Increased bilirubin and jaundice

bilirubin is a yellow-orange waste product from liver, hyper = increased; aemia = ‘in blood’.

	About increased bilirubin
	What is bilirubin?
	Two types of bilirubin
	Normal lab values and when to change
	Atazanavir: key points
	Other drugs that affect bilirubin

Associated drugs: atazanavir (Reyataz); indinavir (Crixivan)

About increased bilirubin

An increase in bilirubin is a common side effect in 25– 50% of people who use the protease inhibitors atazanavir or indinavir. Only a small percentage of people with increases in bilirubin develop jaundice.

The main symptoms of jaundice are a yellowing skin, or the white of the eyes being more yellow. This side effect in itself does not damage your body.

What is bilirubin?

Bilirubin is an orange-yellow part of bile. Bile is the bright green fluid secreted by the liver to help digestion. Bilirubin is mainly formed by the normal breakdown of haemoglobin. Haemoglobin carries oxygen in red blood cells.

Bilirubin passes through the liver. It is then excreted as bile through the intestines.

When this process is interrupted, excess bilirubin stains other body tissues yellow. Fatty tissues like skin, eye tissue and blood vessels are the most easily affected.

Increased levels of bilirubin are linked with a range of illnesses and conditions. This includes jaundice associated with hepatitis and cirrhosis, anaemia, Gilbert's disease and sickle cell disease. Jaundice is common in babies. Very high levels in babies can cause permanent damage.

Two types of bilirubin

There are two types of bilirubin in the blood.

	Unconjugated (indirect) bilirubin is insoluble in water. This is the bilirubin before it reaches the liver
	Conjugated (direct) bilirubin has been converted to soluble bilirubin in the liver. It then goes into the bile to be stored in the gall bladder or sent to the intestines.

Routine blood tests for total bilirubin measure both unconjugated and conjugated bilirubin.

Increases in bilirubin with atazanavir are of unconjugated bilirubin. This occurs in around 30% of people using atazanavir. People who have lower levels of the enzymes responsible for converting bilirubin in the liver will be at a higher risk of increases in bilirubin from atazanavir.

Normal lab values and when to change

	Total bilirubin (normal range) 3 – 17 mmol/l.
	Direct bilirubin (normal range) 0 – 3 mmol/l.

Normal values may vary between different labs.

Jaundice becomes clinically detectable at levels above 40 mmol/l. You need good natural light to see this.

Treatment should be changed or the dose of atazanavir (or ritonavir) should be modified if bilirubin levels become five times the upper limit of normal (5xULN). This is at around 60-70 mmol/l.

This yellowish skin can be unusual. When related to atazanavir though it is harmless and it is not causing damage to your body.

Only a few percent of people using atazanavir discontinue because of jaundice. Jaundice reverses within a couple of days of stopping atazanavir.

Atazanavir: key points

	When related to atazanavir, high billirubin is not causing your body any damage.
	If this is too disturbing or unpleasant then it often disappears when using higher dose atazanavir without ritonavir.
	Check atazanavir levels with therapeutic drug monitoring (TDM).

Using ritonavir

Just like many other protease inhibitors, atazanavir produces better results when used with ritonavir.

	Atazanavir levels are higher after you have taken a dose, and lowest when you are due to take the next dose. Ritonavir produces higher and more consistent levels of atazanavir thoughout.
	The higher levels of atazanavir at the end of the dose will reduce the risk of resistance in people with low levels. Higher drug levels may make atazanavir stronger at reducing viral load.
	Atazanavir needs the lowest daily dose of ritonavir compared to other ritonavir-boosted regimens.

Because some people absorb higher levels of drugs anyway, some people may not need the additional boost from ritonavir. High levels of bilirubin may be a marker of high levels of atazanavir. You can’t guess this though. is best confirmed using TDM.

In practice, people who get yellow skin or eyes when they use 300 mg/day atazanavir boosted with 100 mg ritonavir are often able to change to unboosted atazanavir (at 400 mg/day). Note that the daily unboosted dose of atazanavir (2 x 200 mg) is a higher dose than the boosted dose (2 x 150 mg capsules).

It is very important that your doctor changes the formulation when not using ritonavir.

Other drugs that affect bilirubin

Many other drugs can also increase bilirubin levels. This includes anabolic steroids, some antibiotics, anti-malaria drugs, codeine, diuretics, morphine, oral contraceptives, rifampin and sulfonamides.

Drugs that can decrease bilirubin measurements include barbiturates, caffeine and penicillin.