Sickle cell disease (SCD) is one of the most common genetic diseases in the world (1,2). The liver involvement is frequent, but often thought to be limited to biliary lithiasis. Gallstones are indeed frequent and can cause significant complications, but acute and chronic liver disease, with the generic name of “sickle cell hepatopathy,” is increasingly recognized as responsible for severe symptoms, even death (3–7). The misdiagnosis of cholestatic jaundice may delay the emergency treatment of an acute hepatic crisis with exchange transfusion, leading to potentially irreversible multiorgan failure (8,9). In children, the risk of death is unknown, as isolated cases only were reported, or the cause of death could have gone unrecognized (10). In adults, 7% of patients died of liver failure in a recent series (11).
Chronic biliary disease is the second more severe complication, due to a conjunction of chronic ischemia and immune-mediated damage, maybe associated with a genetic susceptibility. Iron overload due to repeated blood transfusions, and hepatotoxicity especially from iron chelators, are also concerns, although rare in childhood. Blood-transmitted hepatitis B and C are rare in the Western world, but remain important comorbidities in low-income countries.
In our large recent series of more than 600 children with SCD (7), approximately 40% had a history of liver or biliary complication. A close collaboration between SCD specialists and pediatric hepatologists is mandatory to avoid the dramatic evolution of misdiagnosed acute hepatic crises, or to diagnose and properly manage cholangiopathy or autoimmune liver disease (Table 1).
TABLE 1 -
Classification of hepatobiliary complications in sickle cell disease
||Asymptomatic gallstones (gallbladder)
||Pain from gallstone migration
||Autoimmune sclerosing cholangitis
| Sickle cell trapping in sinusoids, liver hypoxemia
||Acute sickle cell hepatic crisis
||Sickle cell intrahepatic cholestasis
||Acute hepatic sequestration
| Autoimmune liver disease
||Autoimmune sclerosing cholangitis
| Iron overload
| Drug toxicity: chelator
| Posttransfusion viral hepatitis B or C
SCD is due to the presence of abnormal hemoglobin S (HbS), either homozygous (HbSS) or combined with another abnormal hemoglobin, C or β-thalassemia. HbS makes the erythrocytes prone to premature hemolysis. This delivers a high bilirubin load to the bile, unbalancing its content with insoluble bilirubin, which precipitates to form gallstones.
HbS polymerizes on deoxygenation, inducing a shape change of erythrocytes. “Sickled” erythrocytes clog up the small vessels, arterioles, or sinusoids, with subsequent ischemia, inflammation, endothelial dysfunction, and reperfusion injury. Sinusoidal obstruction is worsened by Kupffer cell erythrophagocytosis and hyperplasia. Hepatocyte ischemia induces ballooning and intracanalicular cholestasis (Fig. 1). Impaired bile secretion and altered bile acid pool secondary to sustained inflammation have recently been demonstrated in animal models (12). Direct damage to the endothelium of sinusoids and central veins, like in sinusoidal obstruction syndrome, has also been postulated, explaining the sinusoidal and centrilobular fibrosis (13,14). Vascular obstruction may also cause red cell and platelet trapping, called “sequestration,” in the liver or the spleen.
Depending on the degree of ischemia, trapping, and cholestasis, the crises present as liver failure, sequestration, or intrahepatic cholestasis. This is probably a spectrum of the same phenomenon, which prompts the emergency replacement of sickle cells to relieve ischemia. Recurrent crises and subsequent ischemia are responsible for fibrosis, nodular regenerative hyperplasia, and cirrhosis, contributing to the chronic debilitating disease of adults with SCD (3,4,11).
The origin of cholangiopathy in SCD is multifactorial. The bile ducts receive blood from terminal arterial branches in the peribiliary plexus, where sickling and chronic hypoxemia could favor the formation of strictures. Dilation of bile ducts was found in one fourth of young adults with cholestatic jaundice (15). It seems also that autoimmune diseases are more frequent in SCD (16,17): autoimmunity is a main major factor of cholangiopathy in our experience, with a relatively common diagnosis of primary sclerosing cholangitis or autoimmune sclerosing cholangitis. Other genetic susceptibilities, such as polymorphisms in the MDR3 gene (18), may also be cofactors.
Gallstones are found in at least 25% of children after 5 years of age (7,10,19). More than half of them are incidentally discovered on protocol ultrasound. Complications may, however, arise, especially pain, in one third of patients. Cholecystitis, cholangitis, and pancreatitis are rare (probably <10% of patients with gallstones) but potentially severe (19–21). Endoscopic retrograde cholangiopancreatography is discussed in emergency, with the necessary preparation for all procedures in SCD, if gallstones are obstructive.
Elective cholecystectomy is recommended by some experts, even for asymptomatic gallstones, based on the morbidity of emergency surgery (22). It has to be balanced against the low rate of severe complications of lithiasis, and the persistent risks of anesthesia and preoperative transfusion in these patients (19,23). Gallstones may develop, albeit rarely, in intrahepatic ducts after cholecystectomy. Ursodeoxycholic acid is useless, as it dissolves cholesterol gallstones, and not the pigment stones of SCD.
