What is Unconjugated Hyperbilirubinemia?
Hyperbilirubinemia refers to a situation when there’s too much bilirubin in your blood. Bilirubin is a substance that your body makes when it breaks down red blood cells. The amount of bilirubin in your blood can get too high if there’s a problem with how your body is breaking it down. This condition can be sorted into two types, unconjugated (indirect) or conjugated (direct).
Unconjugated hyperbilirubinemia usually happens if there is too much production, poor absorption by the liver, or if your body isn’t able to break down the bilirubin properly. This condition is often seen in newborn babies, causing them to look yellow or jaundiced. This is because the high levels of unconjugated bilirubin can get into the brain causing a condition called bilirubin-induced brain damage, or kernicterus.
Furthermore, there are also some inherited conditions that can result in unconjugated hyperbilirubinemia. These include Gilbert syndrome, Crigler-Najjar syndromes type I and II, and certain inherited disorders that lead to a type of anemia known as hemolytic anemia, which is a rapid breakdown of red blood cells.
What Causes Unconjugated Hyperbilirubinemia?
Bilirubin, a yellow-orange pigment found in the bile (a liquid the liver makes), is a breakdown product of heme metabolism. Heme is part of hemoglobin in red blood cells. Most of the heme comes from the breakdown of worn-out red blood cells, while the rest comes from the breakdown of other proteins that contain heme, including proteins like myoglobin (found in muscle cells) and cytochromes.
The process of converting heme to bilirubin involves two steps. First, an enzyme called heme oxygenase transforms heme into a compound called biliverdin. This compound is then turned into an early form of bilirubin, known as unconjugated bilirubin. This last transformation is carried out by an enzyme called biliverdin reductase.
The unconjugated bilirubin is carried to the liver by a protein called albumin. In the liver, it gets processed further and combines with a substance called glucuronic acid for easier removal from the body. This combination creates a new form of bilirubin called conjugated bilirubin. The liver then releases this conjugated bilirubin into the bile, which helps it to be eliminated from the body.
However, if there is any problem with this process, unconjugated bilirubin can build up in the blood and cause an issue called hyperbilirubinemia, where there is too much bilirubin in the blood. This might happen because the body is producing too much bilirubin, the liver is not collecting it effectively, or the liver is not processing it properly. In newborns, inefficient processing of bilirubin is common and leads to a harmless type of jaundice.
Having too much bilirubin produced can be due to increased breakdown of hemoglobin and other heme proteins, for instance due to accelerated breakdown of red blood cells, a large bruise, or destruction of red blood cells in a blood transfusion. In these scenarios, people with a normal liver can efficiently process and excrete the excess bilirubin. The most severely elevated levels of unconjugated bilirubin typically occur in people with ongoing red blood cell breakdown coupled with some form of liver dysfunction.
The uptake of bilirubin by the liver can be affected by reduced blood flow to the liver such as in congestive heart failure or portosystemic shunts (when blood bypasses the liver), and some medications or contrast agents used in imaging studies. However, the hyperbilirubinemia tends to resolve once the medication is discontinued.
Lastly, the process of conjugating bilirubin (combining it with glucuronic acid) can be impaired due to genetic disorders such as Gilbert syndrome and Crigler-Najjar syndrome, which affect the activity of the enzyme UGT1A1, responsible for this step. Newborns often develop elevated levels of unconjugated bilirubin due to immature liver function and low activity of this enzyme from day 2 to 5. Furthermore, exclusive breastfeeding can cause higher bilirubin levels in the infant, leading to breast milk jaundice. Some medications, including certain antibiotics and antiviral agents, can cause elevated bilirubin levels by inhibiting the activity of the UGT1A1 enzyme. Finally, blood group incompatibility between the newborn and the mother can lead to too much bilirubin and as a consequence, newborn jaundice.
Risk Factors and Frequency for Unconjugated Hyperbilirubinemia
About half of full-term babies, and 80% of preterm babies, develop jaundice a few days after birth when their bilirubin levels in the blood are high. A very rare disease that affects bilirubin levels is Crigler-Najjar syndrome, with less than fifty known cases in the United States and around one case per million births worldwide.
In the United States, Gilbert syndrome, another disorder related to bilirubin levels, is more common, affecting approximately 9% of the population. It is usually associated with a specific genetic mutation. This mutation varies among different ethnic groups. For instance, in white populations, the Gilbert syndrome is often tied to a mutation in a specific part of a gene known as UGT1A1.
