How we treat sickle hepatopathy and liver transplantation in adults

Blood ◽  
2014 ◽  
Vol 123 (15) ◽  
pp. 2302-2307 ◽  
Author(s):  
Kate Gardner ◽  
Abid Suddle ◽  
Pauline Kane ◽  
John O’Grady ◽  
Nigel Heaton ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Sickle Cell ◽  
Liver Dysfunction ◽  
Therapeutic Option ◽  
Organ Damage ◽  
Treatment Modalities ◽  
Cell Disease ◽  
Limited Evidence ◽  
Acute Form ◽  
Future Work

Abstract Sickle cell disease (SCD) has evolved into a debilitating disorder with emerging end-organ damage. One of the organs affected is the liver, causing “sickle hepatopathy,” an umbrella term for a variety of acute and chronic pathologies. Prevalence of liver dysfunction in SCD is unknown, with estimates of 10%. Dominant etiologies include gallstones, hepatic sequestration, viral hepatitis, and sickle cell intrahepatic cholestasis (SCIC). In addition, causes of liver disease outside SCD must be identified and managed. SCIC is an uncommon, severe subtype, with outcome of its acute form having vastly improved with exchange blood transfusion (EBT). In its chronic form, there is limited evidence for EBT programs as a therapeutic option. Liver transplantation may have a role in a subset of patients with minimal SCD-related other organ damage. In the transplantation setting, EBT is important to maintain a low hemoglobin S fraction peri- and posttransplantation. Liver dysfunction in SCD is likely to escalate as life span increases and patients incur incremental transfusional iron overload. Future work must concentrate on not only investigating the underlying pathogenesis, but also identifying in whom and when to intervene with the 2 treatment modalities available: EBT and liver transplantation.

scholarly journals Sickle Cell Disease: Role of Oxidative Stress and Antioxidant Therapy

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 296
Author(s):  
Rosa Vona ◽  
Nadia Maria Sposi ◽  
Lorenza Mattia ◽  
Lucrezia Gambardella ◽  
Elisabetta Straface ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Globin Gene ◽  
Organ Damage ◽  
Cell Disease ◽  
Vessel Occlusion ◽  
Antioxidant Agents ◽  
Oxidant Status

Sickle cell disease (SCD) is the most common hereditary disorder of hemoglobin (Hb), which affects approximately a million people worldwide. It is characterized by a single nucleotide substitution in the β-globin gene, leading to the production of abnormal sickle hemoglobin (HbS) with multi-system consequences. HbS polymerization is the primary event in SCD. Repeated polymerization and depolymerization of Hb causes oxidative stress that plays a key role in the pathophysiology of hemolysis, vessel occlusion and the following organ damage in sickle cell patients. For this reason, reactive oxidizing species and the (end)-products of their oxidative reactions have been proposed as markers of both tissue pro-oxidant status and disease severity. Although more studies are needed to clarify their role, antioxidant agents have been shown to be effective in reducing pathological consequences of the disease by preventing oxidative damage in SCD, i.e., by decreasing the oxidant formation or repairing the induced damage. An improved understanding of oxidative stress will lead to targeted antioxidant therapies that should prevent or delay the development of organ complications in this patient population.

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.

Re: Manuscript titled, “Liver transplantation for sickle cell disease: a systematic review”

HPB ◽  
2021 ◽  
Author(s):  
Juliet Emamaullee ◽  
Linda Sher ◽  
Kambiz Etesami ◽  
Jeff Kahn ◽  
Jim Kim ◽  
...  
Keyword(s):  
Systematic Review ◽  
Liver Transplantation ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Cell Disease

scholarly journals The gut microbiome in sickle cell disease: Characterization and potential implications

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0255956
Author(s):  
Hassan Brim ◽  
James Taylor ◽  
Muneer Abbas ◽  
Kimberly Vilmenay ◽  
Mohammad Daremipouran ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Gut Microbiome ◽  
Tissue Injury ◽  
Organ Damage ◽  
Composition Analysis ◽  
Cell Disease ◽  
Blood Disorder ◽  
Major Player ◽  
Next Generation Sequencing Ngs

