scholarly journals Impaired Hepcidin Metabolism Promotes Hemolysis Induced Hepatobiliary Injury in Sickle Cell Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 28-28
Author(s):  
Ravi Vats ◽  
Enrico M Novelli ◽  
Prithu Sundd ◽  
Mark T Gladwin ◽  
Tirthadipa Pradhan
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Liver Tissue ◽  
Iron Homeostasis ◽  
Genetic Disorder ◽  
Iron Accumulation ◽  
Expression Level ◽  
Blue Staining ◽  
Transmission Electron Micrograph ◽  
Cell Disease

Sickle cell disease (SCD) is an autosomal-recessive-genetic disorder that affects millions of people worldwide. Although hepatic crisis affects 10-40% of hospitalized SCD patients and can progress to fatal liver failure, the current treatment is primarily supportive and the molecular pathophysiology remains largely unknown. We found that transgenic, humanized SCD mice developed liver injury with age, manifested by increased inflammation, necrosis and hepatic iron accumulation. The presence of iron particles in SCD liver was confirmed by transmission electron micrograph (TEM) analysis and prussian blue staining which revealed increased iron accumulation in the central and midzonal region of the SCD liver tissue. An increase in aggregates of iron pigment reminiscent of hemosiderin-laden macrophages was also observed in SCD liver tissue. Interestingly, the SCD mice also showed significant enrichment of both hepatic (p=0.02) and serum iron (p=0.04) compared to control AS mice. We determined the expression level of genes commonly involved in iron homeostasis by RT-PCR. Interestingly, a significantly lower expression level of hepcidin transcripts was observed in the hepatocytes of SCD mice compared to control mice (AS) (p=0.01). In order to define the pathways controllinghepcidintranscription in SCD, we performed an RNA-seq analysis in the liver of SCD mice. Remarkably, our data showed significant misexpression of BMP signaling pathways. Further analysis revealed a significant misexpression in BMP2 and 6 levels in the liver of SCD mice by western blot. Reduced levels of hepcidin were also confirmed in serum samples from SCD patients compared to controls. Work is currently underway to understand how BMP2/6 might hypothetically regulate hepcidin expression in the liver. In summary, our results reveal a significant defect in iron homeostasis in the liver of SCD mice, suggesting that impaired iron homeostasis may contribute to hepatobiliary injury in SCD independent of blood transfusions. Our study also highlights the importance of hepcidin as potential therapeutic target in regulation of hepatic injury in SCD. Disclosures No relevant conflicts of interest to declare.

scholarly journals Sickle Cell Disease Promotes Dysregulation of Hepatic Iron Homeostasis By Regulating Hepcidin Expression

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 958-958
Author(s):  
Tirthadipa Pradhan ◽  
Prithu Sundd ◽  
Satdarshan Pal Monga ◽  
Mark T Gladwin ◽  
Gregory J Kato
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Liver Tissue ◽  
Research Funding ◽  
Iron Homeostasis ◽  
Iron Accumulation ◽  
Expression Level ◽  
Hepatic Iron ◽  
Cell Disease ◽  
Hepcidin Expression

