesized Fe3O4@PB NCs showed good magneton properties and also demonstrated dramatic absorbent properties that empower use as an eco-friendly adsorbent nano agent for the detoxification of toxins. In addition, Fe3O4@PB nanoparticles showed high performance of bilirubin absorption in the serum and blood of sickle cell anemia patients. (Temp. 37.7 ºC, the dose of adsorbent: 1 mg/mL, incubation time 30 min, and initial concentration: 0.25 mg/mL). RESULTS The results demonstrated an ideal adsorption capacity (86%) of Fe3O4@PB NCs which is significant compared to the reported adsorbents agents. These results pave the way for the application of Fe3O4@PB NCs for the effective purification of toxins from patients' body fluids.
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Affiliation(s)
- Zainab Ali Hadi
- Department of Chemistry and Biochemistry, College of Medicine, University of Kerbala, Kerbala, Iraq.
| | - Atheer Hameid Odda
- Department of Chemistry and Biochemistry, College of Medicine, University of Kerbala, Kerbala, Iraq.
| | - Ammar Fadhil Jawad
- Department of pharmacognesy, College of pharmacy, University of Kerbala, Kerbala, Iraq.
| | - Fadhil Jawad Al-Tu’ma
- Department of Chemistry and Biochemistry, College of Medicine, University of Kerbala, Kerbala, Iraq.
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10
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Kouroumalis E, Tsomidis I, Voumvouraki A. Iron as a therapeutic target in chronic liver disease. World J Gastroenterol 2023; 29:616-655. [PMID: 36742167 PMCID: PMC9896614 DOI: 10.3748/wjg.v29.i4.616] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 11/03/2022] [Accepted: 12/31/2022] [Indexed: 01/20/2023] Open
Abstract
It was clearly realized more than 50 years ago that iron deposition in the liver may be a critical factor in the development and progression of liver disease. The recent clarification of ferroptosis as a specific form of regulated hepatocyte death different from apoptosis and the description of ferritinophagy as a specific variation of autophagy prompted detailed investigations on the association of iron and the liver. In this review, we will present a brief discussion of iron absorption and handling by the liver with emphasis on the role of liver macrophages and the significance of the iron regulators hepcidin, transferrin, and ferritin in iron homeostasis. The regulation of ferroptosis by endogenous and exogenous mod-ulators will be examined. Furthermore, the involvement of iron and ferroptosis in various liver diseases including alcoholic and non-alcoholic liver disease, chronic hepatitis B and C, liver fibrosis, and hepatocellular carcinoma (HCC) will be analyzed. Finally, experimental and clinical results following interventions to reduce iron deposition and the promising manipulation of ferroptosis will be presented. Most liver diseases will be benefited by ferroptosis inhibition using exogenous inhibitors with the notable exception of HCC, where induction of ferroptosis is the desired effect. Current evidence mostly stems from in vitro and in vivo experimental studies and the need for well-designed future clinical trials is warranted.
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Affiliation(s)
- Elias Kouroumalis
- Liver Research Laboratory, University of Crete Medical School, Heraklion 71003, Greece
| | - Ioannis Tsomidis
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
| | - Argyro Voumvouraki
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
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11
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Dutra VDF, Biassi TP, Figueiredo MS. Sickle cell anemia: hierarchical cluster analysis and clinical profile in a cohort in Brazil. Hematol Transfus Cell Ther 2023; 45:45-51. [PMID: 34930711 PMCID: PMC9938484 DOI: 10.1016/j.htct.2021.08.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 08/04/2021] [Accepted: 08/17/2021] [Indexed: 02/06/2023] Open
Abstract
INTRODUCTION Sickle cell anemia is a monogenic disorder caused by a mutation in the β-hemoglobin gene, resulting in sickle hemoglobin that can polymerize. Presentation and clinical course have significant inter-individual variability and classifying these patients for severity is a challenge. METHODS We applied hierarchical clusters with 10 routine laboratory tests to understand if this grouping could be associated with clinical manifestations. We included 145 adult homozygous patients (SS) at an outpatient clinic in a retrospective study. RESULTS We found five clusters by counting those that had been differentiated by unconjugated bilirubin, reticulocytes, LDH, leukocytes, lymphocytes and monocytes. When comparing groups to clinical findings, the clusters were different only for liver abnormality. Cluster 3 had the lower median of reticulocytes, LDH, leukocytes, lymphocytes and monocytes and a higher percentage of patients under treatment. Clusters 4 and 5 had higher frequencies of liver impairment and higher medians of reticulocytes, LDH, leukocytes, lymphocytes and monocytes. Hemolysis and inflammation seemed to influence the grouping. CONCLUSION In our study, cluster analysis showed five groups that exhibited different degrees of inflammation and hemolysis. When comparing clinical data, the result was different only for the criteria of liver abnormality.
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Affiliation(s)
- Valéria de Freitas Dutra
- Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM/UNIFESP), São Paulo, SP, Brazil.
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12
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Levy JA, Burnett AL, Minniti CP, Ennis W, Vittal A, Heller T, Kleiner D, Thein SL. Clinical Vignettes Part I. Hematol Oncol Clin North Am 2022; 36:1187-1199. [PMID: 36400538 DOI: 10.1016/j.hoc.2022.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Patients with sickle cell disease and/or (rarely) trait are at increased risk for developing recurrent episodes of priapism, also known as stuttering priapism, and major ischemic priapism. Treatment of acute ischemic priapism is reactive; whereas ideal management consists of preventative approaches to ultimately promote the best improvement in patient's quality of life. Leg ulcers in patients with sickle cell disease (SCD) are quite common, with ∼20 % of patients with HBSS reporting either having an active or a past ucler. They can be confused with venous ulcers, with lower extremity hyperpigmentation confounding further the diagnosis. Several factors believed to contribute to the development of leg ulcers in patients with SCD are discussed in this article. Sickle cell liver disease (SCLD) occurs because of a wide variety of insults to the liver that happen during the lifetime of these patients. SCLD includes a range of complications of the hepatobiliary system and is increasing in prevalence with the aging adult sickle population. Liver nodular regenerative hyperplasia (NRH) is more common than realized and underappreciated as a diagnosis and requires liver biopsy with reticulin staining. Undiagnosed, the insidious damage from liver NRH can lead to noncirrhotic portal hypertension or cirrhosis.
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13
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Vázquez-Carballo C, Herencia C, Guerrero-Hue M, García-Caballero C, Rayego-Mateos S, Morgado-Pascual JL, Opazo-Rios L, González-Guerrero C, Vallejo-Mudarra M, Cortegano I, Gaspar ML, de Andrés B, Egido J, Moreno JA. Role of Toll-like receptor 4 in intravascular hemolysis-mediated injury. J Pathol 2022; 258:236-249. [PMID: 35903022 DOI: 10.1002/path.5995] [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: 01/29/2022] [Revised: 07/17/2022] [Accepted: 07/25/2022] [Indexed: 01/07/2023]
Abstract
Massive intravascular hemolysis is a common characteristic of several pathologies. It is associated with the release of large quantities of heme into the circulation, promoting injury in vulnerable organs, mainly kidney, liver, and spleen. Heme activates Toll-like receptor 4 (TLR4), a key regulator of the inflammatory response; however, the role of TLR4 in hemolysis and whether inhibition of this receptor may protect from heme-mediated injury are unknown. We induced intravascular hemolysis by injection of phenylhydrazine in wildtype and Tlr4-knockout mice. In this model, we analyzed physiological parameters, histological damage, inflammation and cell death in kidney, liver, and spleen. We also evaluated whether heme-mediated-inflammatory effects were prevented by TLR4 inhibition with the compound TAK-242, both in vivo and in vitro. Induction of massive hemolysis elicited acute kidney injury characterized by loss of renal function, morphological alterations of the tubular epithelium, cell death, and inflammation. These pathological effects were significantly ameliorated in the TLR4-deficient mice and in wildtype mice treated with TAK-242. In vitro studies showed that TAK-242 pretreatment reduced heme-mediated inflammation by inhibiting the TLR4/NF-κB (nuclear factor kappa B) axis. However, analysis in liver and spleen indicated that TLR4 deficiency did not protect against the toxic accumulation of heme in these organs. In conclusion, TLR4 is a key molecule involved in the renal inflammatory response triggered by massive intravascular hemolysis. TLR4 inhibition may be a potential therapeutic approach to prevent renal damage in patients suffering from hemolysis. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Cristina Vázquez-Carballo
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain
| | - Carmen Herencia
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain
| | - Melania Guerrero-Hue
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), UGC Nefrología, Hospital Universitario Reina Sofía, Córdoba, Spain
| | - Cristina García-Caballero
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), UGC Nefrología, Hospital Universitario Reina Sofía, Córdoba, Spain
| | - Sandra Rayego-Mateos
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain
| | - José Luis Morgado-Pascual
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), UGC Nefrología, Hospital Universitario Reina Sofía, Córdoba, Spain.,Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain
| | - Lucas Opazo-Rios
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain.,Health Science Faculty, Universidad de Las Américas, Concepción-Talcahuano, Chile
| | - Cristian González-Guerrero
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain
| | - Mercedes Vallejo-Mudarra
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), UGC Nefrología, Hospital Universitario Reina Sofía, Córdoba, Spain
| | - Isabel Cortegano
- Immunobiology Department, Carlos III Health Institute, Madrid, Spain
| | | | - Belén de Andrés
- Immunobiology Department, Carlos III Health Institute, Madrid, Spain
| | - Jesús Egido
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain.,Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
| | - Juan Antonio Moreno
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), UGC Nefrología, Hospital Universitario Reina Sofía, Córdoba, Spain.,Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain.,Biomedical Research Networking Center on Cardiovascular Diseases (CIBERCV), Madrid, Spain
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14
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Vittal A, Alao H, Hercun J, Sharma B, Khan A, Sharma D, Lee W, Kapuria D, Hsieh M, Tisdale J, Fitzhugh C, Kleiner D, Levy E, Chang R, Conrey A, Rivera E, Huang A, Yakov GB, Kato GJ, Gladwin MT, Thein SL, Koh C, Heller T. Safety of liver biopsy in patients with sickle cell related liver disease: A single-center experience. Am J Hematol 2022; 97:E257-E260. [PMID: 35384045 PMCID: PMC9942185 DOI: 10.1002/ajh.26560] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 03/30/2022] [Accepted: 03/31/2022] [Indexed: 11/10/2022]
Affiliation(s)
- Anusha Vittal
- Translational Hepatology Section, Liver Diseases Branch, NIDDK, NIH, Bethesda, MD
| | - Hawwa Alao
- Translational Hepatology Section, Liver Diseases Branch, NIDDK, NIH, Bethesda, MD
| | - Julian Hercun
- Translational Hepatology Section, Liver Diseases Branch, NIDDK, NIH, Bethesda, MD
| | - Bashar Sharma
- Department of Medicine, SUNY Upstate Medical University, Syracuse, NY
| | - Arsalan Khan
- Translational Hepatology Section, Liver Diseases Branch, NIDDK, NIH, Bethesda, MD
| | - Disha Sharma
- Translational Hepatology Section, Liver Diseases Branch, NIDDK, NIH, Bethesda, MD
| | - Wilson Lee
- MedStar Health Internal Medicine Program, Baltimore, MD
| | - Devika Kapuria
- Translational Hepatology Section, Liver Diseases Branch, NIDDK, NIH, Bethesda, MD
| | - Matthew Hsieh
- Molecular and Clinical Hematology Branch, NHLBI, NIH, Bethesda, MD
| | - John Tisdale
- Molecular and Clinical Hematology Branch, NHLBI, NIH, Bethesda, MD
| | | | | | - Elliot Levy
- Interventional Radiology, Department of Diagnostic Radiology, NIH, Bethesda, MD
| | - Richard Chang
- Interventional Radiology, Department of Diagnostic Radiology, NIH, Bethesda, MD
| | - Anna Conrey
- Sickle Cell Branch, NHLBI, NIH, Bethesda, MD
| | - Elenita Rivera
- Translational Hepatology Section, Liver Diseases Branch, NIDDK, NIH, Bethesda, MD
| | - Amy Huang
- Translational Hepatology Section, Liver Diseases Branch, NIDDK, NIH, Bethesda, MD
| | - Gil Ben Yakov
- Translational Hepatology Section, Liver Diseases Branch, NIDDK, NIH, Bethesda, MD
| | | | - Mark T. Gladwin
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | | | - Christopher Koh
- Translational Hepatology Section, Liver Diseases Branch, NIDDK, NIH, Bethesda, MD
| | - Theo Heller
- Translational Hepatology Section, Liver Diseases Branch, NIDDK, NIH, Bethesda, MD
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15
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Pradhan-Sundd T, Kato GJ, Novelli EM. Molecular Mechanisms of Hepatic Dysfunction in Sickle Cell Disease: Lessons From The Townes Mouse Model. Am J Physiol Cell Physiol 2022; 323:C494-C504. [PMID: 35759437 PMCID: PMC9359658 DOI: 10.1152/ajpcell.00175.2022] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Sickle cell disease (SCD) is an autosomal-recessive-genetic disorder that affects ~100,000 Americans and millions of people worldwide. Erythrocyte sickling, vaso-occlusion, sterile inflammation and hemolysis are the major pathophysiological pathways leading to liver injury in SCD. Although hepatic dysfunction affects up to 10-40% of SCD patients, therapeutic approaches to prevent liver injury in SCD are not known, and the molecular mechanisms promoting progressive liver injury in SCD remain poorly understood. Animal models have been beneficial in bridging the gap between preclinical and translational research in SCD. Recent advances in methodology have allowed the development of several humanized mouse models to address various aspects of SCD related liver diseases. This review provides an overview of current knowledge of the molecular mechanisms and potential therapeutic options of SCD associated liver dysfunction using the Townes mouse model.
