Sickle Hepatopathy Research Articles

GBT1118, a Voxelotor Analog, Ameliorates Hepatopathy in Sickle Cell Disease.

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.

Hepatopathy in sickle cell disease with osteomyelitis: a challenging diagnosis: case report

‘Sickle hepatopathy’ is a condition which is seen in only 10% cases of sickle cell disease (SCD). Sickle hepatopathy could be due to acute sickle crisis, sequestration, cholangiopathy, severe intrahepatic cholestasis or as a result of chronic blood transfusion related infection and hemosiderosis. Differentiating the cause for hepatopathy in SCD is challenging. Hepatopathy manifestation can range from mild liver function test abnormality to life threatening fulminant hepatic failure. Hence, demanding prompt recognition and management. Here we reported a one such case of 13 year old male with progressing jaundice and bony pain with swelling of lower limbs was diagnosed as SCD with right proximal tibia sickle osteomyelitis and left knee septic arthritis with hepatopathy who was managed with supportive care and surgical intervention.

Effect of ABO Mismatch and RBC Alloimmunization on the Outcomes of Patients with Sickle Cell Disease Undergoing Hematopoietic Stem Cell Transplantation

Background: Hematopoietic stem cell transplantation (HSCT) remains the only well-established curative option for sickle cell disease (SCD) patients. Non-myeloablative (NMA) conditioning has been used to improve the outcomes and reduce toxicities in adult SCD patients. However, Recipient/Donor (R/D) ABO incompatibility and alloimmunization could be significant impediments to successful outcomes when transplanting SCD patients due to risks of hemolysis, delayed engraftment, poor graft function and graft failure (GF). Herein, we report our experience with allogeneic HSCT for SCD and the effects of RBC groups mismatch and alloimmunization on the outcome of transplanted patients. Methods: We conducted a retrospective analysis of all adolescents and adult SCD patients (age >14 year) that underwent HSCT from January 2015 to February 2022 at our center. All patients received Intravenous alemtuzumab (1 mg/kg divided over 5 days on days -7 to -3) and 300 cGy TBI on day -2 or -1 for conditioning. Pre-transplant preparation consisted of hydroxyurea at maximum tolerated dose for 2-3 months and one session of exchange transfusion. Peripherally mobilized stem cells targeting 10x106 /kg of CD34 cells were used. For graft versus host disease (GVHD) prophylaxis sirolimus was started on day -1 and continued for one year with tapering if lymphoid chimerism was > 50%. For Patients with major ABO incompatibility, we administered 2 doses of rituximab (375 mg/m2) and 3 sessions of plasmapheresis before starting the conditioning regimen targeting an isoheamagglutinin titer < 1/32. The primary objective was to determine the impact of RBC groups mismatch and alloimmunization on the outcome of transplanted patients. The secondary objective was to assess the impact of GF on overall survival (OS). Logistic regression was done to evaluate predictors for GF. Kaplan-Meier method was used for survival analysis. Results: A total of 194 patients were included with a median age of 26 years and 55.6% being males. The median baseline Hgb and HbS were 93 g/L and 71.3%, respectively. Indications of stem cell transplantations were most commonly due to recurrent vaso-occlusive crisis in 52.57% of patients, CNS disease in 19.58%, and acute chest syndrome in 17.01%. Other indications included sickle nephropathy, sickle hepatopathy, priapism and AVN in 10.82% of patients collectively. Around 59% of donors were sickle cell disease carriers, and 41% were healthy donors. After a median follow up of 28.8 months (5-83), sixteen patients (8%) experienced graft failure (3 with primary GF and 13 with secondary GF). On univariate analysis (table 1a), ABO minor incompatibility (odds ratio (OR), 3.63; 95% confidence interval (CI), 1.13 -11.65, P=0.029, and RBC alloantibodies against donor non-ABO antigens (OR, 4.22; 95% CI, 1.17 -15.14, P=0.039) were predictive for GF. However, on multivariate analysis (table 2a), only RBC alloantibodies against donor non-ABO antigens (OR, 8.29; 95% CI, 2.01 to 34.05, P=0.0033) was predictive of GF. None of the 16 patients with major ABO incompatibility developed GF. Two-years OS for all patients was 95%. The median OS for patients with GF was 98% compared to 74% patients without GF, P<0.0001) (Figure 1). Conclusion: In our SCD transplanted patients, RBC alloantibodies against donor non-ABO antigens was an independent risk factor for GF. Patients with GF had an inferior survival and strategies for decreasing the risks are needed. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

S3313 Acute Sickle Intrahepatic Cholestasis From Sickle Cell SC Disease Causing Acute on Chronic Liver Failure

