What is Sickle Cell Hepatopathy?
Sickle cell disease (SCD) is a blood disorder caused by a mutation in a part of the blood called the beta-globin chain. This mutation changes an amino acid in a protein that forms a different type of red blood cells, the so-called sickle cell hemoglobin (HbS). When these cells don’t get enough oxygen, they shape like a sickle and can cause blockages in the blood vessels, leading to both sudden and ongoing health issues. These health issues can vary from acute chest pain, strokes, sudden anemia, liver crisis, gall bladder inflammation, and a persistent painful erection to long-term complications like kidney disease, gallstones, viral hepatitis, high blood pressure in the lungs, bone death, and blood clots.
People who only have one copy of the HbS gene (meaning they’re heterozygous for the ßs allele) have what’s called sickle cell trait and don’t develop sickle cell disease. However, those with two copies (homozygous for the ßs allele) do develop sickle cell anemia. The gene that leads to this is common in African countries, India, the Caribbean, and Central and South America. In the US alone, it affects 1 in 360 African American newborns.
Sickle cell hepatopathy (SCH) is a broad term that encompasses several liver-related issues caused by sickle cell disease. These can include acute liver crisis, buildup of bile in the liver, sudden liver sequestration, chronic liver disease, chronic bile buildup, and complications related to receiving multiple blood transfusions like viral hepatitis and excess iron in the body.
What Causes Sickle Cell Hepatopathy?
The causes of sickle cell hepatopathy (SCH) are numerous. In a state with less oxygen, molecules of haemoglobin S (HbS), which usually carry oxygen in our blood, stick to each other more easily. This forms long chains that cause red blood cells to become sickle-shaped. This sickling process can block blood vessels inside the liver, leading to liver damage due to lack of oxygen.
Repeated episodes of such acute damage may result in chronic liver disease over time.
When sickle-shaped cells affect the liver, it results in enlarged blood vessels within the organ. This enlargement can put pressure on the bile ducts. A rare but potentially fatal condition associated with SCH is acute intrahepatic cholestasis. This happens when sickle-shaped blood cells block the liver’s small blood vessels, inducing widespread lack of oxygen and dilation of these vessels, which results in the impaired release of bile.
This condition is mainly seen in patients with two copies of the sickle cell gene. High rates of red blood cell breakdown generally lead to an excess of bilirubin, a yellowish substance, in the blood and the formation of gallstones.
Furthermore, regular blood transfusions can lead to an overload of iron in the liver and heighten the risk of hepatitis infections, like Hepatitis C. The risk of getting Hepatitis C rises with the need for multiple transfusions. This infection can worsen the damage from other viruses that target the liver and raise the chances of developing cirrhosis (liver scarring) and liver cancer.
Risk Factors and Frequency for Sickle Cell Hepatopathy
The HbS gene, which is primarily responsible for Sickle Cell Disease (SCD), is most common in Africa, India, the Caribbean, Central, and South America. In the U.S, it is found in 1 out of every 600 African Americans. The HbS gene, also known as the βs allele, is often studied because of its high prevalence in malaria-prone areas like sub-Saharan Africa. This is due to its protective properties against certain types of malaria. Presently, the impact of this condition is most significant in sub-Saharan Africa. This is mainly because of the high number of child deaths from complications such as pneumonia and malaria.
- The HbS gene is widespread in areas like Africa, India, the Caribbean, and Central and South America.
- In the USA, 1 in every 600 African Americans has this gene.
- The gene is commonly found in malaria-prone areas because it provides some protection against the disease.
- Today, sub-Saharan Africa experiences the most significant impact from SCD.
- Between 50 to 90% of kids with SCD in these regions die before age 5 due to complications such as pneumonia and malaria.
Due to ongoing population movements, SCD is expected to become even more widespread, with estimations of an additional 400,000 new patients per year by 2050. SCD can also lead to other health conditions. For example, about 10% of patients with SCD also have Sickle Cell Hepatopathy (SCH), which is a liver condition. In people with SCD, about a third may have abnormal liver function tests, 91% could show liver enlargement upon autopsy, and 16 to 29% may have cirrhosis, which is a severe liver disease.
- Due to population movements, it’s projected that 400,000 newborns will have SCD annually by 2050.
- About 10% of people with SCD also develop a liver condition known as Sickle Cell Hepatopathy (SCH).
- Among people with SCD, approximately a third might have abnormal liver function.
- Autopsies usually show that 91% of SCD patients had an enlarged liver.
- Cirrhosis, a severe liver disease, is found in 16 to 29% of autopsies of SCD patients.
