Please refer to the medical glossary (Appendix 1).
Description of the condition
Sickle cell disease (SCD) is an inherited condition and the most common hemoglobinopathy occurring worldwide (Ballas 2010; Ballas 2012; Orkin 2010; Rees 2010; Weatherall 2011). The sickle hemoglobin is an abnormal hemoglobin due to a point mutation of the β globin gene resulting in the substitution of glutamic acid by valine at position 6 of the β globin polypeptide chain (Ballas 2011; Ballas 2012).
According to the WHO, SCD is a major public health problem (WHO 2006; Modell 2008) with an estimated 70% of sufferers living in Africa (Makani 2007). It is common among people with sub-Saharan African, Indian, Middle Eastern or Mediterranean ancestry (Creary 2007; Modell 2008). The term SCD includes sickle cell anaemia (Hb SS), haemoglobin S combined with haemoglobin C (Hb SC), haemoglobin S associated with ß thalassemia (Sß0 Thal and Sß+ Thal) and other less prevalent double heterozygous conditions which cause clinical disease (Steinberg 2009; Weatherall 2006). Haemoglobin S combined with normal haemoglobin (A) is known as the sickle cell trait (AS), which is generally asymptomatic and is not part of this review. Recently, the clinical history and other aspects of SCD have been reviewed (Mousa 2010; Nikhar 2011; Prabhakar 2010; Serjeant 2010).
The disease affects the hepatobiliary system (Ballas 2012; Ebert 2010), with recurrent ischemia and bilirubin stones resulting from vascular obstruction and red cell hemolysis of the sickle cell (Ballas 2012). Acute pain in the right upper quadrant is common in patients with SCD and described as right upper quadrant syndrome (Ballas 2012). This syndrome must be separated from the more common symptoms of SCD, i.e., hepatic crisis, hepatic sequestration, autoimmune hepatitis, viral hepatitis, hepatic siderosis, sickle cell intrahepatic cholestasis or sickle cell hepatopathy, cholelithiasis, biliary sludge, choledocholithiasis, acute cholecystitis, and chronic cholecystitis (Ballas 2012). Hepatic sequestration is a component of the right upper quadrant syndrome and it is best diagnosed by a rapid enlargement of the liver with a concurrent drop in hemoglobin concentration. Furthermore, the bilirubin will also be elevated, with a high percentage of direct bilirubin (Ballas 2012).
Sickle cell intrahepatic cholestasis or sickle cell hepatopathy is a hepatic complication long recognized in people with SCD (Ballas 2012). The cholestatic liver diseases are uncommon conditions characterized by impaired formation or excretion (or both) of bile from the liver. Biochemical abnormalities, including elevation of alkaline phosphatases, total bilirubin, and g-glutamyl transpeptidase, typically precede the development of jaundice (Carey 2012). Fatigue and pruritus are the most common symptoms associated with cholestasis (Carey 2012).
Controversy exists regarding the definition of sickle cell intrahepatic cholestasis or sickle cell hepatopathy. One definition is of a serum bilirubin level greater than 13 mg/dl without evidence for viral hepatitis or extrahepatic obstruction due to gallstones or hepatic sequestration (Ahn 2005). In contrast to this, it has been suggested that sickle cell intrahepatic cholestasis is a condition with marked hyperbilirubinemia (> 50 mg/dL) and a high fraction of direct (conjugated) bilirubin (approximately 50%) (Ballas 2012). Characteristic features include hepatomegaly, extreme total hyperbilirubinemia, coagulopathy, and acute liver failure (Shao 1995).
Sickle cell intrahepatic cholestasis is an uncommon but potentially fatal complication with a high death rate (Brunetta 2011; Khan 2011). The disease is caused by diffuse sickling within the hepatic sinusoids that ultimately leads to hypoxic hepatic damage and acute hepatic failure (Khan 2011). Liver biopsies of these patients show erythrocytosis, erythrophagocytosis, sinusoidal dilatation and hyperplasia in Kupffer cells (Johnson 1985; Omata 1986; Savafi 2006). Furthermore, sickle cell intrahepatic cholestasis is associated with an increased risk of pericardial tamponade (Khurshid 2002), and renal failure (Khan 2011). Older age and underlying hepatic disease have been suggested as poor prognostic factors for sickle cell intrahepatic cholestasis in adults (Costa 2006). The differential diagnosis of sickle hepatopathy includes viral hepatitis and extrahepatic obstruction due to choledocholithiasis. Both of these conditions may have similar clinical and laboratory findings to sickle hepatopathy (Ahn 2005).
