Hepatic manifestations of sickle cell disease

INTRODUCTION — Sickle cell disease (SCD) encompasses a group of hemoglobinopathies characterized by a single amino acid substitution in the beta-globin chain. The most frequently occurring form of SCD is sickle cell anemia (HbSS), followed by sickle-hemoglobulin C (HbSC) and sickle-beta (HbS/beta)-thalassemia. In SCD, the majority of the hemoglobin (greater than 50 percent) is hemoglobin S. Sickle cell trait (HbSA) is not considered SCD. (See "Hemoglobin variants including Hb C, Hb D, and Hb E".)

The liver can be affected by a number of complications due to SCD. In addition to the vascular complications from the sickling process, patients with SCD have often received multiple transfusions, placing them at risk for viral hepatitis, iron overload, and (combined with the effects of chronic hemolysis) the development of pigment gallstones, all of which may contribute to the development of liver disease. (See "Epidemiology and transmission of hepatitis C virus infection", section on 'Blood transfusion' and "Epidemiology, transmission, and prevention of hepatitis B virus infection", section on 'Transfusion' and "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Excessive iron stores'.)

The term "sickle cell hepatopathy" has sometimes been used to reflect the overlapping causes of liver dysfunction in individuals with SCD, not SCT. Sickle cell hepatopathy occurs predominantly in patients with homozygous sickle cell anemia, and to a lesser extent in patients with HbSC disease or HbS/beta-thalassemia.

This topic will review the hepatobiliary manifestations of SCD. Related topics on SCD are discussed separately:

•Clinical manifestations – (See "Overview of the clinical manifestations of sickle cell disease".)

•Diagnosis – (See "Diagnosis of sickle cell disorders".)

•Laboratory methods – (See "Methods for hemoglobin analysis and hemoglobinopathy testing".)

•Management – (See "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance" and "Overview of the management and prognosis of sickle cell disease".)

Sickle cell trait (generally a benign carrier state) is also discussed separately. (See "Sickle cell trait".)

EPIDEMIOLOGY — The incidence of liver disease in patients with sickle cell disease (SCD) has not been well established due to the lack of prospective studies. Traditionally, the major risk factor for liver disease in individuals with SCD is receiving multiple blood transfusions. Liver disease is attributed to bloodborne infections, particularly hepatitis B virus (HBV) infection and hepatitis C virus (HCV) infection, coupled with excessive iron stores from blood transfusions. With the decreased incidence of transfusion-related HBV and HCV infection to approximately one in two million transfusions and with routine HBV vaccination, the epidemiology of liver disease for children and young adults with SCD has likely evolved over time but has not been well studied [1]. In addition, literature published over 20 years ago on liver disease in SCD may not reflect the changes in epidemiology.

LABORATORY AND RADIOLOGIC LIVER TESTS — Biochemical and radiologic liver abnormalities are common in individuals with sickle cell disease (SCD). A major risk factor for liver biochemical abnormalities in patients with SCD is infection (hepatitis B virus [HBV] infection or hepatitis C virus [HCV] infection) or excessive iron stores related to multiple blood transfusions. (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Excessive iron stores'.)

Biochemical tests — Elevated bilirubin levels, predominantly unconjugated, are universal in patients with SCD due to chronic hemolysis. Total bilirubin concentrations are usually <6 mg/dL (102.6 micromol/L), but may double during sickle hepatic crises [2]. In one series, 72 of 100 patients with sickle cell anemia had an isolated elevation of bilirubin, with no other clinical or laboratory evidence of liver disease [3]. Bilirubin levels correlated with lactic dehydrogenase levels, suggesting that variable levels found in patients are related to the degree of hemolysis, ineffective erythropoiesis, or both, rather than to disorders of bilirubin transport or processing. Similarly, aspartate transaminase (AST) levels are elevated due to intravascular hemolysis. AST levels correlate with lactic dehydrogenase levels, another biomarker associated with hemolysis, while serum alanine aminotransferase (ALT) levels may more accurately reflect hepatocyte injury [3]. Generally, AST and ALT levels are less than 100 units/L in individuals with SCD [4]. In a study of 330 individuals with SCD, the increases in AST levels were higher compared with ALT levels. The AST to ALT ratio was >1 in approximately 96 percent of patients but without evidence of liver disease [5].

