Jaundice or Hyperbilirubinemia
This section deals with questions concerning bilirubin, its dangers and the body's normal protections.
C1. WHAT IS JAUNDICE?
Jaundice is caused by excessive concentrations of bilirubin in circulating blood, technically known as Hyperbilirubinemia (high bilirubin). Jaundice is characterised by an abnormal yellow/orange colouration of the tissue, particularly noticeable in the skin and the whites of the eyes. In adults, jaundice is often associated with a range of medical conditions that adversely affect many of the functions of the liver.
Many babies are jaundiced during the first few days of life, but soon recover, sometimes with the benefit of a few days of low-level blue light phototherapy. A few babies continue to be jaundiced after ten days of life and there are a number of conditions that can cause this.
Crigler Najjar Syndrome involves persistent jaundice. If untreated, it frequently leads to dangerously high levels of bilirubin in the blood. For people with CNS, the other liver enzymes and functions are almost always normal. Other than the yellow/orange colouring, individuals are normally healthy. (However, see Question C3 and Question C12.)
C2. WHAT IS BILIRUBIN?
Bilirubin is one of the products of the normal process of breakdown of red blood cells. About 1% of red blood cells is broken down each day and is replaced. Bilirubin produced by the body is a very small molecule by biological standards. It is an orange coloured substance that is not soluble in water. The blood distributes the bilirubin and deposits it in all parts of the tissues. When blood bilirubin accumulates, deposits in the skin and eyes cause the person to appear jaundiced.
C3. WHY IS HIGH BILIRUBIN DANGEROUS?
A membrane called the blood-brain barrier protects the brain by allowing only those compounds essential to its function to pass through into the brain. Unfortunately, because of its small size, the bilirubin molecule can, under certain conditions, pass through the blood-brain barrier. It lodges in the brain and can cause serious damage to its function. This is known as kernicterus.
Kernicterus can manifest itself in a range of neurological symptoms including deafness, loss of balance, and confusion. Ultimately, death can occur. Prior to the extensive use of blue light phototherapy for CNS people some 35 years ago, most CNS people died in infancy. Even today, it is likely that this continues in some parts of the world.
The body has two natural mechanisms for guarding against this danger. Firstly, the liver normally functions so as to remove bilirubin almost as quickly as it is produced. For people with CNS this mechanism either works imperfectly or fails totally. Secondly, albumin in the blood binds to bilirubin and this provides an important defence, provided bilirubin levels do not overwhelm albumin levels. (See Question C8).
C4. HOW IS BILIRUBIN MEASURED?
In much the same way as distance in various parts of the world is measured in miles or kilometres, two different units are commonly used to report bilirubin levels in blood serum.
In the USA, bilirubin is normally reported in milligrams per decilitre (mg/dL). Laypeople familiar with this reporting will often just refer to the number, without stating the units. Thus, people with a fully functioning liver would be referred to as having bilirubin of less than 1 and people with Gilbert Syndrome (See Question C6) a bilirubin of about 3. People with CNS would routinely have levels between 10 and 20. Bilirubin levels above 20 are regarded as seriously health threatening.
In Europe, Australia and some other countries, bilirubin is reported in micromoles per litre (umol/L). One milligram/decilitre (mg/dL) is equivalent to 17.1 micromoles/litre (umol/L). Thus, when someone in the USA says that their bilirubin is 10, in Europe this would be referred to as 171.
To avoid confusion in these notes serum or plasma bilirubin concentrations will be referred to in milligrams/decilitre (mg/dL), with micromoles per litre (umol/L) given in parenthesis.
C5. HOW IS BILIRUBIN NORMALLY REMOVED FROM THE BODY?
Bilirubin is virtually insoluble in the water component of blood. With normal liver function an enzyme attaches one or two sugar molecules to the bilirubin to form glucuronides, making it water-soluble. This process is known as 'conjugation'. The conjugated bilirubin is transferred into the water-based bile and is ultimately removed from the body via the faeces and urine. For the vast majority of people, blood bilirubin remains below one mg/dL (equivalent to less than 17 umol/L).
C6. WHAT IS GILBERT SYNDROME?
About 10% of people in the general population have serum bilirubin levels of about 3 mg/dL (about 50 umol/L). This is known as Gilbert Syndrome. Many people with Gilbert Syndrome are unaware that they have it and it is usually regarded as benign. At this level of blood bilirubin, albumin provides adequate protection from possible brain damage. (For an understanding of why this is so see Question C8).
C7. WHAT IS CRIGLER NAJJAR SYNDROME?