- Jaundice is more common in male newborns, while Crigler-Najjar syndrome affects both sexes equally.
- Once they reach puberty, males are more likely to have Gilbert syndrome than females, possibly due to boys having higher bilirubin production rates.
- Between 0.5% and 2.4% of infants experience breast milk jaundice. This typically begins around 2 to 5 days after birth because of increased recycling of bilirubin in the liver. The condition usually peaks at two weeks and resolves between 3 to 12 weeks.
Signs and Symptoms of Unconjugated Hyperbilirubinemia
Unconjugated hyperbilirubinemia is a condition where there’s too much bilirubin in the blood. It’s often discovered during routine blood tests, even in patients who don’t show any symptoms. However, some people may experience jaundice, a yellowing of the skin and eyes.
To determine the cause, doctors look at many factors, including the patient’s age, ethnicity, family medical history, recent medications, diet, any genetic disorders, and any history of liver disease.
Most commonly, about half of all newborns will experience a harmless condition known as ‘physiologic jaundice’ within the first five days of life. There’s another type of jaundice, called ‘Lucey-Driscoll syndrome’, which comes from the mother’s blood and occurs within the first four days after birth.
People with a condition called Gilbert syndrome usually don’t have symptoms. They occasionally have mild jaundice but no liver disease or hemolysis (breakdown of red blood cells). They may feel tired, have stomach cramps, or generally feel unwell.
Crigler-Najjar type I syndrome is a serious condition where infants show jaundice within a few days after birth and have neurological complications when bilirubin levels exceed 20 mg/dL. It quickly becomes severe and life-threatening if not treated with procedures like blood transfusion, phototherapy, or liver transplantation.
Meanwhile, patients with Crigler-Najjar type II syndrome are often symptomless and seldom show signs of jaundice and kernicterus (brain damage from severe jaundice).
During a physical exam, the doctor will look carefully at the color of the patient’s skin and eyes, especially under light, to check for jaundice. For instance, if the bilirubin level is between 2 to 3 mg/dL, only the whites of the eyes may turn yellow. With hemolytic anemia, signs of anemia and an enlarged spleen may be present.
Testing for Unconjugated Hyperbilirubinemia
If you visit your doctor with yellowish skin or eyes, also known as jaundice, the first step is to figure if your blood has too much of a substance called bilirubin. Bilirubin has two forms: unconjugated and conjugated. A urine test positive for bilirubin suggests that the levels of conjugated bilirubin are high. Since conjugated bilirubin dissolves in water, it can be passed out in your urine. The unconjugated form, however, can’t dissolve in water and hence, can’t be passed out in urine.
Your doctor’s next step might be to run some more tests. Firstly, they’ll measure your blood levels of total bilirubin, which represents both unconjugated and conjugated bilirubin. This will be followed by tests that check levels of liver enzymes (substances important for liver functions) such as aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase, and γ-glutamyl transpeptidase (GGT). They’ll also conduct a complete blood count to check for the number of different blood cells and a direct Coombs test that checks if your body’s immune system is destroying red blood cells. Other tests include measuring levels of a protein called haptoglobin and an enzyme called lactate dehydrogenase (LDH). All of these tests will help your doctor pinpoint the cause of your jaundice.
If you look sick, have a fever, or your white blood cell levels are abnormal, it could mean that you have sepsis, a serious infection that needs immediate treatment. High levels of AST and ALT indicate damage to liver cells, while high levels of alkaline phosphatase and GGT can indicate a condition called cholestasis where the flow of bile from the liver is reduced.
Other tests include a reticulocyte count, which checks if your body is making enough blood cells, and a blood smear, which checks for damaged red blood cells. Jaundice becomes noticeable when the serum total bilirubin levels exceed 3.0 mg/dL. Hyperbilirubinemia, or too much bilirubin in your blood, is said to be unconjugated when the conjugated bilirubin level is less than 15% of the total bilirubin. On the other hand, when it is conjugated, the bilirubin level is high and more than 20% of the total bilirubin.
Sometimes, people with a condition called carotenemia, which is caused by consuming too much carotene-rich food like carrots and peaches, can also present with yellow skin. But unlike jaundice, this condition doesn’t result in high bilirubin levels and doesn’t cause yellowing of the white part of the eyes, known as scleral icterus. It can be distinguished from jaundice during the physical examination with the presence of skin pigmentation on palms, soles, and other areas.