ACUTE SICKLE CELL HEPATIC CRISIS, SICKLE CELL INTRAHEPATIC CHOLESTASIS, AND ACUTE HEPATIC SEQUESTRATION
These are the more severe liver complications of SCD, observed in about 6% of children and 10% of adults (3–8,11).
Acute sickle cell hepatic crisis presents as an acute right abdominal pain, often associated with hepatomegaly, and increased jaundice with dark urines. Alanine aminotransferases (ALTs) are elevated (aspartate aminotransferases present in erythrocytes are increased with hemolysis), as well as conjugated bilirubin. Sickle cell intrahepatic cholestasis is the severe variant of hepatic crisis, with liver failure and coagulopathy, which can rapidly lead to multiorgan failure.
In acute hepatic sequestration, the liver size increases suddenly and painfully, together with an acute decrease in hemoglobin level (>2 g/dL), and sometimes thrombocytopenia. When it is associated with increased transaminases, conjugated bilirubin, and liver failure, it can be considered a variant of acute hepatic crisis.
Acute sickle cell hepatic crises can arise together with other complications such as acute chest syndrome or abdominal crises, and this could be misleading. First-line physicians should be regularly reminded that conjugated bilirubin is a sign of liver disease, clinically associated with dark urines, and that both total and conjugated bilirubin levels should be monitored, especially in children with increased jaundice.
Hepatic crises can develop despite monthly exchange transfusions. The percentage of HbS during severe hepatic crises can be <30%, and is not diagnostic.
Acute liver failure often presents with coagulopathy, encephalopathy, hyperammonemia, and renal failure. In our experience, the emergency correction of liver anoxia with exchange transfusion can reverse even an extremely severe condition, with complete recovery in a few days. Exchange transfusion by erythrocytapheresis more efficiently decreases HbS percentage, faster restoring the blood flow than simple transfusion. Hemodialysis should be performed as needed to correct the renal function and ammonia level. In some cases, the role as a co-factor of the iron chelator deferasirox, known to induce hyperammonemia, is debated (7,24), and it should be immediately suspended.
We thus recommend an urgent exchange transfusion, as soon as a diagnosis of biliary complication is excluded, if the prothrombin time is abnormal (<65% or international normalized rate—>1.4) with increased conjugated bilirubin and ALT, and also if the coagulation is normal but conjugated bilirubin is >50 μmol/L (3 mg/L). Simple transfusion should be discussed in other cases. Urgent red cell transfusion is also indicated in pure hepatic sequestration, cautiously to avoid a rapid release of the trapped sickled cells and subsequent stroke.
CHOLANGIOPATHY AND AUTOIMMUNE LIVER DISEASES
Cholangiopathy is rare in our experience (1% of children), but it is the second most severe complication, prompting in some cases discussion of liver transplantation. In another series, autoimmune sclerosing cholangitis was diagnosed in 8% of children with SCD referred for hepatic dysfunction (16). Abnormal bile ducts with stenosis and dilations are seen on ultrasonography and magnetic resonance (MR) cholangiography. Gammaglutamyltransferase (GGT) is usually elevated, more than ALT. Antineutrophil cytoplasmic antibodies (ANCA) are often found, making together with the MR findings the diagnosis of primary sclerosing cholangitis. If neither ANCA nor other autoantibodies, such as antinuclear antibodies (ANAs) or antismooth muscle antibodies (SMAs), are found, the cholangiopathy would better be called ischemic (15,25,26). The biliary disease can be unusually early and severe, complicated with gallstones and cholangitis, maybe because immune-mediated biliary strictures are worsened by the chronic hypoxemia. The treatment with ursodeoxycholic acid can improve the liver tests, without changing the evolution (27). Endoscopic or percutaneous treatment of major strictures, drainage, and ultimately liver transplantation, may have to be discussed. An associated inflammatory bowel disease should be screened and treated, with biologicals if needed.
Autoimmune hepatitis is diagnosed when ANA or SMA (rarely anti-liver-kidney microsomes antibodies) are found together with abnormal liver tests (16,17). Bilirubin and ALT are usually very elevated as well as gammaglobulins. When biliary lesions are also present on MR cholangiography, the disease is called autoimmune sclerosing cholangitis. Misdiagnosis with a sickle cell intrahepatic cholestasis can lead to a delay in the specific treatment with steroids. A liver biopsy should be performed, to show the typical lymphoplasmacytic portal inflammation and interface hepatitis, always associated with the lesions of SCD, sinusoidal dilation, sickled red cells, perisinusoidal fibrosis, and hemosiderosis (14,16,28). Liver biopsy is a dangerous procedure in SCD, which cannot be performed without at least a transfusion (29). Steroids can induce sickle crises, and exchange transfusions could have to be regularly performed (16,30). Alternative treatments such as calcineurin inhibitors may be discussed.