Sickle cell disease (SCD) is an autosomal-recessive-genetic disorder that affects millions of people worldwide. Although hepatic crisis affects 10-40% of hospitalized SCD patients and can progress to fatal liver failure, the current treatment is primarily supportive and the molecular pathophysiology remains largely unknown. We found that transgenic, humanized SCD mice developed liver injury with age, manifested by increased inflammation, necrosis and hepatic iron accumulation. The presence of iron particles in SCD liver was confirmed by transmission electron micrograph (TEM) analysis and prussian blue staining which revealed increased iron accumulation in the central and midzonal region of the SCD liver tissue. An increase in aggregates of iron pigment reminiscent of hemosiderin-laden macrophages was also observed in SCD liver tissue. Interestingly, the SCD mice also showed significant enrichment of both hepatic (p=0.02) and serum iron (p=0.04) compared to control AS mice. We determined the expression level of genes commonly involved in iron homeostasis by RT-PCR. Interestingly, a significantly lower expression level of hepcidin transcripts was observed in the liver of SCD mice compared to control mice (AS) (p=0.01). In order to define the pathways controlling hepcidin transcription in SCD, we performed an RNA-seq analysis in the liver of SCD mice. Remarkably, our data showed significant misexpression of hypoxia signaling pathways. Further analysis revealed a significant increase in hypoxia-inducible factor (HIF)-2α levels in the liver of SCD mice by western blot. Reduced levels of Hepcidin were also confirmed in serum samples from SCD patients compared to controls. Work is currently underway to understand how HIF2α might hypothetically regulate hepcidin expression in the liver. This is particularly relevant because HIF2a translation is known to be regulated by iron through an iron response element at the 5' end of its transcript. In summary, our results reveal a significant defect in iron homeostasis in the liver of SCD mice, suggesting that impaired iron homeostasis may contribute to hepatobiliary injury in SCD independent of blood transfusions. Our study also highlights the importance of hepcidin as potential therapeutic target in regulation of hepatic injury in SCD. Disclosures Gladwin: Bayer Pharmaceuticals: Other: Co-investigator; United Therapeutics: Patents & Royalties: Co-inventor on an NIH government patent for the use of nitrite salts in cardiovascular diseases ; Globin Solutions, Inc: Patents & Royalties: Provisional patents for the use of recombinant neuroglobin and heme-based molecules as antidotes for CO poisoning. Kato:Novartis, Global Blood Therapeutics: Consultancy, Research Funding; Bayer: Research Funding.

scholarly journals Targeting pain at its source in sickle cell disease

2018 ◽  
Vol 315 (1) ◽  
pp. R104-R112 ◽  
Author(s):  
Kanika Gupta ◽  
Om Jahagirdar ◽  
Kalpna Gupta
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Genetic Disorder ◽  
Somatosensory System ◽  
Organ Damage ◽  
Mast Cell Activation ◽  
Cell Disease ◽  
Central Nervous Systems

Sickle cell disease (SCD) is a genetic disorder associated with hemolytic anemia, end-organ damage, reduced survival, and pain. One of the unique features of SCD is recurrent and unpredictable episodes of acute pain due to vasoocclusive crisis requiring hospitalization. Additionally, patients with SCD often develop chronic persistent pain. Currently, sickle cell pain is treated with opioids, an approach limited by adverse effects. Because pain can start at infancy and continue throughout life, preventing the genesis of pain may be relatively better than treating the pain once it has been evoked. Therefore, we provide insights into the cellular and molecular mechanisms of sickle cell pain that contribute to the activation of the somatosensory system in the peripheral and central nervous systems. These mechanisms include mast cell activation and neurogenic inflammation, peripheral nociceptor sensitization, maladaptation of spinal signals, central sensitization, and modulation of neural circuits in the brain. In this review, we describe potential preventive/therapeutic targets and their targeting with novel pharmacologic and/or integrative approaches to ameliorate sickle cell pain.

scholarly journals Prevalence of Sickle Cell Disease and Other Haemoglobin Variants in Calabar, Cross River State, Nigeria

2019 ◽  
pp. 1-6
Author(s):  
Akaba Kingsley ◽  
Ofem Enang ◽  
Ofonime Essien ◽  
Annette Legogie ◽  
Omini Cletus ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Genetic Disorder ◽  
Globin Gene ◽  
Specific Gene ◽  
Cell Disease ◽  
Cellulose Acetate Electrophoresis ◽  
Genetic Changes ◽  
Female Ratio ◽  
Cross River State

