Sickle Cell Hepatopathy

Etiology

The etiology of sickle cell hepatopathy is multifactorial, involving ischemia, hemolysis, iron overload, and infectious complications. In the deoxygenated state, HbS undergoes polymerization due to the hydrophobic interaction introduced by the valine substitution at the sixth position of the β-globin chain. This polymerization forms rigid fibers within red blood cells, causing them to assume a sickle-shaped form. This sickling can cause vaso-occlusion intrahepatically, leading to ischemic liver damage from sinusoidal obstruction. Recurrent episodes of acute damage can result in chronic liver disease.

In sickle cell disease, sickling within the hepatic sinusoids leads to vascular congestion, sinusoidal dilation, and hepatocellular ischemia. In rare cases, this process results in acute intrahepatic cholestasis—a life-threatening complication of sickle cell hepatopathy. Acute intrahepatic cholestasis secondary to sickle cell disease is characterized by diffuse sinusoidal sickling, extensive hepatic ischemia, hepatocellular dysfunction, and impaired bile excretion, leading to severe hyperbilirubinemia, coagulopathy, and liver failure.[6] This condition is primarily found in individuals with homozygous sickle cell disease.[7] Increased hemolysis, in general, leads to hyperbilirubinemia and the formation of pigment gallstones. Further, chronic transfusions can lead to hepatic iron overload and increase the risk of infections, eg, hepatitis C viral infection.[5][8] Hepatitis C can compound the damage from other hepatotropic viruses, as well as predispose to cirrhosis and hepatocellular carcinoma. 

Epidemiology

The HbS gene is found in African countries, India, the Caribbean, Central, and South America. In the United States, 1 in every 600 African Americans has the HbSS genotype.[3] Please see StatPearls' companion resource, "Sickle Cell Anemia", for further information. The distribution of the ßs allele is concentrated in malaria-endemic regions and has been shaped by both natural selection and historical population movements.

Extensive studies have shown that the high prevalence of the ßs allele in sub-Saharan Africa is linked to the protective effect of the heterozygous state (sickle cell trait) against severe Plasmodium falciparum malaria, illustrating a classic example of balanced polymorphism. The spread of the ßs allele to North America and Western Europe can be attributed to population movements, eg, those associated with the slave trade. In today's world, the sickle cell disease burden is highest in sub-Saharan Africa, where the majority of affected births occur and access to early diagnosis and comprehensive care remains limited, contributing to high childhood mortality. An estimated 50% to 90% of affected children die before the age of 5 years from pneumococcal and malarial infections.

Continued population movements are projected to increase the incidence of sickle cell disease, with an estimated 400,000 affected newborns annually by 2050.[2] Overall, sickle cell hepatopathy can be seen in about 10% of patients with sickle cell disease, with abnormal liver function tests in one-third, hepatomegaly noted in 91% of autopsies of those with sickle cell disease, and cirrhosis noted in 16% to 29% of autopsies.[9] The presence of liver fibrosis correlates with increasing age, male gender, cholelithiasis, elevated LDH, INR, and bilirubin levels.[10]

Pathophysiology

Sickle cell hepatopathy can be divided into acute and chronic manifestations. Acute sickle cell hepatic crisis, hepatic sequestration, intrahepatic cholestasis, and severe liver injury or failure are common entities of acute sickle cell hepatopathy. More chronically, sickle cell hepatopathy includes viral hepatitis, transfusion overload, gallstone disease, and sickle cell cholangiopathy.[5]

Acute Manifestations of Sickle Cell Hepatopathy

Acute sickle cell hepatic crisis

One of the presentations of vaso-occlusive crisis is acute sickle cell hepatic crisis, which happens in 10% of patients with sickle cell disease.[11] This is characterized by sinusoidal obstruction and Kupffer cell hyperplasia from widespread sickling, with manifestations ranging from transient hepatic ischemia to infarction.[6] The presence of significant portal or lobular inflammation, as well as bile duct injury, should alert a clinician to other etiologies [12]

Acute hepatic sequestration

Acute hepatic sequestration, which can be precipitated in the setting of infection or hepatotoxic drugs, results in erythrocytes accumulating in the liver. This can present as acute right upper quadrant pain, rapidly increasing liver size, and rapidly worsening anemia. These erythrocytes are phagocytosed by Kupffer cells, resulting in sinusoidal dilation and vascular congestion, which can eventually lead to more severe symptomatic anemia if a significant number of erythrocytes are sequestered in the reticuloendothelial system, potentially causing the patient to enter hypovolemic shock.

