Summary
Bilirubin is the orange-yellow pigment produced when the liver breaks down haemoglobin from ageing red blood cells. Elevated serum bilirubin causes jaundice — the yellow discolouration of skin and eyes — and indicates either impaired liver processing, blocked bile flow, or excessive red blood cell destruction. Understanding whether bilirubin is predominantly 'direct' (conjugated) or 'indirect' (unconjugated) identifies the cause.
Approximately 75% of bilirubin comes from the breakdown of haemoglobin in ageing red blood cells; the remaining 25% comes from other haem-containing proteins (myoglobin, cytochromes). The liver conjugates bilirubin (making it water-soluble), then excretes it into bile for elimination via the gut.
A mildly elevated bilirubin with otherwise normal liver tests in a young person is most commonly Gilbert’s syndrome — a benign genetic variant affecting bilirubin metabolism. Gilbert’s affects around 5–10% of the UK population and requires no treatment.
Significantly elevated bilirubin (> 50 μmol/L) causing visible jaundice always warrants investigation. Distinguishing pre-hepatic (haemolysis), hepatic (hepatitis, cirrhosis), and post-hepatic (bile duct obstruction) jaundice guides management.
What It Is
Haemoglobin released from red blood cells is broken down by macrophages in the spleen and liver. The haem ring is cleaved to form biliverdin, which is rapidly reduced to unconjugated (indirect) bilirubin. This is insoluble in water and is transported to the liver bound to albumin.
In hepatocytes, bilirubin is conjugated with glucuronic acid (by UGT1A1) to form water-soluble conjugated (direct) bilirubin, which is secreted into bile and then the intestine. Gut bacteria convert it to urobilinogen, which is partially reabsorbed (enterohepatic circulation) and excreted renally, giving urine its yellow colour.
Total serum bilirubin reference range: < 21 μmol/L in most UK adults. Direct bilirubin < 5 μmol/L. Indirect bilirubin = total − direct. Jaundice becomes visible when bilirubin exceeds 35–50 μmol/L.
Functions
Liver excretory function marker
Bilirubin must be conjugated and excreted by the liver — elevated levels reveal failure at any step: conjugation, secretion, or bile flow.
Jaundice aetiology guide
The direct vs indirect bilirubin pattern distinguishes pre-hepatic (haemolysis), hepatic, and post-hepatic (obstructive) jaundice.
Liver disease severity indicator
Rising bilirubin in chronic liver disease signals decompensation and is a key component of Child-Pugh and MELD scoring.
Haemolysis detector
Elevated indirect bilirubin with normal liver enzymes points to increased red blood cell breakdown — haemolytic anaemia.
Reference Ranges
Total Serum Bilirubin
Measured in μmol/L| Status | Range (μmol/L) | Range (mg/dL) | What it means |
|---|---|---|---|
| Normal | < 21 | < 1.2 | Normal bilirubin metabolism and excretion. |
| Mildly elevated | 21–50 | 1.2–2.9 | Mild elevation — consider Gilbert's syndrome, early liver disease, or mild haemolysis. |
| Elevated | > 50 | > 2.9 | Clinical jaundice — investigate for liver disease, bile duct obstruction, or haemolysis. |
Jaundice becomes visible at approximately 35–50 μmol/L. Gilbert's syndrome causes benign mild elevation (17–70 μmol/L) without other liver enzyme abnormalities. Always fractionise (direct vs indirect) to distinguish the cause.
Symptoms of Imbalance
Elevated bilirubin is most visibly manifested as jaundice — though mild elevations are usually asymptomatic.
- Low bilirubin is not clinically significant.
- Jaundice — yellow discolouration of skin and white of the eyes (sclera)
- Dark urine (bilirubin excreted by the kidneys)
- Pale, clay-coloured stools (bile duct obstruction)
- Itching (pruritus) from bile salt deposition in skin
- Fatigue and malaise
- Nausea and abdominal pain
Causes of Imbalance
- Very low bilirubin has no established clinical significance.
- Gilbert's syndrome — benign, most common cause of mild isolated elevation
- Viral hepatitis (A, B, C, E)
- Alcoholic hepatitis
- Drug-induced liver injury
- Gallstones or bile duct obstruction
- Primary biliary cholangitis
- Haemolytic anaemia — excess red cell breakdown
- Cirrhosis
FAQs
Gilbert’s syndrome is the most common inherited cause of mildly elevated bilirubin, affecting 5–10% of the UK population. It results from a variant in the UGT1A1 gene that reduces the efficiency of bilirubin conjugation by about 30%. Bilirubin rises mildly (typically 17–70 μmol/L) during fasting, illness, or physical stress, causing transient yellow tinge to the eyes. All other liver tests are normal. It is completely benign and requires no treatment.
Jaundice (visible yellowing of skin and eyes) appears when bilirubin exceeds approximately 35–50 μmol/L. It can result from: (1) Pre-hepatic causes — excess red cell destruction (haemolysis); (2) Hepatic causes — impaired liver conjugation or excretion (hepatitis, cirrhosis); (3) Post-hepatic causes — bile duct obstruction by gallstones, tumours, or strictures. Each pattern has a distinct set of accompanying blood test abnormalities.
Dark ‘tea-coloured’ urine is caused by conjugated bilirubin being excreted in the urine — which only happens when the liver’s excretion of bilirubin into bile is impaired. Combined with pale stools (no bile reaching the gut), this pattern of ‘dark urine + pale stools + jaundice’ is classic for biliary obstruction — gallstones, pancreatic cancer, or bile duct stricture — and requires urgent investigation.
A mildly elevated bilirubin (17–50 μmol/L) with entirely normal ALT, GGT, ALP, and albumin in a young, otherwise healthy person is almost always Gilbert’s syndrome — a benign genetic condition requiring no treatment. However, any bilirubin elevation with abnormal liver enzymes, pale stools, dark urine, or persistent symptoms should be investigated promptly.
Yes. Drug-induced liver injury (DILI) is a common cause of elevated bilirubin. Common culprits include antibiotics (flucloxacillin, nitrofurantoin, co-amoxiclav), anabolic steroids, anti-TB drugs (rifampicin, isoniazid), and herbal supplements. Raised bilirubin from drugs typically occurs weeks after starting the medication. Always disclose all medications and supplements when investigating liver function.
References
- Fevery J. Bilirubin in clinical practice: a review. Liver Int. 2008;28(5):592–605. View source
- Bosma PJ, et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N Engl J Med. 1995;333(18):1171–1175. View source
- Roche SP, Kobos R. Jaundice in the adult patient. Am Fam Physician. 2004;69(2):299–304. View source