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Affiliation(s)
- Tirthadipa Pradhan-Sundd
- Pittsburgh Heart, Liver and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.,Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | | | - Enrico M Novelli
- Pittsburgh Heart, Liver and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.,Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
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16
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Barbetta A, Goldbeck C, Lim A, Martin SP, Kahn JA, Sheikh MR, Emamaullee J. Treatment and outcomes of hepatocellular carcinoma in patients with Sickle cell disease: a population-based study in the U.S. HPB (Oxford) 2022; 24:234-243. [PMID: 34294525 PMCID: PMC8733051 DOI: 10.1016/j.hpb.2021.06.420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/27/2021] [Accepted: 06/21/2021] [Indexed: 01/09/2023]
Abstract
BACKGROUND Sickle cell disease (SCD) is a rare hemoglobinopathy which can result in chronic liver disease and cirrhosis. Patients with SCD have an increased risk of hematologic malignancy, but the prevalence of hepatocellular carcinoma (HCC) in this population is unknown. Herein, the association of SCD with HCC was examined using registry data. METHODS The SEER-Medicare database was queried to identify patients diagnosed with HCC between 2000 and 2015, and further stratified by SCD status. Propensity matching was performed to examine cancer-related survival and treatment outcomes. RESULTS Overall 56,934 patients with HCC were identified, including 81 patients with SCD. Patients with SCD more frequently had cirrhosis [48.1% (39/81) vs 23.5% (13,377/56,853), p < 0.01] yet presented with smaller tumors [<5 cm: 51.9% (42/81) vs 38.5% (21,898/56,853), p = 0.01]. After propensity matching, SCD was not associated with attenuated survival (aHR 0.73 95%CI 0.52-1.01). When stratified by treatment, patients with SCD had equivalent outcomes to chemotherapy (p = 0.65), TACE/TARE (p = 0.35), resection (p = 0.15) and transplantation (p = 0.67) when compared to non-SCD patients. CONCLUSION This study confirms that a subset of patients with SCD will develop HCC. Importantly, therapeutic options for HCC should not be limited by pre-existing SCD, and similar survival should be expected when compared to non-SCD patients.
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Affiliation(s)
- Arianna Barbetta
- Division of Hepatobiliary and Abdominal Organ Transplant Surgery, Department of Surgery, University of Southern California, 1510 San Pablo St, Los Angeles, 90033, CA, USA
| | - Cameron Goldbeck
- Division of Hepatobiliary and Abdominal Organ Transplant Surgery, Department of Surgery, University of Southern California, 1510 San Pablo St, Los Angeles, 90033, CA, USA
| | - Angelina Lim
- Division of Hepatobiliary and Abdominal Organ Transplant Surgery, Department of Surgery, University of Southern California, 1510 San Pablo St, Los Angeles, 90033, CA, USA
| | - Sean P Martin
- Deparment of Surgery, UPMC Pinnacle, 111 S Front St, Harrisburg, 17101, PA, USA
| | - Jeffrey A Kahn
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, University of Southern California, 1510 San Pablo St, Los Angeles, 90033, CA, USA
| | - M Raashid Sheikh
- Division of Hepatobiliary and Abdominal Organ Transplant Surgery, Department of Surgery, University of Southern California, 1510 San Pablo St, Los Angeles, 90033, CA, USA
| | - Juliet Emamaullee
- Division of Hepatobiliary and Abdominal Organ Transplant Surgery, Department of Surgery, University of Southern California, 1510 San Pablo St, Los Angeles, 90033, CA, USA.
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17
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Nunes-Santos CJ, Koh C, Rai A, Sacco K, Marciano BE, Kleiner DE, Marko J, Bergerson JRE, Stack M, Rivera MM, Constantine G, Strober W, Uzel G, Fuss IJ, Notarangelo LD, Holland SM, Rosenzweig SD, Heller T. Nodular regenerative hyperplasia in X-linked agammaglobulinemia: An underestimated and severe complication. J Allergy Clin Immunol 2022; 149:400-409.e3. [PMID: 34087243 PMCID: PMC8633079 DOI: 10.1016/j.jaci.2021.05.028] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 04/30/2021] [Accepted: 05/14/2021] [Indexed: 01/03/2023]
Abstract
BACKGROUND Late-onset complications in X-linked agammaglobulinemia (XLA) are increasingly recognized. Nodular regenerative hyperplasia (NRH) has been reported in primary immunodeficiency but data in XLA are limited. OBJECTIVES This study sought to describe NRH prevalence, associated features, and impact in patients with XLA. METHODS Medical records of all patients with XLA referred to the National Institutes of Health between October 1994 and June 2019 were reviewed. Liver biopsies were performed when clinically indicated. Patients were stratified into NRH+ or NRH- groups, according to their NRH biopsy status. Fisher exact test and Mann-Whitney test were used for statistical comparisons. RESULTS Records of 21 patients with XLA were reviewed, with a cumulative follow-up of 129 patient-years. Eight patients underwent ≥1 liver biopsy of whom 6 (29% of the National Institutes of Health XLA cohort) were NRH+. The median age at NRH diagnosis was 20 years (range, 17-31). Among patients who had liver biopsies, alkaline phosphatase levels were only increased in patients who were NRH+ (P = .04). Persistently low platelet count (<100,000 per μL for >6 months), mildly to highly elevated hepatic venous pressure gradient and either hepatomegaly and/or splenomegaly were present in all patients who were NRH+. In opposition, persistently low platelet counts were not seen in patients who were NRH-, and hepatosplenomegaly was observed in only 1 patient who was NRH-. Hepatic venous pressure gradient was normal in the only patient tested who was NRH-. All-cause mortality was higher among patients who were NRH+ (5 of 6, 83%) than in the rest of the cohort (1 of 15, 7% among patients who were NRH- and who were classified as unknown; P = .002). CONCLUSIONS NRH is an underreported, frequent, and severe complication in XLA, which is associated with increased morbidity and mortality.