Acute intrahepatic cholestasis

While rare, acute intrahepatic cholestasis manifestation of sickle cell hepatopathy can be the most fatal, presenting with the sudden onset of right upper quadrant pain, hepatomegaly, significant transaminase elevations (reflecting ischemia), fever, leukocytosis, and jaundice.[7] It can rapidly progress to renal and liver failure. There is widespread sinusoidal sickling, resulting in hypoxia that causes hepatocytes to swell, leading to cholestasis in the bile canaliculi. More severe hypoxia can cause necrosis.

Liver failure

Overt liver failure can also occur in sickle cell disease, which has a very high mortality without a liver transplant. Liver biopsy results have shown centrilobular necrosis and very rarely cholestasis.

Chronic Manifestations of Sickle Cell Hepatopathy

Viral hepatitis

Under chronic manifestations, patients with sickle cell disease who have multiple transfusions are at a higher risk for viral hepatitis B or C, depending on the transfusion protocols in their location and vaccination status.[6] Patients who received blood transfusions after 1992 are at a much lower risk of hepatitis.[4] These infections are primarily chronic and occur in the background of sickle cell hepatopathy, as evidenced by histology that reveals sinusoidal dilatation, hyperplastic Kupffer cells (conducted erythrophagocytosis), necrosis of the hepatic parenchyma, along with hepatitis infection, characterized by piecemeal and focal hepatocyte necrosis, portal tract inflammation, and lymphoid follicles.[13]

Iron overload

Recurrent blood transfusions, chronic hemolysis, and increased iron absorption in the gut due to increased erythropoiesis can all cause iron to be deposited in the liver.[6] This form of iron overload is transfusional and distinct from hereditary hemochromatosis. Furthermore, transferrin saturation resulting from iron overload leads to the formation of reactive oxygen species. These oxidants, in turn, interact with iron in the Fe2+ form, causing tissue damage.[14] Iron deposition, which initially starts in the macrophages, also occurs within the reticuloendothelial cells and can ultimately lead to micronodular cirrhosis in the setting of hemochromatosis.

Gallstone disease

Gallstone disease is common in patients with sickle cell disease due to the excessive breakdown of heme, which causes increased unconjugated bilirubin and precipitates pigment gallstones.[3] A significant proportion of these gallstones are composed of calcium bilirubinate (which gives the stones a black color), and they may be radio-opaque and visible on plain film x-rays, though ultrasound is the preferred diagnostic modality.[15] By age 65, 58% of patients with sickle cell disease have cholelithiasis. Unlike most patients with gallstones, those with sickle cell disease and cholelithiasis are at a higher risk for complications such as cholecystitis, choledocholithiasis, ascending cholangitis, and pancreatitis.[3] It is also essential to differentiate an acute hepatic crisis from acute cholecystitis.

Sickle cell cholangiopathy

Sickle cell cholangiopathy results from recurrent episodes of sickle cell crisis, generating ischemic damage of the biliary tree secondary to end-arterial injury. The initial insult causes dilated ducts. Repeated injury results in necrosis of the epithelium, followed by strictures of the biliary ducts. Histologically, this can show up as ischemic bile duct necrosis and biliary fibrosis. This manifestation can be complicated by ascending cholangitis, bilomas, and the formation of biliary abscesses.[11] 