Elevation of the serum alkaline phosphatase is common, particularly during pain crises [4]. However, bone alkaline phosphatase is the major enzyme fraction contributing to this rise [6]. This is supported by the observation that the serum-5' nucleotidase concentration correlates with the ALT and gamma glutamyl transferase levels, but not with alkaline phosphatase levels [7]. (See "Enzymatic measures of hepatic cholestasis (alkaline phosphatase, 5'-nucleotidase, gamma-glutamyl transpeptidase)".)

Acute elevations of the serum ALT and AST are seen in the setting of vaso-occlusive episodes leading to hepatic ischemia, whereas chronic liver function test abnormalities are usually due to coexisting hepatic pathology. In a study of 130 patients with sickle cell anemia or SCD, chronic abnormalities in liver function tests were found in 32 patients [3]. In 30 of these patients, the abnormalities could be explained by coexisting liver pathology, including chronic hepatitis B virus infection, common bile duct obstruction, and alcohol use. Only two patients had unexplained abnormalities, neither of whom had been tested for HCV antibodies. In another series of 121 patients with sickle cell anemia, 11 (9 percent) had chronically raised ALT levels. Of these, nine patients were positive for HCV antibodies, and one patient was positive for hepatitis B surface antigen (HBsAg) [8].

Several studies have demonstrated low protein C and protein S levels in patients with sickle cell anemia [9-11]. It is unclear whether decreased levels of protein C and S were primarily due to decreased hepatic production, or were a consequence of increased consumption. Low levels of protein C and S may increase the risk of stroke [11]. (See "Protein C deficiency".)

Liver histology — Percutaneous liver biopsy has been associated with serious complications when performed in individuals with SCD and acute liver disease [12]. Liver biopsy performed in patients with acute sickle cell hepatopathy has been associated with a high rate of significant bleeding, with mortality noted in 80 percent of affected patients [12]. Thus, the risk-benefit ratio of obtaining liver histology must be strongly considered, particularly in light of how the results will alter management. In addition, noninvasive alternatives to liver biopsy are available, including magnetic resonance imaging (MRI) to quantify hepatic iron and elastography to determine liver stiffness as a surrogate of liver fibrosis. (See 'Imaging tests' below.)

To assess positive net balances of iron, we perform MRI-based estimates of liver iron content; this approach is consistent with guidelines from the American Society of Hematology [13].

Serious complications are less common when liver biopsy is performed in the absence of sickle cell crises. In a series of 132 liver biopsies performed in 106 patients who were at least 14 days beyond a sickle cell crisis, serious complications occurred in two patients (2 percent), whereas pain and a drop in hemoglobin were more commonly reported (25 and 10 percent, respectively) [14]. There were no procedure-related deaths. One patient had significant hepatic bleeding requiring embolization, and one patient developed a bile duct injury requiring endoscopic retrograde cholangiopancreatography for biliary drainage.

Liver histology can be used to determine hepatic iron content and the variation in liver iron concentration based on measurement from multiple needle biopsy specimens [15,16].

When obtained, liver histology may reflect changes of concurrent chronic viral hepatitis, cholestasis due to common bile duct stones, and features primarily due to the sickle cell anemia itself. Histologic features due to sickle cell anemia include intrasinusoidal sickling with proximal sinusoidal dilatation, Kupffer cell hyperplasia with erythrophagocytosis, and hemosiderosis [17-21]. The following findings were observed in a postmortem series of 70 patients [17]: sinusoidal red blood cell distension (71 percent), Kupffer cell erythrophagocytosis (91 percent), iron deposition (47 percent), focal necrosis (35 percent), portal fibrosis (20 percent), regenerative nodules (20 percent), and cirrhosis (16 percent).