Currently, there are no standard diagnostic criteria, nor is there a generally accepted therapeutic approach for this condition (Ahn 2005).
Description of the intervention
1. Simple red blood cell transfusion
2. Exchange transfusion. Red cell exchange or erythrocytapheresis is the most frequently recommended intervention for treating intrahepatic cholestasis in patients with SCD (Chitturi 2002; Costa 2006; Danielson 2002; Horn 1987; Karunatilake 2009; O'Callaghan 1995; Sheehy 1980; Tiftik 2004). In 1980, Sheehy and colleagues pioneered the use of this procedure in SCD (Sheehy 1980). This Cochrane Review will use exchange transfusion as the term for this procedure.
In exchange transfusion the patient’s red cells are removed and replaced by exogenous normal red cells. The aim is to raise the level of hemoglobin A to between 60% and 70% while lowering the level of hemoglobin S to 30% and reverse bilirubin levels to normal values (Delis 2006; Donghaile 2013). This procedure can be carried out manually or mechanically (Kleinman 1984).
2. Liver transplantation
Several pharmacological therapies have been used to treat patients affected by intrahepatic cholestasis in other clinical settings (Angulo 2000; Azzaroli 2011; Carey 2012; Geenes 2009; Muriel 2008). This Cochrane Review will include interventions for treating cholestasis-associated pruritus: bile acid-binding resins, i.e., cholestyramine, colestipol, rifampin, opiate antagonists (naltrexone and nalmefene), sertraline, dexamethasone, gar gum, and activated charcoal. Hydroxyurea will also be included as a pharmaceutical intervention for this condition.
How the intervention might work
Simple red blood cell transfusion increasing the hemoglobin and hematocrit levels.
Exchange transfusion prevents the removed sickle cells from participating in new vaso-occlusive events, reduces hemolytic complications, and provides added oxygen carrying capacity while decreasing the blood viscosity (Swerdlow 2006). Red cell exchange also rapidly decreases the rate of hemolysis, which can decrease liver processing of bilirubin, damage to renal tubular cells and the scavenging of nitric oxide by free hemoglobin released from sickle cells (Akinsheye 2010; Donghaile 2013; Kato 2007; Morris 2008).
Liver transplantation is a transient therapy approach; however, it does not resolve the fundamental issue.
For treating cholestasis-associated pruritus, bile acid-binding resins (cholestyramine, colestipol, rifampin, opiate antagonists (naltrexone and nalmefene), sertraline, dexamethasone, gar gum, and activated charcoal) have the ability to bind biliary acids in the gut lumen and block their absorption (Azzaroli 2011; Carey 2012). However, there is potential for these agents to interfere with the absorption of other medications (Carey 2012). Opiate antagonists reduce the increased level of opioidergic tone associated with cholestatic pruritus.
Why it is important to do this review
While exchange transfusion is used for treating intrahepatic cholestasis in people with SCD, there appears to be no specific evidence supporting this medical approach. Exchange transfusion requires packed red blood cell units which are pre-storage leukoreduced in order to prevent febrile non-hemolytic reactions and which are screened for sickle cell traits to avoid transfusing red cells containing hemoglobin S (Sarode 2006). Due to a discrepancy of red cell antigens between African-Americans and Caucasians (majority blood donors), the incidence of alloantibody formation is very high, which makes it difficult to find compatible red cell units, especially for urgent red cell exchange (Sarode 2006). Therefore, this requires a concerted effort between the apheresis unit, the local blood bank, and the central blood supplier (Sarode 2006). Therapeutic apheresis is a relatively safe procedure; however, it is associated with adverse events. These include hypocalcemia due to citrate; increased frequency of bleeding complications and heparin-induced thrombocytopenia associated with heparin anticoagulation; urticarial reactions to the protein-containing replacement fluid; depletion coagulopathy and immunoglobulin depletion; catheter-related trauma; clotting; infection; and bleeding (Kaplan 2012; Lee 2012).
The benefits and harms of liver transplantation should be assessed in this clinical setting (Baichi 2005; Emre 2000).
Furthermore, clinical effectiveness and safety of the several pharmacological therapies used to treat intrahepatic cholestasis in other clinical settings should be reviewed in patients with SCD affected by this hepatic disorder.