Bilirubin, traditionally viewed as a marker for liver damage, is increasingly recognized as an important endocrine hormone and a potent antioxidant. Low levels of bilirubin are associated with an increased risk of cardiovascular adverse events. This article explores the relationship between weight loss, bilirubin levels, and overall health, drawing upon scientific studies and medical insights.
Understanding Bilirubin
Bilirubin is a brown and yellow pigment produced when the body breaks down red blood cells (RBCs). RBCs contain hemoglobin, which helps transport oxygen around the body. The RBCs have a lifespan of around 120 days, and they renew continually. The process of removing iron from each cell’s hemoglobin helps the cells break down into bilirubin and other substances. The liver plays a crucial role in processing bilirubin, making it water-soluble so that the body can excrete it.
The Journey of Bilirubin
- Production: Bilirubin originates from hemoglobin released from myoglobin and other hemoproteins during the destruction of senescent red blood cells. When a blood cell dies and is lysed, which occurs mostly in the spleen, heme is released and converted to biliverdin by heme oxygenase (HO), which is further metabolized to bilirubin by biliverdin reductase A (BVRA).
- Transportation: Bilirubin is transported to the liver by albumin, a simple protein.
- Conjugation: Liver cells absorb bilirubin, which then undergoes several chemical processes. Once in the liver, bilirubin becomes “conjugated.” This means it is water-soluble, and the body can excrete it.
- Excretion: The body ultimately expels bilirubin through stool. Bilirubin is brown and yellow, and it is this pigment that makes feces brown. In adults, bacteria in the gut break down the conjugated bilirubin to create a by-product called urobilinogen, some of which is excreted by the kidneys as urobilin. The urobilin is also what gives urine its yellow color.
Unconjugated bilirubin is toxic. Conjugated bilirubin is usually not because it can come out of the body as long as nothing interferes with its removal.
Normal Bilirubin Levels
In adults, the approximate normal range of bilirubin in the blood is less than 1.0 milligram per deciliter (mg/dL). The medical community has defined “normal” total plasma bilirubin levels as 1.7-20 µmol/L, while the Child-Pugh index indicates a value of >51 µmol/L is indicative of decompensated liver cirrhosis. Large variations in plasma bilirubin are exhibited among the general population due to age, sex, ethnicity, and other biological factors. Thus, it is difficult to define a particular range for other non-clinical conditions such as long-term exercise, acute exercise, obesity, and lean individuals. A doctor can usually detect a person’s bilirubin levels through a blood test.
High Bilirubin Levels (Hyperbilirubinemia)
High levels of bilirubin in the blood is known as hyperbilirubinemia. Elevated bilirubin levels can cause jaundice. Jaundice makes the skin and the whites of the eyes appear yellow, due to the brown and yellow bilirubin in the blood. Elevated bilirubin can lead to jaundice, which causes yellowing of the skin and eyes. The skin normally becomes yellow once levels reach over 3 mg/dL. Any person who experiences yellowing of the skin or eyes should see a doctor. It may be a sign of a serious condition.
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Causes of Elevated Bilirubin
Several conditions can cause high bilirubin levels before reaching the liver, after leaving the liver, or within the liver itself.
Before Reaching the Liver (Pre-Hepatic Phase)
Some conditions cause elevated bilirubin levels before it reaches the liver. This is the pre-hepatic or the “pre-liver” phase. The cause is hemolytic anemia and the reabsorption of internal pools of blood by the body. Hemolytic anemia occurs when too many red blood cells break down before their natural life cycle ends.
In the Liver
If the liver is not working as it should, it may be unable to make bilirubin water-soluble. This may result in too much bilirubin building up in the liver. This can be caused by:
- viruses, such as hepatitis A
- alcoholic liver disease
- some medication overdoses, including acetaminophen
- autoimmune conditions, where a disorder of the immune system causes it to attack the cells of the body rather than those that cause disease
After Leaving the Liver (Post-Hepatic Phase)
Once bilirubin has left the liver, in the “post-hepatic phase,” its levels may be elevated because it is unable to leave the body. This may result from a blockage in one of the other organs that assist excretion, such as from gallstones in the gallbladder. Other causes may include inflammation or cancer of the gallbladder, or pancreatitis.