Other histologic features may reflect the clinical setting. Mild centrilobular necrosis has been described in patients with sickle hepatic crises [2]. Widespread anoxic necrosis was seen in two postmortem biopsies in patients with sickle cell intrahepatic cholestasis [2,22]. Other findings that may be seen on liver biopsy include perisinusoidal fibrosis, peliosis hepatis [23], and extramedullary erythropoiesis [24].

The degree of intrasinusoidal sickling does not correlate with the serum aminotransferase concentrations [3,21,25]. Sickling observed in liver biopsy specimens may result from fixation with formaldehyde, which in one study increased the sickle cell count from a mean of 12 to 48 percent [3]. We do not assign any clinical relevance to the sickle cell count.

The relationship between liver fibrosis and excessive iron stores has not been well defined. In a retrospective study in individuals with SCD who were receiving regular blood transfusion therapy over a median of 8.4 years (range 2.3 to 24 years), predictors of liver fibrosis were assessed [26]. A total of 26 individuals had at least two liver biopsies, with an average of two years between the first and second biopsy. Each biopsy was scored for fibrosis in a blinded fashion. The primary outcome was assessment of changes in liver fibrosis. Liver fibrosis was rated as grade 0 or 1 in all biopsies. Between the first and second biopsy, there was fibrosis regression in six individuals, development of fibrosis in two patients, persistent fibrosis in one patient, and absence of fibrosis in 17 patients. No association between fibrosis and liver iron content was observed.

Eight individuals had MRI assessment of liver iron content within three months of a liver biopsy. Liver iron content in these individuals did not have any correlation with liver fibrosis. Although this retrospective study has limitations, these data suggest that natural history and risk factors for fibrosis in individuals with SCD receiving regular blood transfusions are poorly defined [26].

Imaging tests — Imaging tests are frequently abnormal in patients with SCD.

Computed tomography — Computed tomography (CT) scanning in patients with HbSS usually reveals diffuse hepatomegaly, possibly a reflection of expansion of the hepatic reticuloendothelial system. The spleen is usually small and atrophic and may have dense calcifications, often due to repeated splenic infarction. Compound SCD heterozygotes (ie, HbSC and HbS beta-thalassemia) usually have splenomegaly and may have infarcts, splenic rupture from extensive infarction and necrosis, hemorrhage, abscess, and acute splenomegaly due to sequestration. A CT scan of the abdomen may also incidentally reveal basal pulmonary pathology, especially in patients presenting with abdominal pain. (See "Overview of the pulmonary complications of sickle cell disease".)

Magnetic resonance imaging — Given the advancement in the use of MRI methods to evaluate liver iron, MRI's reliability, and its noninvasive nature, MRI imaging has become the standard approach for assessing liver iron stores in individuals with SCD who are chronically transfused [27]. Many centers use commercial software to quantify liver iron stores, particularly in such patients. MRI in transfusion dependent patients usually shows decreased signal intensity in the liver and pancreas due to iron deposition [28-31]. (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Excessive iron stores'.)

Ultrasound — Abdominal ultrasound in individuals with SCD is likely to reveal gallstones and increased echogenicity of the liver and pancreas due to iron deposition [29].

Transient elastography — Transient elastography can be useful for evaluating liver stiffness as a marker of hepatic fibrosis. However, we avoid obtaining transient elastography in patients with pain related to an acute vaso-occlusive episode, because liver stiffness measurements (LSM) are increased during such episodes [32].

Cutoff values for diagnosing fibrosis by transient elastography in patients with SCD vary among studies and patient populations [32-34]. In a study including 50 adults with SCD that correlated transient elastography with liver histology, the median LSM in minimal fibrosis was 4.8 kPa and the median LSM in advanced fibrosis was 17.6 kPa [34]. In a study comparing transient elastography with liver histology in 19 children and young adults with SCD, the normal LSM ranged from 4 to 5 kPa, whereas patients with a value of >10 kPa were likely to have liver fibrosis [33].

