scholarly journals Liver injury is associated with mortality in sickle cell disease

2015 ◽  
Vol 42 (7) ◽  
pp. 912-921 ◽  
Author(s):  
J. J. Feld ◽  
G. J. Kato ◽  
C. Koh ◽  
T. Shields ◽  
M. Hildesheim ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Liver Injury ◽  
Sickle Cell ◽  
Cell Disease

Severity of iron overload in patients with sickle cell disease receiving chronic red blood cell transfusion therapy

Blood ◽  
2000 ◽  
Vol 96 (1) ◽  
pp. 76-79 ◽  
Author(s):  
Paul Harmatz ◽  
Ellen Butensky ◽  
Keith Quirolo ◽  
Roger Williams ◽  
Linda Ferrell ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Liver Injury ◽  
Liver Biopsy ◽  
Blood Cell ◽  
Iron Overload ◽  
Sickle Cell ◽  
Red Blood Cell ◽  
Cell Disease ◽  
Liver Iron ◽  
Transfusion Therapy

Chronic transfusion therapy is being used more frequently to prevent and treat the complications of sickle cell disease. Previous studies have shown that the iron overload that results from such therapy in other patient populations is associated with significant morbidity and mortality. In this study we examined the extent of iron overload as well as the presence of liver injury and the predictive value of ferritin in estimating iron overload in children with sickle cell disease who receive chronic red blood cell transfusions. A poor correlation was observed between serum ferritin and the quantitative iron on liver biopsy (mean 13.68 ± 6.64 mg/g dry weight;R = 0.350, P = .142). Quantitative iron was highly correlated with the months of transfusion (R = 0.795, P < .001), but serum ferritin at biopsy did not correlate with months of transfusion (R = 0.308, P = .200). Sixteen patients had abnormal biopsies showing mild to moderate changes on evaluation of inflammation or fibrosis. Liver iron was correlated with fibrosis score (R = 0.50, P = .042). No complications were associated with the liver biopsy. Our data suggest that, in patients with sickle cell disease, ferritin is a poor marker for accurately assessing iron overload and should not be used to direct long-term chelation therapy. Despite high levels of liver iron, the associated liver injury was not severe.

scholarly journals Evidence for Transient Acute Liver Injury in Mouse Models of Sickle Cell Disease during Steady State Health

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1373-1373 ◽  
Author(s):  
Nancy J. Wandersee ◽  
Sandra L. Holzhauer ◽  
Dawn M. Retherford ◽  
Thomas D. Foster ◽  
Cheryl A. Hillery
Keyword(s):  
Steady State ◽  
Sickle Cell Disease ◽  
Liver Injury ◽  
Mouse Models ◽  
Sickle Cell ◽  
Conflicts Of Interest ◽  
Organ Injury ◽  
State Health ◽  
Cell Disease ◽  
Over Time

Abstract Individuals with sickle cell disease experience episodes of acute vaso-occlusive complications interspersed by periods of feeling well and apparent health during “steady state”. It is likely that episodic and subclinical sickling and vaso-occlusion occur on an ongoing basis even during periods of steady state. In order to determine whether mice with sickle disease have acute vaso-occlusion sufficient for organ injury at apparent steady state health, we chose to study 2 mouse models of severe sickle cell disease with serial blood draws over time. Since we have shown in previous studies that the liver is highly susceptible to acute sickling/vaso-occlusion induced by hypoxia, we first examined serial ALT measurements in a total of 13 Berkeley sickle cell (BERK-SS) mice, initially from week-to-week and month-to-month, and then day-to-day time frames. Individual BERK-SS mice showed week-to-week and month-to-month variations of up to 5-fold over baseline ALT levels, followed by return to baseline levels in most mice. This suggests that BERK-SS mice, during steady state health, experience acute, yet transient, liver injury. Surprisingly, we also found day-to-day variations of up to 3-fold in ALT levels in BERK-SS mice. To determine if these changes in ALT levels were mirrored by changes in other biomarkers, we measured serum amyloid P (SAP) as a marker of acute inflammation (similar to CRP in humans) in the same plasma samples. We found up to 1.6-fold variation in SAP over baseline plasma levels over time. However, there was less overall variation in SAP levels in individual mice compared to the striking changes in ALT. In addition, we found that variations in SAP did not consistently precede, follow, or coincide with variations in ALT levels, suggesting that SAP is a marker of sickle cell-induced inflammation or vaso-occlusion independent of liver injury. We next sought to confirm our findings with daily serial ALT and SAP measurements from Townes sickle cell (TOWNES-SS) mice (n=8), a second commonly used mouse model of severe sickle cell disease. Our data showed that baseline ALT levels are higher and SAP levels are lower in TOWNES-SS as compared to BERK-SS mice, likely reflecting differences in strain background between the two models. However, we again found daily fluctuations in ALT and SAP levels in individual TOWNES-SS mice, similar to those seen in individual BERK-SS mice. We propose that these temporal variations indicate that both the Berkeley and Townes mouse models of sickle cell disease exhibit fluctuations in steady state health, similar to those seen in human individuals with sickle cell disease. In addition, the results suggest that studies in these mouse models should be designed and interpreted with these temporal fluctuations in mind. Disclosures No relevant conflicts of interest to declare.

