Homozygous sickle cell anemia, or sickle cell disease (SCD), affects an estimated 1 in 600 African American children.1 Hepatomegaly and liver biochemical abnormalities are nearly universal in affected persons; most patients have increased serum unconjugated bilirubin and aspartate aminotransferase (AST) levels as a result of ongoing hemolysis. Serum alanine aminotransferase (ALT) increases reflect hepatocellular injury, and increased serum alkaline phosphatase levels are usually of bone origin.2 A range of hepatic pathology, often referred to as sickle cell hepatopathy, may arise in patients with SCD as a result of the sickling process or the multiple blood transfusions required over their lifetimes.3
Patients with SCD commonly present with one of several acute hepatic syndromes that manifest clinically as fever, right upper quadrant pain, and jaundice. The differential diagnosis includes acute sickle hepatic crisis (ASHC), sickle cell intrahepatic cholestasis (SCIC), cholecystitis, choledocholithiasis, and acute viral hepatitis.3 Patients with ASHC typically present with increased serum AST and ALT levels up to 300 U/L and an increased serum bilirubin level up to 15 mg/dL. The syndrome, caused by hypoxic injury to hepatocytes as a result of sickling in hepatic sinusoids, is self-limited and usually resolves within 14 days after therapy with intravenous fluids and analgesics. Liver biopsy typically is not required to make the diagnosis of ASHC.4-6
By contrast, SCIC is a rare complication of SCD and carries an ominous prognosis.3, 7 The presenting clinical symptoms and signs are similar to those of ASHC, but jaundice is striking, and acute renal failure, progressive encephalopathy, coagulopathy, and death commonly result. SCIC may present as fulminant hepatic failure.8, 9 In patients with SCIC, serum AST and ALT levels are usually >1,000 U/L, and serum bilirubin increases as high as 273 mg/dL may occur because of a combination of hemolysis, renal failure, and intrahepatic cholestasis.10 The underlying pathophysiology of SCIC is also related to sickling of red blood cells within the hepatic sinusoids and consequent anoxic hepatocyte damage. Liver biopsy specimens typically show ballooning of hepatocytes, Kupffer cell hyperplasia, sickled red blood cells in hepatic sinusoids, erythrophagocytosis, intracanalicular cholestasis with bile plugs, anoxic necrosis, and varying degrees of fibrosis. Treatment is largely supportive, and vigorous exchange transfusion has been reported to be beneficial.3, 7-11
Pigmented gallstones develop in up to 58% of patients with SCD.12 Approximately 17% of patients are found to have choledocholithiasis at the time of cholecystectomy. In patients with SCD, acute cholecystitis or choledocholithiasis may be difficult to distinguish from ASHC. Because the prevalence of cholelithiasis in this patient population is so high, abdominal ultrasonography has limited specificity for diagnosing acute cholecystitis, although biliary scintigraphy may be helpful.13 Given the diagnostic difficulties, cholecystectomy should be considered in patients with SCD, gallstones, and symptoms suggestive of biliary pain or acute cholecystitis. However, cholecystectomy is not without risk in patients with SCD; the development of the potentially fatal acute chest syndrome (the constellation of dyspnea, chest pain, fever, leukocytosis, and pulmonary infiltrate caused by vaso-occlusion, infection, or fat embolism from infarcted bone marrow) has been described in up to 10% of patients with SCD who undergo elective surgery.14
Other acute liver diseases are seen with increased frequency in patients with SCD. Sickling can lead to thrombosis within the hepatic veins and the Budd-Chiari syndrome15 and to hepatic infarction, which may be complicated by pyogenic liver abscess.16 Some reports have suggested that the course of acute hepatitis A is more likely to be fulminant in patients with SCD than in those without SCD.17 Finally, hepatic sequestration crisis, in which sequestration of red blood cells within the liver leads to painful, massive hepatomegaly and a decreasing hematocrit value, has been described in patients with SCD and may be reversed with exchange transfusion.18
Chronic liver disease associated with SCD is also common. Autopsy series have revealed cirrhosis in up to 29% of patients who died of complications of SCD.3, 19 Most cases of chronic liver disease associated with SCD are thought to be the result of hepatic iron overload after numerous blood transfusions or infection by hepatitis B or C virus acquired by transfusion of contaminated blood products before the implementation of universal screening of the blood supply.20, 21 Since the implementation of universal screening of donated blood in the United States and the advent of hepatitis B vaccination, the incidence of viral hepatitis in patients with SCD is presumed to have decreased substantially. Significant iron overload may be prevented by use of exchange transfusion.3
The paper by Mekeel and colleagues22 in this issue of Liver Transplantation adds 3 cases to the growing, but limited, experience with liver transplantation in selected patients with SCD and liver failure.22 Nine cases have been reported previously.23-30 The collective experience includes 7 adults and 5 children with the spectrum of liver diseases that occur in patients with SCD (ASHC, SCIC, chronic hepatitis, cirrhosis, and iron overload) and one case of sclerosing cholangitis. The experience to date suggests that liver transplantation is a feasible option for patients with SCD and liver failure but is fraught with challenges. Chief among the potential complications is the high rate of vascular thrombosis (including graft thrombosis, stroke, and pulmonary embolism) and immunosuppression-related infections. Although no episodes of vascular thrombosis occurred in the 3 patients described by Mekeel and colleagues22 and an aggressive blood transfusion strategy has been reported to reduce the risk of postoperative complications after nontransplant surgery, graft failure from vascular thrombosis may occur after liver transplantation despite an aggressive transfusion regimen.14, 26, 31 Moreover, multiple transfusions increase the risk of infectious complications in these patients. The overall mortality rate associated with liver transplantation in patients with SCD has been approximately 60%, with no difference between adults and children.
Most disappointingly, patients with SCD who survive liver transplantation continue to experience the often painful consequences of the disease, including vaso-occlusive crises. In one of the patients reported in this series,22 recurring painful crises led to narcotic addiction and depression. The course of the disease does not appear to be affected by liver transplantation, and sickle cell hepatopathy, iron overload, and hepatitis C may recur in the graft.
Still, all 3 patients reported by Mekeel and colleagues22 survived for more than 5 years (one patient died 6 years after transplantation from a subdural hematoma after a seizure attributed to cerebral infarction), and the quality of their lives appears to have been no worse that that of nontransplanted patients with SCD. When indicated, liver transplantation is an option for patients with sickle cell hepatopathy. It would appear that candidates are patients in whom liver failure is the sole or predominant threat to survival and in whom dysfunction of other major organs, such as the heart, is absent.
Experience with liver transplantation in patients with SCD is likely to accrue slowly, and many questions will remain for a long time. Among these questions are the benefits of aggressive blood transfusions and exchange transfusion in the transplant setting; the effectiveness of therapeutic measures in reducing the risk of vascular thrombosis; and the place of living donor liver transplantation in this population (for whom the donor is likely to have sickle trait) and the role, if any, of combined bone marrow and liver transplantation. (Although bone marrow transplantation can cure SCD, it has rarely been performed for SCD because of the variable natural history of the disease.) Incremental progress will depend on the willingness of transplant programs to report cases and small case series in the literature, regardless of outcome. An international registry would be helpful.