DISORDERS ASSOCIATED WITH THE SICKLING PROCESS — Liver disease in individuals with sickle cell disease (SCD) can be conceptually divided into disorders caused by the sickling process, and those resulting from complications of the disease or its treatment [35]. However, the distinction between these two categories is not always clear because they often exist concurrently. Furthermore, studies describing liver disease in this population often omitted secondary causes of liver disease such as hepatitis C virus infection. Thus, the relative contribution of these coexisting conditions to the clinical presentation has not always been clear.

Acute pain and jaundice — Acute presentation with pain and jaundice may be due to several different causes that may coexist. These include acute sickle hepatic crisis, sickle cell intrahepatic cholestasis, acute viral hepatitis, cholecystitis, and choledocholithiasis with common bile duct obstruction. The diagnosis can usually be established by the medical history and specific laboratory and radiologic testing.

Acute sickle cell hepatic vaso-occlusive episode — Acute sickle cell hepatic vaso-occlusive pain has been observed in approximately 10 percent of adult patients with SCD [2,36,37]. Patients usually present with acute right upper quadrant pain, nausea, low grade fever, tender hepatomegaly, and elevated bilirubin levels, predominantly conjugated fraction [2,36,37]. The serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations are seldom >300 units/L [2,37], although levels >1000 units/L have been described [19]. The serum total bilirubin concentration is usually <15 mg/dL (256.5 micromol/L) [2]. Liver histology may reveal sickle cell thrombi in the sinusoidal space with engorgement by red blood cells. Other features that have been described include Kupffer cell hypertrophy, mild centrilobular necrosis, and occasional bile stasis [2].

Supportive treatment with intravenous hydration and analgesia is usually sufficient for hepatic vaso-occlusive pain events. Symptoms and laboratory abnormalities usually resolve within 3 to 14 days.

In children with SCD, hepatic crisis is typically a self-limiting course recognized with total bilirubin levels as high as 57.6 g/dL with 50 percent being fractionated.

Sickle cell intrahepatic cholestasis — Sickle cell intrahepatic cholestasis represents a severe variant of sickle cell hepatic crisis. It is due to disseminated vaso-occlusion in the sinusoids, with hepatic ischemia and a possible evolution towards multiple organ failure [38]. Hypoxic damage leads to ballooning of hepatocytes and intracanalicular cholestasis.

The presentation is initially similar to that seen with acute sickle hepatic crises, with right upper quadrant pain, nausea and vomiting, fever, tender hepatomegaly, and leukocytosis. However, striking jaundice then develops, accompanied frequently by kidney impairment, a bleeding diathesis, and increasing encephalopathy.

In various reports, serum ALT levels have ranged from 34 to 3137 units/L, serum AST levels from 100 to 9881 units/L, and alkaline phosphatase levels have ranged from normal to 860 units/L. Total serum bilirubin levels may be strikingly high; levels of up to 273 mg/dL (4668.3 micromol/L) have been observed [39]. In most cases, the conjugated fraction exceeds 50 percent of the total bilirubin [40]. The extremely high bilirubin levels are due to a combination of ongoing hemolysis, intrahepatic cholestasis, and kidney impairment. Lactate dehydrogenase levels are usually elevated in the range of 660 to 7760 units/L. Prolongation of the prothrombin and partial thromboplastin time is common. Elevations in blood urea, creatinine, and ammonia are also seen. Hypofibrinogenemia, thrombocytopenia, and lactic acidosis may accompany liver failure [39].

Postmortem liver biopsies in four patients with sickle intrahepatic cholestasis showed dilated canaliculi with bile plugs [2,22,41,42]. Scattered bile stained microinfarcts were seen in one of these biopsies [42], while widespread anoxic necrosis with areas of acute and chronic inflammation, in addition to the usual findings noted in sickle cell patients, were seen in the other three biopsies [2,22,41]. (See 'Liver histology' above.)