Background Sickle Cell Disease (SCD) is an inherited blood disorder that leads to hemolytic anemia, pain, organ damage and early mortality. It is characterized by polymerized deoxygenated hemoglobin, rigid sickle red blood cells and vaso-occlusive crises (VOC). Recurrent hypoxia-reperfusion injury in the gut of SCD patients could increase tissue injury, permeability, and bacterial translocation. In this context, the gut microbiome, a major player in health and disease, might have significant impact. This study sought to characterize the gut microbiome in SCD. Methods Stool and saliva samples were collected from healthy controls (n = 14) and SCD subjects (n = 14). Stool samples were also collected from humanized SCD murine models including Berk, Townes and corresponding control mice. Amplified 16S rDNA was used for bacterial composition analysis using Next Generation Sequencing (NGS). Pairwise group analyses established differential bacterial groups at many taxonomy levels. Bacterial group abundance and differentials were established using DeSeq software. Results A major dysbiosis was observed in SCD patients. The Firmicutes/Bacteroidetes ratio was lower in these patients. The following bacterial families were more abundant in SCD patients: Acetobacteraceae, Acidaminococcaceae, Candidatus Saccharibacteria, Peptostreptococcaceae, Bifidobacteriaceae, Veillonellaceae, Actinomycetaceae, Clostridiales, Bacteroidacbactereae and Fusobacteriaceae. This dysbiosis translated into 420 different operational taxonomic units (OTUs). Townes SCD mice also displayed gut microbiome dysbiosis as seen in human SCD. Conclusion A major dysbiosis was observed in SCD patients for bacteria that are known strong pro-inflammatory triggers. The Townes mouse showed dysbiosis as well and might serve as a good model to study gut microbiome modulation and its impact on SCD pathophysiology.

scholarly journals Sickle Cell Disease Model Mice Lacking 2,3-Dpg Show Reduced RBC Sickling and Improvements in Markers of Hemolytic Anemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 27-28
Author(s):  
Kelly M. Knee ◽  
Amey Barakat ◽  
Lindsay Tomlinson ◽  
Lila Ramaiah ◽  
Zane Wenzel ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Blood Cell ◽  
Hemolytic Anemia ◽  
Sickle Cell ◽  
Red Blood Cell ◽  
Organ Damage ◽  
Complete Elimination ◽  
Cell Disease ◽  
The Impact ◽  
2,3 Dpg

Sickle cell disease (SCD) is a severe genetic disorder caused by a mutation in hemoglobin (b6Glu-Val), which allows the mutant hemoglobin to assemble into long polymers when deoxygenated. Over time, these polymers build up and deform red blood cells, leading to hemolytic anemia, vaso-occlusion, and end organ damage. A number of recent therapies for SCD have focused on modulating the mutant hemoglobin directly, however, reduction or elimination of 2,3-DPG to reduce Hb S polymerization and RBC sickling has recently been proposed as a therapeutic strategy for SCD. Current clinical studies focus on activation of pyruvate kinase to reduce 2,3-DPG, however, direct targeting of the enzyme which produces 2,3-DPG; Bisphosphoglycerate Mutase (BPGM) may also be possible. In this study we evaluate the impact of elimination of 2,3-DPG on SCD pathology by complete knockout of BPGM in Townes model mice. Animals with complete knockout of BPGM (BPGM -/-) have no detectable 2,3-DPG, while animals that are heterozygous for BPGM (BPGM -/+) have 2,3-DPG levels comparable to Townes mice. Western Blot analysis confirms that BPGM -/- animals completely lack BPGM, while BPGM -/+ animals have BPGM levels that are nearly equivalent to Townes mice. As expected from the lack of 2,3-DPG, BPGM -/- animals have increased oxygen affinity, observed as a 39% decrease in p50 relative to Townes mice. Complete elimination of 2,3-DPG has significant effects on markers of hemolytic anemia in BPGM -/- mice. Mice lacking 2,3-DPG have a 60% increase in hemoglobin (3.7 g/dL), a 53% increase in red blood cell count, and a 29% increase in hematocrit relative to Townes mice. The BPGM -/- mice also have a 57% decrease in reticulocytes, and a 61% decrease in spleen weight relative to Townes animals, consistent with decreased extramedullary hematopoiesis. Consistent with the reduction in hemolysis, BPGM -/- animals had a 59% reduction in red blood cell sickling under robust hypoxic conditions. BPGM -/+ animals had hemoglobin, RBC, and hematocrit levels that were similar to Townes animals, and a similar degree of RBC sickling to Townes mice. Liver phenotype was similar across all variants, with areas of random necrosis observed in BPGM -/-, BPGM -/+ and Townes mice. Higher percentages of microcytic and/or hyperchromic RBCs were observed in BPGM -/- animals relative to BPGM -/+ or Townes animals. These results suggest that modulation of 2,3-DPG has a positive effect on RBC sickling and hemolytic anemia, which may have therapeutic benefits for SCD patients. However, the lack of improvement in organ damage suggests that modulation of 2,3-DPG alone may not be sufficient for complete elimination of SCD phenotypes, and further investigation of this therapeutic avenue may be necessary. Disclosures No relevant conflicts of interest to declare.