Background: Sickle cell disease (SCD) is the commonest genetic disorder worldwide with a global prevalence of 20-25 million. About 12-15 million affected persons are in Sub-Sahara Africa with Nigeria bearing the highest burden of people living with sickle cell disease. SCD is a disease characterized as an autosomal, recessive, heterogeneous, and a monogenetic disorder caused by an A-to-T point mutation in the β-globin gene responsible for the production of abnormal hemoglobin S (HbS), which polymerizes in the deoxygenated state and results in the sickling of erythrocytes.  Haemoglobin variants are mutant forms of haemoglobin in a population usually occurring as a result of genetic changes in specific genes, or globins that causes change on alterations in the amino acid. They could affect the structure, behavior, the production rate and the stability of the specific gene. Well-known haemoglobin variants such as sick-cell anaemia are responsible for diseases and are considered haemoglobinopathies. Other variants cause no detectable pathology and are thus considered as non-pathological variants. Aim: The study is aimed at evaluating the burden of sickle cell disease and other haemoglobin variants in Calabar, South-South Nigeria. Methods: This is a retrospective study done at the haematology laboratory of University of Calabar Teaching Hospital, Calabar. Cellulose acetate electrophoresis at alkaline pH was used for the evaluation of haemoglobinopathies. The data were entered into Microsoft Excel 2016 spreadsheet and analysed with the IBM SPSS Version 22. Data were summarized into percentage of different phenotypes. Results: Results of the total 3648 haemoglobin electrophoresis recorded, 1368 (37.50%) were male while the remaining 2280 (62.5%) females given a male to female ratio of 1:1.7. Five haemoglobin phenotypes were identified as HbAA, HbAS, HbAC, HbSC and HbSS. The overall average values of their prevalence were HbAA 64.78%, HbAS 32.62%, HbSS 2.14%, HbAC 0.33%, HbSC 0.14%. Thus, the prevalence of SCD (Prevalence of HbSS+HbSC) was 2.28%. The highest proportion of SCD was observed in 2011 with least in 2016 and 2017 respectively. Conclusion: The prevalence of SCD and other haemoglobin variants in Calabar is similar to that of the national prevalence rate. There is need for continuous enlightenment and premarital counselling on the pattern of inheritance of SCD most especially with the increased burden of sickle traits in the environment has reported in this study.

scholarly journals Sickle Cell Disease: An Overview of Oral Health Considerations for Pediatric Patients

2021 ◽  
Vol 2 (3) ◽  
pp. 9-17
Author(s):  
Dafni Eleftherou ◽  
Aristidis Arhakis ◽  
Sotiria Davidopoulou
Keyword(s):  
Oral Health ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Pediatric Patients ◽  
Genetic Disorder ◽  
The Body ◽  
Common Finding ◽  
Cell Disease ◽  
Preventive Dental Care ◽  
Periodontal Inflammation

Aim: This literature review aims to update the evidence for orofacial manifestations and current treatment recommendations for children and adolescents with sickle cell disease. Background: Sickle cell disease is a frequent hemoglobinopathy and a life-threatening genetic disorder. The lifelong condition is characterized by chronic hemolytic anemia and vaso-occlusive crisis that may occur in a variable range of clinical presentations in different regions of the body, including the oral cavity. Review results: This review explored the most common orofacial alterations of pediatric patients with SCD. Dental caries is a common finding in SCD pediatric patients, especially in those who are socio-economically vulnerable. Moreover, malocclusions occur in high prevalence in SCD pediatric patients. Other oral health complications seen in SCD patients include periodontal inflammation, bone changes, infections, mental nerve neuropathy, facial overgrowth, delayed tooth eruption, dental anomalies, pulp necrosis, soft tissue alterations and salivary changes. Dental infections may trigger a vaso-occlusive crisis leading the patient to a higher probability on arriving in hospital emergency departments and in need for further hospital admission to deal with the correlated complications. Thus, preventive dental care and non-invasive dental procedures are the principal focus in SCD patients in order to avoid possible subsequent complications. Conclusion: The review showed that in pediatric patients with SCD the risk for orofacial manifestations and complications depends not only on the presence of SCD but also on other confounding factors such as oral hygiene, diet habits and social conditions. Moreover, more well-designed epidemiological studies are necessary to assess the real link between SCD disease and its impact on stomatognathic health.