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Affiliation(s)
- CJ Nunes-Santos
- Immunology Service, Department of Laboratory Medicine, National Institutes of Health (NIH) Clinical Center, Bethesda, MD, USA
| | - C Koh
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, NIH, Bethesda, MD, USA
| | - A Rai
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, NIH, Bethesda, MD, USA
| | - K Sacco
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA
| | - BE Marciano
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA
| | - DE Kleiner
- Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, MD, USA
| | - J Marko
- Department of Radiology and Imaging Sciences, Clinical Center, NIH, Bethesda, MD
| | - JRE Bergerson
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA
| | - M Stack
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA
| | - MM Rivera
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, NIH, Bethesda, MD, USA
| | - G Constantine
- National Institute of Allergy and Infectious Diseases Allergy and Immunology Fellowship Program, NIH, Bethesda, Maryland
| | - W Strober
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA
| | - G Uzel
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA
| | - IJ Fuss
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA
| | - LD Notarangelo
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA
| | - SM Holland
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA
| | - SD Rosenzweig
- Immunology Service, Department of Laboratory Medicine, National Institutes of Health (NIH) Clinical Center, Bethesda, MD, USA, corresponding authors Sergio D. Rosenzweig, MD, PhD, ; Immunology Service, Department of Laboratory Medicine, NIH Clinical Center, Building 10, Room 2C306, 10 Center Drive, Bethesda, MD, 20892 and Theo Heller, MD, ; Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, NIH, 10 Center Drive, Bethesda, MD 20892
| | - T Heller
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, NIH, Bethesda, MD, USA, corresponding authors Sergio D. Rosenzweig, MD, PhD, ; Immunology Service, Department of Laboratory Medicine, NIH Clinical Center, Building 10, Room 2C306, 10 Center Drive, Bethesda, MD, 20892 and Theo Heller, MD, ; Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, NIH, 10 Center Drive, Bethesda, MD 20892
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Njoku F, Zhang X, Shah BN, Machado RF, Han J, Saraf SL, Gordeuk VR. Biomarkers of clinical severity in treated and untreated sickle cell disease: a comparison by genotypes of a single center cohort and African Americans in the NHANES study. Br J Haematol 2021; 194:767-778. [PMID: 34268729 PMCID: PMC8373676 DOI: 10.1111/bjh.17682] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 06/10/2021] [Accepted: 06/15/2021] [Indexed: 12/12/2022]
Abstract
Haemolysis and vaso-occlusion underlie multi-organ system complications in sickle cell disease (SCD). We assessed real-world biomarkers in University of Illinois adult SCD patients, categorised as severe (HbSS/Sβ0 -thalassaemia; n = 342) or mild (HbSC/Sβ+ -thalassaemia; n = 100) genotypes and stratified according to treatment. African-American controls from the National Health and Nutrition Examination Survey (NHANES) were matched with each genotype category. Most measures of haemolysis, anaemia, inflammation and function of kidneys, liver and lungs differed markedly in untreated severe genotype patients compared to NHANES controls. These same biomarkers were significantly closer to the NHANES control range in untreated mild versus severe genotype patients, but they were not improved in severe genotype patients receiving treatment with hydroxycarbamide or blood transfusions, except that haemoglobin and HbF were higher with hydroxycarbamide. Systolic blood pressures did not differ among the SCD and NHANES groups, but diastolic pressures were higher in mild genotype patients. Ferritin in severe genotype patients on chronic transfusions was 50-fold higher than NHANES controls. The cross-sectional real-world biomarkers of patients on hydroxycarbamide or transfusions were not markedly improved compared to untreated patients. This may be due partly to poor compliance or more severe disease. Our findings highlight the need for more effective treatments.
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Affiliation(s)
- Franklin Njoku
- Division of Hematology and Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL
| | - Xu Zhang
- Division of Hematology and Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL
| | - Binal N. Shah
- Division of Hematology and Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL
| | - Roberto F. Machado
- Division of Pulmonary, Critical Care, Sleep, and Occupational Medicine, Department of Medicine, Indiana University, Indianapolis, IN
| | - Jin Han
- Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, IL
| | - Santosh L. Saraf
- Division of Hematology and Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL
| | - Victor R. Gordeuk
- Division of Hematology and Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL
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Garcia-Casal MN, Pasricha SR, Martinez RX, Lopez-Perez L, Peña-Rosas JP. Serum or plasma ferritin concentration as an index of iron deficiency and overload. Cochrane Database Syst Rev 2021; 5:CD011817. [PMID: 34028001 PMCID: PMC8142307 DOI: 10.1002/14651858.cd011817.pub2] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND Reference standard indices of iron deficiency and iron overload are generally invasive, expensive, and can be unpleasant or occasionally risky. Ferritin is an iron storage protein and its concentration in the plasma or serum reflects iron stores; low ferritin indicates iron deficiency, while elevated ferritin reflects risk of iron overload. However, ferritin is also an acute-phase protein and its levels are elevated in inflammation and infection. The use of ferritin as a diagnostic test of iron deficiency and overload is a common clinical practice. OBJECTIVES To determine the diagnostic accuracy of ferritin concentrations (serum or plasma) for detecting iron deficiency and risk of iron overload in primary and secondary iron-loading syndromes. SEARCH METHODS We searched the following databases (10 June 2020): DARE (Cochrane Library) Issue 2 of 4 2015, HTA (Cochrane Library) Issue 4 of 4 2016, CENTRAL (Cochrane Library) Issue 6 of 12 2020, MEDLINE (OVID) 1946 to 9 June 2020, Embase (OVID) 1947 to week 23 2020, CINAHL (Ebsco) 1982 to June 2020, Web of Science (ISI) SCI, SSCI, CPCI-exp & CPCI-SSH to June 2020, POPLINE 16/8/18, Open Grey (10/6/20), TRoPHI (10/6/20), Bibliomap (10/6/20), IBECS (10/6/20), SCIELO (10/6/20), Global Index Medicus (10/6/20) AIM, IMSEAR, WPRIM, IMEMR, LILACS (10/6/20), PAHO (10/6/20), WHOLIS 10/6/20, IndMED (16/8/18) and Native Health Research Database (10/6/20). We also searched two trials registers and contacted relevant organisations for unpublished studies. SELECTION CRITERIA We included all study designs seeking to evaluate serum or plasma ferritin concentrations measured by any current or previously available quantitative assay as an index of iron status in individuals of any age, sex, clinical and physiological status from any country. DATA COLLECTION AND ANALYSIS We followed standard Cochrane methods. We designed the data extraction form to record results for ferritin concentration as the index test, and bone marrow iron content for iron deficiency and liver iron content for iron overload as the reference standards. Two other authors further extracted and validated the number of true positive, true negative, false positive, false negative cases, and extracted or derived the sensitivity, specificity, positive and negative predictive values for each threshold presented for iron deficiency and iron overload in included studies. We assessed risk of bias and applicability using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 tool. We used GRADE assessment to enable the quality of evidence and hence strength of evidence for our conclusions. MAIN RESULTS Our search was conducted initially in 2014 and updated in 2017, 2018 and 2020 (10 June). We identified 21,217 records and screened 14,244 records after duplicates were removed. We assessed 316 records in full text. We excluded 190 studies (193 records) with reasons and included 108 studies (111 records) in the qualitative and quantitative analysis. There were 11 studies (12 records) that we screened from the last search update and appeared eligible for a future analysis. We decided to enter these as awaiting classification. We stratified the analysis first by participant clinical status: apparently healthy and non-healthy populations. We then stratified by age and pregnancy status as: infants and children, adolescents, pregnant women, and adults. Iron deficiency We included 72 studies (75 records) involving 6059 participants. Apparently healthy populations Five studies screened for iron deficiency in people without apparent illness. In the general adult population, three studies reported sensitivities of 63% to 100% at the optimum cutoff for ferritin, with corresponding specificities of 92% to 98%, but the ferritin cutoffs varied between studies. One study in healthy children reported a sensitivity of 74% and a specificity of 77%. One study in pregnant women reported a sensitivity of 88% and a specificity of 100%. Overall confidence in these estimates was very low because of potential bias, indirectness, and sparse and heterogenous evidence. No studies screened for iron overload in apparently healthy people. People presenting for medical care There were 63 studies among adults presenting for medical care (5042 participants). For a sample of 1000 subjects with a 35% prevalence of iron deficiency (of the included studies in this category) and supposing a 85% specificity, there would be 315 iron-deficient subjects correctly classified as having iron deficiency and 35 iron-deficient subjects incorrectly classified as not having iron deficiency, leading to a 90% sensitivity. Thresholds proposed by the authors of the included studies ranged between 12 to 200 µg/L. The estimated diagnostic odds ratio was 50. Among non-healthy adults using a fixed threshold of 30 μg/L (nine studies, 512 participants, low-certainty evidence), the pooled estimate for sensitivity was 79% with a 95% confidence interval of (58%, 91%) and specificity of 98%, with a 95% confidence interval of (91%, 100%). The estimated diagnostic odds ratio was 140, a relatively highly informative test. Iron overload We included 36 studies (36 records) involving 1927 participants. All studies concerned non-healthy populations. There were no studies targeting either infants, children, or pregnant women. Among all populations (one threshold for males and females; 36 studies, 1927 participants, very low-certainty evidence): for a sample of 1000 subjects with a 42% prevalence of iron overload (of the included studies in this category) and supposing a 65% specificity, there would be 332 iron-overloaded subjects correctly classified as having iron overload and 85 iron-overloaded subjects incorrectly classified as not having iron overload, leading to a 80% sensitivity. The estimated diagnostic odds ratio was 8. AUTHORS' CONCLUSIONS At a threshold of 30 micrograms/L, there is low-certainty evidence that blood ferritin concentration is reasonably sensitive and a very specific test for iron deficiency in people presenting for medical care. There is very low certainty that high concentrations of ferritin provide a sensitive test for iron overload in people where this condition is suspected. There is insufficient evidence to know whether ferritin concentration performs similarly when screening asymptomatic people for iron deficiency or overload.
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Affiliation(s)
| | - Sant-Rayn Pasricha
- Division: Population Health and Immunity, Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Australia
| | | | | | - Juan Pablo Peña-Rosas
- Department of Nutrition and Food Safety, World Health Organization, Geneva, Switzerland
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Gao E, Hercun J, Heller T, Vilarinho S. Undiagnosed liver diseases. Transl Gastroenterol Hepatol 2021; 6:28. [PMID: 33824932 DOI: 10.21037/tgh.2020.04.04] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 03/19/2020] [Indexed: 02/06/2023] Open
Abstract
The landscape of chronic liver disease has drastically changed over the past 20 years, largely due to advances in antiviral therapy and the rise of metabolic syndrome and associated non-alcoholic fatty liver disease (NAFLD). Despite advances in the diagnosis and treatment of a variety of liver diseases, the burden of chronic liver disease is increasing worldwide. The first step to addressing any disease is accurate diagnosis. Here, we discuss liver diseases that remain undiagnosed, either because they are difficult to diagnose or due to hepatic manifestations of an unrecognized systemic disease. Additionally, their underlying etiology may remain unknown or they represent previously uncharacterized and therefore novel liver diseases. Our goal is to provide a framework for approaching undiagnosed liver diseases which elude standard hepatic diagnostic work-up and whose patterns of disease are often overlooked.
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Affiliation(s)
- Emily Gao
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA
| | - Julian Hercun
- Translational Hepatology Section, National Institute of Diabetes & Digestive & Kidney Diseases, National Institute of Health, Bethesda, MD, USA
| | - Theo Heller
- Translational Hepatology Section, National Institute of Diabetes & Digestive & Kidney Diseases, National Institute of Health, Bethesda, MD, USA
| | - Sílvia Vilarinho
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA.,Department of Pathology, Yale School of Medicine, New Haven, CT, USA
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21
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Kyrana E, Rees D, Lacaille F, Fitzpatrick E, Davenport M, Heaton N, Height S, Samyn M, Mavilio F, Brousse V, Suddle A, Chakravorty S, Verma A, Gupte G, Velangi M, Inusa B, Drasar E, Hadzic N, Grammatikopoulos T, Hind J, Deheragoda M, Sellars M, Dhawan A. Clinical management of sickle cell liver disease in children and young adults. Arch Dis Child 2021; 106:315-320. [PMID: 33177052 PMCID: PMC7610372 DOI: 10.1136/archdischild-2020-319778] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 08/02/2020] [Accepted: 08/30/2020] [Indexed: 11/03/2022]
Abstract
Liver involvement in sickle cell disease (SCD) is often referred to as sickle cell hepatopathy (SCH) and is a complication of SCD which may be associated with significant mortality. This review is based on a round-table workshop between paediatric and adult hepatologists and haematologists and review of the literature. The discussion was prompted by the lack of substantial data and guidance in managing these sometimes very challenging cases. This review provides a structured approach for the diagnosis and management of SCH in children and young adults. The term SCH describes any hepatobiliary dysfunction in the context of SCD. Diagnosis and management of biliary complications, acute hepatic crisis, acute hepatic sequestration and other manifestations of SCH are discussed, as well as the role of liver transplantation and haemopoietic stem cell transplantation in the management of SCH.
