Elevated bilirubin is one of the most frequent "unexplained" findings in the biochemistry of athletes. For the most part, it is safe, but in some cases it signals serious damage to the liver. The editors explain how to distinguish one from the other, which reasons are most typical for people who exercise, and what to do with the result.
First step: which faction is promoted
Elevated total bilirubin is only the beginning of the diagnostic search. The most important question is which fraction is responsible for the increase - indirect (unconjugated) or direct (conjugated). The further direction of the examination depends on the answer.
The causes of hyperbilirubinemia are classically divided into three groups. Suprahepatic (prehepatic) are associated with excessive formation of bilirubin, especially with hemolysis. Hepatic - with impaired capture, conjugation or removal of bilirubin by liver cells. Subhepatic - with an obstruction to the outflow of bile, for example, a stone in the bile duct.
If mainly indirect bilirubin is elevated, and ALT, AST, GGT and alkaline phosphatase are normal, it is most likely Gilbert's syndrome or hemolysis. If direct bilirubin predominates, especially with elevated liver enzymes, liver or biliary tract involvement should be sought (Fevery, 2008).
Before conclusions, it is also necessary to take into account the conditions of the intake. Fasting for more than a day, dehydration, lack of sleep, acute infection, and very intense training the day before can markedly raise indirect bilirubin, especially in people with Gilbert's syndrome.
| type | The dominant faction | Examples of reasons | Accompanying signs |
|---|---|---|---|
| Suprahepatic | Indirect | Hemolysis, including sports; hematoma disintegration | ↑ reticulocytes, ↓ haptoglobin, ↑ LDH |
| Hepatic (conjugation) | Indirect | Gilbert's syndrome | The rest of the liver parameters are normal |
| Hepatic (cell damage) | Mixed or straight | Hepatitis, toxic damage by drugs or supplements | ↑ ALT, AST |
| Cholestatic / subhepatic | Direct | Cholestasis from drugs and anabolics, stones, narrowing of the ducts | ↑ GGT, LF; dark urine, light stool, itching |
Increased indirect bilirubin in athletes
The most common cause of isolated increase in indirect bilirubin in young athletes is Gilbert's syndrome. This common hereditary feature, associated with reduced activity of the UGT1A1 enzyme (Bosma et al., 1995), does not harm health, but makes bilirubin sensitive to starvation, dehydration, stress, and exercise.
The second reason is hemolysis. In runners, erythrocytes are destroyed in the vasculature of the feet with each landing (Telford et al., 2003), and prolonged running, especially on hard surfaces, can increase the formation of bilirubin. Large hematomas after injuries also provide an additional source of heme.
The third reason is lack of energy. Calorie restriction, "drying" and weight loss before weighing increase indirect bilirubin even in people without Gilbert's syndrome, and significantly more so in people with it.
Rarely, the cause is hereditary diseases of erythrocytes (for example, hereditary spherocytosis or glucose-6-phosphate dehydrogenase deficiency), which may first appear precisely during high loads or after taking certain medications. If, along with increased bilirubin, hemoglobin decreases and reticulocytes increase, a hematologist's consultation is required.
- Gilbert's syndrome — isolated ↑ indirect bilirubin, the rest is normal.
- Hemolysis after exercise — ↑ indirect bilirubin, ↑ LDH, ↓ haptoglobin, sometimes ↑ reticulocytes.
- Starvation, dehydration — temporary ↑, disappears after normalization of nutrition.
- Hereditary anemia — ↑ bilirubin + changes in general blood analysis.
Elevated direct bilirubin: alarm signal
An increase in direct bilirubin almost always requires investigation. It means that the liver cannot normally remove already processed bilirubin or that the outflow of bile is disturbed. Typical symptoms are jaundice, itchy skin, dark tea-colored urine, and light-colored stools.
Among the reasons that are of particular importance for athletes are medicinal and toxic damage to the liver. Oral 17-alpha-alkylated anabolic steroids are associated with cholestatic jaundice, which can be prolonged and severe (Pope et al., 2014). Cholestatic and mixed lesions have also been described when taking some herbal and dietary supplements (Navarro et al., 2017).
Other causes are viral and autoimmune hepatitis, gallstone disease with duct obstruction, bile duct disease, alcoholic liver damage. Liver enzymes, ultrasound and other examinations prescribed by the doctor help to determine the cause.