Introduction: Acute on Chronic Liver Failure (ACLF) is a disorder that results in grave systemic consequences. The dysregulated inflammatory response caused by an acute liver injury often results in multi-organ dysfunction. And while alcoholic/viral hepatitis or infections are common causes of ACLF, hematologic disorders are unusual. We present a case of ACLF due to sickle cell intrahepatic cholestasis from SC disease. Case Description/Methods: A 61-year-old man with history of HTN, sickle-cell trait, alcoholic cirrhosis presented for altered mental status. Initial labs showed TBili 30.7, DBili >20.0, AST/ALT 308/123, ALP 532 and INR 1.6. Phosphatidylethanol level negative. No new history of medication/herbal use, new sexual contacts, or drug use. Workup negative for hepatitis A/B/C/E. ANA negative, ASMA 26.7, IgG 2742. MRI Abdomen showed no liver mass with patent hepatic vasculature/biliary tree. LDH 531, Haptoglobin < 10, reticulocyte count 11.2, and Coombs test was positive. Hb electrophoresis showed 44.4% Hb C and 49.5% Hb S, consistent with SC disease. Hb was 8.5 (baseline), with no known crises since youth. Liver biopsy findings were consistent with sickle cell hepatopathy (sinusoidal dilation and congestion of sickled cells, ballooning degeneration of hepatocytes, and marked intracanalicular cholestasis). Patient had exchange blood transfusion (EBT) with improvement in Hb to 11.8 and decrease in retic count, LDH. Patient however continued to deteriorate, with increasing aminotransferases into thousands, worsening mental status, AKI, and coagulopathy. Patient made hospice care and eventually expired. Discussion: Hemoglobin SC (HbSC) disease is a less common form of sickle cell disease (SCD). Patients with HbSC disease have milder symptoms than SCD but more severe than sickle cell trait. Acute sickle hepatic crisis occurs in 10% of patients with SCD. Acute sickle intrahepatic cholestasis is the most severe form of sickle hepatopathy, associated with increased mortality. It is usually seen in SCD, but rarely in HbSC. Clinical presentation is more severe, with significant hyperbilirubinemia >15 mg/dL and aminotransferase elevations >1000 IU/L, reflecting ischemic injury. ALF/ACLF can evolve rapidly with multi-organ failure. EBT is considered in these situations. Non-responders have poor prognosis. Clinicians should be aware of the liver complications that can arise in patients with sickle cell-related disorders, including HbSC, particularly in patients with chronic liver disease.

P-096: ACUTE SICKLE CELL INTRAHEPATIC CHOLESTASIS: RARE DISEASE WITH UNUSUAL PRESENTATION, LESSONS LEARNT FROM AN INTERESTING CASE.

Purpose: Management of Sickle cell disease in India the is evolving. The pediatric fatal disease is shifting to adult chronic organ disease. Sickle hepatopathy is an umbrella term which covers hepatic sickle crisis, acute hepatic sequestration crisis although uncommon but manageable. Acute sickle cell intrahepatic cholestasis (SCIC) is a rare phenomenon, difficult to treat and has very high mortality. The pathogenesis of Acute sickle cell intrahepatic cholestasis involves sickling within the hepatic sinusoids leading to vascular stasis, hypoxia, and ballooning of the hepatocytes, resulting in intracanalicular cholestasis. We describe a difficult case of Acute sickle cell intrahepatic cholestasis which has a subacute course, challenges faced, and lessons learnt from managing it. Materials and methods: A 14-year-old girl with sickle cell anemia who was non-compliant with hydroxyurea treatment presented to us with complaints of pain in the right side of abdomen, drowsiness, lethargy, nausea and loss of appetite. She was transfused twice at another center before reaching our center. On examination, she was disoriented, febrile, icteric, severely pale with active bleeding from gums and mouth and moderate hepatosplenomegaly. Hemoglobin was 7.2 grams/ dl with reticulocyte count of 2%, with neutrophilic leukocytosis and normal platelet count. Hemoglobin S was 42%. Serum bilirubin was 68 mg/dl with direct fraction of 65.3mg/dl. SGPT and SGOT were 263 and 202 IU/dl respectively and prothrombin time was raised with INR of 1.79. Viral hepatitis A, B, C and E were ruled out. Bacterial infections were ruled out. The possibility of Acute sickle cell intrahepatic cholestasis was considered, and the child was managed with partial exchange transfusion till Hemoglobin S was brought to <10%. She also received fresh frozen plasma in view of raised prothrombin time and active bleeding. Results: She did not improve until 14 days after admission.Gradually after 20 days she started talking and eating. However, liver enzymes and bilirubin normalized only after 40 days. She was discharged in stable condition and is continued on follow up. Conclusion: Sickle cell hepatopathy is an umbrella diagnosis for all the varied causes of hepatic dysfunction ranging from sickling crisis to transfusion transmitted viral infections. In our case, viral hepatitis was ruled out conclusively.A very rare condition Acute sickle cell intrahepatic cholestasis was considered in view of the clinical presentation serum bilirubin was extremely high and mildly elevated transaminases. However. Hepatic sequestration was unlikely based on the hemoglobin level and reticulocyte count. Differentiating the varied causes in resource constrained centers can be often a daunting task and multipronged management needs to be initiated at the earliest to ensure a positive outcome. The authors do not declare any conflict of interest