History and Physical

Sickle Cell Hepatopathy Clinical Features

Clinical presentations and distinguishing features of sickle cell hepatopathy vary based on the underlying acute or chronic processes, including hepatic crises, intrahepatic cholestasis, hepatic sequestration, and iron overload. Patients with acute sickle cell hepatic crises and acute sickle cell intrahepatic cholestasis present with right upper quadrant pain and fever. On physical exam, they may have jaundice and tender hepatomegaly, with jaundice typically being more prominent in intrahepatic cholestasis.[6]

Patients undergoing hepatic sequestration present with rapidly progressive anemia, right upper quadrant pain, and a rapidly enlarging, tender liver.[11] Overt liver failure presents similarly to acute liver failure in patients without sickle cell disease. Patients present with encephalopathy, right upper quadrant pain, and tender hepatomegaly.

Acute viral hepatitis presentation includes jaundice, malaise, and right upper quadrant pain with tender hepatomegaly; chronic viral hepatitis, on the other hand, is mainly asymptomatic. Dengue virus can also cause fulminant hepatitis in sickle cell disease, carrying a high mortality risk.[16]

In more advanced cases of iron overload where patients have cirrhosis, they can present with signs of chronic liver disease, including ascites, gastrointestinal bleeding, and hepatosplenomegaly. Additionally, noting other signs of iron overload involving the cardiovascular and endocrine system, such as lower extremity edema, paroxysmal nocturnal dyspnea, orthopnea indicating heart failure, and endocrine involvement characterized by diabetes mellitus and hypogonadism is essential. 

Patients with cholelithiasis can present with complications, including acute cholecystitis and choledocholithiasis. Both can present with right upper quadrant pain that is intermittent, worse with fatty foods. This can be complicated with jaundice and fever secondary to obstruction, resulting in ascending cholangitis. Patients with sickle cell cholangiopathy in the early stages present with jaundice from the initial cholestasis; however, with disease progression involving biliary strictures, symptoms can include pruritus, clay-colored stools, and dark urine, indicating obstructive jaundice.[6] 

Evaluation

Evaluation of Sickle Cell Hepatopathy Manifestations

Sickle cell hepatopathy encompasses a range of hepatic complications in sickle cell disease, broadly categorized into acute and chronic presentations, and is a significant contributor to morbidity and mortality. While the central pathophysiologic process—vaso-occlusion due to sickled erythrocytes—is shared across organ systems, liver involvement exhibits distinct manifestations with varying diagnostic findings.

Acute sickle cell hepatic crisis

In acute sickle cell hepatic crisis, serum alanine transaminase (ALT) and aspartate transaminase (AST) are typically mildly elevated, about 1 to 3 times above normal. They can occasionally rise into the hundreds, with a rapid downward trend once the crisis is resolved. Serum bilirubin, with a higher conjugated component, can be up to 15 mg/dL, but rarely above this value.

Acute hepatic sequestration

In acute hepatic sequestration, an acute drop in hemoglobin is noted, along with significant reticulocytosis. Bilirubin can also be significantly elevated up to 15 to 20 mg/dL, with a predominantly conjugated component. Alkaline phosphatase (ALP) is also elevated as high as 650 IU/L, and transaminases are typically normal or mildly elevated.[11][6]

Acute sickle intrahepatic cholestasis

Acute sickle intrahepatic cholestasis causes extremely high elevations of bilirubin, levels in the 200s are noted, AST and ALT levels above 1000 mg/dL are seen, and ALP can be normal or as high as 1000 IU/L. A bleeding diathesis is reflected in the elevated prothrombin time (PT), partial thromboplastin time (PTT), INR, and hypofibrinogenemia. The renal function panel can be significant for elevated creatinine, as this condition is associated with acute renal failure.

Liver failure

In overt liver failure, the workup reveals an extremely high PT/INR, serum bilirubin, and mild to moderately elevated transaminases, consistent with synthetic dysfunction.

Acute viral hepatitis

Acute viral hepatitis can be diagnosed in those patients with sickle cell disease. They have very high transaminases, up to 1000 IU/mL, and the bilirubin averages around 45 mg/dL, which is higher than that of patients without sickle cell disease due to baseline hemolysis. Patients with chronic viral hepatitis usually have persistently elevated transaminases, prompting further workup for hepatitis serologies.

