What is Impaired Bilirubin Conjugation?
Bilirubin, a substance found in the blood, comes in two forms – conjugated (combined with other elements) and unconjugated (not combined with other elements), with the latter being more common. Some health problems can cause issues with the body’s ability to combine, or ‘conjugate’, bilirubin. These problems could lead to an increase in the amount of unconjugated, or ‘indirect’, bilirubin in the blood.
The issues that interfere with bilirubin conjugation can be inherited (passed down from parents), or caused secondarily by things like medicine. Depending on the situation, these disorders might cause no symptoms at all, or they could result in a serious condition called bilirubin encephalopathy (or kernicterus), which affects the brain. This article will primarily explore the inherited disorders involving the conjugation of bilirubin and how they are managed.
What Causes Impaired Bilirubin Conjugation?
Seventy to ninety percent of a substance called bilirubin comes from the heme inside red blood cells. Heme gets changed into another substance called biliverdin, which is then changed into a form of bilirubin that isn’t water-soluble.
This form of bilirubin, bound to a protein called albumin, then enters a type of liver cell, where other proteins attach to it and present it for modification. This modification, called conjugation, happens in two steps and involves the addition of two parts of a molecule called glucuronic acid. Once this process is complete, bilirubin becomes water-soluble, which makes it easier to transport.
This water-soluble form of bilirubin, bilirubin diglucuronide, can then be eliminated in bile or released back into the bloodstream. When the UGTA1A enzyme, which is crucial for the conjugation process, isn’t working well, problems with bilirubin conjugation can occur.
Some inherited diseases, like Gilbert syndrome and Crigler-Najjar syndrome, can cause problems with bilirubin conjugation. Another rare inherited disorder, Lucy-Driscoll syndrome, can also contribute to too much non-water soluble bilirubin in a baby’s blood shortly after birth. This syndrome involves an unknown factor that inhibits the activity of the UGTA1A enzyme.
Excess non-water soluble bilirubin can also show up as newborn jaundice due to immature UGTA1A enzyme activity and increased breakdown of fetal red blood cells. Some common drugs that can inhibit the UGTA1A enzyme include protease inhibitors, pregnanediol, novobiocin, chloramphenicol, and gentamycin.
Risk Factors and Frequency for Impaired Bilirubin Conjugation
Crigler-Najjar syndrome is a very rare condition, affecting around 1 in a million newborns. On the other hand, Gilbert syndrome is fairly common in the United States, affecting between 5% to 10% of the population, especially those of European descent. In cases of Gilbert syndrome, the location of the UGTA1A gene mutation can vary depending on a person’s ethnic background. For instance, in white populations, the mutation is usually found in a specific area of the gene known as the TATAA element of the promoter region.
Signs and Symptoms of Impaired Bilirubin Conjugation
Gilbert syndrome is a situation where patients experience mild, long-lasting, and recurring high levels of unconjugated bilirubin (a substance that might cause jaundice) in their blood without having any damage to their blood cells. This condition also typically doesn’t affect normal liver functioning and doesn’t cause any visible changes to the liver when visualized with ultrasound. Many times, people with Gilbert syndrome may not show any signs, and the syndrome itself is discovered accidentally when conducting routine blood tests for other reasons. However, when symptoms do appear, they can include yellowish skin and the whites of the eyes (jaundice), abdominal cramping, feeling fatigued, and generally not feeling well. It’s important to know whether the patient is on certain medications like tolbutamide, rifamycin, HIV protease inhibitors, gemfibrozil, and statins, as these are broken down by the body in a certain manner and can cause toxicity in people with Gilbert syndrome.
In addition to Gilbert syndrome, there’s Crigler-Najjar type 1 syndrome, where infants show signs of jaundice a few days after being born. The jaundice tends to rapidly worsen in the second week of the infant’s life, leading to potential complications like involuntary muscle contractions, hearing loss, and difficulty controlling eye movements. There’s also a less severe version of this condition, Crigler-Najjar type 2 syndrome, which normally doesn’t cause apparent signs or symptoms but can cause jaundice and the same complications as type 1, especially during life stressors, illnesses, or fasting when bilirubin levels exceed 15 mg/dl.
Testing for Impaired Bilirubin Conjugation
If a doctor suspects a person might have Gilbert syndrome, hyperbilirubinemia, a condition that can be detected on routine blood tests and is characterized by increased levels of a substance called unconjugated bilirubin, can be an indicator. The doctor needs to exclude liver disease and hemolysis (a condition where red blood cells break early) through additional tests for at least 6 months before they can make a definite diagnosis of Gilbert syndrome.