As the incidence of autoimmune diseases, especially liver and inflammatory bowel diseases, is increasing worldwide (31), more cases will probably be diagnosed in SCD, as we are recently experiencing.
IRON OVERLOAD AND TOXICITY OF CHELATORS
Transfusion-related liver iron overload is diagnosed on an increased ferritin level with MRI-measured liver iron content of >3 mg iron per gram of dry weight. It is not usually a significant concern in children, and is rarely responsible for elevated liver tests. In our patients, the median ferritin level was about 3000 ng/mL, and none had a severe overload on MRI, or cardiac involvement (32). An autopsy series of relatively young adults, however, found 11% with cirrhosis, iron overload being present in nearly half of them, whereas it was absent in those without cirrhosis (33).
Iron chelation is thus necessary. With deferasirox, the most frequently used oral chelator, increased ALTs are reported in 1% to 2% of children (34). As said supra, the responsibility of deferasirox in acute liver failure is debated (7,24), as many patients who developed severe hepatic crises were on regular exchange transfusions and chelation because of a severe phenotype. The experience with the other oral chelator deferiprone is scarce in SCD. The subcutaneously delivered deferoxamine has no liver toxicity.
The discussion of liver transplantation in SCD is difficult. About 40 cases were reported in both adults and children, results are poor, continuation of exchange transfusions mandatory, and long-term evolution uncertain. The largest recent positive experience is in 9 adults with chronic liver disease, 7 of them alive 5 years after transplantation (35). The outcomes are generally worse in acute liver failure, 5 of 12 adults surviving long term in the same recent series: we emphasize that the urgent and most often efficient treatment in this condition is exchange transfusion, whatever the level of HbS. In our experience, liver transplantation is a difficult procedure, which should be performed only in specialized units for both SCD and transplantation, with facilities for exchange transfusion any time. Sickle crises can relapse, especially in the transplanted liver. Drug toxicity may add to the neurological and renal morbidities of SCD. Exchange transfusions should be maintained together with iron chelators, preferably deferoxamine.
STEM CELL TRANSPLANTATION
Stem cell transplantation is discussed in patients with a genoidentical donor and severe complications of SCD, including severe or repeated hepatic crises and cholangiopathy. Beside SCD, it could probably control autoimmune disorders. Conditioning drugs are hepatotoxic, and the discussion should take place before the development of severe fibrosis precluding the procedure. A liver biopsy (after exchange transfusion) should be performed in patients with liver disease, to evaluate the extent of lesions and prepare for the frequent liver complications of stem cell transplantation.
Liver tests (mainly ALT, gammaglutamyltransferase, and total and conjugated bilirubin) should be performed twice a year, and abdominal ultrasonography yearly from age 5. Liver MRI for liver iron content measurement should be performed yearly in children older than 5 years on a monthly transfusion program.
In acute conditions (Fig. 2), liver tests are not discriminant for the cause but useful for monitoring. In case of acute abdominal pain and elevated liver tests, ultrasound should rule out a complication of gallstones, coagulation should be monitored, and tests for viral hepatitis obtained (cytomegalovirus; Epstein-Barr virus; and hepatitis A, E and B). Hepatotoxic drugs, such as deferasirox, should be suspended. An abnormal coagulation profile (international normalized rate >1.4, or prothrombin time <65%) should indicate exchange transfusion. Causes of acute liver failure unrelated to SCD should also be suspected, especially if the patient does not improve, such as autoimmune hepatitis (other autoimmune conditions in the patient or relatives ?) or fulminant Wilson disease.
In chronic conditions (Fig. 3), ultrasonography looks for bile duct dilation. In patients with dilated bile ducts, MR cholangiography should be performed and autoantibodies for autoimmune liver diseases screened (ANA, SMA, anti-liver-kidney microsomes antibodies, ANCA). A liver biopsy is discussed if they are present (cf supra). If autoantibodies are not found, an endoscopic retrograde cholangiopancreatography should be discussed to look for an obstruction not seen on MRI. If the bile ducts are not dilated, tests for other liver diseases should be obtained: chronic viral hepatitis (B, C, E), autoimmune liver diseases, Wilson disease, and alpha-1-antitrypsin deficiency. If the patient is treated with hepatotoxic drugs such as an iron chelator, suspension and challenge should be discussed. It should also be inquired about herbal medicine and recreative drugs. Clinically asymptomatic gallstones should not modify the liver tests. Depending on the apparent severity of liver disease and the diagnostic suspicion, a liver biopsy could be discussed.
Acute and chronic liver complications are frequent in SCD. A close collaboration between specialists is mandatory, and all procedures, such as biopsy or surgery, should be discussed together and adequately prepared. Emergency exchange transfusion is the treatment of severe acute hepatic crisis, together with supportive care as needed. Liver transplantation is exceptionally performed, with many difficulties. If stem cell transplantation is feasible, it should be discussed early, after either a severe hepatic crisis, or the diagnosis of a chronic liver disease, before the development of significant fibrosis. We should be aware that more cases of autoimmune liver diseases will probably be observed in children with SCD.
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