scholarly journals Marked Direct Hyperbilirubinemia due to Ceftriaxone in an Adult with Sickle Cell Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-4
Author(s):  
Daniyeh Khurram ◽  
Leonid Shamban ◽  
Robert Kornas ◽  
Maryann Paul
Keyword(s):  
Sickle Cell Disease ◽  
Liver Injury ◽  
Sickle Cell ◽  
Middle Lobe ◽  
Cell Disease ◽  
Drug Induced ◽  
Elevated Bilirubin ◽  
Chest X Ray ◽  
Conjugated Hyperbilirubinemia ◽  
Mixed Pattern

Drugs are a significant cause of liver injury. Drug-induced liver injury (DILI) can cause acute hepatitis, cholestasis, or a mixed pattern. Ceftriaxone is a commonly used antibiotic and has been associated with reversible biliary sludge, pseudolithiasis, and cholestasis. A 32-year-old male with sickle cell disease was admitted to the hospital for acute sickle cell crisis. On the second day of hospitalization, he developed cough and rhonchi with chest X-ray revealing right middle lobe infiltrates. Ceftriaxone and azithromycin were initiated. Subsequently, he developed conjugated hyperbilirubinemia and mild transaminitis. His total bilirubin trended upwards from 3.3 mg/dL on admission to 17 mg/dL. It was predominantly conjugated bilirubin, with preadmission bilirubin levels of 3-4 mg/dL. His transaminases were mildly elevated as well compared to previous levels. Extensive workup for bilirubin elevation was unremarkable. Ceftriaxone was switched to levofloxacin and the hyperbilirubinemia improved. On ambulatory follow-up, his bilirubin remained below 4 mg/dL. Ceftriaxone may be associated with marked direct hyperbilirubinemia particularly in sickle cell patients with chronic liver chemistry abnormalities. In the case of elevated bilirubin with concomitant ceftriaxone use, elimination of the offending agent should be considered.

scholarly journals Serum ferritin level changes in children with sickle cell disease on chronic blood transfusion are nonlinear and are associated with iron load and liver injury

Blood ◽  
2009 ◽  
Vol 114 (21) ◽  
pp. 4632-4638 ◽  
Author(s):  
Thomas V. Adamkiewicz ◽  
Miguel R. Abboud ◽  
Carole Paley ◽  
Nancy Olivieri ◽  
Melanie Kirby-Allen ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Liver Injury ◽  
Blood Transfusion ◽  
Iron Overload ◽  
Sickle Cell ◽  
Serum Ferritin ◽  
Ferritin Level ◽  
Liver Weight ◽  
Cell Disease ◽  
Iron Load

AbstractChronic blood transfusion is increasingly indicated in patients with sickle cell disease. Measuring resulting iron overload remains a challenge. Children without viral hepatitis enrolled in 2 trials for stroke prevention were examined for iron overload (STOP and STOP2; n = 271). Most received desferrioxamine chelation. Serum ferritin (SF) changes appeared nonlinear compared with prechelation estimated transfusion iron load (TIL) or with liver iron concentrations (LICs). Averaged correlation coefficient between SF and TIL (patients/observations, 26 of 164) was r = 0.70; between SF and LIC (patients/observations, 33 of 47) was r = 0.55. In mixed models, SF was associated with LIC (P = .006), alanine transaminase (P = .025), and weight (P = .026). Most patients with SF between 750 and 1500 ng/mL had a TIL between 25 and 100 mg/kg (72.8% ± 5.9%; patients/observations, 24 of 50) or an LIC between 2.5 and 10 mg/g dry liver weight (75% ± 0%; patients/observations, 8 of 9). Most patients with SF of 3000 ng/mL or greater had a TIL of 100 mg/kg or greater (95.3% ± 6.7%; patients/observations, 7 of 16) or an LIC of 10 mg/g dry liver weight or greater (87.7% ± 4.3%; patients/observations, 11 of 18). Although SF changes are nonlinear, levels less than 1500 ng/mL indicated mostly acceptable iron overload; levels of 3000 ng/mL or greater were specific for significant iron overload and were associated with liver injury. However, to determine accurately iron overload in patients with intermediately elevated SF levels, other methods are required. These trials are registered at www.clinicaltrials.gov as #NCT00000592 and #NCT00006182.

