Causes of Low Bilirubin: Current Insights and Health Impact

Bilirubin is a yellow pigment produced during red blood cell breakdown and plays a role in antioxidant defense. While high bilirubin levels are often linked to liver disease, low levels can also have clinical significance but receive less attention.

Recent research suggests reduced bilirubin may be influenced by genetic factors, diet, medications, and certain health conditions. Understanding these causes is essential for assessing potential health risks and ensuring proper management.

Bilirubin Metabolism in the Body

Bilirubin is a byproduct of heme catabolism, primarily originating from the breakdown of aging red blood cells in the spleen. Macrophages degrade hemoglobin into heme and globin, with heme undergoing enzymatic conversion by heme oxygenase to produce biliverdin. Biliverdin is then rapidly reduced by biliverdin reductase to form unconjugated bilirubin, a hydrophobic molecule that must be transported to the liver for further processing. Since unconjugated bilirubin is poorly soluble in water, it binds to albumin in the bloodstream, preventing tissue accumulation and facilitating delivery to hepatocytes.

In the liver, hepatocytes conjugate bilirubin with glucuronic acid via UDP-glucuronosyltransferase (UGT1A1), increasing its solubility for excretion into bile. Conjugated bilirubin is transported through bile ducts into the small intestine, where gut microbiota metabolize it into urobilinogen. Some urobilinogen is reabsorbed into the enterohepatic circulation, while the rest is excreted in feces as stercobilin, giving stool its brown color. A small fraction is filtered by the kidneys and excreted in urine as urobilin, contributing to its yellow hue.

Genetic Factors Linked to Low Bilirubin

Genetic variations significantly influence bilirubin levels by affecting the enzymes and transporters involved in its metabolism. One of the most studied genetic factors associated with low bilirubin is increased activity of UGT1A1, the enzyme responsible for bilirubin conjugation. Individuals with genetic variants that enhance UGT1A1 function tend to have more efficient bilirubin clearance, leading to lower circulating levels. Studies have identified specific single nucleotide polymorphisms (SNPs) in the UGT1A1 gene that contribute to this effect, particularly in certain populations.

Beyond UGT1A1, variations in bilirubin transport proteins also influence systemic levels. The ABCC2 gene encodes multidrug resistance-associated protein 2 (MRP2), a transporter that secretes conjugated bilirubin into bile. Polymorphisms enhancing MRP2 activity can accelerate bilirubin excretion, reducing its concentration in the bloodstream. Similarly, genetic modifications affecting organic anion transporting polypeptides (OATPs), such as OATP1B1 and OATP1B3, can alter bilirubin uptake into hepatocytes.

Genome-wide association studies (GWAS) have identified additional genetic loci affecting bilirubin concentrations. Variants in the SLCO1B1 gene, which encodes OATP1B1, have been linked to bilirubin level variations. These findings suggest bilirubin concentration is a polygenic trait influenced by multiple interacting genetic factors rather than a single mutation.

Nutritional and Dietary Influences

Dietary patterns and nutrient intake can affect bilirubin levels by modulating liver function, oxidative stress, and red blood cell turnover. Macronutrient composition, antioxidant content, and micronutrient availability all play a role. Low-fat diets may reduce bilirubin levels due to decreased bile production and altered hepatic processing. Since bilirubin is excreted via bile, insufficient lipid intake can impair its enterohepatic circulation, leading to lower circulating levels.

Protein intake also affects bilirubin transport, as albumin binds to unconjugated bilirubin in the bloodstream. A diet deficient in high-quality protein sources may alter bilirubin homeostasis, though individual effects vary. Additionally, micronutrients such as vitamin C and vitamin E, both potent antioxidants, may reduce the body’s reliance on bilirubin for oxidative defense, potentially lowering its concentration.

Fasting and caloric restriction influence bilirubin fluctuations. Short-term fasting tends to elevate bilirubin due to increased hemolysis and reduced hepatic clearance, while prolonged caloric restriction can have the opposite effect. When energy intake remains persistently low, liver enzyme activity and bile production may decrease, leading to diminished bilirubin metabolism. This has been observed in individuals undergoing extreme dietary interventions or suffering from malnutrition.

Medication-Related Causes

Certain medications lower bilirubin levels by enhancing hepatic clearance, altering enzyme activity, or modifying red blood cell turnover. Drugs that induce UGT1A1 expression accelerate bilirubin metabolism and excretion. Phenobarbital, a barbiturate used to treat seizures, upregulates UGT1A1 activity, leading to decreased circulating bilirubin. Clinical studies have shown phenobarbital administration results in a measurable reduction in bilirubin levels over time.

Lipid-lowering agents such as fibrates also affect bilirubin metabolism. Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPAR-α) agonist, enhances hepatic uptake and conjugation of bilirubin by stimulating UGT1A1 expression. A study in Hepatology found that patients receiving fenofibrate exhibited significantly lower bilirubin levels. Statins, primarily used to manage cholesterol, have also been noted to reduce bilirubin concentrations, though the mechanisms remain less well-defined.

Associations with Underlying Health Conditions

Low bilirubin levels have been linked to various medical conditions, particularly those affecting liver function, red blood cell turnover, and metabolic processes. While elevated bilirubin often signals hepatic dysfunction, decreased levels may indicate altered physiological states affecting its production or circulation.

One key association is with cardiovascular health. Research suggests bilirubin has antioxidant and anti-inflammatory properties, and lower levels correlate with increased risk of atherosclerosis and coronary artery disease. A study in the Journal of the American College of Cardiology found individuals with lower bilirubin concentrations had higher incidences of arterial plaque formation, reinforcing its potential protective role against oxidative stress in blood vessels.

Endocrine disorders, particularly those involving insulin resistance and metabolic syndrome, have also been linked to reduced bilirubin levels. Patients with type 2 diabetes often exhibit lower concentrations, possibly due to increased oxidative stress and impaired hepatic function. A study in Diabetes Care observed that lower bilirubin levels were independently associated with higher fasting glucose and insulin resistance markers. Additionally, thyroid dysfunction, particularly hyperthyroidism, has been associated with decreased bilirubin levels due to accelerated red blood cell metabolism and increased hepatic clearance. These findings highlight the complex interplay between bilirubin regulation and systemic health, emphasizing its relevance in clinical evaluations.