Acute Hepatic Crisis Research Articles

S3160 Sickle Hepatopathy: An Uncommon Sickle Cell Crisis

Introduction: Intrahepatic vaso-occlusive syndrome, or sickle cell hepatopathy (SCH), is a rare complication of sickle cell disease. We present a case of acute hepatic sequestration in the setting of bacteremia. Case Description/Methods: 32 male with history of sickle cell disease, auto-splenectomy and end stage renal disease presented with fatigue and diffuse myalgia. Physical exam was notable for scleral icterus, left knee swelling and erythema, and crackles in bilateral lungs. Initial labs showed leukocytosis (WBC 43,000/μL), profound anemia (Hgb 3.7 g/dL) and coagulopathy (INR 2.1). Liver enzymes were elevated at ALP 527 U/L, ALT 48 U/L, AST 209 U/L. Total bilirubin was 39 mg/dL with conjugated fraction 34.4 mg/dL, blood urea nitrogen 67mg/dL, creatinine of 4.34mg/dL, and ferritin >10,000. Blood cultures revealed Staphylococcus Aureus, likely due to left knee septic joint. US showed hepatomegaly with liver span of 24 cm. Clinical picture consistent with sepsis secondary to MSSA bacteremia in setting of sickle cell crisis and hepatopathy. Patient was admitted to ICU for hypoxic respiratory failure due to fluid overload. Clinical course was complicated by septic shock with multi-organ dysfunction including acute liver failure due to hepatic sequestration crisis, hemochromatosis, encephalopathy and disseminated intravascular coagulation. Patient required CRRT and supportive care including treatment of underlying infection, PRBC transfusions, and vitamin K administration to reverse coagulopathy (Figure). Discussion: Hepatopathy occurs in 10% of homozygous sickle cell patients. It can be self resolving or lead to fulminant hepatic failure. Subsets of SCH include Acute Hepatic Crisis(AHC), Hepatic Sequestration, Intrahepatic Cholestasis(IC). Sickling in the sinusoids leading to hepatocellular necrosis, engorgement of Kupffer cells and bile stasis. Common presentation of all three conditions includes acute RUQ pain, nausea, fever, and elevated liver enzymes. IC is severe presentation of SCH with hypoxic injury leading to blockage and cholestasis. Presentation overlaps with AHC with addition of hyperbilirubinemia, severe jaundice, renal impairment, and encephalopathy. Total bilirubin is typically markedly elevated due to combination of hemolysis, cholestasis and renal dysfunction. Sequestration presents with significant rapid onset hepatomegaly, drop in hemoglobin with RUQ pain, which can ultimately lead to cardiac and pulmonary instability. Treatment is supportive with exchange transfusion, fresh plasma for coagulopathy.Figure 1.: Top: Contrast enhanced spiral CT of the chest, abdomen and pelvis showing markedly enlarged measuring 20 cm in craniocaudal dimension with lobulated contour and non visualized spleen Bottom: Liver biopsy showing dilated sinusoids with aggregates of sickled red blood cells. There is also presence of canalicular cholestasis.

Hepatic Complications in Children with Sickle Cell Anemia Are Rare but Potentially Lethal