Severity of iron overload in patients with sickle cell disease receiving chronic red blood cell transfusion therapy

Blood ◽  
2000 ◽  
Vol 96 (1) ◽  
pp. 76-79 ◽  
Author(s):  
Paul Harmatz ◽  
Ellen Butensky ◽  
Keith Quirolo ◽  
Roger Williams ◽  
Linda Ferrell ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Liver Injury ◽  
Liver Biopsy ◽  
Blood Cell ◽  
Iron Overload ◽  
Sickle Cell ◽  
Red Blood Cell ◽  
Cell Disease ◽  
Liver Iron ◽  
Transfusion Therapy

Abstract Chronic transfusion therapy is being used more frequently to prevent and treat the complications of sickle cell disease. Previous studies have shown that the iron overload that results from such therapy in other patient populations is associated with significant morbidity and mortality. In this study we examined the extent of iron overload as well as the presence of liver injury and the predictive value of ferritin in estimating iron overload in children with sickle cell disease who receive chronic red blood cell transfusions. A poor correlation was observed between serum ferritin and the quantitative iron on liver biopsy (mean 13.68 ± 6.64 mg/g dry weight;R = 0.350, P = .142). Quantitative iron was highly correlated with the months of transfusion (R = 0.795, P &lt; .001), but serum ferritin at biopsy did not correlate with months of transfusion (R = 0.308, P = .200). Sixteen patients had abnormal biopsies showing mild to moderate changes on evaluation of inflammation or fibrosis. Liver iron was correlated with fibrosis score (R = 0.50, P = .042). No complications were associated with the liver biopsy. Our data suggest that, in patients with sickle cell disease, ferritin is a poor marker for accurately assessing iron overload and should not be used to direct long-term chelation therapy. Despite high levels of liver iron, the associated liver injury was not severe.

scholarly journals Loss of FXR Signaling Promotes Chronic Liver Injury in Sickle Cell Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 16-16
Author(s):  
Ravi Vats ◽  
Enrico M Novelli ◽  
Mark T Gladwin ◽  
Prithu Sundd ◽  
Tirthadipa Pradhan
Keyword(s):  
Sickle Cell Disease ◽  
Liver Injury ◽  
Sickle Cell ◽  
Conflicts Of Interest ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Bile Secretion ◽  
Cell Disease ◽  
Genes Encoding ◽  
Mice Liver

Hepatic crisis is an emergent complication affecting sickle cell disease (SCD) patients, however, the molecular mechanism of sickle cell hepatobiliary crisis remains poorly understood. We have used intravital imaging to show that sinusoidal ischemia occurs in the liver of transgenic-humanized SCD mice under basal condition. SCD mice manifested progressive hepatomegaly, liver injury and hyperbilirubinemia. RNA-sequence analysis identified dysregulation of genes encoding proteins responsible for fibrosis, bile acid synthesis, and bile transport in the SCD mice liver. Live injury was the result of NF-κB-dependent inhibition of FXR signaling and its downstream targets in hepatocytes, leading to loss of canalicular bile transport and bile metabolism. Blocking NF-κB activation rescued FXR-signaling, ameliorated liver injury and resolved sinusoidal ischemia in SCD mice. Moreover, administration of FXR agonist (GW4064) also ameliorated liver injury seen in SCD mice. These findings are the first to identify that FXR-dependent impaired bile secretion promotes intrahepatic bile accumulation, which contributes to hepatobiliary injury of SCD. Improved understanding of these pathways could potentially benefit the development of new therapies to treat sickle cell hepatic crisis. Disclosures No relevant conflicts of interest to declare.