Imaging techniques like a computed tomography (CT) scan or ultrasonography can also help doctors differentiate between cholestasis and liver disease, particularly when the elevated bilirubin is the conjugated form.
Treatment Options for Unconjugated Hyperbilirubinemia
For mild cases of newborn jaundice, usually, no treatment is needed, and it goes away on its own within a few weeks. But in more severe cases, a safe treatment option is phototherapy. This is a process where the baby’s skin is exposed to a special light that transforms the substance causing jaundice, bilirubin, into a different form that can be easily flushed out of the body through urine or stool. It’s important to keep the baby well hydrated during this treatment. Outdoor sunlight is not used for this therapy as it contains harmful ultraviolet light, which can lead to sunburn and skin cancer.
In some cases, the mother’s antibodies can cause the baby’s red blood cells to break down quickly. When this happens, the baby might need a treatment called intravenous immunoglobulin therapy which lowers the levels of these antibodies. In only very rare and severe cases, where other treatments haven’t worked, a procedure called exchange transfusion might be used. It’s a process of swapping out the baby’s blood with donor blood to reduce the levels of bilirubin and maternal antibodies.
Gilbert syndrome is another condition related to jaundice, but the important thing to remember is that it’s generally harmless and has a good prognosis. The main features of this condition are normal liver function and high bilirubin levels which are confirmed with tests. As the condition is not harmful in the long run, medication is usually not needed for treatment. However, you need to be careful with certain medications like acetaminophen and irinotecan as there might be an increased risk of side effects.
Another condition that can cause jaundice is Crigler-Najjar Type II Syndrome. The bilirubin levels of patients with this syndrome can be effectively reduced with a medication called phenobarbital. Patients with severe bilirubin levels might need phototherapy or even exchange transfusions. However, many patients with this syndrome might not need any treatment but should still be routinely monitored to control their bilirubin levels.
Patients with Crigler-Najjar Type I Syndrome, unlike those with Type II, do not respond to phenobarbital due to the absence of a key enzyme. The treatment for bilirubin encephalopathy, a condition caused by high bilirubin levels, is plasma exchange transfusion followed by long-term phototherapy. In plasma exchange transfusion, the bilirubin-saturated blood protein is replaced with free protein, which helps remove bilirubin from the tissues. Phototherapy helps convert bilirubin into a form that can be eliminated in urine. However, it may cause some short-term complications like reduced cardiac output, renal perfusion, increased cerebral perfusion, overheating, skin rash, and rarely, bronze baby syndrome.
Oral calcium phosphate is sometimes used in conjunction with phototherapy. Calcium phosphate interrupts the cycle of bilirubin in the body, helping in the control of bilirubin levels. Other potential treatments include filtering of blood using a plasmapheresis machine and a liver transplant. Furthermore, there is ongoing research to investigate the possibilities of hepatocyte transplantation and gene therapy for treating Crigler-Najjar Type I Syndrome.
Lastly, Crigler-Najjar Type II Syndrome and Gilbert syndrome typically do not require treatment. For patients with Crigler-Najjar Type I Syndrome, medications like phenobarbital, calcium infusions, ursodeoxycholic acid, metalloporphyrins, chlorpromazine, and cholestyramine may be used. Specific therapies help stimulate enzymes that process bilirubin, increase bile flow, inhibit bilirubin production, or increase the elimination of bilirubin from the body.
What else can Unconjugated Hyperbilirubinemia be?
Unconjugated hyperbilirubinemia is a health condition that can occur when there is a disruption in how the body processes bilirubin. This can lead to high levels of this substance in the blood, causing a yellowing of the skin and eyes, a condition known as jaundice. There are various causes of this condition, and it’s essential for healthcare professionals to distinguish it from similar conditions or diseases.
For instance, certain diseases that result in the destruction of red blood cells, such as glucose-6-phosphate dehydrogenase (G6PD) deficiency, sickle cell anemia, thalassemia, and autoimmune disorders, can lead to a significant increase in unconjugated bilirubin levels. Some conditions and diseases can disrupt the conjugation of bilirubin within the body, causing an increase in unconjugated bilirubin.