Gilbert’s Syndrome
Gilbert’s syndrome is a mild form of high bilirubin. The levels go up and down because Gilbert’s syndrome slows down the process of removing it from the body. The fluctuation is rarely enough to cause the skin to yellow, but some people may experience symptoms such as stomach pain or fatigue. Doctors estimate that about 1 in 3 people with Gilbert’s syndrome do not experience any symptoms at all. In fact, doctors often discover the condition with a blood test performed for some other reason. There is a gene linked to Gilbert’s syndrome that shows family patterns of heredity. This gene codes for an enzyme that enables the liver to convert bilirubin to its conjugated form. The absence of this gene in Gilbert’s syndrome means that this enzyme does not work. Gilbert syndrome is a harmless liver condition in which the liver doesn't properly process bilirubin. Gilbert (zheel-BAYR) syndrome is a genetic condition passed down from your parents. This gene usually controls an enzyme that helps break down bilirubin in the liver. When someone has this ineffective gene, their blood contains too much bilirubin. This is because the body isn't producing enough of the enzyme. The modified gene that causes Gilbert syndrome is common. Many people carry one copy of this gene. In most cases, two modified copies are needed to cause Gilbert syndrome. Although it's present from birth, Gilbert syndrome usually isn't noticed until puberty or later. This is because bilirubin production increases during puberty.
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Neonatal Jaundice
Newborns with elevated levels of bilirubin have a condition that doctors call neonatal hyperbilirubinemia or jaundice in neonates. According to a 2023 overview of research, approximately 50% of full-term infants and 80% of preterm infants have visible jaundice in the first 2-4 days after birth if their serum bilirubin levels are at or above 5 mg/dL. In neonates, the liver takes several days to start adequately processing bilirubin. Neonatal jaundice occurs when the liver is not quite ready to process the bilirubin, and the accumulation in the blood causes certain tissues to look yellow.
Concerns and Significance
The seriousness and medical significance of elevated bilirubin will depend on the cause. The infant’s age, as well as whether they were born premature, is also a factor. Doctors need to distinguish whether the cause is pathologic or non-pathologic. Doctors consider jaundice in newborns to be pathologic if:
- jaundice is present on the first day of life
- bilirubin levels rise by 5 mg/dL per day or more per day, or more than 0.2 mg/dL per hour
- jaundice is present for over 2-3 weeks
For premature infants, the earlier the delivery occurs in the gestation period, the lower the threshold at which health professionals consider bilirubin levels to be excessive. High bilirubin levels can be toxic to the nervous system and cause brain damage. However, most jaundice in infants is not severe, and the symptoms resolve naturally. Prolonged jaundice is more common in infants who are breastfeeding. This type of jaundice is usually not harmful but requires close monitoring. The neonatal doctor might recommend seeing a lactation consultant, among other treatments if they diagnose jaundice.
Risk factors
If you have Gilbert syndrome, talk to a healthcare professional before taking new medicines.
Symptoms
The most common sign of Gilbert syndrome is an occasional yellowish tinge of the skin and the whites of the eyes, called jaundice. Make an appointment with a healthcare professional if you have jaundice, which has many possible causes.
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Diagnosing High Bilirubin Levels
Blood tests can measure bilirubin levels. In adults, a healthcare professional will collect a blood sample via a needle from a vein in the arm. A healthcare professional will collect a blood sample in newborns via a heel-prick. In some cases, they may instead place a device called a transcutaneous bilirubin meter on the skin. However, this may still need to be followed up with a blood test. A doctor will often request a bilirubin blood test alongside other laboratory tests to assess the function of the liver.
Additional Diagnostic Tests
Other tests may include:
- further blood tests to assess liver function and test for hepatitis, if indicated
- a physical exam, where a doctor may feel the abdominal area to see if the liver is swollen or tender
- imaging tests to visualize the liver, which might include an ultrasound, computerized X-ray with a CT scan, or high-powered images with an MRI scan
- endoscopic retrograde cholangiopancreatography if imaging tests suggest there is an obstruction of the bile duct or pancreatic duct
- an endoscopy to look at the ducts in which the bile travels to the gut
- a liver biopsy, while uncommon, involves a small sample of liver tissue evaluated at a lab
Treatment Options
Treatment depends on the underlying cause of the high bilirubin. If the cause is known, a person might remove bilirubin through treatment or lifestyle changes, such as avoiding alcohol. Infants may need phototherapy, which helps the liver break down bilirubin using a special type of blue-green light, to treat their high bilirubin levels. Some infants receive phototherapy, where a physician exposes the baby to a special kind of blue-green light. This is a standard treatment in which the light converts the bilirubin to a different form that the liver and kidneys can remove. An exchange transfusion may also be necessary to remove the blood through a thin plastic tube and replace it with blood from a suitable donor.
Weight Loss and Bilirubin: A Closer Look
Weight reduction is known to reduce several cardiovascular risk factors, but effects on bilirubin levels have not been widely reported until more recently. Emerging research suggests a link between weight loss and increased bilirubin levels.
Study on Weight Loss Therapy
One study analyzed data from the first 4 weeks of the lead-in period of the Sibutramine Cardiovascular Outcome study. A total of 10 198 patients provided body weight measurements before and after 4 weeks of sibutramine treatment (10 mg daily). The study found that short-term weight loss during administration of sibutramine in combination with diet and exercise advice is effective in increasing bilirubin levels within the reference range, with bilirubin increasing as a linear function of weight change.