At least 17 probable cases have been described [2,22,39,41-48]. The syndrome was fatal in nine early cases; other reports have described reversal of this process within 48 hours in eight patients, with vigorous exchange transfusions and correction of coagulopathy with fresh frozen plasma [22,39,43,45-48]. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Simple versus exchange transfusion' and "Clinical use of plasma components", section on 'Plasma products'.)

Kidney impairment in sickle intrahepatic cholestasis has not been well studied, but appears to be reversible and improves concurrently with hepatic improvement [22,46,48]. Urine electrolytes were measured in a single case and suggested acute tubular necrosis [46], but the authors attributed this to the patient's aminoglycoside therapy. Kidney ultrasound done in a single case demonstrated mildly altered corticomedullary differentiation [39]. Multiple focal acute kidney infarcts were described on gross examination in a single case at postmortem [2]. Kidney histology was done in a single patient postmortem and showed numerous hemoglobin casts in the distal convoluted tubules [44]. Hemodialysis was instituted in two patients for anuria [22,48], and peritoneal dialysis was carried out in another patient for refractory hyperkalemia [2]. Two of these patients succumbed to their illness, but one of the patients treated with hemodialysis survived. (See "Sickle cell disease effects on the kidney".)

Optimal management of hepatic crises has not been elucidated. However, a reasonable strategy has been to consider initial simple blood transfusion, particularly if there is a drop in hemoglobin greater than 2 g/dL, or evidence of hemodynamic instability (increased pulse rate, increased work of breathing, decreased hemoglobin oxygen saturation). If there is limited or no improvement in liver disease, then automated exchange transfusion should be considered the next intervention [35].

Acute hepatic sequestration — Acute hepatic sequestration is defined as the sudden increase in liver size, associated with right upper quadrant abdominal pain and an acute decrease in hemoglobin level >2 g/dL. Other features include thrombocytopenia, normal or increased reticulocyte count, and increased conjugated bilirubin level. Hepatic sequestration may progress to liver failure.

Hepatic sequestration is a well-recognized complication of SCD associated with inability of red blood cells in the liver to circulate, hence the term sequestration [49]. Patients with hepatic sequestration usually present with right upper quadrant pain, rapidly increasing hepatomegaly, and a falling hematocrit [49,50]. One report described two patients with hepatic sequestration who initially presented with bone pain [49]. A rapid fall in the hemoglobin level paralleled a dramatic increase in the liver size, which returned to baseline after three to four days. Tests associated with liver dysfunction may not substantially change. Regression of hepatic size was associated with a rapid increase in hemoglobin from 4.2 to 7.5 g/dL in one patient, indicating that not all sequestered cells were destroyed, and that some may return to the circulation upon resolution of the crisis and relief of sinusoidal obstruction. The management of hepatic sequestration is focused on hemodynamic and cardiopulmonary stability. If there is hemodynamic or cardiopulmonary instability (eg, congestive heart failure, postural hypotension, tachycardia, increased respiratory effort, altered mental status), a simple transfusion should be given. However, only small aliquots of red blood cell transfusions should be given to decrease the chance of autotransfusion, a process where cells sequestered in the spleen, lung, liver are suddenly released and that results in hyperviscosity syndrome [51]. A case of fatal auto-transfusion was described in which resolution of hepatic and pulmonary sequestration was accompanied by a spontaneous and rapid rise in the hemoglobin, from 5.1 to 12.3 g/dL over 24 hours, presumably from the release of viable sequestered cells back into the circulation [51]. Death occurred from the resultant hypervolemia, hypertension, heart failure, and intracerebral hemorrhage.

For adults with hepatic sequestration with hemodynamic or cardiopulmonary instability, we give one unit of packed red blood cells. For children with hepatic sequestration, we give 5 cc/kg of packed red blood cells. After transfusion, if the patient has clinically improved, no further transfusion is needed [52,53]. Following transfusion, patients should have their posttransfusion hemoglobin levels monitored closely (at least daily for several days following the transfusion or more frequently if the patient is symptomatic). If there is an abrupt rise in hemoglobin concentration to above 11 g/dL, consideration should be made for phlebotomy. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques".)