That’s the case for inherited disorders like Gilbert syndrome and Crigler-Najjar syndromes, as well as conditions like shunts in the liver’s blood vessels, heart failure, liver damage, and problems with red blood cell production. There are also some medications, liver diseases, overactive thyroid gland, infections, and normal newborn jaundice that should be considered when diagnosing the causes of unconjugated hyperbilirubinemia.
Here are the major factors to consider:
- Hemolytic disorders, which cause the destruction of red blood cells
- Inherited disorders of the enzyme glucuronosyltransferase (UGT1A1)
- Other conditions affecting the liver and heart
- Medications that interfere with bilirubin processing
- Chronic liver diseases
- Overactive thyroid condition
- Infections
- Newborn jaundice
What to expect with Unconjugated Hyperbilirubinemia
If a newborn baby experiences jaundice and receives the recommended treatment, their outlook is usually very good. In most scenarios, the condition subsides within a week or two. In certain cases, such as when the jaundice is resulted from breast milk or related to a mother’s serum, the symptoms can last for several weeks. This is why it’s important to continuously monitor the infant’s levels of bilirubin, a substance that causes the yellowish skin and eye color in jaundice, making any necessary adjustments to their treatment to prevent the buildup of too much bilirubin in the blood, a condition known as hyperbilirubinemia. The consequence of this can be potential damage to the brain, known as kernicterus or bilirubin-induced neurological dysfunction.
In cases where the body makes too much bilirubin due to ineffective erythropoiesis, which is when the body does not make enough red blood cells, the outcome is typically very good as well, depending on the underlying cause. Individuals with a genetic disorder called Crigler Najjar Syndrome Type I have a high risk of developing kernicterus, so their outlook is not as good and they need close monitoring and prompt treatment. Conversely, the outlook for patients with Crigler Najjar Syndrome Type II is more promising, as they are rarely associated with kernicterus.
People with Gilbert Syndrome, another benign or non-dangerous condition, also have a very good outlook. Individuals with this hereditary disorder can lead a normal life. Interestingly, recent studies have shown that people with Gilbert Syndrome may even have a lower risk of heart diseases. This could potentially be due to an increase in bilirubin reducing oxidative stress, which is an imbalance in the body that contributes to disease development. Finally, liver transplantation has been linked to long-term survival in patients with conditions related to jaundice.
Possible Complications When Diagnosed with Unconjugated Hyperbilirubinemia
When bilirubin levels get extremely high (25 to 30 mg/dL), it can cause a condition called bilirubin encephalopathy, also known as Kernicterus. This condition is usually seen as yellow staining in brain cells due to bilirubin build up. When this happens, cells in the brain may die or get damaged, especially in the areas responsible for regulating hormones and electrolytes, eye movement, hearing, and coordination.
The buildup of bilirubin can affect one’s vision, hearing, speech, thinking, walking, and language skills. Some common signs of this condition include cerebral palsy, hearing loss, seizures, abnormal eye movements, and underdeveloped tooth enamel. The bilirubin accumulates in the brain as a result of its combination with a substance called phosphatidylcholine.
Potential Effects:
- Vision impairment
- Hearing problems
- Speech difficulties
- Problems with thinking and coordination
- Damaged walking and language skills
- Cerebral palsy
- Hearing loss
- Seizures
- Abnormal eye movements
- Underdeveloped tooth enamel
Preventing Unconjugated Hyperbilirubinemia
Patients and their families need to be informed about jaundice and what it can lead to. Jaundice, a medical condition that makes the skin and eyes turn yellow, can sometimes be due to a state called ‘unconjugated hyperbilirubinemia’. Patients should understand that this condition can cause jaundice and determine its severity. They need to learn about what jaundice looks like and any warning signs or symptoms.
If a newborn baby has jaundice, it’s crucial for parents to understand the source of this condition, which could be either ‘physiologic’ (natural and usually harmless) or ‘non-physiologic’ (possible sign of an underlying problem), and to know what treatment options are available.
If a patient notices any changes in their mental state or in their neurological functions, such as movement or sensation, they should immediately see a doctor. Additionally, people who plan to have children and have a family history of inherited Crigler-Najjar syndromes, a rare genetic disorder that leads to severe jaundice, should seek advice from a genetics expert.
Patients and families must also be educated about how Crigler-Najjar syndromes are passed down through generations. This condition is inherited in an ‘autosomal recessive’ pattern, which means both parents need to have a copy of the mutated gene for a child to inherit the condition.