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Affiliation(s)
- Eirini Kyrana
- Children’s Live Unit, Leeds General Infirmary, Leeds, UK
| | - David Rees
- King’s College London, Department of Haematological Medicine, King’s College Hospital, Denmark Hill, London
| | - Florence Lacaille
- Gastroenterology-Hepatology-Nutrition Unit, Hôpital Universitaire Necker-Enfants Malades, 149 rue de Sèvres, 75015 Paris
| | - Emer Fitzpatrick
- Institute of Liver Studies, King’s College London, Denmark Hill, London, UK
| | - Mark Davenport
- Department of Paediatric Surgery, King’s College Hospital, Denmark Hill, London SE5 9RS, UK
| | - Nigel Heaton
- Hepatobiliary and Pancreatic Surgery/Liver Transplantation, King’s College Hospital NHS Trust, Denmark Hill, SE9 5RS, London, UK
| | - Sue Height
- Paediatric Haematology, King’s College Hospital NHS Trust, London
| | - Marianne Samyn
- Paediatric Liver, GI and Nutrition Centre, King’s College Hospital NHS Trust, London, UK
| | - Fulvio Mavilio
- Department of Life Sciences, University of Modena and Reggio Emilia Via Campi, 287; 41125 Modena – Italy
| | - Valentine Brousse
- Service de Pédiatrie Générale et Maladies Infectieuses, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75015 Paris
| | - Abid Suddle
- Institute of Liver Studies, King’s College Hospital NHS Trust, Denmark Hill, SE9 5RS, London, UK
| | - Subarna Chakravorty
- Paediatric Haematology, King’s College Hospital NHS Trust, Denmark Hill, London, UK
| | - Anita Verma
- Institute of Liver Studies, Kings College Hospital, Denmark Hill, SE9 5RS, London UK
| | - Girish Gupte
- Liver Unit (including small bowel transplantation), Birmingham Women’s and Children’s Hospital, Steelhouse Lane, Birmingham B4 6NH
| | - Mark Velangi
- Department of Haematology, Birmingham Women’s and Children’s Hospital, Steelhouse Lane, Birmingham B4 6NH
| | - Baba Inusa
- Children's sickle cell and thalassaemia centre at Evelina London Children’s Hospital, St Thomas’ Hospital, Westminster Bridge Road, London SE1 7EH
| | - Emma Drasar
- Department of Clinical Haematology, University College London Hospitals, 250 Euston Roads Bloomsbury, London NW1 2PG
| | - Nedim Hadzic
- Paediatric Centre for Hepatology, Gastroenterology and Nutrition, King's College Hospital, Denmark Hill, London SE5 9RS, UK
| | - Tassos Grammatikopoulos
- Paediatric Liver, GI & Nutrition Centre and MowatLabs King's College Hospital NHS Foundation Trust, London and Institute of Liver Studies, King’s College London, Denmark Hill, London, SE5 9RS
| | - Jonathan Hind
- Paediatric Liver, GI and Nutrition Centre, King’s College Hospital NHS Trust, London, UK
| | - Maesha Deheragoda
- Liver Histopathology Laboratory, Institute of Liver Studies, King’s College Hospital, London, UK
| | - Maria Sellars
- Department of Radiology, Kings College Hospital, Denmark Hill, London, UK
| | - Anil Dhawan
- Paediatric Liver, GI and Nutrition Centre and MowatLabs, King's College Hospital NHS Foundation Trust, London, UK
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22
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Alzahrani M, Damlaj M, Jeffries N, Alahmari B, Singh A, Rondelli D, Tisdale JF, Saraf SL, Hsieh MM. Non-myeloablative human leukocyte antigen-matched related donor transplantation in sickle cell disease: outcomes from three independent centres. Br J Haematol 2021; 192:761-768. [PMID: 33534948 DOI: 10.1111/bjh.17311] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 12/14/2020] [Indexed: 12/31/2022]
Abstract
Non-myeloablative haematopoietic progenitor cell transplantation (HPCT) from matched related donors (MRD) has been increasingly utilized in sickle cell disease (SCD). A total of 122 patients received 300 cGy of total body irradiation (TBI), alemtuzumab, unmanipulated filgrastim-mobilized peripheral blood HPC and sirolimus. The median follow-up was four years; median age at HPCT was 29 years. Median neutrophil and platelet engraftment occurred on day 22 and 19 respectively; 41 patients required no platelet transfusions. Overall and sickle-free survival at one and five years were 93% and 85% respectively. Age, sex, pre-HPCT sickle complications, ferritin and infused HPC numbers were similar between graft failure and engrafted patients. Mean donor myeloid chimaerism at one and five years post HPCT were 84% and 88%, and CD3 was 48% and 53% respectively. Two patients developed grade 1 and 2 skin graft-versus-host disease (GVHD) with no chronic GVHD. Median days of recipients taking immunosuppression were 489; 83% of engrafted patients have discontinued immunosuppression. Haemoglobin, haemolytic parameters and hepatic iron levels improved post HPCT. Pulmonary function testing, hepatic histology and neurovascular imaging remained stable, suggesting cessation of further sickle-related injury. Fourteen patients had children. In this largest group of adult SCD patients, this regimen was highly efficacious, well-tolerated despite compromised organ functions pre HPCT, and without clinically significant GVHD.
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Affiliation(s)
- Mohsen Alzahrani
- Division of Hematology & Hematopoietic Stem Cell Transplantation, Department of Oncology, King Abdulaziz Medical City, Riyadh, Saudi Arabia
| | - Moussab Damlaj
- Division of Hematology & Hematopoietic Stem Cell Transplantation, Department of Oncology, King Abdulaziz Medical City, Riyadh, Saudi Arabia
| | - Neal Jeffries
- Office of Biostatistics Research, National Heart, Lung, and Blood Institute, Bethesda, MD, USA
| | - Bader Alahmari
- Division of Hematology & Hematopoietic Stem Cell Transplantation, Department of Oncology, King Abdulaziz Medical City, Riyadh, Saudi Arabia
| | - Avani Singh
- Division of Hematology/Oncology, University of Illinois Hospital and Health Science Systems, Chicago, IL, USA
| | - Damiano Rondelli
- Division of Hematology/Oncology, University of Illinois Hospital and Health Science Systems, Chicago, IL, USA
| | - John F Tisdale
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, Bethesda, MD, USA
| | - Santosh L Saraf
- Division of Hematology/Oncology, University of Illinois Hospital and Health Science Systems, Chicago, IL, USA
| | - Matthew M Hsieh
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, Bethesda, MD, USA
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23
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Gbotosho OT, Kapetanaki MG, Kato GJ. The Worst Things in Life are Free: The Role of Free Heme in Sickle Cell Disease. Front Immunol 2021; 11:561917. [PMID: 33584641 PMCID: PMC7873693 DOI: 10.3389/fimmu.2020.561917] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 12/04/2020] [Indexed: 12/15/2022] Open
Abstract
Hemolysis is a pathological feature of several diseases of diverse etiology such as hereditary anemias, malaria, and sepsis. A major complication of hemolysis involves the release of large quantities of hemoglobin into the blood circulation and the subsequent generation of harmful metabolites like labile heme. Protective mechanisms like haptoglobin-hemoglobin and hemopexin-heme binding, and heme oxygenase-1 enzymatic degradation of heme limit the toxicity of the hemolysis-related molecules. The capacity of these protective systems is exceeded in hemolytic diseases, resulting in high residual levels of hemolysis products in the circulation, which pose a great oxidative and proinflammatory risk. Sickle cell disease (SCD) features a prominent hemolytic anemia which impacts the phenotypic variability and disease severity. Not only is circulating heme a potent oxidative molecule, but it can act as an erythrocytic danger-associated molecular pattern (eDAMP) molecule which contributes to a proinflammatory state, promoting sickle complications such as vaso-occlusion and acute lung injury. Exposure to extracellular heme in SCD can also augment the expression of placental growth factor (PlGF) and interleukin-6 (IL-6), with important consequences to enthothelin-1 (ET-1) secretion and pulmonary hypertension, and potentially the development of renal and cardiac dysfunction. This review focuses on heme-induced mechanisms that are implicated in disease pathways, mainly in SCD. A special emphasis is given to heme-induced PlGF and IL-6 related mechanisms and their role in SCD disease progression.
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Affiliation(s)
- Oluwabukola T. Gbotosho
- Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Maria G. Kapetanaki
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Gregory J. Kato
- Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
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24
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Abstract
Sickle hepatopathy is an umbrella term describing various pattern of liver injury seen in patients with sickle cell disease. The disease is not uncommon in India; in terms of prevalence, India is second only to Sub-Saharan Africa where sickle cell disease is most prevalent. Hepatic involvement in sickle cell disease is not uncommon. Liver disease may result from viral hepatitis and iron overload due to multiple transfusions of blood products or due to disease activity causing varying changes in vasculature. The clinical spectrum of disease ranges from ischemic injury due to sickling of red blood cells in hepatic sinusoids, pigment gall stones, and acute/chronic sequestration syndromes. The sequestration syndromes are usually episodic and self-limiting requiring conservative management such as antibiotics and intravenous fluids or packed red cell transfusions. However, rarely these episodes may present with coagulopathy and encephalopathy like acute liver failure, which are life-threatening, requiring exchange transfusions or even liver transplantation. However, evidence for their benefits, optimal indications, and threshold to start exchange transfusion is limited. Similarly, there is paucity of the literature regarding the end point of exchange transfusion in this scenario. Liver transplantation may also be beneficial in end-stage liver disease. Hydroxyurea, the antitumor agent, which is popularly used to prevent life-threatening complications such as acute chest syndrome or stroke in these patients, has been used only sparingly in hepatic sequestrations. The purpose of this review is to provide insights into epidemiology of sickle cell disease in India and pathogenesis and classification of hepatobiliary involvement in sickle cell disease. Finally, various management options including exchange transfusion, liver transplantation, and hydroxyurea in hepatic sequestration syndromes will be discussed in brief.