Signs and Symptoms of Sickle Cell Hepatopathy
Sickle cell hepatopathy is a liver condition linked with sickle cell disease, and the symptoms can be quite diverse. Here’s what patients might experience depending on what exact issue they are dealing with:
- Patients with acute sickle cell hepatic crises and acute sickle intrahepatic cholestasis usually have pain in the upper right part of the abdomen and fever. They might also appear yellowish (jaundice) and have a tender, enlarged liver.
- Patients undergoing hepatic sequestration often experience a rapidly enlarging, tender liver.
- Overt liver failure can cause symptoms like disorientation, pain in the upper right abdomen, and a tender, enlarged liver. This is similar to the symptoms of acute liver failure in patients without sickle cell disease.
- Acute viral hepatitis can involve symptoms like jaundice, tiredness, and a sore, enlarged liver. In contrast, chronic viral hepatitis usually doesn’t cause symptoms.
- Patient with advanced iron overload and cirrhosis can exhibit signs of chronic liver disease, which include fluid accumulation in the abdomen (ascites), bleeding in the digestive tract, and an enlarged liver and spleen. They may also show signs of iron overload in the heart and endocrine system, like swollen lower limbs, difficulty breathing at night or when lying down, diabetes, and decreased sex drive.
- Patients with gallstones (cholelithiasis) can have complications like acute inflammation of the gallbladder (cholecystitis) and stones in the bile duct (choledocholithiasis). The symptoms usually include intermittent pain in the upper right abdomen that worsens after eating fatty foods. If the bile duct becomes blocked, the patient may develop jaundice and fever.
- Early stages of sickle cell cholangiopathy comes with jaundice due to bile duct obstruction. As the disease progresses and the bile ducts become narrower (biliary strictures), the patient may start feeling itchy, notice their stools turning pale and their urine dark, indicating obstructive jaundice.
Testing for Sickle Cell Hepatopathy
In a severe liver issue related to sickle cell disease, levels of liver enzymes such as serum alanine transaminase (ALT) and aspartate transaminase (AST) may be one to three times higher than usual. When the crisis is managed, these levels can fall sharply. The level of a substance called serum bilirubin may also rise up to 15 mg/dL but no higher. In such a serious situation, it can be risky to perform a liver biopsy due to the possibility of serious complications, like bleeding or even patient death.
When sickle cell disease causes a swift buildup of sickle cells in the liver, there’s a quick decline in hemoglobin, a protein that carries oxygen in the blood. The level of bilirubin may rise up to 24 mg/dL while another substance known as alkaline phosphatase could go as high as 650 IU/L with normal transaminases.
In acute sickle intrahepatic cholestasis, a condition where the liver cannot move bile efficiently, levels of bilirubin can surge extremely high. AST and ALT levels could also exceed 1000 mg/dL. The condition may interfere with normal blood clotting, causing prolonged clotting times, and can damage the kidneys, leading to higher creatinine levels.
If the liver starts to fail completely, blood tests will reveal significantly high blood clotting times, high levels of bilirubin, and slightly high transaminases.
In patients with sickle cell disease who also have acute viral hepatitis, liver enzyme levels can be very high – up to 1000 IU/mL – and bilirubin may average around 45 mg/dL. Patients with chronic viral hepatitis typically have consistently high enzyme levels, indicating a need for further tests for hepatitis.
If a patient has been regularly getting blood transfusions, doctors can use serum ferritin levels to estimate the amount of iron, but it’s best to perform these tests when patients are not experiencing a pain crisis related to sickle cell disease. The best way to measure iron stores is by examining a liver biopsy and using a device to measure the iron levels. Anyone with more than ten blood transfusions a year or a ferritin level higher than 1000 μg/L should get an MRI to check for iron levels annually.
If someone with sickle cell disease gets acute cholecystitis, a condition where the gallbladder gets inflamed, this can cause white blood cell levels and liver enzyme levels to rise slightly. In contrast, if there is a gallstone blockage in the bile ducts, both bilirubin and alkaline phosphatase can increase. Imaging tests such as ultrasounds and liver scans can help diagnose the cause if it’s not clear.
In sickle cell cholangiopathy, a condition that affects the bile ducts in the liver, laboratory tests may show high levels of direct bilirubin, alkaline phosphatase, and liver enzymes.
Treatment Options for Sickle Cell Hepatopathy
The treatment of acute sickle cell liver crisis mainly involves supportive care such as providing fluids and oxygen. In serious cases, exchange transfusions may be needed. This is a procedure where the patient’s blood is replaced with donor blood, which effectively lowers the harmful components in the blood tied to sickle cell disease.
In cases of acute liver issues due to sickle cell, a blood transfusion can help boost blood levels. However, if the liver isn’t functioning well, an exchange transfusion may be needed instead. These patients should be put into intensive care as soon as possible due to the high risk associated with this condition.