28-Year-Old Man With Joint Pain

28-Year-Old Man With Joint Pain

Molecular Mechanism of Intrahepatic Cholestasis in Sickle Cell Disease

Sickle cell disease (SCD) is an autosomal recessive genetic disorder that affects over three million people worldwide. Sickle Cell Anemia, the most common form of SCD is caused by the substitution of hydrophilic glutamic acid with hydrophobic valine at the sixth position in β-globin chain. The mutated hemoglobin (HbS) polymerizes under hypoxic conditions to promote erythrocyte sickling. Sickling promotes vaso-occlusion (ischemia) and hemolysis, which are two major pathophysiological events contributing to end organ damage. SCD patients can develop Sickle Cell Intrahepatic Cholestasis (SCIC), which is a rare but lethal form of hepatopathy. Besides SCIC, cholethiasis (gallstone formation), viral hepatitis and choledocholithiasis (stones in bile duct) have also been reported in SCD patients. The morbidity associated with sickle hepatopathy is expected to rise with growing life expectancy of SCD patients. Rescue therapies to halt the progression of sickle hepatopathy will be highly beneficial, however, development of such therapies is stalled by the lack of understanding of the molecular mechanism underlying sickle hepatopathy.We assessed the liver pathophysiology in a humanized mouse model of SCD in Townes SS mice homozygous for Hbatm1(HBA)Tow and homozygous for Hbbtm2(HBG1,HBB*)Tow). Littermate sickle cell trait mice (Townes AS mice homozygous for Hbatm1(HBA)Tow and compound heterozygous for Hbbtm2(HBG1,HBB*)Tow/Hbbtm3(HBG1,HBB)Tow) were used as control mice. Our findings reveal that SCD but not control mice developed progressive intrahepatic cholestasis with age characterized by increased level of serum bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and cholesterol. Immunohistochemical analysis of SCD mice liver revealed increased ductular reaction, inflammation, and fibrosis, which is hallmark of cholestatic liver disease. Immunoelectron microscopy revealed damage to bile canalicular structure and loss of several bile transporters from hepatocyte membrane. Remarkably, biochemical analysis revealed that intrahepatic cholestasis in SCD mice was associated with loss of Wnt signaling in hepatocytes. Our preliminary findings suggest that further studies are needed to elucidate the molecular mechanism underlying progressive cholestasis in SCD mice. Profound understanding of the regulation of cholestasis and hepatobiliary injury in SCD could potentially benefit the development of new therapies to attenuate sickle hepatopathy in SCD patients. DisclosuresNo relevant conflicts of interest to declare.

Red Cell Exchange: A Concise Review of Indications and Management

▪Sickle cell disease (SCD), a common hemoglobinopathy in the United States affecting approximately one in 500 African-Americans, is associated with numerous potential complications related to both anemia and the presence of hemoglobin S (HbS). Red blood cell (RBC) transfusion and exchange (RCE) to improve oxygen carrying capacity and to treat or decrease the risk of complications due to sickling has been an important part of treatment for many years. While some treatment guidelines exist, there is still significant variation in the management of SCD patients.Fifteen physicians in the active practice of apheresis from 12 institutions representing different geographic regions within the United States discussed how they manage RCE. Additionally, a literature review was performed and data from a prior practice survey were evaluated.Simple transfusion is recommended to treat symptomatic anemia with hemoglobin <9 g/dL. RCE is indicated to prevent or reverse complications arising from the presence of HbS.Indications for RCE in SCD : Common indications include treatment of stroke, acute chest syndrome, and sickle hepatopathy. Primary and secondary stroke prevention is an accepted, well studied indication, although optimal duration of treatment is unknown. RCE may be indicated prior to planned surgical procedures, may be necessary during pregnancy in women who have a history of severe SCD-related complications, and is indicated prior to stem cell mobilization. Pain crisis in the absence of other symptoms is generally not accepted as an indication. The role of RCE is not determined for pulmonary hypertension, end stage renal disease, and progressive sickle retinopathy.Goals of RCE : The most important goals are to reduce the level of HbS while also preventing development of hyperviscosity. In most situations, a target HbS of ≤30% and target hemoglobin <10 g/dL (or hematocrit <30%) will treat and/or prevent SCD related complications without causing hyperviscosity.Access: Peripheral veins are the preferred means of access when possible. Treatment of acute complications of SCD usually requires a temporary central venous catheter. Options for long-term access include tunneled central venous catheters, implantable ports, or arteriovenous fistulas.RBC units: These should be HbS negative and leukodepleted. Units are commonly matched for C, E, and Kell antigens to help prevent alloimmunization in addition to being negative for antigens against which the patient has already formed antibodies. RBC phenotyping commonly is performed and molecular typing may be indicated in selected patients.Complications: These include risks related to central venous access, transfusion reactions, iron overload, alloimmunization, transfusion-transmitted infection, development of warm autoantibodies, and hyperhemolysis syndrome.There are many issues that need to be taken into consideration when evaluating a patient with SCD for transfusion treatment. A prior practice survey indicated that there are variations in the clinical management of these patients. While every case must be evaluated individually, we have presented some common practices. DisclosuresBoggio:Grifols: Consultancy, Honoraria.

