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.