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Key Words
- AASLD, American Association for the Study of Liver Diseases
- ACLF, Acute on chronic liver failure
- ALF, Acute liver failure
- ALT, Alanine transaminase
- AST, Aspartate transaminase
- FFP, Fresh frozen plasma
- GIT, Gastrointestinal tract
- HAV, Hepatitis A virus
- HBV, Hepatitis B virus
- HCV, Hepatitis C virus
- HEV, Hepatitis E virus
- HIC, Hepatic iron content
- HbS, Sickle hemoglobin
- HbSS, Sickle cell disease homozygous
- INR, International normalized ratio
- PT, Prothrombin time
- RUQ, Right upper quadrant
- SC, Scheduled caste
- SCD, Sickle cell disease
- SCIC, Sickle cell intrahepatic cholestasis
- ST, Scheduled tribe
- TJLB, Transjugular liver biopsy
- UDCA, Ursodeoxycholic acid
- cholelithiasis
- intrahepatic cholestasis
- sickle cell hepatopathy
- sickle cholangiopathy
- sickle hepatic crisis
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Affiliation(s)
| | - Anil C. Anand
- Address for correspondence. Anil C Anand, Professor and Head, Department of Gastroenterology & Hepatology, Kalinga Institute of Medical Sciences, Bhubneshwar, India.
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Abstract
Sickle cell disease is an umbrella term for a group of hemoglobinopathies characterized by the presence of 2 β-globin gene mutations or deletions, at least 1 of which is the point mutation that leads to the production of hemoglobin S. Sickle cell disease is associated with hemolytic anemia, significant chronic end-organ damage, and early death. In high-income countries, at least 95% of children with the disease survive into adulthood, resulting in a growing population of affected adults with significant comorbidities, complex medical issues, and not enough specialists to provide care. Hydroxyurea is the primary therapy, and recent advances in understanding disease pathophysiology have led to new therapies; progress in bone marrow transplant and gene editing has resulted in cure in some patients. The purpose of this review is to provide an overview of the diagnosis, common acute and chronic clinical manifestations, and best practices for management of sickle cell disease.
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Affiliation(s)
- Lydia H Pecker
- Johns Hopkins University School of Medicine, Baltimore, Maryland (L.H.P., S.L.)
| | - Sophie Lanzkron
- Johns Hopkins University School of Medicine, Baltimore, Maryland (L.H.P., S.L.)
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26
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Kelly S, Rodeghier M, DeBaun MR. Automated exchange compared to manual and simple blood transfusion attenuates rise in ferritin level after 1 year of regular blood transfusion therapy in chronically transfused children with sickle cell disease. Transfusion 2020; 60:2508-2516. [PMID: 32812667 DOI: 10.1111/trf.15982] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Revised: 06/16/2020] [Accepted: 06/22/2020] [Indexed: 11/28/2022]
Abstract
BACKGROUND Optimal strategies for regular blood transfusion therapy are not well defined in sickle cell disease (SCD). This analysis tested the hypothesis that in the first of year of regular transfusions, when chelation therapy use is minimal, automated exchange transfusion would be the superior method for attenuating the rise in ferritin levels compared to simple and manual exchange transfusions. STUDY DESIGN AND METHODS The Silent Cerebral Infarct Multi-Center Clinical Trial randomly allocated children with SCD and silent cerebral infarcts to receive standard care or regular transfusions with a target pre-transfusion HbS concentration ≤ 30% and minimum hemoglobin level > 9.0 g/dL. Participants with at least nine transfusions and sufficient ferritin testing in the first year of the trial were included in a planned secondary analysis. Ferritin levels by the end of the first study year were compared between participants receiving automatic exchange transfusion, manual exchange transfusion, and simple transfusion. RESULTS A total of 83 participants were analyzed. During the first year of the study, 75.9% of the participants had >80% of transfusions via one transfusion method. At baseline no significant differences in ferritin levels were observed in the three transfusion groups (p = 0.1). After 1 year of transfusions the median (interquartile range) ferritin levels in the simple transfusion (n = 40), manual exchange transfusion (n = 34) and automatic exchange transfusion (n = 9) groups were 1800 ng/mL (1426-2204 ng/mL), 1530 ng/mL (1205-1805 ng/mL), and 355 ng/mL (179-579 ng/mL), respectively (p < 0.001). CONCLUSION Automated exchange transfusion, when compared to other transfusion methods, is the optimal transfusion strategy for attenuating increase in ferritin levels in children with SCD.
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Affiliation(s)
- Shannon Kelly
- Department of Epidemiology, Vitalant Research Institute, San Francisco, California, USA.,Department of Pediatrics, Division of Hematology/Oncology, UCSF Benioff Children's Hospital Oakland, Oakland, California, USA
| | | | - Michael R DeBaun
- Department of Pediatrics, Division of Hematology/Oncology, Vanderbilt-Meharry Center for Excellence in Sickle Cell Disease, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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Oldham M, Conrey A, Pittman C, Fisher C, Hargrett S, West K, Jackson M, Martin S, Hsieh MM, Jeffries N, Kaplarevic M, Johnson D, Olkhanud P, Fitzhugh CD. Computer Algorithm-Based Hydroxyurea Dosing Facilitates Titration to Maximum Tolerated Dose in Sickle Cell Anemia. J Clin Pharmacol 2020; 61:41-51. [PMID: 32673439 DOI: 10.1002/jcph.1699] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 06/22/2020] [Indexed: 12/15/2022]
Abstract
Adults with sickle cell disease (SCD) experience acute and chronic complications and die prematurely. When taken at maximum tolerated dose (MTD), hydroxyurea prolongs survival; however, it has not consistently reversed organ dysfunction. Patients also frequently do not take hydroxyurea, at least in part because of physician discomfort with prescribing hydroxyurea. We sought to develop a computer program that could easily titrate hydroxyurea to MTD. This was a single-arm, open-label pilot study. Fifteen patients with homozygous SCD were enrolled in the protocol, and 10 patients were followed at baseline and then for 1 year after hydroxyurea initiation or dose titration. Fetal hemoglobin significantly increased in all 10 patients from 8.3% to 25.1% (P < .001). Nine patients were titrated to MTD in an average of 7.9 months, and the tenth patient's hydroxyurea dose was increased to 33 mg/kg/day. Computer program dosing recommendations were the same as manual dosing decisions made using the same algorithm for all patients and at all times. We also evaluated markers of cardiopulmonary, liver and renal damage. Although cardiopulmonary function did not significantly improve, direct bilirubin and alanine aminotransferase levels significantly decreased (P < .001 and P < .01, respectively). Last, although kidney function did not improve, degree of proteinuria was significantly reduced (P < .05). We have developed a computer program that reliably titrates hydroxyurea to MTD. A larger study is indicated to test the program either as a computer program or a downloadable application.
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Affiliation(s)
| | - Anna Conrey
- Sickle Cell Branch, NHLBI, NIH, Bethesda, Maryland, USA
| | | | | | | | - Kamille West
- Department of Transfusion Medicine, Clinical Center, NIH, Bethesda, Maryland, USA
| | - Mary Jackson
- Sickle Cell Branch, NHLBI, NIH, Bethesda, Maryland, USA
| | - Staci Martin
- Pediatric Oncology Branch, NCI, NIH, Bethesda, Maryland, USA
| | | | - Neal Jeffries
- Office of Biostatistics Research, NHLBI, NIH, Bethesda, Maryland, USA
| | | | - Dachelle Johnson
- Pharmacy Department, Clinical Center, NIH, Bethesda, Maryland, USA
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Kelly S, Belisário AR, Werneck Rodrigues DO, Carneiro-Proietti ABF, Gonçalez TT, Loureiro P, Flor-Park MV, Maximo C, Mota RA, Dinardo C, Brambilla D, Preiss L, Sabino E, Custer B. Blood utilization and characteristics of patients treated with chronic transfusion therapy in a large cohort of Brazilian patients with sickle cell disease. Transfusion 2020; 60:1713-1722. [PMID: 32579245 DOI: 10.1111/trf.15818] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 01/13/2020] [Accepted: 01/13/2020] [Indexed: 12/01/2022]
Abstract
BACKGROUND Red blood cell (RBC) transfusions are used in sickle cell disease (SCD) to treat acute complications or as chronic transfusion therapy (CTT) to prevent severe manifestations. The objectives of this study were to describe blood utilization and adverse events (AEs) associated with RBCs in the Brazilian SCD population and compare characteristics of patients treated or not with CTT. STUDY DESIGN AND METHODS A SCD cohort was established at six Brazilian centers. Medical and blood bank records were abstracted for clinical and transfusion history. Two controls not treated with CTT matched on center, SCD genotype, sex, and age were selected for each CTT case within the cohort to compare characteristics between the two groups. RESULTS Most of the 2794-member cohort had received a transfusion (75.0% of children and 89.2% of adults) with 29.2% of patients receiving transfusion in the prior year. There were 170 (10.6%) children and 115 (9.2%) adults treated with CTT. Children not treated with CTT were more likely to have pain and acute chest hospitalizations in the prior year (25.3% vs. 11.9%, p = 0.0003; and 22.0% vs. 10.7%, p = 0.002, respectively). Both iron overload and alloimmunization were more common in CTT cases compared to controls (65.6% vs. 17.0% and 36.2% vs. 15.9%, respectively). A higher proportion of adults treated with CTT demonstrated oxygen saturation of greater than 95% compared to controls not treated (51.1% vs. 39.2%), while there was no difference in oxygenation between children treated or not. Of 4501 transfusion episodes, 28 (0.62%) AEs were reported. There was no difference in AEs associated with transfusions for acute indications versus CTT. CONCLUSION Red blood cell transfusion was common in Brazilian SCD patients, with utilization driven by CTT. Transfusion reactions were not common; however, alloimmunization and iron overload were frequent among those on CTT, highlighting the need for novel clinical strategies to mitigate these risks.