Liver damage and sickle cell disease: genotype relationship.

Sickle hepatopathy is a severe and not rare complication of sickle cell disease (SCD), showing mainly a cholestatic pattern. So far, no effective approaches to prevent or treat this condition have been recognized. We conducted a single-center observational study in 68 adult sickle cell patients, encompassing 17 with sickle cell anemia (SCA), 38 with sickle cell thalassemia (HbS/β-Thal), and 13 with HbSC disease. The aim of our study was to assess liver damage in the three main forms of SCD, through the evaluation of clinical, laboratory, and imaging findings. In our population, the role of hepatotropic viruses, high BMI, and alcohol consumption in liver damage was ruled out. SCA and HbS/β-Thal patients with lower Hb (p < 0.001), higher HbS (p < 0.001), and frequent vaso-occlusive crises showed functional (GGT values: SCA and HbS/β-Thal vs HbSC p = 0.047 and p = 0.009, respectively) and structural liver abnormalities, defined by abdominal ultrasound and vibration-controlled transient elastography (liver stiffness values: SCA and HbS/β-Thal vs HbSC p 0.022 and p 0.19, respectively), more severe than HbSC patients. Through univariate and multivariate analyses, male sex, SCA genotype, lower HbF, frequent transfusions, increased GGT values, and abnormal liver ultrasound and stiffness were identified as potentially early markers of sickle hepatopathy.

Posterior Reversible Encephalopathy Syndrome Following Orthotopic Liver Transplantation for Sickle Hepatopathy

Posterior reversible encephalopathy syndrome (PRES) occurs with increased frequency in solid organ transplant recipients and sickle cell disease patients. Sickle hepatopathy patients who require liver transplantation may be at markedly increased risk for developing PRES in the post-operative setting. Here, we describe two such cases and carefully consider causative factors.

Role of Automated Red Cell Exchange in Acute and Chronic Complications of Sickle Cell Disease

Background. Automated red cell exchange transfusion (ARCET) is commonly used in patients with sickle cell disease, but objective data on its impact on acute and chronic complications are limited.Methods. Fifty-two sickle cell disease patients at the University of Illinois at Chicago underwent exchange transfusion from January 2011 to January 2016. Six patients were excluded due to incomplete data leaving 46 patients available for analysis. We collected data from the year before, year after and the year of ARCET to study the impact of red cell exchange on clinical, biological and hematological parameters.Results. There were 435 procedures with average of 9.45 per patient (range 4-14). The mean age of our cohort was 58.2 years. There were 22 (47.8%) males and 24 (52.2%) females. Genotypes include 42 (91.3%) HbSS, 1 (2.2%) HbSC, 1 (2.2%) HbSBeta+thalassemia and 2 (4.3%) HbSBeta0thalassemia. The most common indication for ARCET in our cohort was prior stroke in 32 patients (69.6%) and prevention of stroke in 7 patients (15.2%), followed by frequent vaso-occlusive crisis (VOC) 8 patients (17.4%), multiple acute chest syndrome 6 patients (13%), pulmonary hypertension 6 patients (13%) and chronic kidney disease 5 patients (8.9%). Iron overload, sickle hepatopathy, cardiomyopathy and seizure were some of the other indications. Twenty-five patients (54.3%) had more than one indication to undergo the ARCET. Thirty-one patients (67.4%) are still continuing the treatment. Thirty patients (65.2%) were on hydroxyurea (HU) prior to ARCET and 8 patients (17.4%) were still on HU while on ARCET. The mean frequency of ARCET was every 6 weeks. The mean pre and post ARCET values for hemoglobin(Hb), hematocrit (Hct), Hemoglobin S %(HbS), white cell count (wbc) and platelets(plt) are shown in Table 1. Paired t-test and Wilcoxon signed-rank test were used to analyze the clinical and hematological parameters. Analysis shows increase in mean Hb and Hct post ARCET and decrease in mean wbc, plt and HbS % post ARCET and the difference is statistically significant. (Table 3). Post ARCET body mass index (BMI) and weight are increased and the difference is statistically significant with p value 0.002 for BMI and 0.003 for weight. (Table 3). Ten (21.7%) patients showed decrease in the ferritin level post exchange. Thirty patients (65%) had VORTEX port whereas 29 patients (63%) had central venous access for procedures prior to Vortex placement (17/29, 59%). Nine patients (20%) had peripheral access mostly power port (for access) with one peripheral vein for return (6/9 67%). There were 10 access related complications and there were 3 port replacements due to septum damage and infection. There were 10 procedure related complications and 10 transfusion reactions as described in Table 2. ED admissions were decreased in 13(28.3%) patients from mean 7.69 to 2.92 admissions. The annual inpatient admissions showed a decrease in 18(39.2%) patients from mean 4.6 days pre ARCET to 1.6 admissions post ARCET. The acute care admissions showed an increase due to program expansion of our acute care center during this study period.Discussion. Our study shows that red cell exchange is an effective treatment modality for patients with sickle cell disease. It contributes to improvement in weight, increase in Hb and Hct and decrease in wbc, plt, HbS% and iron overload. It also decreases inpatient and ED admissions. The procedure is safe and tolerable with minimal complications. Long term studies are needed study the efficacy of this treatment modality and its contribution to improvement of quality of life and life expectancy in sickle cell disease patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Noninvasive Assessment of Liver Fibrosis in Patients with Sickle Cell Disease