scholarly journals Liver Transplantation in Patients with Sickle Cell Disease in the United States

2020 ◽  
Vol 255 ◽  
pp. 23-32 ◽  
Author(s):  
Rachel Hogen ◽  
Michelle Kim ◽  
Yelim Lee ◽  
Mary Lo ◽  
Navpreet Kaur ◽  
...  
Keyword(s):  
United States ◽  
Liver Transplantation ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
The United States ◽  
Cell Disease

scholarly journals Potential role of LSD1 inhibitors in the treatment of sickle cell disease: a review of preclinical animal model data

2018 ◽  
Vol 315 (4) ◽  
pp. R840-R847 ◽  
Author(s):  
Angela Rivers ◽  
Ramasamy Jagadeeswaran ◽  
Donald Lavelle
Keyword(s):  
Reactive Oxygen Species ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Globin Gene ◽  
Reactive Oxygen ◽  
Organ Damage ◽  
The United States ◽  
Oxygen Species ◽  
Cell Disease ◽  
Hematopoietic Stem

Sickle cell disease (SCD) is caused by a mutation of the β-globin gene (Ingram VM. Nature 180: 326–328, 1957), which triggers the polymerization of deoxygenated sickle hemoglobin (HbS). Approximately 100,000 SCD patients in the United States and millions worldwide (Piel FB, et al. PLoS Med 10: e1001484, 2013) suffer from chronic hemolytic anemia, painful crises, multisystem organ damage, and reduced life expectancy (Rees DC, et al. Lancet 376: 2018–2031, 2010; Serjeant GR. Cold Spring Harb Perspect Med 3: a011783, 2013). Hematopoietic stem cell transplantation can be curative, but the majority of patients do not have a suitable donor (Talano JA, Cairo MS. Eur J Haematol 94: 391–399, 2015). Advanced gene-editing technologies also offer the possibility of a cure (Goodman MA, Malik P. Ther Adv Hematol 7: 302–315, 2016; Lettre G, Bauer DE. Lancet 387: 2554–2564, 2016), but the likelihood that these strategies can be mobilized to treat the large numbers of patients residing in developing countries is remote. A pharmacological treatment to increase fetal hemoglobin (HbF) as a therapy for SCD has been a long-sought goal, because increased levels of HbF (α2γ2) inhibit the polymerization of HbS (Poillin WN, et al. Proc Natl Acad Sci USA 90: 5039–5043, 1993; Sunshine HR, et al. J Mol Biol 133: 435–467, 1979) and are associated with reduced symptoms and increased lifespan of SCD patients (Platt OS, et al. N Engl J Med 330: 1639–1644, 1994; Platt OS, et al. N Engl J Med 325: 11–16, 1991). Only two drugs, hydroxyurea and l-glutamine, are approved by the US Food and Drug Administration for treatment of SCD. Hydroxyurea is ineffective at HbF induction in ~50% of patients (Charache S, et al. N Engl J Med 332: 1317–1322, 1995). While polymerization of HbS has been traditionally considered the driving force in the hemolysis of SCD, the excessive reactive oxygen species generated from red blood cells, with further amplification by intravascular hemolysis, also are a major contributor to SCD pathology. This review highlights a new class of drugs, lysine-specific demethylase (LSD1) inhibitors, that induce HbF and reduce reactive oxygen species.