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Affiliation(s)
- Shannon Kelly
- Vitalant Research Institute, San Francisco, California, USA.,UCSF Benioff Children's Hospital Oakland, Oakland, California, USA
| | | | | | | | | | - Paula Loureiro
- Hemope/University of Pernambuco, Recife, Pernambuco, Brazil
| | - Miriam V Flor-Park
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Instituto da Criança, São Paulo, Brazil
| | - Claudia Maximo
- Hemorio, Rio de Janeiro Hemocenter, Rio de Janeiro, Brazil
| | | | - Carla Dinardo
- Pró-Sangue, São Paulo Hemocenter, São Paulo, Brazil.,Institute of Tropical Medicine, University of São Paulo, São Paulo, Brazil
| | - Don Brambilla
- Research Triangle Institute (RTI) International, Triangle Park, North Carolina, USA
| | - Liliana Preiss
- Research Triangle Institute (RTI) International, Triangle Park, North Carolina, USA
| | - Ester Sabino
- Institute of Tropical Medicine, University of São Paulo, São Paulo, Brazil
| | - Brian Custer
- Fundação Hemominas/Minas Gerais Hemocenter, Minas Gerais, Brazil.,Department of Laboratory Medicine, University of California at San Francisco, San Francisco, California, USA
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Ataga KI, Gordeuk VR, Agodoa I, Colby JA, Gittings K, Allen IE. Low hemoglobin increases risk for cerebrovascular disease, kidney disease, pulmonary vasculopathy, and mortality in sickle cell disease: A systematic literature review and meta-analysis. PLoS One 2020; 15:e0229959. [PMID: 32243480 PMCID: PMC7122773 DOI: 10.1371/journal.pone.0229959] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 02/17/2020] [Indexed: 12/20/2022] Open
Abstract
Sickle cell disease (SCD) is characterized by deoxygenation-induced polymerization of hemoglobin in red blood cells, leading to hemolytic anemia, vaso-occlusion, and the development of multiple clinical complications. To characterize the clinical burden associated with differences in hemoglobin concentration and hemolysis measures, a systematic literature review of MEDLINE, EMBASE, and related meta-analyses was undertaken. For quantitative analyses related to hemoglobin concentration, pooled results were analyzed using random effects models to control for within-and between-study variability. To derive risk ratios associated with hemoglobin concentration change, we combined ratios of means from select studies, which reported hazard and odds ratios in meta-analyses for hemoglobin concentration-related outcomes and changes between groups. Forty-one studies were identified for inclusion based on relating hemoglobin concentration to clinical outcomes. Meta-analyses demonstrated that mean hemoglobin concentration was significantly lower in patients with cerebrovascular disease (0.4 g/dL), increased transcranial Doppler velocity in cerebral arteries (0.6 g/dL), albuminuria (0.6 g/dL), elevated estimated pulmonary artery systolic pressure (0.9 g/dL), and in patients that subsequently died (0.6 g/dL). In a risk reduction meta-analysis, modeled increased hemoglobin concentrations of 1 g/dL or greater resulted in decreased risk of negative clinical outcomes of 41% to 64%. In conclusion, chronic anemia is associated with worse clinical outcomes in individuals with SCD and even modest increases in hemoglobin concentration may be beneficial in this patient population. This systematic review has been registered on Prospero (Registration number CRD42018096860; https://www.crd.york.ac.uk/prospero/).
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Affiliation(s)
- Kenneth I. Ataga
- University of Tennessee Health Science Center, Memphis, TN, United States of America
| | - Victor R. Gordeuk
- University of Illinois at Chicago College of Medicine, Chicago, IL, United States of America
| | - Irene Agodoa
- GBT, South San Francisco, CA, United States of America
| | | | | | - Isabel E. Allen
- School of Medicine, University of California, San Francisco, San Francisco, CA, United States of America
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30
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Pompeo CM, Cardoso AIDQ, Souza MDC, Ferraz MB, Ferreira Júnior MA, Ivo ML. Fatores de risco para mortalidade em pacientes com doença falciforme: uma revisão integrativa. ESCOLA ANNA NERY 2020. [DOI: 10.1590/2177-9465-ean-2019-0194] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
RESUMO Objetivo Sumarizar fatores de risco e indicadores de mortalidade em pacientes com doença falciforme. Método Revisão integrativa em periódicos indexados nas bases de dados CINAHL, PubMed/MEDLINE, Science Direct/SCOPUS, SciELO e Web of Science. A questão norteadora foi elaborada por meio da estratégia Population, variable, outcome (PVO). A busca ocorreu no portal de periódicos da Coordenação de Aperfeiçoamento de Pessoal de Nível Superior entre outubro e novembro de 2018. Resultados Dos 19 artigos, 18 eram coorte e um ensaio clínico randomizado. A amostra foi constituída, em sua maioria, pelo sexo feminino e genótipo HbSS. Se repetiram mais a taxa de mortalidade cumulativa e a curva de mortalidade global. Sete estudos identificaram fatores de risco com associação estatisticamente significativa para morte. Os mais frequentes foram o baixo nível de hemoglobina, variáveis hepáticas (enzimas fosfatase alcalina e transaminase glutâmico oxalacética) e cardiovasculares (velocidade de regurgitação da válvula tricúspide ≥ 2,5m/s). Conclusão e implicações para a prática Indicadores de mortalidade constituem ferramentas de manejo de pacientes com doença falciforme e prevenção de riscos e complicações. Há necessidade de estudos sobre os fatores relacionados à mortalidade desses pacientes. A prevenção do óbito, certamente, promoverá uma melhoria na qualidade de vida e na sobrevida dessa população.
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31
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Suddle AR. Management of liver complications in sickle cell disease. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2019; 2019:345-350. [PMID: 31808845 PMCID: PMC6913458 DOI: 10.1182/hematology.2019000037] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Abstract
Liver disease is an important cause of morbidity and mortality in patients with sickle cell disease (SCD). Despite this, the natural history of liver disease is not well characterized and the evidence basis for specific therapeutic intervention is not robust. The spectrum of clinical liver disease encountered includes asymptomatic abnormalities of liver function; acute deteriorations in liver function, sometimes with a dramatic clinical phenotype; and decompensated chronic liver disease. In this paper, the pathophysiology and clinical presentation of patients with acute and chronic liver disease will be outlined. Advice will be given regarding initial assessment and investigation. The evidence for specific medical and surgical interventions will be reviewed, and management recommendations made for each specific clinical presentation. The potential role for liver transplantation will be considered in detail.
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Affiliation(s)
- Abid R Suddle
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
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32
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Hepatobiliary Complications in Children with Sickle Cell Disease: A Retrospective Review of Medical Records from 616 Patients. J Clin Med 2019; 8:jcm8091481. [PMID: 31540390 PMCID: PMC6780325 DOI: 10.3390/jcm8091481] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Revised: 09/06/2019] [Accepted: 09/16/2019] [Indexed: 12/19/2022] Open
Abstract
Hepatobiliary complications in children with sickle cell disease (SCD) are rarely reported but can be life-threatening. We retrospectively assessed their prevalence in a cohort of 616 children followed in a French university-hospital SCD reference center. Eligibility criteria were the following: age <18 years, seen at least twice with an interval of more than 6 months from January 2008 to December 2017, with all genotypes of SCD. Patients with hepatobiliary complications were identified via the local data warehouse and medical files were thoroughly reviewed. At least one hepatobiliary complication was reported in 37% of the children. The most frequent was cholelithiasis, in 25% of cases, which led to systematic screening and elective cholecystectomy in the case of gallstones. Overall, 6% of the children experienced acute sickle cell hepatic crisis, sickle cell intra-hepatic cholestasis, or acute hepatic sequestration, with severity ranging from mild liver pain and increased jaundice to multiple organ failure and death. Emergency treatment was exchange transfusion, which led to normalization of liver tests in most cases. Five children had chronic cholangiopathy, associated with auto-immune hepatitis in two cases. One needed liver transplantation, having a good outcome but with many complications. Transfusion iron load and infectious hepatitis cases were mild. Hepatotoxicity of an iron chelator was suspected to contribute to abnormal liver test results in five patients. We propose recommendations to prevent, explore, and treat hepatobiliary complications in SCD children. We underline the need for emergency exchange transfusion when acute liver failure develops and warn against liver biopsy and transplantation in this condition.
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33
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Ben Yakov G, Sharma D, Alao H, Surana P, Kapuria D, Etzion O, Hsieh MM, Tisdale JF, Fitzhugh CD, Kleiner DE, Levy EB, Chang R, Rivera E, Huang A, Koh C, Heller T. Vibration Controlled Transient Elastography (Fibroscan®) in sickle cell liver disease - could we strike while the liver is hard? Br J Haematol 2019; 187:117-123. [PMID: 31218662 DOI: 10.1111/bjh.16047] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 04/23/2019] [Indexed: 01/22/2023]
Abstract
Vibration controlled transient elastography (VCTE) is validated for the evaluation of hepatic fibrosis in different liver diseases. Sickle cell liver disease (SCLD) results from a cumulative hepatic injury and its lifelong and progressive nature raises the need for a non-invasive tool for fibrosis evaluation. Fifty patients, aged between 23 and 59 years with sickle cell disease and suspected SCLD underwent a VCTE followed by a liver biopsy. Biopsies were evaluated for various scores of liver disease that were then correlated to VCTE score. 90% of our patients had an Ishak Fibrosis (IF) score between 0-2 (Group A-minimal to no fibrosis) and 10% of the patients had IF score between 3-6 (Group B-advanced fibrosis). The median Transient Elastography (TE) for patients in Groups A and B was 4·8 kilopascals (kPa) and 17·6 kPa, respectively. A positive correlation was shown between TE and IF score, R = 0·0·68 (P = <0·0001); a positive correlation was also shown with Histology Activity Index fibrosis score, R = 0·64 (P = <0·0001). This study emphasises the need for further studies of non-invasive tools and their utility in liver fibrosis evaluation of patients with SCLD.
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Affiliation(s)
- Gil Ben Yakov
- Liver Diseases Branch, NIDDK, NIH, Bethesda, MD, USA
| | - Disha Sharma
- Liver Diseases Branch, NIDDK, NIH, Bethesda, MD, USA
| | - Hawwa Alao
- Liver Diseases Branch, NIDDK, NIH, Bethesda, MD, USA
| | | | | | - Ohad Etzion
- Liver Diseases Branch, NIDDK, NIH, Bethesda, MD, USA
| | - Matthew M Hsieh
- Molecular and Clinical Hematology Branch, NHLBI, NIH, Bethesda, MD, USA
| | - John F Tisdale
- Molecular and Clinical Hematology Branch, NHLBI, NIH, Bethesda, MD, USA
| | | | | | - Elliot B Levy
- Interventional Radiology, Department of Diagnostic Radiology, NIH, Bethesda, MD, USA
| | - Richard Chang
- Interventional Radiology, Department of Diagnostic Radiology, NIH, Bethesda, MD, USA
| | | | - Amy Huang
- Liver Diseases Branch, NIDDK, NIH, Bethesda, MD, USA
| | | | - Theo Heller
- Liver Diseases Branch, NIDDK, NIH, Bethesda, MD, USA
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34
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Abstract
Patients with sickle cell disease can develop liver disease as a result of intrahepatic sickling of erythrocytes, viral hepatitis and iron overload secondary to multiple blood transfusions, and gallstone disease as a result of chronic hemolysis. The spectrum of clinical liver disease is wide and often multifactorial. Some patients develop cirrhosis that may progress to end-stage liver failure. Limited evidence exists for medical treatments. Exchange blood transfusions may improve outcomes in the acute liver syndromes. Liver transplantation may be an option for chronic liver disease. The role for prophylactic cholecystectomy in preventing complications of gallstone disease is controversial.