▪Background: Liver disease in sickle cell anemia (SCA) can be due to several pathophysiological processes, including acute or chronic ischemia/reperfusion injuries, increased bilirubin load in bile secondary to chronic hemolysis, iron overload, viruses, and autoimmune disorders. Severe hepatic impairment is rarely reported in children but may be underdiagnosed and insufficiently treated. We report 12 cases, highlighting the need for urgent recognition and treatment of SCA hepatic dysfunction.Patients and methods: We performed a single-center retrospective cohort study in our French Teaching Hospital SCA Referral Centre. We analyzed the medical files of 1532 children hospitalized between 2009 and 2017 and identified 12 patients aged 0.6 to 18 years (11 HbSS, 1 HbS/beta 0thalassemic) with severe liver dysfunction.Results: Acute hepatic crisis developed in 7 patients, age 4.5 to 17 years. Previous treatments were hydroxycarbamide (HC) (n=5), and monthly red blood cell (RBC) exchange transfusions coupled with deferasirox (n=3, including 1 case of documented overdosage). Bilirubin was 31-139 µM, more than half conjugated in 4/7 cases. ALT was 39-1305 IU. Three patients had liver failure at presentation, with encephalopathy, low prothrombin time (14-29 %) and hyperammoniemia (240-338 µM). RBC exchange transfusion was emergently performed in 5/7 patients, and a single RBC transfusion was performed in one patient without liver failure. All 6 patients recovered. One patient received an urgent liver transplantation without exchange transfusion, and died during surgery.Three patients, aged 3 to 14 years, developed a cholangiopathy, evidenced on MR-cholangiography. Additional factors were autoimmunity in one patient with treated autoimmune hepatitis and positive p-ANCA, and a heterozygous mutation in a gene involved in bile formation (MDR3) in another patient. Two patients needed a temporary biliary drainage to control infectious cholangitis, and one of them underwent subsequent biliary-digestive anastomosis followed with liver transplantation, with a good result (follow-up 2.5 years).Another patient, aged 18 years had autoimmune hepatitis, diagnosed on high ALT, positive autoantibodies and liver biopsy. He was successfully treated with prednisone and azathioprine.A 7-month-old child developed acute hepatic sequestration associating major hepatomegaly and drop in hemoglobin level (48 g/l), and received RBC transfusion with a good evolution.Discussion: Acute hepatic crisis is rare but potentially devastating and may develop in SCA patients undergoing chronic RBC exchange transfusions, even with HbS < 20%. It is assumed to be due to acute extensive sickling in liver sinusoids resulting in hepatocyte ischemia. The liver involvement should urgently be recognized, when hepatomegaly, conjugated bilirubin and/or high ALT are present. RBC exchange transfusion must be performed in emergency, and is often efficient to reverse liver failure. Liver transplantation does not appear to be a good option, as observed in our experience. Additional infectious or toxic factors may be involved and should be looked for.Cholangiopathies are probably caused by chronic ischemia of the bile ducts, maybe favored by a genetic or immunological predisposition. The main complication is chronic infectious cholangitis. Liver transplantation may be discussed. Autoimmune liver diseases seem to be more frequent in SCA patients. Liver biopsy when needed should only be performed after RBC exchange transfusion. Steroid treatment should be associated with intensification of SCA treatment (HC or chronic RBC transfusion). Liver sequestration is exceptional. DisclosuresDe Montalembert:Novartis: Consultancy, Honoraria, Research Funding; Addmedica: Consultancy, Honoraria, Research Funding. Brousse:Add Medica: Membership on an entity's Board of Directors or advisory committees.

Agonistic Anti-CD40 Antibody Triggers an Acute Liver Crisis With Systemic Inflammation in Humanized Sickle Cell Disease Mice.

Sickle cell disease (SCD) is an inherited hemolytic disorder, defined by a point mutation in the β-globin gene. Stress conditions such as infection, inflammation, dehydration, and hypoxia trigger erythrocyte sickling. Sickled red blood cells (RBCs) hemolyze more rapidly, show impaired deformability, and increased adhesive properties to the endothelium. In a proinflammatory, pro-coagulative environment with preexisting endothelial dysfunction, sickled RBCs promote vascular occlusion. Hepatobiliary involvement related to the sickling process, such as an acute sickle hepatic crisis, is observed in about 10% of acute sickle cell crisis incidents. In mice, ligation of CD40 with an agonistic antibody leads to a macrophage activation in the liver, triggering a sequence of systemic inflammation, endothelial cell activation, thrombosis, and focal ischemia. We found that anti-CD40 antibody injection in sickle cell mice induces a systemic inflammatory and hemodynamic response with accelerated hemolysis, extensive vaso-occlusion, and large ischemic infarctions in the liver mimicking an acute hepatic crisis. Administration of the tumor necrosis factor-α (TNF-α) blocker, etanercept, and the heme scavenger protein, hemopexin attenuated end-organ damage. These data collectively suggest that anti-CD40 administration offers a novel acute liver crisis model in humanized sickle mice, allowing for evaluation of therapeutic proof-of-concept.