CNS people have one or more defects in the relevant part of the genetic code of the DNA acquired from both parents. The defects can either prevent or limit the amount of enzyme produced or the enzyme may be totally or partially ineffective. (For further information on the genetic causes of CNS see Section D-Genetics).
In the most serious cases, there is virtually no effective enzyme activity. Bile analysis shows little, if any, conjugated bilirubin. In the absence of phototherapy, bilirubin recirculates in the blood and can build up to dangerous levels of 20 mg/dL (342 umol/L) and beyond.
In less serious cases there is limited activity of the enzyme and there may be some conjugated bilirubin in the bile. In some cases, treatment with the drug phenobarbital can bring about a limited increase in the amount of enzyme produced and assist in the control of serum bilirubin concentration. These cases typically maintain a serum bilirubin concentration of between 6 and 20 mg/dL (103 to 342 umol/L) depending on the type of genetic defect and the amount, if any, of phototherapy treatment received.
Because people with CNS have a reduced or absent capacity for bilirubin removal, an abnormal increase in bilirubin concentration due to accident or other illness may require urgent medical attention to prevent brain damage.
C8. HOW DOES ALBUMIN PROVIDE PROTECTION?
In well-nourished individuals the blood normally has an albumin concentration in the range 35 to 55 grams/litre. Albumin is a molecule with a molecular weight more than one hundred times that of bilirubin. It has binding sites where bilirubin molecules can and do attach themselves. Combined bilirubin/albumin molecules are too large to pass through the blood-brain barrier and thus the brain can be protected.
To visualise this it is possible to think of bilirubin having the volume of a golf ball and albumin the volume of a soccer ball. If the blood brain barrier membrane is thought of as the equivalent of the net of a soccer goal, it will be realised that the golf ball by itself could pass through the net, but it could not do so if it were firmly attached to a soccer ball.
In people with normal glucuronyl transferase production, the numbers of albumin molecules present in the blood provide many more binding sites than the number of bilirubin molecules present. As a result, virtually all of the bilirubin is attached to albumin and there is little, if any, of the dangerous so called “free” (not bound to albumin) bilirubin.
If bilirubin is not removed from the body, it builds up, and starts occupying more and more of the available albumin binding sites. Eventually it uses up virtually all the albumin sites and dangerous “free” bilirubin accumulates to do its damage.
It will be appreciated that the ratio of bilirubin molecules to albumin molecules (the molar ratio) in the blood is an important factor in the management of CNS, particularly in emergency situations.
C9. WHAT IS THE BILIRUBUN TO ALBUMIN MOLAR RATIO?
The bilirubin to albumin molar ratio is the number of bilirubin molecules present divided by the number of albumin molecules present.When the number of molecules is equal this is referred to as a molar ratio of one. When the molar ratio is close to or greater than one, there will be dangerous “free” bilirubin molecules.
For people with fully functioning livers, the molar ratio is only about 0.01. This is only about one hundredth of the very dangerous level. For people with Gilberts Syndrome the ratio is about 0.1 or about one tenth of the very dangerous level.
For people with CNS, the molar ratio of bilirubin to albumin is higher, but should be kept as low as possible. A molar ratio of 0.5 (half as many bilirubin molecules as albumin molecules) is considered relatively safe. Molar ratios above 0.7 require medical supervision and perhaps medical intervention. Molar ratios approaching 1 are dangerous and require emergency treatment to increase albumin concentration and decrease bilirubin concentration.
Because the albumin level for people obtaining good nutrition is normally within the range 35-55 grams per litre (3.5-5.5 g/dl), the molecular ratio depends mainly on the serum bilirubin concentration.
In emergency situations due to illness or accident or situations where the bilirubin concentration becomes high, the molar ratio is of critical importance. Frequent measurement of bilirubin and albumin concentrations, correct calculation of the molar ratios, and providing appropriate medical responses is essential.
C10. HOW IS THE BILIRUBIN TO ALBUMIN MOLAR RATIO MEASURED?
Clinicians do not measure molar ratios directly. They must calculate the ratio from numbers and the units in which blood test results are reported to them. The critical nature of the ratio, particularly in emergency situations, means that it is imperative that the ratio is calculated correctly. The calculations for the various units that may be used are as follows
For example, a blood test that showed 20 mg/dL of bilirubin and 4.0 g/dL of albumin would provide a bilirubin to albumin molar ratio of 0.62
A blood test that showed 250 micromoles/litre of bilirubin and 45 grams/litre of albumin would provide a bilirubin to albumin molar ratio of 0.40
C11. WHAT LEVEL OF BILIRUBIN IS REGARDED AS SAFE?