Alterations of Hemoglobin Fractionation in a Sickle Cell Disease Patient on Voxelotor Therapy

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S100-S101
Author(s):  
S S Karimi ◽  
H Ni ◽  
L L Hsu
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Exchange Transfusion ◽  
Recent Literature ◽  
Disease Patient ◽  
Oxygen Affinity ◽  
Treatment Modalities ◽  
Cell Disease ◽  
Low Oxygen ◽  
Hydroxyurea Treatment

Abstract Introduction/Objective Voxelotor is a molecule that allosterically binds to the alpha-chain of hemoglobin, resulting in increased oxygen affinity. This allosteric inhibition leads to prevention of hemoglobin polymerization and sickling of red blood cells in response to low oxygen tension. Voxelotor has been used to treat patients with Sickle Cell Disease (SCD) and recent literature indicates it may contribute to complex hemoglobin fractionation (HF) elution patterns. We report a novel case of a SCD patient on concurrent Hydroxyurea, Voxelotor and chronic RBC exchange transfusion treatment and discuss the implications of these three treatment modalities on HF and monitoring of SCD. Methods A 17-year-old female with SCD complicated by frequent vaso-occlusive crisis, and avascular necrosis managed with chronic RBC exchange and Hydroxyurea. Her HF prior to initiation of Voxelotor treatment showed 3.2% HbA2, 51% HbA, 6.0% HbF, and 41% HbS. Voxelotor therapy was initiated at 1500mg/day and HF was performed 10 days later. Whole blood was collected and subjected to High Performance Liquid Chromatography (HPLC) with reflex to RBC solubility and Capillary Electrophoresis. Results HF performed post-Voxelotor therapy revealed positive sickle solubility with a complex pattern of 2.7% HbA2, 49.2% HbA, 5.3% HbF, 15.7% HbS, 0% HbC, and two additional peaks of a 6.3% peak in the window-D region (retention time of 4.34) and 20.8% of an atypical Hb peak pattern (at the retentuin time of 4.18). The results reflected a complex HF of a HbSS patient on concurrent chronic RBC exchange transfusion, hydroxyurea therapy, and Voxelotor treatment. Post Voxelotor-therapy HF revealed a reduction in HbS from 41% to 15.7% with the emergence of two additional peaks. Chronic RBC exchange transfusion and Hydroxyurea treatment account for the observed fractionation of HbA and HbF, respectively. Based on recent literature, we attribute the emergence of the two additional peaks to Voxelotor therapy. All three therapies led to reduction in HbS. Conclusion Routine HF serves as an essential modality in diagnosis and monitoring of SCD. Voxelotor treatment alters the HF profile and may cause difficulty for interpretation. With the emergence of novel therapies, it is imperative for clinicians to provide medication information to clinical laboratories and pathologists to be fully aware of the effects of current treatments to correctly interpret and monitor SCD.

scholarly journals Current and novel therapies for the prevention of vaso-occlusive crisis in sickle cell disease

2020 ◽  
Vol 11 ◽  
pp. 204062072095500
Author(s):  
Ifeyinwa Osunkwo ◽  
Deepa Manwani ◽  
Julie Kanter
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Severe Pain ◽  
Management Strategies ◽  
Organ Damage ◽  
Care Utilization ◽  
Cell Disease ◽  
High Resource ◽  
Emerging Treatments

Individuals with sickle cell disease (SCD) are living further into adulthood in high-resource countries. However, despite increased quantity of life, recurrent, acute painful episodes cause significant morbidity for affected individuals. These SCD-related painful episodes, also referred to as vaso-occlusive crises (VOCs), have multifactorial causes, and they often occur as a result of multicellular aggregation and vascular adherence of red blood cells, neutrophils, and platelets, leading to recurrent and unpredictable occlusion of the microcirculation. In addition to severe pain, long-term complications of vaso-occlusion may include damage to muscle and/or bone, in addition to vital organs such as the liver, spleen, kidneys, and brain. Severe pain associated with VOCs also has a substantial detrimental impact on quality of life for individuals with SCD, and is associated with increased health care utilization, financial hardship, and impairments in education and vocation attainment. Previous treatments have targeted primarily SCD symptom management, or were broad nontargeted therapies, and include oral or parenteral hydration, analgesics (including opioids), nonsteroidal anti-inflammatory agents, and various other types of nonpharmacologic pain management strategies to treat the pain associated with VOC. With increased understanding of the pathophysiology of VOCs, there are several new potential therapies that specifically target the pathologic process of vaso-occlusion. These new therapies may reduce cell adhesion and inflammation, leading to decreased incidence of VOCs and prevention of end-organ damage. In this review, we consider the benefits and limitations of current treatments to reduce the occurrence of VOCs in individuals with SCD and the potential impact of emerging treatments on future disease management.