When someone is experiencing a severe blockage in the liver (cholestasis), aggressive supportive therapy, exchange transfusions, and plasma transfusion might be required. Plasma transfusion is used to correct blood clotting issues resulting from liver dysfunction. If the exchange transfusion doesn’t work, a liver transplant may be considered.
For patients with chronic Hepatitis C infection, new anti-viral treatments are available with high success rates. Those with chronic Hepatitis B infection can be treated with specific medications. The vaccination against Hepatitis A and B is recommended for those who don’t have antibodies for these diseases.
If a patient develops gallbladder inflammation (cholecystitis), broad-spectrum antibiotics and surgery to remove the gallbladder may be considered. For patients with high risk of gallstone formation in the bile duct, non-surgical treatments to widen or place a tube in the duct may be employed.
For patients with severe liver disease related to sickle cell, a liver transplant is considered for those without complications in other organs. Hematopoietic stem cell transplant, a procedure to replace the patient’s unhealthy blood-forming cells with healthy ones, could also be beneficial in halting the progression of liver disease but it cannot reverse existing issues such as liver scarring. More research is needed in this area, along with studies on gene therapy and gene editing which have the potential to greatly benefit these patients in the future.
What else can Sickle Cell Hepatopathy be?
SCH is a term that covers a range of conditions. For a patient who has sudden, sharp pain in the upper right part of the abdomen and jaundice (a yellowing of the skin), a doctor should think about several possible causes:
- An acute sickle cell hepatic crisis
- Acute hepatic sequestration
- Acute intrahepatic cholestasis
- Acute viral hepatitis
- Acute cholecystitis
- Choledocholithiasis (gallstones)
It’s also important to remember that medication or toxins could be causing acute hepatitis, which would show the same symptoms.
In cases of SCH where the patient has ongoing liver disease with consistently high liver enzyme levels, the doctor should consider:
- Chronic viral hepatitis
- Overload from blood transfusions
- Sickle cell cholangiopathy (a liver issue specific to people with sickle cell disease)
The doctor should also consider genetic conditions like hereditary hemochromatosis, and other liver diseases such as autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis. Infections caused by bacteria or fungi should be kept in mind as potential causes as well.
What to expect with Sickle Cell Hepatopathy
Studies from autopsies reveal that approximately 16% to 29% of people with SCD (Sickle Cell Disease) suffer from cirrhosis, making chronic liver disease a significant issue for these individuals. It’s recommended that people with SCD undergo yearly liver function tests. If the level of serum ALT (a liver enzyme) is twice the normal limit, it suggests there may be an ongoing issue with the liver, which should be investigated further. However, patients with SCD may commonly have mildly increased ALT and AST (another liver enzyme) levels due to the process of red blood cells breaking down.
There’s limited evidence in regards to identifying those at risk of developing chronic liver disease and the best preventive measures to hinder further disease progression. Possible interventions such as hydroxyurea (used for those with numerous episodes of blood vessels getting blocked), exchange transfusions to maintain HbS levels below 30%, and ursodeoxycholic acid (a medicine for liver diseases) could be considered as they have shown some benefit.
Possible Complications When Diagnosed with Sickle Cell Hepatopathy
SCH, which is a health issue involving the liver, can either be a mild, self-resolving problem or it can become quite severe and lead to serious liver damage. In extreme cases, it might even require an urgent procedure known as an exchange transfusion.
A past research study which focused on severe cases of SCH — characterized by extremely high bilirubin levels (with total bilirubin exceeding 13.0 mg/dL) — concluded that these patients suffered a significantly increased amount of organ failure. It is also worth noting that approximately 7% of SCD-related deaths are attributed to complications resulting from SCH.
Preventing Sickle Cell Hepatopathy
Teaching patients about sickle cell disease (SCD) and sickle cell hepatic crisis (SCH) is highly important, especially since there isn’t a lot of simple-to-understand information about SCH. Patients need to learn the signs of a severe sickle cell crisis, which could involve a sudden liver crisis requiring a hospital stay. It’s also vital that patients keep a regular schedule of check-ups with their blood specialists or primary physicians. In routine health screenings, liver function tests should be carried out to keep track of the liver’s health, and if any issues are found, more tests will be required.
Patients also need to learn about gallstones, a widely found issue. They should be able to recognize the signs, like pain in the upper right area of the stomach that gets worse when they consume fatty foods. They should avoid spicy and fatty food, and if this is an ongoing problem, they might need to learn about potential surgery. Patients with SCH also need to understand the importance of getting vaccines like Hepatitis A and B. Those with less severe forms of SCH need to be aware of what cirrhosis looks like and should keep in close contact with their doctors to ensure no serious issues go unnoticed.
