Sickle Cell Hepatopathy

Etiology

The etiology of SCH is multifactorial. In the deoxygenated state, HbS molecules end up binding to each other at the site of the substitution resulting in the formation of long-chain polymers causing sickling of the erythrocytes. 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.

When sickling occurs in the liver, it results in dilated sinusoids which causes compression of the biliary tree. A rare yet fatal entity of SCH is acute intrahepatic cholestasis, which also occurs due to sinusoidal sickling. Only this time, it causes diffuse ischemia and diffuse dilation of sinusoids resulting in intrahepatic cholestasis.[5]  It is found mainly in homozygous sickle cell disease [6].   Increased hemolysis, in general, leads to hyperbilirubinemia and the formation of gallstones. Further, chronic transfusions can lead to hepatic iron overload and increase the risk of hepatitis infections.[7]  An example of the latter is Hepatitis C (HCV) [8].  Its risk increases with multiple transfusion requirements.   It 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, and Central and South America. In the United States, 1 in every 600 African Americans has the HbSS genotype, which means most hemoglobin is HbS.[3] The distribution of the ßs allele occurs mainly in malaria-endemic regions and is secondary to population movements. It has been the target of repeated study that has shown that the ßs allele, which is more prevalent in sub-Saharan Africa, is likely due to malaria endemicity and the protection offered from HbAS against P. falciparum malaria. The spread of the ßs allele in North America and Western Europe can be seen as a result of population movements such as during the slave trade. In today's world, the disease burden is higher in sub-Saharan Africa.

An estimated 50 to 90% of affected children die before five years of age from pneumococcal and malarial infections. Continued population movements are projected to increase the incidence of SCD, with an estimated 400,000 newborns annually by 2050.[2] Overall, SCH can be seen in about 10% of patients with SCD, with abnormal liver function tests in one-third, hepatomegaly noted in 91% of autopsies of those with SCD, and cirrhosis noted in 16 to 29% of autopsies.[9]

Pathophysiology

SCH can be divided into acute and chronic manifestations. Acute sickle cell hepatic crisis, hepatic sequestration, intrahepatic cholestasis, and overt liver failure are common entities of acute SCH. More chronically, SCH includes viral hepatitis, transfusion overload, gallstone disease, and sickle cell cholangiopathy.[7]

• One of the presentations of vaso-occlusive crisis is acute sickle cell hepatic crisis, which happens in 10% of patients with SCD.[10] This is characterized by sinusoidal dilation/obstruction caused by Kupffer cell engorgement from widespread sickling with manifestations ranging from transient hepatic ischemia to infarction.[5]  The presence of significant portal or lobular inflammation, as well as bile duct injury, should alert one to other etiologies [11]. 
• Acute hepatic sequestration, which can be precipitated in the setting of infection or hepatoxic drugs, results in erythrocytes accumulating in the spleen, lungs, and less frequently 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 consequently biliary tree compression, which can eventually lead to more acute symptomatic anemia if a significant amount of erythrocytes are sequestered in the reticuloendothelial system, which can cause the patient to go into hypovolemic shock.
• While rare, acute intrahepatic cholestasis manifestation of SCH 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[6]. It can rapidly progress to renal and liver failure. There is widespread sinusoidal sickling, with resulting hypoxia causing the hepatocytes to balloon out, creating cholestasis in the bile canaliculi, with more severe hypoxia causing necrosis.
• Overt liver failure can also occur in SCD, which has very high mortality without a liver transplant. Liver biopsy results have shown centrilobular necrosis and very rarely cholestasis.
• Under chronic manifestations, patients with SCD who have multiple transfusions are at a higher risk for viral hepatitis B or C, depending on transfusion protocols in their location and vaccination status.[5] Patients who received blood transfusions after 1992 are at a much lower risk for hepatitis.[4] These infections are primarily chronic and occur in a background of sickle cell hepatopathy as evidenced by histology pertinent for sinusoidal dilatation, hyperplastic Kupffer cells (conducting erythrophagocytosis), necrosis of the hepatic parenchyma, along with hepatitis infection shown by piecemeal and focal hepatocyte necrosis, portal tract inflammation with lymphoid follicles.[12]
• 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.[5] Further, transferrin saturation from iron overload causes reactive oxygen species to form. These oxidants, in turn, interact with iron in the Fe2+ form, causing tissue damage.[13] 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 is common in patients with SCD due to excessive breakdown of heme, causing increased unconjugated bilirubin, precipitating pigment gallstones.[3] Fifty percent of these gallstones are made of calcium bilirubin, which is radio-opaque and can be seen on a plain film X-ray. By age 65, 58% of patients with SCD have cholelithiasis. Unlike most patients with gallstones, those with SCD 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 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 biliary abscess formation.[10]