scholarly journals Sickle Cell Disease: Management options and challenges in developing countries

2013 ◽  
Vol 5 (1) ◽  
pp. e2013062 ◽  
Author(s):  
Daniel Ansong ◽  
Alex Osei-Akoto ◽  
Delaena Ocloo ◽  
Kwaku Ohene-Frempong Ohene-Frempong
Keyword(s):  
Developing Countries ◽  
Sickle Cell Disease ◽  
Newborn Screening ◽  
Sickle Cell ◽  
Health Care Professionals ◽  
Genetic Disorder ◽  
Sub Saharan Africa ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Management Options

Sickle Cell Disease (SCD) is the most common genetic disorder of haemoglobin in sub-Saharan Africa. This commentary focuses on the management options available and the challenges that health care professionals in developing countries face in caring for patients with SCD. In developing countries like Ghana, newborn screening is now being implemented on a national scale.  Common and important morbidities associated with SCD are vaso-occlusive episodes, infections, Acute Chest Syndrome (ACS), Stroke and hip necrosis. Approaches to the management of these morbidities are far advanced in the developed countries. The differences in setting and resource limitations in developing countries bring challenges that have a major influence in management options in developing countries. Obviously clinicians in developing countries face challenges in managing SCD patients. However understanding the disease, its progression, and instituting the appropriate preventive methods are paramount in its management. Emphasis should be placed on newborn screening, anti-microbial prophylaxis, vaccination against infections, and training of healthcare workers, patients and caregivers. These interventions are affordable in developing countries.

Multicenter Evaluation of HemoTypeSC as a Point-of-Care Sickle Cell Disease Rapid Diagnostic Test for Newborns and Adults Across India

2019 ◽  
Vol 153 (1) ◽  
pp. 82-87 ◽  
Author(s):  
Malay B Mukherjee ◽  
Roshan B Colah ◽  
Pallavi R Mehta ◽  
Nikhil Shinde ◽  
Dipty Jain ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Newborn Screening ◽  
Sickle Cell ◽  
High Performance ◽  
Screening Program ◽  
Point Of Care ◽  
Genetic Disorder ◽  
Cell Disease ◽  
Point Of Care Test ◽  
Tribal Areas

Abstract Objectives Sickle cell anemia is the commonest genetic disorder in India, and the frequency of the sickle cell gene is very high in the remote tribal areas where facilities are generally limited. Therefore, a rapid and affordable point-of-care test for sickle cell disease is needed. Methods The diagnostic accuracy of HemoTypeSC was evaluated against automated high-performance liquid chromatography (HPLC) as the gold standard for its efficacy in a newborn screening program. Results A total of 1,559 individuals (980 newborns and 579 adults) from four participating centers were analyzed by both methods. HemoTypeSC correctly identified 209 of 211 total hemoglobin (Hb) SS cases, for a 99.1%/99.9% total HbSS sensitivity/specificity. Overall, HemoTypeSC exhibited sensitivity and specificity of 98.1% and 99.1% for all possible phenotypes (HbAA, HbAS, and HbSS) detected. HPLC is relatively expensive and not available in most laboratories in remote tribal areas. Conclusions We conclude that the rapid, point-of-care testing device HemoTypeSC test is suitable for population and newborn screening for the HbS phenotype.

scholarly journals Pregnancy in Sickle Cell Disease Is a Very High-Risk Situation: An Observational Study

2016 ◽  
Vol 2016 ◽  
pp. 1-5 ◽  
Author(s):  
Narcisse Elenga ◽  
Aurélie Adeline ◽  
John Balcaen ◽  
Tania Vaz ◽  
Mélanie Calvez ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Genetic Disorder ◽  
Care Physician ◽  
Intrauterine Fetal Death ◽  
Cell Disease ◽  
Risk Situation ◽  
High Risk Situation ◽  
Twin Pregnancies