Transfusion iron overload

In patients with transfusion iron overload, serum ferritin levels can be used to estimate iron levels. These should be obtained when patients are not in an acute vaso-occlusive crisis. Ferritin is an acute-phase reactant, which can be elevated in response to inflammation, infection, ischemia, and necrosis. The gold standard of iron store assessment is the hepatic iron concentration (HIC), which can be determined by liver biopsy and atomic absorption spectrophotometry. The HIC in liver fibrosis is >15 mg/g (normal 0.4 to 2.2 mg/g).

Other imaging modalities, eg, magnetic resonance imaging (MRI), can also be utilized.[6] For patients who receive more than 10 transfusions per year or those with a ferritin level exceeding 1000 μg/L, annual MRI screening is recommended.[5] An elevated ferritin in the presence of an elevated erythrocyte sedimentation rate and C-reactive protein limits its specificity for iron overload. 

Acute cholecystitis

In patients with acute cholecystitis, leukocytosis and mild elevation in transaminases may occur. In contrast, in choledocholithiasis, there is also an elevation in bilirubin and ALP levels secondary to biliary obstruction. Different imaging modalities, including ultrasound and hepatobiliary radionuclide scans, can be used to diagnose these patients if the etiology is unclear.[6]

Sickle cell cholangiopathy

In sickle cell cholangiopathy, laboratory values are notable for elevated direct bilirubin, ALP, and transaminases.[5] 

Autoimmune hepatitis

Experts advocate that patients with elevated liver function studies, during a noncrisis period, be evaluated with liver imaging and biopsy to rule out autoimmune hepatitis.[17] This rare malady is treated with a steroid regimen and carries an entirely different approach.

Treatment / Management

Liver failure

Overt liver failure carries a very poor prognosis in the absence of hepatic transplantation. Zinc deficiency frequently occurs in patients with elevated ammonia levels. Patients with acute hepatic failure may have underlying zinc deficiency, given zinc's essential role as a cofactor for the ornithine transcarbamylase enzyme in the urea cycle. Zinc levels should be assessed, and supplementation provided when indicated.[6]

Viral hepatitis

Chronic hepatitis C infection can be treated with novel antiviral therapies with an above 95% eradication rate. Chronic hepatitis B infection can be treated with nucleotide/nucleoside analogs.[11] Patients who do not have hepatitis A or B antibodies should be vaccinated against both.[18]

Iron overload

Both deferoxamine, which can be given intravenously or subcutaneously, and deferasirox, given orally, can be used to manage transfusion iron overload. Note that deferasirox can cause transaminitis and rare cases of hepatic failure, so liver function tests should be closely monitored before starting treatment and every 2 weeks during the initial month and then every month. Transaminitis of unexplained etiology is likely due to the iron chelator, which must be held and restarted at a much lower dose once transaminases are within normal limits.[5]

Acute cholecystitis

In acute cholecystitis, management should include broad-spectrum antibiotic coverage for anaerobic organisms and Salmonella species.[11] Elective cholecystectomy is indicated, and in cases of choledocholithiasis, an endoscopic retrograde cholangiopancreatography (ERCP) should be performed first. Whether a prophylactic cholecystectomy should be performed in patients with asymptomatic cholelithiasis is debated, given that postoperative complications may be higher in patients with sickle cell disease.[6]

Sickle cell cholangiopathy

Patients with sickle cell cholangiopathy are at a high risk of choledocholithiasis; they should be treated endoscopically with biliary dilatation or stenting as needed.[5]

Liver Transplantation

The role of liver transplantation comes into question with more severe sickle cell hepatopathy; while data is still limited, transplantation has some possible benefits depending on the patient. The literature has noted 1 and 5-year patient survival rates of approximately 88% and 59%, respectively.[19] Patients with end-stage liver disease without neurologic, cardiovascular, pulmonary, and renal complications are good candidates for orthotopic liver transplants.