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Affiliation(s)
- Eleni Theocharidou
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS, UK
| | - Abid R Suddle
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS, UK.
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35
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Haydek JP, Taborda C, Shah R, Reshamwala PA, McLemore ML, Rassi FE, Chawla S. Extreme hyperbilirubinemia: An indicator of morbidity and mortality in sickle cell disease. World J Hepatol 2019; 11:287-293. [PMID: 30967906 PMCID: PMC6447425 DOI: 10.4254/wjh.v11.i3.287] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2018] [Revised: 01/16/2019] [Accepted: 01/28/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Sickle cell disease (SCD) is a disorder that results in increased hospitalizations and higher mortality. Advances in management have resulted in increases in life expectancy and led to increasing awareness of sickle cell hepatopathy (SCH). However, its impact in patients on the natural history and outcomes of SCD is not known. Our study aims to describe the prevalence of extreme hyperbilirubinemia (EH), one form of SCH, its effect on morbidity and mortality, and correlations between sickle cell genotype and SCH type. We hypothesize that EH is associated with higher morbidity and mortality.
AIM To investigate the effects of EH on morbidity and mortality among patients with SCD.
METHODS This retrospective cohort study was performed using a database of patients with SCD treated at Grady Memorial Hospital between May 2004 and January 2017. Patients with EH (defined as total bilirubin above 13.0 mg/dL) were identified. A control group was identified from the same database with patients with total serum bilirubin ≤ 5.0 mg/dL. Electronic medical records were used to extract demographic information, laboratory values, radiology results, current medications, need for transfusions and mortality data. Two samples T-test, chi-squared test and Fisher’s exact test were then used to compare the parameters between the two groups.
RESULTS Out of the database, fifty-seven charts were found of patients with bilirubin > 13 mg/dL. Prevalence of severe SCH as defined by EH was 4.8% (57/1172). There were no demographic differences between patients with and without EH. Significant genotypic differences existed between the two groups, with hemoglobin SS SCD being much higher in the EH group (P < 0.001). Patients with severe EH had a significant elevations in alanine aminotransferase (157.0 ± 266.2 IU/L vs 19.8 ± 21.3 IU/L, P < 0.001), aspartate aminotransferase (256.5 ± 485.9 U/L vs 28.2 ± 14.7 U/L, P < 0.001) and alkaline phosphatase (218.0 ± 176.2 IU/L vs 85.9 ± 68.4 IU/L, P < 0.001). Patients with EH had significantly higher degree of end organ failure measured with quick Sequential Organ Failure Assessment scores (0.42 ± 0.68 vs 0.01 ± 0.12, P < 0.001), increased need for blood products (63% vs 5%, P < 0.001), and exchange transfusions (10.5% vs 1.3%, P = 0.022).
CONCLUSION Among patients with SCD, elevated levels of total bilirubin are rare, but indicative of elevated morbidity, mortality, and need for blood transfusions. Large differences in sickle cell genotype also exist, but the significance of this is unknown.
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Affiliation(s)
- John Paul Haydek
- Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, United States
| | - Cesar Taborda
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30329, United States
| | - Rushikesh Shah
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30329, United States
| | - Preeti A Reshamwala
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30329, United States
| | - Morgan L McLemore
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30329, United States
| | - Fuad El Rassi
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30329, United States
| | - Saurabh Chawla
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30329, United States
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36
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Pecker LH, Maher JY, Law JY, Beach MC, Lanzkron S, Christianson MS. Risks associated with fertility preservation for women with sickle cell anemia. Fertil Steril 2019; 110:720-731. [PMID: 30196969 DOI: 10.1016/j.fertnstert.2018.05.016] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Revised: 05/14/2018] [Accepted: 05/14/2018] [Indexed: 01/01/2023]
Abstract
OBJECTIVE To highlight the risk of complications among women with sickle cell anemia (SCA) receiving fertility preservation treatment (FPT) before hematopoietic stem cell transplant (HSCT). DESIGN Single-center case series. SETTING Academic fertility center. PATIENT(S) Women aged 15-32 years with SCA undergoing FPT before HSCT. INTERVENTION(S) Retrospective, systematic review. MAIN OUTCOME MEASURE(S) FPT modality, SCA complications during FPT. RESULT(S) Over an 8-year period (2009-2017), seven women with SCA ages 15-32 years (mean 28.5 years) underwent FPT with embryo cryopreservation (n = 1), oocyte cryopreservation (n = 4), and ovarian tissue cryopreservation (n = 2). The five women subjects who underwent oocyte or embryo cryopreservation were treated with an antagonist controlled ovarian hyperstimulation protocol and individualized gonadotropin dosing. The trigger medications included leuprolide acetate (n = 2), and human chorionic gonadotropin (n = 3). Most patients (n = 5) received a disease-modifying therapy for SCA (hydroxyurea or chronic transfusions) before FPT. Three patients experienced periprocedural SCA complications that included life-threatening respiratory failure, painful crisis requiring interruption of a stimulation cycle, and severe postharvest painful crisis. CONCLUSION(S) Women with SCA may choose to undergo diverse FPT strategies before HSCT and are at risk for serious SCA-related complications. Evidence-based strategies to mitigate SCA-related morbidity and to optimize fertility preservation outcomes are needed.
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Affiliation(s)
- Lydia H Pecker
- Division of Pediatric Hematology, Department of Pediatrics, School of Medicine, Johns Hopkins University, Baltimore, Maryland.
| | - Jacqueline Y Maher
- Department of Gynecology and Obstetrics, Division of Reproductive Endocrinology, School of Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Jennie Y Law
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, School of Medicine, University of Maryland, Baltimore, Maryland
| | - Mary Catherine Beach
- Berman Institute of Bioethics, Johns Hopkins University, Baltimore, Maryland; Department of Internal Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Sophie Lanzkron
- Division of Adult Hematology, Department of Internal Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Mindy S Christianson
- Department of Gynecology and Obstetrics, Division of Reproductive Endocrinology, School of Medicine, Johns Hopkins University, Baltimore, Maryland
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Pecker LH, Patel N, Creary S, Darbari A, Meier ER, Darbari DS, Fasano RM. Diverse manifestations of acute sickle cell hepatopathy in pediatric patients with sickle cell disease: A case series. Pediatr Blood Cancer 2018; 65:e27060. [PMID: 29667721 DOI: 10.1002/pbc.27060] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 02/09/2018] [Accepted: 03/01/2018] [Indexed: 12/15/2022]
Abstract
The hepatic complications of sickle cell disease (SCD) are associated with increased morbidity and mortality in adults; children usually survive but may suffer significant sequelae. Few diagnostic tools differentiate the various hepatic manifestations of SCD. Why patients exhibit one hepatic pathology versus another is unclear. We report four pediatric patients with hemoglobin SS disease with diverse manifestations of acute hepatic involvement including acute sickle hepatic crisis, hepatic sequestration, sickle cell intrahepatic cholestasis, and a non-SCD cause of hepatopathy in a patient with viral hepatitis. These complications require a systematic approach to extensive evaluation and coordinated multidisciplinary care.
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Affiliation(s)
- Lydia H Pecker
- Division of Hematology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Nidhi Patel
- Department of Pediatrics, Children's Hospital of Los Angeles, Los Angeles, California
| | - Susan Creary
- Center for Innovation in Pediatric Practice, Division of Hematology/Oncology/BMT, Nationwide Children's Hospital, Columbus, Ohio
| | - Anil Darbari
- Division of Gastroenterology, Hepatology, and Nutrition, Children's National Health System, Washington, District of Columbia
| | | | - Deepika S Darbari
- Division of Hematology, Children's National, Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia
| | - Ross M Fasano
- Center for Transfusion and Cellular Therapies, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia
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38
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Guilcher GMT, Truong TH, Saraf SL, Joseph JJ, Rondelli D, Hsieh MM. Curative therapies: Allogeneic hematopoietic cell transplantation from matched related donors using myeloablative, reduced intensity, and nonmyeloablative conditioning in sickle cell disease. Semin Hematol 2018; 55:87-93. [PMID: 29958564 DOI: 10.1053/j.seminhematol.2018.04.011] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2017] [Accepted: 04/19/2018] [Indexed: 01/08/2023]
Abstract
Sickle cell disease (SCD) chronically damages multiple organs over the lifetime of affected individuals. Allogeneic hematopoietic cell transplantation (allo-HCT) is the most studied curative intervention. Fully matched related marrow, peripheral blood derived, or cord blood HCT have the best transplant outcome for symptomatic patients with SCD. For patients with asymptomatic or milder disease who have this donor option available, risks and benefits of HCT should be discussed among the patient, family, treating hematologist, and transplant physician, and decision to proceed to HCT should be individualized. Myeloablative conditioning with busulfan, cyclophosphamide, and ATG has been a commonly employed regimen for children and young adults. Recently, low intensity conditioning with low dose total body irradiation and alemtuzumab is emerging as an efficacious and safe regimen for adults, young adults, and possibly children. Mixed donor chimerism (minimum ≥20% myeloid cells), from myeloablative or nonmyeloablative conditioning regimen, produces robust normal donor erythropoiesis and is sufficient to provide a clinical cure. The proportion of patients remaining on immunosuppression beyond 2 years post-HCT is likely <10% with either myeloablative or low intensity regimens. Late effects from myeloablative or reduced intensity conditioning, or from several more months of immunosuppression in low intensity conditioning may be less common than those observed in HCT for malignant indications. Nonmyeloablative approaches with low toxicities should be the focus of future research efforts. Prevention of GVHD is a shared goal in all approaches of allo-HCT in SCD.