Complications affecting multiple organs, including the liver, contribute to early mortality in patients with sickle cell disease (SCD). Earlier diagnosis and monitoring of "sickle hepatopathy", preferably using non-invasive methods, would enable earlier intervention and therefore, potentially a better outcome for patients.In many non-SCD chronic liver diseases, fibrosis stage is the most important predictor of morbidity and mortality. Two non-invasive methods of assessing liver fibrosis are used: Transient Elastography (TE, Echosens) and Enhanced Liver Fibrosis Score™ (ELF, iQUR). TE detects fibrosis using ultrasound and low frequency elastic waves with a propagation velocity directly related to the stiffness of the liver. The ELF score examines the balance between matrix deposition and degradation using levels of three proteins analysed using a patented formula.We report a prospective study correlating liver function tests (LFTs) with the level of liver fibrosis (as ascertained by TE and ELF) in a cohort of patients with SCD. Ethical approval for this study was obtained from the NHS ethics committee (11/LO/0005) and patients were consecutively recruited in the steady-state sickle cell clinic at Kings' College Hospital, London, during 2012. Patients were excluded if they had viral hepatitis or were pregnant. Clinical (transfusion and hydroxyurea therapy), imaging (liver iron concentration, LIC) and laboratory data were collected during steady-state.TE and ELF were performed on 194 patients. The patients ranged from 17-72 years (mean age 35 years); 78 (40%) were male, 134 (68%) had HbSS or HbSb0 (SCA), 48 (26%) Hb SC, and the remainder, Hb Sβ+ (excluded due to low numbers). Statistical analysis was undertaken in IBM SPSS version 20.There was significant correlation between both TE and ELF with age, when corrected for sickle genotype (TE β = 0.19, p = 0.006 and ELF β = 0.2, p = 0.005) (Figure). Patients with SCA had significantly higher TE results and mean ELF scores than those with HbSC (TE, 6.8 vs 5.3, p<0.0001 and ELF, 9.2 vs 8.6 p <0.0001) (Table).In SCA patients, TE correlated significantly with all serum LFTs (Albumin R = -0.35 p<0.0001, AST R = 0.44 p<0.0001, ALP R = 0.29 p<0.0001, GGT R = 0.40 p<0.0001, conjugated bilirubin R = 0.26 p = 0.004). Positive correlation was found with LDH (R = 0.24 p = 0.004) and negative correlation with Hb (R= -0.25 p = 0.002). In the Hb SC group, TE correlations were weaker for AST (R = 0.39 p = 0.004), ALP (R = 0.30 p = 0.03), WBC (R = 0.39 p = 0.02) and reticulocyte count (R = 0.35 p = 0.01). All markers of iron loading correlated with TE values, when corrected for sickle genotype (serum ferritin β = 0.25, p <0.0001, total top-up units β = 0.22, p = 0.001, total units transfused β = 0.25, p <0.0001 and LIC β = 0.32, p = 0.046).In SCA patients, ELF score correlated with serum LFTs (Albumin R = -0.30 p<0.0001, AST R = 0.39 p<0.0001, ALP R = 0.25 p = 0.003, GGT R = 0.28 p = 0.001, conjugated bilirubin R = 0.36 p<0.0001). Positive correlation was seen with LDH (R = 0.26 p = 0.002) and negative correlation with Hb (R = -0.25 p = 0.004). Negative correlation was also seen with HbF levels (R = -0.24 p = 0.01). In the HbSC group, there were no significant correlations between ELF and serum LFTs. However associations were seen between ELF score and LDH (R = 0.40 p = 0.004) and Hb level (R = -0.31 p = 0.01). ELF score correlated with serum ferritin (β = 0.25 p <0.0001), and total blood transfusion units (β = 0.24 p = 0.001).These data show significant levels of liver dysfunction in our SCD population using both TE and ELF score which correlated significantly with abnormal LFTs and markers of hemolysis and iron overload. The role of TE and ELF in monitoring liver dysfunction in SCD needs to be further validated, preferably with longitudinal, and if possible histological data.Table 1Range and mean TE results and ELF score for whole cohort and subgroups.Whole cohort n = 194 (%)SCA n = 134 (%)Hb SC n = 48 (%)p valueFibroScan results (kPa)Mean (range)6.3 (2.0 - 21.3)6.8 (2.0 - 21.3)5.3 (2.0 - 16.0)< 0.0001None/mild (0-7.65)153 (79)98 (73)43 (90)Moderate (7.66-13.00)33 (17)29 (22)4 (8)Severe (≥13.01)8 (4)7 (5)1 (2)ELF scoreMean (range)9.1 (7.1 - 11.6)9.2 (7.1 - 11.6)8.6 (7.5 - 10.3)<0.0001None/mild (≤9.7)164 (84)107 (79)46 (96)Moderate (9.8 - 11.2)27 (14)24 (19)2 (4)Severe (≥11.3)3 (2)3 (2)0 (0) [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Five Year Experience of Acute Intrahepatic Cholestasis in Patients with Sickle Cell Disease at a Large Teaching Hospital in London