Patients with liver disease, eg, chronic autoimmune liver disease, along with sickle cell disease, also benefit from transplantation. However, patients with acute hepatic crisis secondary to sickle cell hepatopathy have very high mortality after transplantation.[4] Survival is dependent on the intensity of the pretransplant and posttransplant care.[20] Neurological symptoms warrant imaging in view of the danger of cerebral bleeding and vascular occlusion. The latter is an especially important issue, as exchange transfusion may be employed to bring the HbS level <20. Due to the increased rate of sepsis, prophylactic antibiotics are also recommended. Increasing transaminase levels may prompt consideration of a graft biopsy.

Predicting which patient with sickle cell hepatopathy will ultimately need a liver transplant is challenging, yet transplantation remains an option, especially in patients with progressive sickle cell cholangiopathy. Other treatment options, including hematopoietic stem cell transplant (HSCT), can potentially stop the progression of liver disease. HSCT cannot, however, reverse or correct any preexisting issues, eg, hepatic fibrosis or siderosis.[21] Under these circumstances, liver transplant after HSCT would be in order. This approach has been successful in matched-sibling donor transplants; however, matched-unrelated donor trials have been limited due to graft-versus-host disease. Further studies with half-matched donors in haploidentical stem cell transplants are also underway. This option, along with gene therapy and gene editing, can be greatly beneficial for this population in the future.[1][5] (B3)

Differential Diagnosis

Sickle cell hepatopathy is a broad term encompassing multiple entities. In a patient presenting with acute right upper quadrant pain and jaundice, clinicians must differentiate between an acute sickle cell hepatic crisis, acute hepatic sequestration, acute intrahepatic cholestasis, acute viral hepatitis, acute cholecystitis, and choledocholithiasis. Clinicians must also keep in mind that acute hepatitis secondary to drugs or toxin use can precipitate a similar presentation.

Under sickle cell hepatopathy, chronic viral hepatitis, transfusion-related iron overload, and sickle cell cholangiopathy should be considered in a more chronic hepatopathy that can present with persistently elevated transaminases. Moreover, hereditary hemochromatosis and other liver conditions, including autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis, must be excluded. Other etiologies, including infections (eg, bacterial or fungal), should also be considered. 

Prognosis

Autopsy studies have shown that approximately 16% to 29% of individuals with sickle cell disease develop cirrhosis, highlighting chronic liver disease as a significant complication in this population. Annual monitoring of liver function tests is recommended for these patients. When serum ALT levels remain persistently elevated at twice the upper limit of normal, further evaluation for chronic sickle cell hepatopathy becomes necessary. Mild, chronic elevations in ALT and AST often occur due to ongoing hemolysis associated with the disease.[5] 

Current evidence remains insufficient to clearly identify which patients face the greatest risk of developing chronic liver disease or to determine the most effective preventive interventions. However, therapies, eg, hydroxyurea for individuals experiencing frequent vaso-occlusive crises, chronic exchange transfusions to maintain HbS levels below 30%, and ursodeoxycholic acid for those with cholestasis or gallstone disease have demonstrated potential benefits in slowing disease progression.[11]

Complications

Sickle cell hepatopathy can have a milder self-limited presentation, or it can be more severe, resulting in acute liver failure requiring urgent exchange transfusion. One retrospective study, which defined severe sickle cell hepatopathy as extreme hyperbilirubinemia (total bilirubin above 13.0 mg/dL), concluded that these patients had a significantly increased degree of end-organ failure.[22] Sickle cell hepatopathy complications, which cause mortality, account for about 7% of sickle cell disease deaths.[5] 

Hepatocellular carcinoma (HCC) occurs in livers with sickle-cell disease, similar to those in patients without sickle-cell disease, although the tumors are noted to be smaller at diagnosis.[23] Generally, HCC in patients with sickle cell disease shows no significant differences compared to patients without sickle cell disease in terms of outcomes to chemotherapy, surgery, and transplantation. Especially noted was that transplantation survival rates for HCC in the setting of sickle hepatopathy are comparable to those with HCC alone.