Sickle cell disease is a serious genetic disorder affecting 1/235 births in French Guiana. This study aimed to describe the follow-up of pregnancies among sickle cell disease patients in Cayenne Hospital, in order to highlight the most reported complications. 62 records of pregnancies were analyzed among 44 females with sickle cell disease, between 2007 and 2013. Our results were compared to those of studies conducted in Brazil and Guadeloupe. There were 61 monofetal pregnancies and 2 twin pregnancies, 27 pregnancies among women with SS phenotype, 30 SC pregnancies, and five S-beta pregnancies. The study showed that the follow-up of patients was variable, but no maternal death was found. We also noted that the main maternofetal complications of pregnancies were anemia (36.5%), infection (31.7%), vasoocclusive crisis (20.6%), preeclampsia (17.5%), premature birth (11.1%), intrauterine growth retardation (15.9%), abnormal fetal heart rate (14.3%), and intrauterine fetal death (4.8%). Pregnancies were more at risk among women with SS phenotype. Pregnancy in sickle cell disease patients requires a supported multidisciplinary team including the primary care physician, the obstetrician, and the Integrated Center for Sickle Cell Disease.

scholarly journals Counselling Needs of Sickle-Cell Anaemia Adolescents in Ekiti State, Nigeria

2020 ◽  
Vol 30 (6) ◽  
Author(s):  
Lateef Omotosho Adegboyega
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anaemia ◽  
Rank Order ◽  
Genetic Disorder ◽  
Research Question ◽  
Sampling Technique ◽  
Cell Disease ◽  
Significant Difference ◽  
Counselling Needs

BACKGROUND፡ Sickle-cell disease is an autosomal recessive genetic disorder of hemoglobin (Hb) structure and the most common of the hemoglobinopathies. Hence, this study investigated counseling needs of sickle-cell anaemia adolescents in Ekiti State.METHODS: Descriptive survey design was adopted for this study. Purposive sampling technique was adopted to draw a total of 121 respondents. A questionnaire was used to collect data for the study. Mean and rank order were used to answer the research question while chi-square and Analysis of Variance (ANOVA) were used to test the hypotheses at 0.05 level of significance.RESULTS: The findings revealed that counselling needs of adolescents with sickle-cell anaemia include counsellors are expected to encourage adolescents with sickle-cell anaemia to have confidence in self among others. The findings also revealed that there was a significant difference in the counselling needs of adolescents with sickle-cell anaemia based on gender while there was no significant difference in the counselling needs of adolescents with sickle-cell anaemia based on religion.CONCLUSION: The counselling needs of adolescents with sickle-cell anaemia include adolescents with sickle-cell anaemia easily comprehend the counselling therapy of counselloramong others. It was recommended that Government should offer standard health care for all adolescents with Sickle-cell disease.

scholarly journals Protection of Microvascular Liver Perfusion with 5-Hydroxymethylfurfural in Sickle Cell Disease Mice Following Hypoxia-Induced Vasoocclusion

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3382-3382 ◽  
Author(s):  
Michael Wright ◽  
Derek Sim ◽  
Magdalena Alonso-Galicia ◽  
Katalin Kauser ◽  
Keith Abe
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Genetic Disorder ◽  
Liver Perfusion ◽  
Organ Damage ◽  
Extramedullary Hematopoiesis ◽  
T Test ◽  
Vehicle Group ◽  
Cell Disease ◽  
And Control