Key Findings:
- A significant portion of participants experienced weight loss: 1467 (13.7%) lost greater than 0% to 1%, 2492 (23.2%) lost greater than 1% to 2%, 2280 (21.2%) lost greater than 2% to 3%, 1498 (13.9%) lost greater than 3% to 4%, and 1402 (13.1%) lost greater than 4% of their initial weight, respectively.
- Bilirubin concentrations increased linearly as a function of weight loss.
- The effect was significantly more pronounced in men compared with women (P for interaction = .003).
- Adjusted for multiple variables, each 1% increase in weight loss was associated with 0.21-micromol/L (+/- standard error 0.027) increase in men (P < .0001) and 0.11-micromol/L (+/-0.024) increase in women (P < .0001).
- At screening, bilirubin concentrations were similar between weight loss groups (around 11 micromol/L, P = .7)
Exercise and Bilirubin
Exercise training can promote the physiological health of every organ system in the body, carrying a myriad of benefits, including improving blood glucose control, cardiovascular capacity, arterial compliance, skeletal muscle function, and energy metabolism. Exercise also increases hepatic glycogen mobilization when exercise bouts are sustained beyond short bursts of high-intensity activity that rely on intramuscular stores of glucose and fat. Studies also show that increasing bilirubin levels decreases liver fat content and reduces oxidative stress in obese mice, improving adiposity and blood glucose. Other work has shown that aerobic exercise protects the liver and cardiometabolic health and adipose tissue remodeling under metabolic stress.
Exercise-Induced Mechanisms
One theory is that heme catabolism could result from exercise (especially aerobic exercise) induced damage such as repeated foot strikes, elevated core temps, and skeletal muscle breakdown (myoglobin release). In this scenario, red blood cells may become lysed and release heme (hemolysis). This released heme can be broken down to biliverdin by heme oxygenase-1 (HO-1) and further catabolized by BVRA to eventually form a stable, unconjugated bilirubin. Another hypothesis is that exercise-induced increases in bilirubin are the result of a feedback mechanism to regulate the increased oxidative stress that accompanies physical training. Indeed, the long-term exercise effect on bilirubin is associated with an increase in other antioxidant reserves as well, including total antioxidant status.
The Dose-Response Relationship
Exercise meeting or slightly exceeding the recommended 150 min of moderate to vigorous physical activity per week appears necessary to observe physiological (beneficial) increases in the plasma bilirubin. Associations have also been drawn between usual exercise behavior, where aerobic and strength training participation was positively related to plasma bilirubin levels among women. In contrast, only aerobic training participation was positively correlated in the men. There is also evidence that an acute bout of exercise (often exhaustive) can upregulate plasma bilirubin.
Bilirubin as an Antioxidant
New findings have revealed that the antioxidant bilirubin may be significantly elevated in athletes. Traditionally viewed as a marker for liver damage, bilirubin is becoming recognized as an important endocrine hormone and a potent antioxidant that activates nuclear receptors to control gene transcription that promotes many aspects of physiological health (cardiovascular health, blood glucose control, oxidative stress, and improves liver function). Increased plasma bilirubin levels can have several beneficial effects on the cardiovascular system in the context of exercise. First, bilirubin is a potent antioxidant compound that can scavenge ROS both directly and through the inhibition of the NAD(P)H oxidase.
Implications and Considerations
While elevated bilirubin levels can indicate underlying health issues, the increase associated with weight loss and exercise may reflect positive physiological adaptations. Bilirubin's role as an antioxidant and its potential benefits for cardiovascular health suggest that moderate increases within the normal range could be beneficial. However, it's essential to consider individual health conditions and consult with healthcare professionals to interpret bilirubin levels accurately.
Who is at a Higher Risk?
According to a 2023 review, newborns and older adults are at a higher risk for developing jaundice caused by elevated bilirubin levels. However, the prevalence of specific causes of elevated bilirubin can also vary depending on several factors, including age and sex.
Elevated Bilirubin with Normal Liver Enzymes
If a person has normal levels of liver enzymes, it may mean that there is another condition contributing to the elevated bilirubin levels besides liver disease. However, keep in mind that a person can still have liver damage with normal liver enzyme levels, so it is best to talk with a medical professional to determine the cause and best course of treatment.
Is High Bilirubin Life Threatening?
High levels of bilirubin are often a symptom of another underlying health condition, which can range in terms of severity and prognosis.
In infants, high levels of bilirubin in the blood can lead to serious complications if left untreated, including kernicterus, a condition that can lead to brain damage, intellectual disabilities, and issues with hearing or vision.