Benign hyperbilirubinemia — In contrast with the severe cholestasis, marked "benign" predominantly conjugated hyperbilirubinemia of up to 57 mg/dL (974.7 micromol/L) with only a mild elevation in serum ALT has been described in children and adults who had minimal or no symptoms [3,54]. The hyperbilirubinemia resolved spontaneously within two to eight weeks with no subsequent recurrences. It is possible that these cases represent a benign variant of intrahepatic cholestasis.

Chronic intrahepatic cholestasis — A case report described a patient with sickle cell anemia and very high bilirubin levels of >88 mg/dL (1504.8 micromol/L) due to chronic intrahepatic cholestasis [55]. He had no abdominal pain and no hematological evidence of increased hemolysis. He responded dramatically to an exchange transfusion, with his bilirubin falling to 10 mg/dL. He developed repeated episodes of hyperbilirubinemia during a three-year follow-up, requiring regular exchange transfusions to keep his hemoglobin S levels <20 percent to prevent recurrent intrahepatic cholestasis.

DISORDERS RELATED TO COEXISTING CONDITIONS

Cholelithiasis — The prevalence of pigmented gallstones in sickle cell disease (SCD) is directly related to the rate of hemolysis [56,57]. Gallstones occur in children as young as three to four years of age, and the incidence increases with age, reaching 50 percent by the age of 22 years. Gallstones are eventually found in approximately 70 percent of older adults with SCD [58-62]. Genetic variation contributes to the risk of cholelithiasis in SCD. Individuals with a higher rate of SCD-related hemolysis have a higher rate of cholelithiasis. In an observational study including 131 patients with SCD, gallstones were detected by ultrasound or at cholecystectomy in 58 percent of patients with HbSS, 17 percent of patients with HbSC, and 17 percent of patients with beta-thalassemia [56,61]. The presence of alpha-thalassemia gene deletion when compared with those without alpha-thalassemia in SCD is associated with a lower incidence of cholelithiasis. Genetic variance of uridine diphosphate glucuronosyltransferase 1 has been associated with cholelithiasis [63], an increase in mean serum bilirubin levels [64] and increased symptomatic cholelithiasis risk in SCD and in Gilbert syndrome [63,65], a disease associated with increased unconjugated hyperbilirubinemia. (See "Gilbert syndrome".)

The approach to screening patients with SCD varies among centers, and routine evaluations for patients with SCD are discussed in more detail separately. (See "Overview of the management and prognosis of sickle cell disease", section on 'Routine evaluations and treatments' and "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance".)

Most patients with gallstones are asymptomatic, and observation of such patients has been supported by expert consensus [52,53,66]. Risks that have been associated with elective surgery include risk of postoperative, life-threatening acute chest syndrome, and need for red blood cell transfusions [67-69].

However, observational data suggested that cholecystectomy was common in patients with SCD. In a study of 509 adult patients with SCD, the reported rates of cholecystectomy for patients 18 to 47 years of age and for patients ≥47 years of age were 48 and 69 percent, respectively [57].

The clinical presentation of acute cholecystitis and sickle hepatic crisis can be similar. Biliary scintigraphy may be useful in ruling out acute cholecystitis, although it is not always diagnostic [70]. Elective cholecystectomy should be considered in patients with symptomatic gallstones and in patients in whom gallstone-related symptomatology cannot be differentiated from sickle cell hepatic crises [71]. We do not typically perform cholecystectomy while patients are acutely ill, but rather wait until the acute illness has resolved.

We do not use cholecystectomy as a preventive strategy in asymptomatic individuals with gallstones due the risk of postoperative complications, including life-threatening acute chest syndrome. (See "Acute calculous cholecystitis: Clinical features and diagnosis", section on 'Diagnostic approach'.)

If a decision is made to perform cholecystectomy, the preferred surgical strategy is a laparoscopic cholecystectomy. The laparoscopic approach has been associated with a shorter length of stay and lower rates of postoperative complications, although it has not reduced the risk of sickle cell-related complications compared with open cholecystectomy [71-73].