Background:Acute intrahepatic cholestasis (AIC) is a rare but severe form of sickle hepatopathy, caused by sickling within hepatic sinusoids, leading to vascular stasis, hypoxic damage and can lead to acute hepatic failure. It is characterised by a combination of clinical, laboratory and radiological features. There is tender hepatomegaly, hyperbilirubinaemia without evidence of extrahepatic biliary obstruction, coagulopathy and thrombocytopenia. Transaminitis, if present is mild or moderate.AIC has a high fatality rate if not treated promptly. Although there is a dearth of evidence on how to treat AIC, the most frequently recommended intervention is by exchange blood transfusion. We report our experience of managing patients with this rare yet serious complication of sickle cell disease at a large tertiary centre over the course of 5 years.Methods:A retrospective review of adult patients who attended the sickle cell service from 1st January 2010 to 30th June 2015 was undertaken. All patients who had had a bilirubin level greater than 300umol/L were identified. Patients with evidence of 'secondary' causes of hyperbilirubinaemia such as biliary sepsis, acute biliary or extrahepatic duct dilatation were excluded.For the remaining patients, clinical notes were reviewed for history of tender right upper quadrant, peak bilirubin levels, coagulation studies, ferritin, ultrasonography or other liver imaging, pre-existing co-morbidities and immediate and long-term clinical outcome were recorded.Results:We identified 16 cases of AIC in 15 patients, out of an excess of 582 patients who attended the Sickle Cell Department over the course of 5 years. In three of these cases, there was also an associated generalised vaso-occlusive crisis. There were 10 male and five female, all of whom had sickle cell anaemia (HbSS), with a median age of 30years (20-48 years).In terms of pre-existing liver disease, one patient had autoimmune hepatitis; another two had chronically deranged liver functions with radiological features suggestive of cirrhosis. Table 1AgeSexPeak bilirubin; conjugated%INRAPTRThrombocytopeniaConcurrent crisis (VOC)Outcome25F398; 65%1.281.17NoNoAlive25F386; 61%1.221.97NoNoAlive36M299; 69%1.281.33NoYesAlive20M299; 63%1.491.22NoNoAlive37M693; 74%1.371.54NoNoAlive38F671; 100%1.211.41YesNoAlive25F686; 83%1.071.53YesNoAlive25M585; 78%1.251.14NoNoAlive34M450; 88%1.121.58YesNoAlive30M694; 96%2.593.77YesNoDeceased48M719; 66%3.002.33YesNoDeceased22M975; 98%4.0>5NoNoDeceased25F310; N/A1.472.06YesYesAlive25M1043; 99%3.43>5YesNoDeceased44F478; 100%1.331.40NoNoAlive46M644; 91%2.081.2YesNoDeceasedThe findings on ultrasonography included increased liver reflectivity, hepatomegaly and in two cases, cirrhosis. Choledolithiasis was present in 6 cases, with no evidence of gall bladder infection, inflammation or duct obstruction. Cholecystectomy had been performed in 3 cases; two of these patients had chronically dilated intrahepatic ducts.All patients received transfusions to lower the Haemoglobin S% to less than 30%. Eleven patients received exchange blood transfusions within 72hours of presentation. The remainder, who had received transfusion recently (majority at local hospital) received further transfusions within a week of admission to keep HbS% <20%.Seven of the 11 patients who recovered now have normal transaminases with mildly elevated bilirubin levels. Three patients have markedly elevated transaminases and bilirubinaemia, two of whom had previous cholecystectomy and chronically dilated intrahepatic ducts. The third has a heterogenous liver with features of sickle hepatopathy and probable early features of liver fibrosis, while the fourth went on to have a successful liver transplant.There were 5 deaths; all in male patients aged between 22 and 48 years. Two had established cirrhosis; one also had autoimmune hepatitis and CMV viraemia. A third patient had liver biopsy evidence of fibrosis, while a fourth had a CT description of liver with a nodular contour. The fifth patient,was previously fit and well and adenoviraemia was diagnosed.Discussion:Our experience supports the view that AIC can successfully be reversed by timely exchange blood transfusion, and suggests that underlying liver disease and viraemia confer a poor outcome, irrespective of age. DisclosuresNo relevant conflicts of interest to declare.