The combination of a significant increase in ALT (over 3 upper limits of normal) with total bilirubin over 2 upper limits of normal with normal alkaline phosphatase in pharmacovigilance is known as Hayman's rule (Hy's law). It indicates a high risk of severe drug-induced liver damage, so such a combination requires immediate medical attention and discontinuation of the suspected agent (EASL, 2019).
Low bilirubin: should you worry?
Low bilirubin rarely attracts the attention of doctors, and such values alone do not require treatment. Many laboratories do not specify a lower limit or specify it as very low.
At the same time, bilirubin is a powerful endogenous antioxidant. Epidemiological evidence suggests that people with lower bilirubin levels have a slightly higher risk of cardiovascular disease and metabolic disorders, while moderately elevated bilirubin, such as in Gilbert's syndrome, is associated with a lower risk (Vítek, 2012). This is an association, not a proven causation.
Among the factors associated with lower bilirubin, studies mention smoking, obesity and metabolic syndrome, as well as taking certain drugs that accelerate the conjugation of bilirubin in the liver.
For an athlete with low bilirubin and normal well-being, no specific actions are required. However, this indicator can become another reason to pay attention to the general factors of cardiometabolic risk: smoking, body composition, lipids and pressure.
What to do: practical steps
If only indirect bilirubin is elevated, and other liver parameters are normal, it is reasonable to repeat the analysis under standard conditions: after a normal diet, without fasting for more than 12 hours, after a day of rest, with sufficient sleep and hydration. If the pattern is repeated, the doctor may suggest a test confirming Gilbert's syndrome and tests to rule out hemolysis.
People with confirmed Gilbert syndrome should avoid prolonged fasting and drastic calorie reduction, drink plenty of water, and plan to lose weight gradually. This is not a treatment, but a way to reduce bilirubin fluctuations and not to alarm doctors during medical examinations. Gilbert's syndrome should be reported to the doctor before prescribing new medications.
If direct bilirubin is elevated or ALT, AST, GGT, or alkaline phosphatase are elevated together with bilirubin, a doctor's examination is required. You should stop taking optional supplements and tell your doctor about all drugs, including hormonal ones. Self-administration of "biliary" means without an established diagnosis is dangerous: if the duct is blocked, it can worsen the condition.
You should immediately seek medical help if jaundice appears along with abdominal pain, fever, confusion, bleeding, or if you feel unwell.
| The situation | action |
|---|---|
| Isolated ↑ indirect bilirubin, everything else is normal | Repetition under standard conditions; discuss Gilbert's syndrome with your doctor |
| ↑ indirect + ↓ hemoglobin, ↑ reticulocytes | Examination for hemolysis, consultation of a hematologist |
| ↑ direct bilirubin ± enzymes | Doctor, ultrasound, stopping optional supplements |
| Jaundice + pain, fever, confusion | Emergency medical care |
Editorial conclusion
The assessment of elevated bilirubin begins with the determination of the fraction. An isolated increase in indirect bilirubin in athletes is most often associated with Gilbert's syndrome, starvation, dehydration, or hemolysis after exercise and is usually safe.
An increase in direct bilirubin indicates a problem with the liver or bile flow and always requires examination. Among the significant causes for athletes is toxic liver damage from supplements and oral anabolic steroids.
Low bilirubin itself is not treated, but it can be an additional reason to assess cardiometabolic risk.
We also advise you to read our articles "Bilirubin: what the analysis shows and why it is important for an athlete", "ALT and AST above or below the norm" and "Hemoglobin above or below the norm: causes in athletes and what to do".
References
- Fevery J. Bilirubin in clinical practice: a review. Liver Int. 2008;28(5):592â605.
- Bosma PJ, Chowdhury JR, Bakker C, 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):1171â1175.
- VÃtek L. The role of bilirubin in diabetes, metabolic syndrome, and cardiovascular diseases. Front Pharmacol. 2012;3:55.
- Telford RD, Sly GJ, Hahn AG, Cunningham RB, Bryant C, Smith JA. Footstrike is the major cause of hemolysis during running. J Appl Physiol. 2003;94(1):38â42.
- European Association for the Study of the Liver. EASL Clinical Practice Guidelines: drug-induced liver injury. J Hepatol. 2019;70(6):1222â1261.
- Navarro VJ, Khan I, Björnsson E, et al. Liver injury from herbal and dietary supplements. Hepatology. 2017;65(1):363â373.
- Pope HG Jr, Wood RI, Rogol A, et al. Adverse health consequences of performance-enhancing drugs: an Endocrine Society scientific statement. Endocr Rev. 2014;35(3):341â375.