We routinely give simple blood transfusion for individuals with HbSS with hemoglobin less than 9 g/dL undergoing cholecystectomy, with the goal of raising the hemoglobin to approximately 10 g/dL. The efficacy of preoperative simple transfusion in preventing potentially life-threatening acute chest syndrome and other complications, as well as other perioperative issues, are discussed separately. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Prophylactic preoperative transfusion'.)

In an observational study including 427 adults with SCD who underwent laparoscopic cholecystectomy, 393 patients (92 percent) received prophylactic blood transfusion, the mean operation time was 76 minutes, and the mean length of stay was 2.6 days [74]. Postoperative complications included acute vaso-occlusive pain of the extremities in 13 patients (3 percent), acute chest syndrome in eight patients (1.8 percent), vaso-occlusive abdominal crisis in six patients (1.4 percent), and superficial wound infection in four patients (0.9 percent).

Excessive iron stores — The likelihood of developing excessive iron stores is a direct function of the number of blood transfusions received. We typically obtain MRI of the liver to measure total iron stores, because this method is considered more accurate than liver biopsy or ferritin levels after the first 12 months of regular blood transfusion therapy.

We typically use ferritin levels to monitor adherence to chelation therapy and perform liver MRI annually for individuals receiving blood transfusion therapy. In patients with sickle cell anemia, ferritin levels correlate with the number of units of blood transfused [75]. Rises in serum ferritin occur during painful vaso-occlusive sickle crises [76]; thus, steady state ferritin levels provide a more accurate estimate of the degree of iron overload [75].

For patients receiving regular blood transfusion therapy, we prefer automatic exchange transfusion, because it has been associated with lower net iron stores. In a study including 83 children with SCD who received regular blood transfusion therapy, the median (interquartile range) ferritin levels were lower with automated exchange transfusion compared with simple transfusion or manual exchange transfusion (355 ng/mL versus 1800 ng/mL and 1530 ng/mL, respectively) [77]. (See "Approach to the patient with suspected iron overload".)

In individuals with SCD, data on histologic progression to fibrosis with excessive iron stores have been limited. In an autopsy series of 70 patients with sickle cell anemia and sickle beta-thalassemia, 33 patients were found to have variable degrees of parenchymal iron deposition [17]. Cirrhosis was seen in three of these patients, and parenchymal iron accumulation was severe enough to make a diagnosis of hemochromatosis as the etiology for the cirrhosis. However, hepatic iron content was not determined on biopsy, and other etiologies contributing to the cirrhosis were not excluded.

Another series focused on 11 individuals with HbSS who were followed over 5 to 10 years, during which time they received a mean of 180 units of packed red blood cells together with an intravenous chelating agent, deferoxamine (2 g), with each transfusion [78]. Despite the deferoxamine, two patients went on to develop significant hepatic iron overload [78].

Monitoring for excessive iron stores in patients with SCD is discussed separately. (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Excessive iron stores'.)

Viral hepatitis — The reported prevalence of chronic viral hepatitis has been increased in patients with SCD compared with the general population. In addition, patients with SCD may be more susceptible to developing severe disease when acutely infected [79]. Thus, all patients with SCD and chronic liver disease should be vaccinated against hepatitis A virus and hepatitis B virus infection.

Hepatitis B virus infection — The prevalence of chronic hepatitis B virus (HBV) infection in patients with SCD has been low in large studies from the United States (0 to 3.3 percent seropositivity for HBsAg), reflecting the low prevalence of infection in the general population [8,80]. Additionally, the rates of HBV infection in patients with SCD have been decreasing. In a study using data from the National Hospital Discharge Survey, the prevalence of HBV infection in patients with SCD was 6 percent from the time period from 1997 to 2003, while the prevalence was 0.9 percent from 2004 to 2009 [81]. In parts of the world with a higher baseline prevalence of HBV infection, higher rates of chronic HBV have been reported in patients with SCD compared with the general population. HBV immunization is discussed separately. (See "Hepatitis B virus immunization in adults".)