History and Physical

Symptoms of sickle cell hepatopathy vary based on the underlying acute or chronic processes.

• Patients with acute sickle cell hepatic crises and acute sickle intrahepatic cholestasis present with right upper quadrant pain and fever, physical exam revealed jaundice and tender hepatomegaly, with jaundice being more prominent in the latter.[5]
• Patients undergoing hepatic sequestration present with rapidly increasing, tender hepatomegaly.[10]
• Overt liver failure presents similarly to acute liver failure in patients without SCD. 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 high mortality [14]. 
• 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. It is important to also look for 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 decreased libido.
• 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 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 pruritis, clay-colored stools, and dark urine, indicating obstructive jaundice.[5]

Evaluation

In acute sickle cell hepatic crisis, serum alanine transaminase (ALT) and aspartate transaminase (AST) are 1-3 times above normal. They can go up to the thousands, with a rapid downward trend once the crisis is resolved. Serum bilirubin with higher conjugated bilirubin can be up to 15 mg/dL, but rarely above. There is no synthetic liver failure in this crisis, and this would be characterized by a prolonged international normalized ratio (INR) above 1.5.  Under these circumstances, the use of liver biopsy does carry a significant risk of bleeding and geath[6].   

In acute hepatic sequestration, an acute drop in hemoglobin is noted, along with significant reticulocytosis. Bilirubin can also be significantly elevated up to 24 mg/dL, with fractionated bilirubin being in the conjugated form. Alkaline phosphatase (ALP) is also elevated as high as 650 IU/L, with normal transaminases.[10][5]

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

In overt liver failure, workup reveals extremely high PT, serum bilirubin, and mildly elevated transaminases.

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

In patients with transfusion iron overload, serum ferritin levels can be used to estimate iron levels. However, these should be obtained when patients are not in an acute vaso-occlusive crisis. However, 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 such as Magnetic Resonance Imaging (MRI) can also be utilized.[5] In patients who receive greater than ten transfusions per year or those with a ferritin level that is greater than 1000 μg/L, it is recommended that they be screened with an MRI annually.[7]

In patients with acute cholecystitis, there can be leukocytosis and mild elevation in transaminases. 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 etiology is unclear.[5]

In sickle cell cholangiopathy, laboratory values are significant for elevated direct bilirubin, ALP, and transaminases.[7]

Treatment / Management

Treatment of acute sickle cell hepatic crisis is mainly supportive, including intravenous fluids and oxygenation.[5] In more severe cases, patients could require an exchange transfusion, wherein the patient's blood is replaced by the donor's blood; this is very effective in lowering the level of HbS below 30% of the total hemoglobin without raising the total hemoglobin level above 10g/dL.[2]

In acute hepatic sequestration, a simple transfusion can help increase hemoglobin levels; however, if there is hepatic dysfunction as evidenced by elevated INR, then an exchange transfusion is needed.[7] Given the high mortality of this presentation, it is recommended that patients be transferred to an intensive care unit earlier in the disease course.[4] Acute sequestration takes 2 to 5 days to resolve, and patients' hematocrit should be closely monitored. If there is an acute increase in hematocrit, this is evidence against diffuse hemolysis of all the sequestered erythrocytes. The rapid rise of hematocrit during the resolution of this process can lead to hyperviscosity, requiring phlebotomy. Therefore, exchange transfusion is most likely preferred given the rapid rise in hematocrit during the resolution phase in acute hepatic sequestration.[15]

Acute intrahepatic cholestasis must be treated with aggressive supportive therapy, exchange transfusion, and fresh frozen plasma (to correct the coagulopathy resulting from hepatic dysfunction). Exchange transfusion is advocated as it decreases viscosity, and disrupts Vasco-occlusive disease with a target HbS level set at 20%.  Some cases have required dialysis due to renal failure from the resulting hepatic failure.