Phosphodiesterase-4 Inhibition Reduces Ischemic/Reperfusion Liver Injury in a Mouse Model for Sickle Cell Disease.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1444-1444
Author(s):  
Alida Filippini ◽  
Giorgio Malpeli ◽  
Anne Janin ◽  
Orah S Platt ◽  
Christhope Leboeuf ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Liver Injury ◽  
Sickle Cell ◽  
Liver Cell ◽  
Inflammatory Infiltrate ◽  
Serum Levels ◽  
Matrix Remodeling ◽  
Red Cell ◽  
Cell Disease ◽  
Down Regulation

Abstract Ischemic/reperfusion (I/R) injury plays a critical role in the pathogenesis of several clinical manifestations of sickle cell disease (SCD) and it results from complex interactions between cells and plasma factors. Hepatic dysfunction has been described in SCD and the pathophysiology of liver I/R damage in SCD is only partially known. The liver is highly vascular organ with high metabolic rate, susceptible to stress-induced by hypoxia. Here, we studied the effects of acute and chronic hypoxia on liver function and pathology in transgenic sickle mice (SAD mice). We evaluated the following parameters at baseline, at 4, 48 and 168 hours (hrs) of exposure to hypoxia (8% oxygen) followed by 2 hrs reoxygenation (21% oxygen): complete blood counts with retic, red cell density, serum AST and ALT levels, liver pathology and expression by RT-PCR of the following genes: TNF-a, IL-1b as inflammatory response markers; TgfB1 (involved in control cell growth and extracellular matrix formation), mmp9 (marker of hepatic matrix remodeling), NfKb (transcription effector involved in liver cell death and regeneration), Icam1 (endothelial damage and vascular remodeling marker), in addition to heme oxygenase-1 (Homx1), eNOS (Nos3) and iNOS (Nos2). SAD mice at baseline exhibited liver infiltrates of inflammatory cells, no thrombi and a mild hepatic injury (pathological score: 1.4±0.02; n=5); up-regulation of TgfB1, Icam1, Nos3 and down-regulation of Nfkb compared to normoxic WT mice. One SAD mice died at 48 hrs hypoxia and 2 SAD mice died at 96 hrs hypoxia. In SAD mice I/R induced: increased red cell density at 48 and 168 hrs of hypoxia; increased peripheral neutrophil count at 48 and 168 hrs; increased retic count at 168 hrs; increased serum levels of AST/ALT; increased liver cell inflammatory infiltrate at 48 hrs (n=5) and 168 hrs (n=6); increased pathological score at 48 hrs (2.3±0.02 n=5) and at 168 hrs (3.2±0.05 n=6; P&lt;0.05). In SAD mice I/R induced changes in the expression of the following genes: 4hrs: up-regulation of Nfkb, Ilb1, Nos2 and down-regulation of Tgfb1, Icam1, homx1 and Nos3; 48 hrs: up-regulation of Icam1, Nos2, Tnfa and down-regulation of TgfB1, Nos3, homx1, Nfkb, Ilb1; 168 hrs: up-regulation of TgfB1, Icam1, Nos 3, homx1, Nfkb, Ilb1, Nos2 and down-regulation of Nos2. In WT mice I/R induced increased neutrophils and retic count at 168 hrs; increased serum levels of AST/ALT at 48 and 168 hrs; increased liver cell inflammatory infiltrate at 168 hrs (n=7) and pathological score at 168 hrs and modulation of the following genes at 4hrs: up-regulation of Nfkb, Icam1, Ilb1, Nos2, mmp9 and down-regulation of TgfB1 and homx1; at 48 hrs: up-regulation of TgfB1, Icam1, homx1, Nos2, Tnfa, mmp9 and down-regulation of Ilb1; at 168 hrs: up-regulation of Icam1, Nfkb, Nos 3, Nos2, Tnfa, mmp9 and down-regulation of Il1b, homox1, TnfB1. Then, we investigated the effects of a PDE-4 inhibitor (Rolipram) on hepatic I/R injury in sickle cell SAD mice, since cAMP cell content has been recently described to be crucial in I/R liver damage and PDE-4 is a key regulator of cAMP metabolism. In SAD mice, Rolipram reduced the hypoxia induced peripheral neutrophilia and serum AST/ALT increase, prevented the I/R liver injury as supported by reducing cell inflammatory infiltrate, pathological score (1.8±0.02, n= 6, P&lt;0.05) and the modulation of the following genes: TgfB1, Icam1, Nos3, Ilb1, Tnfa and mmp9 These data suggest that the inhibition of PDE-4 protects from I/R related sickle cell liver injury, most likely by inducing over-expression of Nos3, reducing vascular activation, modulating matrix remodeling and immune-inflammatory response.

Hemolysis in sickle cell disease

1974 ◽  
Vol 133 (4) ◽  
pp. 624-631 ◽  
Author(s):  
T. A. Bensinger
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Cell Disease
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