Abstract Introduction: Sickle cell disease (SCD) is a debilitating genetic disorder, and the resultant "sickling" deformity of red blood cells leads to acute vasoocclusive (VOC) events and chronic disease in multiple organs. Sickle cell hepatopathy, arising from VOC events in the hepatic sinusoids, which can lead to fatal sickle cell intrahepatic cholestasis, is estimated to occur in approximately 10% of the SCD population. Using contrast-enhanced ultrasound (CEUS), we measured microvascular liver perfusion (MVLP) in SCD and control mice at basal levels to determine if noninvasive CEUS can be utilized to assess the underlying extent of disease and also investigated the effect of hypoxia-induced VOC with and without treatment with an antisickling agent, 5-hyroxymethylfurfural (5-HMF). Methods: Townes sickle cell mice (SCD), homozygous for hα:βs -globulin, approximately 7−9 weeks of age (n=28), and control mice, homozygous for hα:β-globulin (n=11), were used in these studies. CEUS perfusion imaging (Vevo® 2100) was performed on a central cross-section of the liver at the renal artery. Contrast agent was administered as an intravenous bolus via tail vein to anesthetized mice (isoflurane with ~21% O2); peak enhancement (PE) was analyzed with VisualSonics software. CEUS measurements were obtained at baseline and following either (1) hypoxia, 60 minutes with 5.5.% O2 followed by ~60 minutes of reoxygenation at room oxygen (~21% O2) or (2) normoxia, ~120 minutes at room oxygen. 5-HMF at 20 and 200 mg/kg PO or vehicle was administered following baseline PE measurement and approximately 30 minutes before start of hypoxia. Results: MVLP in SCD (n=28) was significantly reduced by approximately 40% compared with controls (n=11) at baseline (PE of 14.0±0.7 linear arbitrary units [l.a.u.] vs. 23.6±2.1 l.a.u.), respectively, P<0.001 [Student t test]). Normoxic SCD maintained similar PE to baseline levels (Table 1); however, hypoxia significantly reduced MVLP by 49% in SCD mice. In contrast, hypoxia had no significant effect in control mice. 5-HMF at 20 and 200 mg/kg resulted in a dose-dependent increase in posthypoxia MVLP. 5-HMF at 200 mg/kg was not significantly different from baseline PE, and 5-HMF at 20 mg/kg increased MVLP by approximately 50% compared with the vehicle group posthypoxia (26% vs 49% reduction in MVLP, respectively). Pathologic evaluation of naive SCD formalin-fixed liver tissues (n=10) showed congestion, necrosis, hepatocellular hypertrophy, and extramedullary hematopoiesis. Table 1. CEUS-Acquired Microvascular Liver Perfusion in SCD and Control Mice (mean ± SEM) Strain Dose Oxygen Status Mice, n Baseline PE, l.a.u. Posthypoxia/Normoxia PE, l.a.u. Change From Baseline, % Control Vehicle Hypoxic 11 23.6±2.1 22.1±2.1 -7 SCD Vehicle Normoxic 4 14.0±2.1 13.3±1.6 -3 SCD Vehicle Hypoxic 8 15.4 ±1.6 7.0±0.9* -49 SCD HMF, 20 mg/kg Hypoxic 8 12.8±0.9 9.2±0.7* -26 SCD HMF, 200 mg/kg Hypoxic 8 13.8±1.5 11.9±1.2 -12 *Statistically significant reduction compared with baseline PE (P <0.01, Student t test). Summary: CEUS measured lower basal levels of MVLP in SCD compared with control mice, which correlated with pathologic findings of congestion and necrosis in the livers of SCD mice. The hypoxia-induced VOC decrease in MVLP was present only in the SCD mice; no effect was observed in control mice. Treatment with the antisickling agent, 5-HMF, dose-dependently ameliorated the hypoxia-induced VOC decrease in MVLP in SCD mice. Based on these results, CEUS may be considered as a noninvasive method to measure acute and chronic organ perfusion changes for evaluating new therapeutics for sickle cell-mediated VOC events and end-organ damage. Disclosures Wright: Bayer HealthCare LLC: Employment. Sim:Bayer HealthCare LLC: Employment. Alonso-Galicia:Bayer HealthCare LLC: Employment. Kauser:Bayer HealthCare LLC: Employment. Abe:Bayer HealthCare LLC: Employment.

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