The Liver in Sickle Cell Disease

Liver involvement is found in nearly 40% of children with sickle cell disease. The most frequent complication is cholelithiasis. The most severe complication is acute hepatic crisis, with symptoms ranging from increasing jaundice to multiple organ failure and death. The emergency and mostly efficient treatment is exchange transfusion. Chronic cholangiopathy is increasingly recognized, with autoimmune features in most cases, worsened by chronic ischemia. Transfusion-related iron overload is not yet a concern in children, and hepatotoxicity of iron chelators is rare. We propose recommendations to prevent, explore, and treat these complications. We emphasize the close collaboration required between hepatologists and specialists of sickle cell disease.

Acute Hepatic Crisis in Sickle Cell Anemia: Favorable Outcome After Exchange Transfusion

Pediatric acute liver sickle crisis, also known as sickle cell intrahepatic cholestasis (SCIC), is an uncommon but fatal complication of sickle cell disease observed mainly in patients with homozygous sickle cell anemia. Herein we describe a case of pediatric SCIC treated successfully with manual exchange transfusion (ET). The patient was admitted for jaundice, enlarged liver and signs of hepatic failure, such as hyperbilirubinemia and coagulopathy. There was no evidence of viral hepatitis or biliary obstruction. We performed a session of ET in order to reduce the percentage of Hb S to level inferior to 30% which was successfully accomplished. The patient had complete recovery of hepatic function. This case has shown that ET is an effective treatment of pediatric SCIC and should be introduced early on the onset of this severe complication. J Hematol. 2016;5(4):138-141 doi: https://doi.org/10.14740/jh304w

Type 1 Tyrosinemia with Hypophosphatemic Rickets: A Case Report

Background: Tyrosinemia type 1 is an autosomal recessive metabolic disorder, which typically affects liver and kidneys. It is caused by a defect in fumarylacetoacetate hydrolase or fumarylacetoacetase (FAH) enzyme, the final enzyme in the tyrosine degradation pathway. The disease typically manifests as early onset type in early infancy with acute hepatic crisis with hepatomegaly and bleeding tendency. In 1992, a new drug orfadin (NTBC, Nitisinone) which is a potent inhibitor of 4 hydroxy phenyl pyrovate dioxygenase has revolutionized the treatment of tyrosinemia type 1 and is now the mainstry of therapy. Case presentation: Our case was a girl in midchidhood period with profound rickets and slowly progressing liver disease who presented with difficulty walking and weakness of muscles. She had an elevated serum tyrosine and urinary succinylacetone, which confirmed the diagnosis of tyrosinemia type 1 and after treatment with NTBC significant remission, was achieved.

Acute Hepatic Crisis in Children With Sickle Cell Disease

Acute Hepatic Crisis in Children With Sickle Cell Disease

Cholelithiasis in Children With Sickle Cell Disease

A group of 47 children with homozygous sickle cell disease ranging in age from 2 to 18 years was studied for the prevalence of gallstones. All of these patients had oral cholecystogram and cholecystosonogram. Eight of the 47 patients (17%) had gallstones both on oral cholecystography and on cholecystosonography. These eight patients had a history of recurrent abdominal pain usually localized to the right upper quadrant. All were admitted on several occasions for sickle cell abdominal crises and four of these were admitted for acute hepatic crisis. These patients have undergone elective cholecystectomy and gallstones were found in every patient. The patients have been followed up from seven to 17 months after cholecystectomy and none have had abdominal symptoms or required hospitalization for abdominal crises.