A specific genetic test can provide definitive diagnosis. This test checks for a mutation known as the A(TA)7TAA genotype. But this test is performed only when the serum bilirubin level is greater than 5.0 mg/dl or if a treatment with a drug named irinotecan is considered. Sometimes, the doctor might choose to confirm the diagnosis by measuring bilirubin levels before and after an extended period of fasting as it tends to increase unconjugated bilirubin. However, this additional step is rarely required.
Diagnosing Crigler Najjar syndrome type 1 is a bit more challenging as there are no simple tests for it. Genetic testing can be used to check for specific known mutations such as exons 2 to 5 in a gene called UGT1A1 and confirm the diagnosis.
To tell the difference between Crigler Najjar syndrome type 1 and type 2, several tests may be used. In type 2, bilirubin levels in the blood are usually less than 15 mg/dL, and there is a decrease by more than 30% after the administration of a drug named phenobarbital. In contrast, type 1 syndrome does not react to phenobarbital treatment. Analyzing the bile pigment can also provide clues: type 1 has very low levels of conjugated bilirubin while type 2 has high levels of mono-conjugated bilirubin.
Treatment Options for Impaired Bilirubin Conjugation
If you are diagnosed with a condition called Gilbert syndrome, don’t worry – it is not harmful. Treatment is usually not needed, but if you develop severe jaundice (yellowing of the skin and eyes), a type of medication called phenobarbital might be used. It’s important to use certain drugs like statins (used to lower cholesterol), protease inhibitors (used to treat viral infections), and especially Irinotecan (a cancer medication) with caution. This is because Gilbert syndrome can slow down the processing of these drugs in the body, which could lead to severe side effects like diarrhea and myelosuppression (a decrease in the ability of the bone marrow to produce cells). Hence, being aware and careful about these medications can help avoid these severe side effects.
Crigler Najjar syndrome type 1 is a different condition that also involves the buildup of bilirubin, a substance that your body creates when it replaces old cells. The main goal of treatment for this condition is to keep bilirubin levels below 10 mg/dl, a threshold above which there could be brain damage (kernicterus). This is typically achieved through blood exchange procedures and regular phototherapy (exposure to special light) for 8 to 12 hours daily. Phototherapy changes bilirubin into a form that can be more easily removed from the body in bile and urine. However, the effectiveness of phototherapy can decrease over time.
The most effective and permanent treatment for Crigler Najjar syndrome type 1 is a liver transplant. This procedure can significantly lower the risk of brain damage if done early enough. If the brain damage isn’t too severe, it can even be reversed with a successful transplant. Additionally, gene therapy, which has shown some recent successes, may become a key treatment in the future.
As for Crigler Najjar syndrome type 2, which is less severe, treatment with lifelong phenobarbital therapy should suffice. This medication helps to lower bilirubin levels in the body by more than 25%.
What else can Impaired Bilirubin Conjugation be?
If someone has high levels of bilirubin in their blood that isn’t paired with other substances (we call this “isolated unconjugated hyperbilirubinemia”), a doctor will look to see if certain conditions might be causing it. Bilirubin is a waste product from the breakdown of red blood cells, so high levels can mean something’s not right.
Some possible causes to rule out might include:
- Sickle cell anemia, pyruvate kinase, and G6PD deficiencies: These are disorders where your body destroys red blood cells too quickly.
- Hepatic failure and portosystemic shunts: These conditions can make it harder for your liver to take in and process bilirubin. They usually come with pretty noticeable symptoms.
- Inherited disorders and certain medications: Some people have genetic conditions or take medication that makes it harder for their bodies to process bilirubin.
- Advanced cirrhosis, hyperthyroidism, and immature conjugating ability: In severe liver diseases like advanced cirrhosis, the liver’s ability to work with bilirubin is impaired. Overactive thyroid (hyperthyroidism) and immature conjugating ability (common in newborns) can also block bilirubin from being processed properly.
Figuring out the cause of high bilirubin levels can help the doctor decide on the best treatment.
What to expect with Impaired Bilirubin Conjugation
The outlook for Gilbert syndrome is very good. People with this condition can generally live a normal life. Phenobarbital, a medication, is only used when this condition causes severe jaundice, a yellowing of the skin and eyes due to excess bilirubin, a waste material in the bloodstream.
On the other hand, Crigler Najjar syndrome type 1 has a less positive outlook because it carries a high risk of kernicterus. Kernicterus is a severe form of brain damage caused by very high levels of bilirubin. However, the outlook for people with Crigler Najjar syndrome type 2 is much better.