Hepatitis C virus infection — Antibodies against hepatitis C virus (HCV) have been detected in 10 to 20 percent of patients with SCD [8,82,83]. The risk of infection is increased in patients who have received multiple transfusions. In one study, antibody to HCV was detected more often in patients who had received >10 units of packed red blood cells (23 versus 8 and 0 percent in those who received <10 units or no transfusions, respectively) [80]. The natural history of chronic HCV infection and the rate of progression to cirrhosis in sickle cell anemia patients have been uncertain.

The introduction of screening blood donors for HCV infection has been associated with lower risk of transfusion-related HCV infection. In a study of 130 patients with SCD, the rate of HCV infection (as detected by anti-HCV antibody) was lower in patients who were screened in 1992 or later compared with patients screened before 1992 (22 versus 58 percent) [84]. In a study using data from the National Hospital Discharge Survey, the prevalence of HCV infection in patients with SCD was 2 percent from the time period from 1997 to 2003, while the prevalence was 3 percent from 2004 to 2009 [81].

With improved screening methods, the risk of acquiring HCV infection through blood transfusion in the United States has been extremely low (approximately 1:1,900,000 units when nucleic acid testing is employed) (figure 1). (See "Blood donor screening: Laboratory testing".)

Management of HCV infection is discussed separately. (See "Overview of the management of chronic hepatitis C virus infection".)

Other liver disorders — A number of liver abnormalities have been described in association with SCD including hepatic infarction [85], pyogenic liver abscess [86-89], Budd-Chiari syndrome [90,91], autoimmune hepatitis [92,93], focal nodular hyperplasia [94,95], malignant histiocytosis [96], primary sclerosing cholangitis [93], and mesenteric thrombosis [97]. The etiologic role of the SCD in some of these settings is uncertain.

LIVER TRANSPLANTATION — Liver transplantation (LT) has been infrequently performed in patients with sickle cell disease (SCD), despite estimates that >25 percent of such patients carry a diagnosis of chronic liver disease [98]. Factors associated with low rates of LT have been unclear but may have been related to multiple patient comorbidities, rapid progression from liver failure to multiorgan failure, and access to LT [99-101]. In a study using the Scientific Registry of Transplant Recipients database, patients with SCD undergoing LT had higher rates of intensive care unit admission (44 versus 19 percent), pretransplant dialysis (17 versus 5 percent), and status 1 listing (26 versus 12 percent), in addition to higher Model for End-Stage Liver Disease (MELD) scores (33 versus 21 points) compared with a cohort of LT recipients [102].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sickle cell disease and thalassemias".)

PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Sickle cell disease".)

SUMMARY AND RECOMMENDATIONS

●Background – The liver may be affected by several complications related to sickle cell disease (SCD) or its treatment. In addition to the vascular complications from the sickling process, patients with SCD have often received multiple transfusions, placing them at risk for complications such as iron overload and pigmented gallstones (related to effects of chronic hemolysis). (See 'Introduction' above.)

●Epidemiology – The major risk factor for liver disease in patients with SCD has been receiving multiple blood transfusions, which is associated with excessive iron stores and risk of infection (hepatitis B virus and hepatitis C virus infection). (See 'Epidemiology' above.)

●Clinical features – Liver biochemical and imaging abnormalities have been commonly reported in patients with SCD. (See 'Laboratory and radiologic liver tests' above.)

Several clinical features of liver disease can be attributed to the sickling process, while others may be due to coexisting conditions (eg, viral hepatitis). The distinction between the two is not always clear. (See 'Disorders associated with the sickling process' above and 'Disorders related to coexisting conditions' above.)

●Other aspects of sickle cell disease – Clinical manifestations, management, and prognosis of SCD are discussed elsewhere. (See "Overview of the clinical manifestations of sickle cell disease" and "Overview of the management and prognosis of sickle cell disease" and "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Stanley L Schrier, MD (deceased), who contributed to an earlier version of this topic review.