Systematic Evaluation of Sickle Cell-Related Organ Damage and Complications: Implications for Sickle Cell Disease Management.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3799-3799
Author(s):  
Eduard J. Beers van ◽  
Anna Giessen Van Der ◽  
Charlotte F.J. Tuijn Van ◽  
John-john Schnog ◽  
Bart J. Biemond
Keyword(s):  
Renal Failure ◽  
Sickle Cell ◽  
Organ Damage ◽  
Systematic Evaluation ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Chi Square ◽  
Morbidity Score ◽  
Acute Complications ◽  
History Of

Abstract Sickle cell disease (SCD) is characterised by acute complications such as the painful vaso-occlusive crisis, acute chest syndrome and stroke. Although these acute complications are well known and mostly easy recognised, the impact of sickle cell-related chronic end-organ damage on outcome may well be underappreciated. In fact, often SCD severity is assessed. by the frequency of acute vaso-occlusive crises. However, accumulating chronic organ damage (such as renal failure and pulmonary hypertension) is nowadays recognized as an important determinant of disease morbidity as well. The aim of this study is to evaluate the prevalence of sickle cell-related complications and organ damage and their relation to SCD genotype and to established laboratory parameters of SCD morbidity in a tertiary teaching hospital. Furthermore, relations between complications and different forms of organ damage will also be determined. Sickle cell patients were consecutively and systematically screened for manifestations of chronic organ damage and their history of complications related to SCD and/or SCD-related treatment was retrospectively studied from their medical records. Organ damage and the history of sickle cell-related complications were expressed as a cumulative disease morbidity score (DMS). Every form of organ damage or complication scores 1 point and is divided by the number of screened items resulting in a maximal DMS of 1. Correlations were analysed with the Chi-Square test. All adult sickle cell patients (HbSS, HbSβ and HbSC) were included in our study (n=99). Six patients were excluded from analysis because of incomplete data (less than 7 of the 12 items). Prevalence of specific organ damage and complications Total HbSS HbSβ HbSC P value Numbers are percentages or medians (iqr). * Two-sided Chi-square tests **Two sided Kruskal-Wallis test N 93 49 16 28 Age (year) 28 (22–39) 27 (21–41) 35 (25–41) 28 (20–34) 0.324** Female (%) 65 62 56 71 0.567 Disease Morbidity Score 0.11 (0–0.25) 0.18 (0.09–0.33) 0.09 (0–0.19 0.10 (0–0.17 0.010** Organ damage/ complications (%) Microalbuminuria 22 33 0 15 0.063 Renal failure 10 15 0 7 0.201 Pulmonary hypertension 25 40 0 7 0.006 Retinopathy 41 28 30 65 0.016 Perceptive hearing loss 12 9 27 6 0.205 Iron overload 10 17 0 4 0.063 Cholelithiasis 51 66 43 27 0.009 Avascular osteonecrosis 12 17 13 4 0.242 Leg ulcers 5 11 0 0 0.089 Acute chest syndrome 24 31 25 11 0.128 Frequent vaso-occlusive crises (>2/yr) 14 17 19 4 0.374 Stroke 6 13 0 0 0.053 The DMS correlated significantly with c-reactive protein (R= 0.27, P=0.013), blood urea nitrogen (R=0.422, P>0.001) and hemoglobin (R= −0.326, P=0.003). No statistically significant correlation with leukocyte counts or HbF% was demonstrated. These data underscore the importance of systematic evaluation of all patients with SCD in the outpatient setting since many of the sickle cell-related complications may otherwise go unnoticed, thereby delaying the institution of potential therapeutic measures. Importantly, the lack of any significant association between the frequency of vaso-occlusive crises and manifest sickle cell-related organ damage illustrates its limited value as a marker of disease severity.

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