A Case of Sickle Hepatopathy Secondary to Influenza A

A Case of Sickle Hepatopathy Secondary to Influenza A

Sickle Hepatopathy and Complex Jaundice in a Primigravida with Hepatitis B Virus Infection: Case Report

Background Aim: This article aimed to sensitize the healthcare providers who care for patients with sickle cell disease (SCD) during pregnancy, to the multiple causes of jaundice in sickle hepatopathy, and sift the maze in establishing the dominant cause. Case Presentation: This is a case of a 28-yr-old Gravida 1 Para 0 + 0 health worker, with sickle cell anaemia and background history of peptic ulcer disease, total right hip replacement and previous multiple blood transfusions due to haemolytic crisis. She presented with upper abdominal pain and progressively deepening jaundice. There was minimal relief of the abdominal pain with anti-ulcer medications. She had tender hepatomegaly, positive Murphy’s sign and deranged liver function parameters. She was also positive for viral hepatitis B markers. A remarkable finding on abdominal ultrasonography was that of a gallbladder with normal wall thickness and multiple stones. She was managed conservatively on intravenous fluids, antibiotics and Livolin forte (Phosphatidylcholine) with improved liver function parameters within a week. Conclusion: Since sickle cell hepatopathy is multifactorial, the importance of unravelling the dominant cause of jaundice or liver dysfunction in these patients and the need for immediate intervention are necessary for effective and targeted care, hence this case report. Our patient had background chronic hepatitis B with a superadded acute cholecystitis with non-obstructing gallstones, and possible subsequent bacterial hepatitis, which responded to antibiotics. The most likely dominant cause of jaundice was chronic hepatitis B that was precipitated by acute cholecystitis.

How we treat sickle hepatopathy and liver transplantation in adults

AbstractSickle 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.

Stop Light: Mortality Risk In Adult Sickle Cell Disease and Criteria For Hematopoietic Stem Cell Transplant

▪ IntroductionThe integration of prognostic information into the clinical care of adults with sickle cell disease (SCD) assumes greater importance as more intensive therapeutic strategies are being developed, including hematopoietic stem cell transplantation (HSCT). In addition, more high-risk alternate donor options predominate in SCD, since allogeneic HSCT candidates seldom have matched sibling donors (MSD). We wanted to integrate individual clinical risk factors for death, such as white blood cell count (Platt, NEJM, 1994) or Tricuspid Regurgitant Jet Velocity (TRV), (Gladwin, NEJM, 2004) into eligibility criteria for HSCT. MethodsBaseline demographics, laboratory values, high-risk TRV (greater than 3.0 m/s), and 2-year mortality data on adults with SCD, available from the multi-centered Walk-PHaSST study (n=468 HbSS, 19 deaths), were used to estimate one- and two-variable positive predictive values (PPVs) for short-term mortality (Figure 1A). Using these data, we suggest the basis for a graded (‘stop light') HSCT eligibility schema in which patients with morbid disease and <10% 2-year mortality (green light, ‘low risk' disease) could be considered for standard-risk HSCT (e.g. reduced-intensity MSD) (Figure 1B). 10-15% mortality (yellow light, ‘moderate risk') or highly morbid disease could be considered for alternate donor transplants in which there is published experience in adults (e.g. reduced intensity haploidentical, Bolanos-Meade, Blood 2012). >15% mortality (red light, ‘high risk' disease) could be considered for high-risk alternate donor transplants (without published experience in adults, e.g. cord blood). We then applied this method for estimating HSCT eligibility to HbSS adults followed at University Hospitals Case Medical Center in Cleveland, Ohio (n=122), and contrasted this with criteria based on published recommendations (Hseih, NEJM, 2009), (STRIDE trial: http://clinicaltrials.gov/show/NCT01565616). ResultsWe developed a simple mortality-based prognostic scale with which to estimate SCD severity prior to referring for HSCT. In Walk-PHASST, multiple clinical variables contributed to high risk SCD (red boxes, Figure 1A). The Cleveland population is young (median age 28 years). Nonetheless, 23% (28 of 122) were high risk (red) patients, and 52% (64 of 122) were moderate risk (yellow) or had highly morbid disease. 12% (15 of 122) had low risk (green) SCD and morbid disease, based on our proposed ‘stop light' eligibility schema. Published eligibility criteria, which do not stratify based on SCD prognosis, identify 75-86% of adults in our center as having ≥1 indications for HSCT. [Display omitted] ConclusionsAlthough estimation of risk from transplant is evolving, we believe the proposed ‘stop light' graded eligibility may aid in the selection of appropriate patients and in risk-benefit counseling. We recognize the limitations of a scale based on a modest number of deaths. Nonetheless our simple mortality based prognostic scale is a tool with which to approach the integration of disease severity and HSCT risk in SCD.Yellow: Patients at moderate risk for 2-year (10-15%) mortality (yellow boxes, Figure 1A) or with highly morbid disease (>5 hospitalizations per year, h/o CVA, h/o silent infarct, estimated GFR <90 mL/min, macroalbuminuria, ≥2 ACS within 5 years, or sickle hepatopathy) are eligible for alternate donors with which there is published experience in adults (e.g. haploidentical as well as MSD).Green: Patients with 2-year mortality (<10%) but with morbid disease (>2 hospitalizations per year for two or more years, or acute chest within the past five years) are eligible for standard-risk HSCT (MSD only). Disclosures:No relevant conflicts of interest to declare.