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Affiliation(s)
- Gregory M T Guilcher
- Departments of Paediatrics and Oncology, University of Calgary, Calgary, Alberta, Canada
| | - Tony H Truong
- Departments of Paediatrics and Oncology, University of Calgary, Calgary, Alberta, Canada
| | - Santosh L Saraf
- Department of Medicine, Section of Hematology-Oncology, University of Illinois, Chicago, IL
| | - Jacinth J Joseph
- Department of Hematology, Washington Hospital Center/Georgetown University, Washington, DC; Sickle Cell Branch, NHLBI, NIH, Bethesda, MD
| | - Damiano Rondelli
- Department of Medicine, Section of Hematology-Oncology, University of Illinois, Chicago, IL
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39
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Yahouédéhou SCMA, Carvalho MOS, Oliveira RM, Santiago RP, da Guarda CC, Carvalho SP, Ferreira JRD, Aleluia MM, Adorno EV, Gonçalves MDS. Sickle Cell Anemia Patients in Use of Hydroxyurea: Association between Polymorphisms in Genes Encoding Metabolizing Drug Enzymes and Laboratory Parameters. DISEASE MARKERS 2018; 2018:6105691. [PMID: 29619129 PMCID: PMC5829363 DOI: 10.1155/2018/6105691] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/12/2017] [Revised: 11/25/2017] [Accepted: 12/04/2017] [Indexed: 12/15/2022]
Abstract
This study investigated associations between SNPs in genes encoding metabolizing drug enzymes and laboratory parameters in sickle cell anemia patients under hydroxyurea (SCA-HU+). We evaluated hematologic and biochemical parameters by electronic methods and SNPs by PCR-RFLP and multiplex PCR in 35 SCA-HU+ patients and 67 SCA-HU- patients. The HbS, total cholesterol, lactate dehydrogenase, aspartate aminotransferase, total bilirubin and fractions levels, and leukocyte, eosinophil, monocyte, and erythroblast counts were reduced in SCA-HU+ patients (p < 0.05). Moreover, they presented higher HbF, C-reactive protein, and ferritin levels and elevated MCH and MCV values (p < 0.05). Genotype frequencies of variants GA + AA of MPO -463G>A and c1c2 + c2c2 of CYP2E1 -1293G>C/-1053C>T were higher in SCA-HU+ patients (p < 0.05). Independent associations were found between the variant A allele and lower total cholesterol, between c2 allele and low alpha-1 antitrypsin and between the null GSTT1 variant and high indirect and total bilirubin in SCA-HU+ patients. In SCA-HU- patients, independent associations were found between the variant A allele and high uric acid and between c2 allele and high urea. Our results suggest that SNPs MPO -463G>A, CYP2E1 -1293G>C/-1053C>T, and GSTT1 can be associated with alterations in lipid, inflammatory, renal, hemolytic, and hepatic profiles. However, further studies are needed to elucidate these associations.
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Affiliation(s)
- Sètondji Cocou Modeste Alexandre Yahouédéhou
- Laboratório de Hematologia, Genética e Biologia Computacional (LHGB), Fiocruz Bahia-Instituto Gonçalo Moniz (IGM), Rua Waldemar Falcão 121, Candeal, 40296-710 Salvador, BA, Brazil
- Laboratório de Pesquisa em Anemia (LPA), Departamento de Análises Clínicas, Faculdade de Farmácia, Universidade Federal da Bahia, Rua Barão do Jeremoabo 147, Ondina, 40170-115 Salvador, BA, Brazil
| | - Magda Oliveira Seixas Carvalho
- Laboratório de Hematologia, Genética e Biologia Computacional (LHGB), Fiocruz Bahia-Instituto Gonçalo Moniz (IGM), Rua Waldemar Falcão 121, Candeal, 40296-710 Salvador, BA, Brazil
| | - Rodrigo Mota Oliveira
- Laboratório de Hematologia, Genética e Biologia Computacional (LHGB), Fiocruz Bahia-Instituto Gonçalo Moniz (IGM), Rua Waldemar Falcão 121, Candeal, 40296-710 Salvador, BA, Brazil
| | - Rayra Pereira Santiago
- Laboratório de Hematologia, Genética e Biologia Computacional (LHGB), Fiocruz Bahia-Instituto Gonçalo Moniz (IGM), Rua Waldemar Falcão 121, Candeal, 40296-710 Salvador, BA, Brazil
| | - Caroline Conceição da Guarda
- Laboratório de Hematologia, Genética e Biologia Computacional (LHGB), Fiocruz Bahia-Instituto Gonçalo Moniz (IGM), Rua Waldemar Falcão 121, Candeal, 40296-710 Salvador, BA, Brazil
| | - Suellen Pinheiro Carvalho
- Laboratório de Hematologia, Genética e Biologia Computacional (LHGB), Fiocruz Bahia-Instituto Gonçalo Moniz (IGM), Rua Waldemar Falcão 121, Candeal, 40296-710 Salvador, BA, Brazil
| | - Júnia Raquel Dutra Ferreira
- Laboratório de Hematologia, Genética e Biologia Computacional (LHGB), Fiocruz Bahia-Instituto Gonçalo Moniz (IGM), Rua Waldemar Falcão 121, Candeal, 40296-710 Salvador, BA, Brazil
| | - Milena Magalhães Aleluia
- Laboratório de Hematologia, Genética e Biologia Computacional (LHGB), Fiocruz Bahia-Instituto Gonçalo Moniz (IGM), Rua Waldemar Falcão 121, Candeal, 40296-710 Salvador, BA, Brazil
| | - Elisângela Vitória Adorno
- Laboratório de Pesquisa em Anemia (LPA), Departamento de Análises Clínicas, Faculdade de Farmácia, Universidade Federal da Bahia, Rua Barão do Jeremoabo 147, Ondina, 40170-115 Salvador, BA, Brazil
| | - Marilda de Souza Gonçalves
- Laboratório de Hematologia, Genética e Biologia Computacional (LHGB), Fiocruz Bahia-Instituto Gonçalo Moniz (IGM), Rua Waldemar Falcão 121, Candeal, 40296-710 Salvador, BA, Brazil
- Laboratório de Pesquisa em Anemia (LPA), Departamento de Análises Clínicas, Faculdade de Farmácia, Universidade Federal da Bahia, Rua Barão do Jeremoabo 147, Ondina, 40170-115 Salvador, BA, Brazil
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Pinto VM, Gianesin B, Balocco M, Bacigalupo L, Forni GL. Noninvasive monitoring of liver fibrosis in sickle cell disease: Longitudinal observation of a cohort of adult patients. Am J Hematol 2017; 92:E666-E668. [PMID: 28960409 DOI: 10.1002/ajh.24918] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 09/21/2017] [Accepted: 09/24/2017] [Indexed: 11/07/2022]
Affiliation(s)
- Valeria Maria Pinto
- Centro della Microcitemia e delle Anemie Congenite, Ospedale Galliera, Genoa, Italy
| | - Barbara Gianesin
- Centro della Microcitemia e delle Anemie Congenite, Ospedale Galliera, Genoa, Italy
| | - Manuela Balocco
- Centro della Microcitemia e delle Anemie Congenite, Ospedale Galliera, Genoa, Italy
| | | | - Gian Luca Forni
- Centro della Microcitemia e delle Anemie Congenite, Ospedale Galliera, Genoa, Italy
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Cyclophosphamide improves engraftment in patients with SCD and severe organ damage who undergo haploidentical PBSCT. Blood Adv 2017; 1:652-661. [PMID: 29296707 DOI: 10.1182/bloodadvances.2016002972] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Accepted: 03/07/2017] [Indexed: 12/25/2022] Open
Abstract
Peripheral blood stem cell transplantation (PBSCT) offers a curative option for sickle cell disease (SCD). Although HLA-matched sibling transplantation is promising, the vast majority of patients lack such a donor. We sought to develop a novel nonmyeloablative HLA-haploidentical PBSCT approach that could safely be used for patients with severe organ damage. Based on findings in our preclinical model, we developed a phase 1/2 trial using alemtuzumab, 400 cGy total body irradiation, and escalating doses of posttransplant cyclophosphamide (PT-Cy): 0 mg/kg in cohort 1, 50 mg/kg in cohort 2, and 100 mg/kg in cohort 3. A total of 21 patients with SCD and 2 with β-thalassemia received a transplant. The mean hematopoietic cell transplant-specific comorbidity index of 6 reflected patients with cirrhosis, heart failure, and end-stage renal disease. The engraftment rate improved from 1 (33%) of 3 in cohort 1 to 5 (63%) of 8 in cohort 2 and 10 (83%) of 12 in cohort 3. Percentage of donor myeloid and CD3 chimerism also improved with subsequent cohorts. There was no transplant-related mortality, and overall survival was 87%. At present, 0% in cohort 1, 25% in cohort 2, and 50% in cohort 3 remain free of their disease. There was no grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD). Therefore, PT-Cy improves engraftment and successfully prevents severe GVHD after nonmyeloablative conditioning in patients with SCD who are at high risk for early mortality. Additional strategies are necessary to decrease the graft rejection rate and achieve a widely available cure for all patients with SCD. This trial was registered at www.clinicaltrials.gov as #NCT00977691.
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Oduor H, Minniti CP, Brofferio A, Gharib AM, Abd-Elmoniem KZ, Hsieh MM, Tisdale JF, Fitzhugh CD. Severe cardiac iron toxicity in two adults with sickle cell disease. Transfusion 2016; 57:700-704. [PMID: 28019032 DOI: 10.1111/trf.13961] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 10/21/2016] [Accepted: 10/26/2016] [Indexed: 12/23/2022]
Abstract
BACKGROUND Use of chronic blood transfusions as a treatment modality in patients with blood disorders places them at risk for iron overload. Since patients with β-thalassemia major (TM) are transfusion-dependent, most studies on iron overload and chelation have been conducted in this population. While available data suggest that compared to TM, patients with sickle cell disease (SCD) have a lower risk of extrahepatic iron overload, significant iron overload can develop. Further, previous studies have demonstrated a direct relationship between iron overload and morbidity and mortality rates in SCD. However, reports describing the outcome for patients with SCD and cardiac iron overload are rare. STUDY DESIGN AND METHODS We performed a retrospective analysis and identified two SCD patients with cardiac iron overload. We provide detailed descriptions of both cases and their outcomes. RESULTS Serum ferritin levels ranged between 17,000 and 19,000 μg/L. Both had liver iron concentrations in excess of 35 mg of iron per gram of dried tissue as well as evidence of cardiac iron deposition on magnetic resonance imaging. One patient died of an arrhythmia and had evidence of severe multiorgan iron overload via autopsy. On the other hand, after appropriate therapy, a second patient had improvement in cardiac function. CONCLUSION Improper treatment of iron overload in SCD can lead to a fatal outcome. Alternatively, iron overload may potentially be prevented or reversed with judicious use of blood transfusions and early use of chelation therapy, respectively.
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Affiliation(s)
- Hellen Oduor
- Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland
| | - Caterina P Minniti
- Division of Hematology, Department of Medicine, Einstein College of Medicine, Bronx, New York
| | - Alessandra Brofferio
- Cardiovascular Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland
| | - Ahmed M Gharib
- Biomedical and Metabolic Imaging Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Khaled Z Abd-Elmoniem
- Biomedical and Metabolic Imaging Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Matthew M Hsieh
- Molecular and Clinical Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland
| | - John F Tisdale
- Molecular and Clinical Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland
| | - Courtney D Fitzhugh
- Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland.,Molecular and Clinical Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland
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