Understandably clinicians are reluctant to declare any level of bilirubin above the “normal” level as perfectly safe. Neverthertheless for CNS people, maintaining a normal level is not possible even with phototherapy. The question is: “Where does the balance lie between relatively safe bilirubin levels and phototherapy's adverse impacts on lifestyle?”
Some experienced clinicians who deal with the most serious forms of CNS prefer to focus on the bilirubin to albumin molar ratio and to always keep this at below 0.7. If lower molar ratios, close to 0.5, can be maintained without serious adverse lifestyle implications, this is highly desirable. In times of illness or accident, blood bilirubin concentrations can increase rapidly and thus the lower the molar ratio is maintained the greater the safety margin available for such contingencies.
Albumin in a healthy, well nourished person is normally about 3.5 to 5.5 grams/dL (35-55 g/L). With albumin at 4.5 g/dL, a serum bilirubin concentration of 18 mg/dL (308 umol/L) is equivalent to a molecular ratio of 0.5 Thus maintaining a serum bilirubin concentration of 18 mg/dL (273umol/L) or below is commonly regarded as an acceptable compromise for well-nourished people.
For some people with CNS Type 1 maintaining serum bilirubin at or below 18 mg/L is not easily achieved without unacceptable interference with life's activities. A higher serum bilirubin concentration of say 22 mg/dL (376 umol/L) and a bilirubin to albumin molar ratio of up to 0.7 might have to be accepted, recognising that this provides a substantially lower margin of safety. In these cases it is important to monitor both bilirubin and albumin concentrations and also the molar ratio. It is also important to examine all aspects of the phototherapy to ensure that it is as effective as possible.
If albumin concentrations were at the lower end of the normal range (3.5g/dL or 35 g/L) and serum bilirubin concentration was 25 mg/dL (435 micromoles/litre) the molar ratio would be close to 0.9. This is very serious and requires urgent action to increase albumin or reduce bilirubin, preferably both.
In summary, each CNS person is different and the level at which bilirubin levels are controlled should be established between an experienced clinician and whoever is responsible for day-to-day management of the patient.
C12. ARE ANY DRUGS UNSAFE FOR CRIGLER NAJJAR PATIENTS?
Bilirubin is not the only substance that can occupy the albumin binding sites. Some naturally occurring substances and some drugs compete with bilirubin for these sites.
If the concentration of these substances or drugs is high enough they can leave inadequate sites for bilirubin or even displace it, thus increasing the concentration of dangerous “free” bilirubin. This can be true even when the molar ratio of bilirubin to albumin otherwise appears satisfactory.
Unfortunately some drugs may be administered to CNS people for the first time when they are ill or have had an accident, when the bilirubin to albumin molar ratio may already be high.
A chart showing the tendency for various substances to occupy albumin binding sites, reducing the sites available to bilirubin, is included in Reference 1, Question B2. (See also Question C13 concerning the use of a protocol document.)
Great care needs to be taken with such a list because of new drugs being developed and because it is common for some drugs to be called different names in different countries.
C13. WHAT IS THE EFFECT OF OTHER ILLNESSES ON CNS?
Unrelated illness or accident can have serious implications for people with CNS.
Patients with fever, vomiting, dehydration or painful injuries may have significantly increased levels of non-esterified fatty acids in the blood. These compounds can cause significant displacement of bilirubin from albumin binding sites. The use of high glucose infusion rates should be considered to suppress the effects of illness and non-esterified fatty acids induced by stress.
In some circumstances, accident treatment or other emergency treatment may have to be provided by medical practitioners unfamiliar with Crigler Najjar Syndrome. It is important that alternatives are found for drugs that could have serious adverse effects. Equally, urgent medical treatment should not be delayed by concerns over possible adverse consequences when these do not exist.
For these reasons many CNS people carry with them a protocol that provides advice on dealing with a patient who has CNS. A copy of the protocol is also held in the home and, for children, at school. In some cases a medallion is worn giving access to a Medic-alert database that also has a copy of the protocol. Where this service is available its use should be encouraged.
It is strongly recommended that the medical advisor of every CNS person should develop such a protocol document based on the characteristics of the person and the particular medical environment in which the individual lives. Reference 1, Question B2 provides a basis for developing such a protocol. A protocol developed by the Clinic for Special Children, Strasburg, Pennsylvania is included in the book “God’s Golden Children” (Question B2:Reference 2).