Sickle liver disease—An unusual presentation in a compound heterozygote for HbS and a novel β‐thalassemia mutation

A 38-year-old Ghanaian man presented with a 6-month history of worsening pruritus, jaundice, and ascites. He was previously fit and well and rarely drank alcohol. Screening tests for chronic liver disease including viral, autoimmune, and other metabolic causes including iron overload were unremarkable. A liver biopsy performed at the referring hospital demonstrated intralobular cholestasis and cirrhosis. He was listed for liver transplantation but subsequently developed sepsis with multiple organ failure and died. The sickle solubility test was positive. Blood smear showed cells consistent with liver failure and no sickle cells. Hemoglobin electrophoresis revealed HbA2 2.8%, HbF 0.5%, and HbS greater than HbA (49.6% vs. 41.3%) in the absence of blood transfusion. Sequence analysis of the beta-globin genes showed he was a compound heterozygote for the Hbs mutation at codon 6 (CAG --> GTG) and a novel mutation at position 844 of intron 2 (betaIVS2-844 C --> A). A diagnosis of sickle hepatopathy causing decompensated cirrhosis was made. This case is unusual insomuch as this patient was asymptomatic for over 35 years and represents a novel presentation of sickle cell disease. Sickle cell disease should be considered in appropriate patients when unusual presentations of liver disease arise.

Sickle cell hepatopathy: Clinical presentation, treatment, and outcome in pediatric and adult patients

Standard diagnostic criteria and therapy are lacking for sickle cell hepatopathy, an uncommon complication of sickle cell disease. Here we propose diagnostic and therapeutic guidelines based on our experience and on reported cases. We defined sickle hepatopathy by a total serum bilirubin concentration >13 mg/dl not explained by severe acute hemolysis, viral hepatitis, extrahepatic obstruction, or hepatic sequestration. We reviewed the records of all children with sickle hepatopathy seen at our institution during the past 20 years and the reported cases from the literature. Patients were categorized into two groups based on whether hepatic dysfunction at presentation was mild (Group I) or severe (Group II). Seven patients were identified from our institution and 37 patients from the literature. The 44 patients were evenly divided between the two groups. Group I patients had a significantly lower mean age (11.8 years vs. 24.5 years, P = 0.0001), maximum bilirubin level (36.2 mg/dl vs. 76.8 mg/dl, P = 0.0008), and frequency of treatment with exchange transfusions (P = 0.03). Overall, mortality was 4% in Group I and 64% in Group II (P = 0.0001). Gender and recurrence rate did not differ. Among Group II patients, only two of nine who received exchange transfusion died, whereas 12 of 13 who did not receive exchange transfusion died (P = 0.0015). Sickle cell hepatopathy is an uncommon complication characterized by extreme hyperbilirubinemia and either mild or severe hepatic dysfunction. Children and adults can present with either form; however, adults have a higher frequency of the severe form. Exchange transfusion may be the only effective management for initial episodes of severe sickle cell hepatopathy.

Benign course of extreme hyperbilirubinemia in sickle cell anemia: Analysis of six cases

Since the approach to the management and outcome of extreme hyperbilirubinemia in patients with sickle cell anemia is not clearly defined, we reviewed our experience with marked hyperbilirubinemia in six children with sickle cell disease. Intrahepatic sickling (sickle hepatopathy) rather than hepatitis or biliary stones appeared primarily responsible for the extreme jaundice in at least four children and possibly in all six. Signs and symptoms were few, and laboratory abnormalities were not striking other than marked hyperbilirubinemia (total serum bilirubin concentrations ranging from 20.4 to 57.6 mg/dl with approximately one half conjugated). All of the children improved within days to weeks and currently are well, without recurrence of hyperbilirubinemia or evidence of chronic liver disease. The patients described here suggest that sickling within the liver, previously reported to be a serious and even fatal syndrome, usually is a benign and self-limited process.