If exchange transfusion fails, then hepatic transplantation becomes a serious consideration [6]. 

Overt liver failure has a very poor prognosis without a hepatic transplant. Zinc deficiency has also been noted in patients with high ammonia levels. It is suggested that patients with acute hepatic failure could have underlying zinc deficiency, as it is a cofactor required for the ornithine transcarbamylase enzyme in the urea cycle. Patients should be tested for zinc levels and supplemented as necessary.[5]

Chronic hepatitis C infection can be treated with novel antiviral therapies with above 95% eradication rates. Chronic hepatitis B infection can be treated with nucleotide/nucleoside analogs.[10] Patients who do not have Hepatitis A or B antibodies should be vaccinated against both.[16]

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 some hepatic dysfunction, so liver function tests should be closely monitored before starting treatment and every two 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.[7]

In acute cholecystitis, management should include broad-spectrum antibiotic coverage for anaerobic organisms and Salmonella species.[10] Elective cholecystectomy is indicated, and in cases of choledocholithiasis, an endoscopic retrograde cholangiopancreatography (ERCP) should be performed first. There is controversy on whether a prophylactic cholecystectomy should be performed in patients with asymptomatic cholelithiasis, given that postoperative complications are significant in this population.[5]

Patients with sickle cell cholangiopathy are at a high risk of choledocholithiasis; they should be treated endoscopically with dilatation or stenting.[7]

The role of liver transplantation comes into question with more severe SCH; while data is still limited, transplantation has some possible benefits depending on the patient. Patients with end-stage liver disease without neurologic, cardiovascular, pulmonary, and renal complications are good candidates for orthoptic liver transplants. Patients with liver disease such as chronic autoimmune liver disease along with SCD also benefit from transplantation. However, patients with acute hepatic crisis secondary to SCH have very high mortality after transplantation.[4]

It is challenging to predict which patient with SCH will ultimately need a liver transplant, yet, it 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. It cannot, however,  reverse or correct any pre-existing issues such as hepatic fibrosis or siderosis[17].  Under these circumstances liver transplant after HSCT, would be in order.  This has been successful in matched sibling donors, however, matched unrelated donor trials have been limited because of graft-vs-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][7] (B3)

Differential Diagnosis

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

Under SCH, one must consider chronic viral hepatitis, transfusion overload, and sickle cell cholangiopathy in a more chronic hepatopathy that can present with persistently elevated transaminases. Moreover, one must also rule out hereditary hemochromatosis and other liver conditions such as autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis. Other etiology, including infections such as bacterial or fungal, should also be considered. 

Prognosis

From autopsies, it is known that about 16% to 29% of patients with SCD have cirrhosis, making chronic liver disease an important entity of those with SCD. Annual monitoring of liver function tests is recommended in patients with SCD; if serum ALT is two times the upper limit of normal, further investigation for chronic underlying SCH should be carried out. Note that mild chronic elevation of ALT and AST can be expected in patients with SCD, given underlying hemolysis.[7] 

There is not enough evidence on how to identify patients at risk of developing chronic liver disease and which interventions are best to prevent further disease progression. Interventions such as hydroxyurea in those with multiple vaso-occlusive crises, exchange transfusions to keep HbS levels below 30%, and ursodeoxycholic acid can be considered as they have shown some benefit.[10] 

Complications

SCH can have a milder self-limited presentation, or it can be more severe, resulting in severe liver failure requiring urgent exchange transfusion. One retrospective study which defined severe SCH as extreme hyperbilirubinemia (total bilirubin above 13.0 mg/dL) concluded that these patients had a significantly increased degree of end-organ failure.[15] SCH complications causing mortality accounts for about 7% of SCD deaths.[7]