Overview of Hyperbilirubinemia

Hyperbilirubinemia is an excess accumulation of bilirubin, a brownish-yellow compound that is normally formed when red blood cells are broken down as part of their usual life cycle. Bilirubin is chemically altered by the liver into a form that can be safely excreted in stool and urine.

However, when the amount of red blood cells being broken down is abnormally high or the liver isn't able to get rid of the hemoglobin in the bloodstream, hyperbilirubinemia can occur. In infants, this can occur because the body might not be able to clear bilirubin well in the first few days of life. After that age, it may be indicative of disease.

Hyperbilirubinemia Symptoms

With hyperbilirubinemia, the excessive buildup of bilirubin can manifest with symptoms of jaundice, including:

• Yellowing of the skin and whites of the eyes
• Darkening of urine, sometimes to a brownish tone
• If the liver is the source of the issue, pale, clay-colored stools can be present

The following are symptoms that can occur simultaneously with hyperbilirubinemia as a consequence of the underlying illness (like anemia or liver disease):

• Fever
• Extreme fatigue
• Loss of appetite
• Abdominal pain
• Constipation
• Bloating
• Vomiting

Causes

Red blood cells last an average of about 120 days in our bloodstream. The body normally produces bilirubin as a by-product of the breakdown of red blood cells when they're old or have become damaged. As a consequence, our bloodstream always carries some level of bilirubin in it. When the concentration of bilirubin in our bloodstream is abnormally elevated, this is hyperbilirubinemia.

There are many different reasons why hyperbilirubinemia may occur. The causes can be broadly broken down by the type of bilirubin involved:

• Unconjugated bilirubin: It is formed by the breakdown of red blood cells. It is neither water-soluble nor able to be excreted in the urine.​ ​
• Conjugated bilirubin: Unconjugated bilirubin has been altered by the liver. It is water-soluble and more readily passed in urine and bile.

Causes of unconjugated hyperbilirubinemia include:

• Hemolytic anemia: Red blood cells are rapidly destroyed, often as a result of cancer (such as leukemia or lymphoma), autoimmune diseases (like lupus), or medications (such as acetaminophen, ibuprofen, interferon, and penicillin).
• A lack of digestive bacteria in newborns: This can cause neonatal jaundice due to impaired breakdown of bilirubin.
• Gilbert syndrome: This is a genetic disorder that causes the liver to process bilirubin slowly.
• Liver disease: This can occur if the liver is not functioning as it should.

Causes of conjugated hyperbilirubinemia include:

• Liver disease; This can occur when blood flow through the liver is impaired.
• Bile duct obstruction: Bilirubin cannot be delivered to the small intestine in bile, often as a result of cirrhosis, gallstones, pancreatitis, or tumors.

Moreover, some drugs can induce hyperbilirubinemia by impairing liver function, often due to underlying liver dysfunction or as a result of prolonged use or overuse.

These include:

• Certain antibiotics (like amoxicillin and ciprofloxacin)
• Anticonvulsives (like valproic acid)
• Antifungals (like fluconazole)
• Oral contraceptives
• Statin drugs
• Over-the-counter Tylenol (acetaminophen)

Certain herbs and herbal remedies are known to be highly toxic to the liver, including Chinese ginseng, comfrey, Jin Bu Huan, kava, kombucha tea, and sassafras.

Diagnosis

Hyperbilirubinemia can be diagnosed with a blood test. The test measures the level of total bilirubin (both conjugated and unconjugated) and direct (conjugated) bilirubin in the blood.

The indirect (unconjugated) bilirubin levels can be inferred from the total and direct bilirubin values. Although labs may use different reference ranges, there are generally accepted normal levels.

Bilirubin is often included as part of a panel of tests that evaluate liver function and enzymes, including alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase (GGT) bilirubin.

Additional tests may be ordered to pinpoint the underlying cause of the dysfunction, particularly in the presence of jaundice.

• Urinalysis: May be ordered to evaluate the amount of bilirubin excreted in the urine.
• Imaging tests: Ultrasound and computed tomography (CT) can help distinguish between biliary obstruction and liver disease, including cancer.
• Ultrasound doesn't use ionizing radiation.
• CT scans are more sensitive in detecting abnormalities of the liver or pancreas.
• Liver biopsy: This would be considered if there is a concern about possible liver cancer.

Bilirubin testing would typically be repeated to monitor your response to treatment or to track the progression or resolution of disease.

Differential Diagnoses

If your bilirubin levels are elevated, your healthcare provider will need to identify the underlying cause. It is important to remember that hyperbilirubinemia is not a disease, per se, but rather a characteristic of a disease.

To this end, your healthcare provider will classify the cause as follows:

• Pre-hepatic: The underlying process is due to a problem occurring before the liver processes bilirubin, as the result of the rapid breakdown of red blood cells.
• Hepatic: The problem involves the liver.
• Post-hepatic: The problem is the result of something occurring after the liver processes bilirubin, as the result of bile duct obstruction.

Pre-Hepatic Causes

Pre-hepatic causes are differentiated by the lack of bilirubin in the urine since unconjugated bilirubin cannot be excreted in the urine.

In addition to a panel of red blood cell tests, your healthcare provider may request a bone marrow biopsy if cancer or other serious diseases are suspected.

Hepatic Causes

Hepatic causes are characterized by elevated liver enzymes and evidence of bilirubin in the urine. A full liver function panel and imaging tests might help with identifying the problem.

A liver biopsy may be recommended if there is a possibility of liver cancer. Genetic testing may be used to distinguish between the different types of viral hepatitis or to confirm genetic disorders like hemochromatosis or Gilbert's syndrome.

Post-Hepatic Causes

Post-hepatic causes are characterized by normal unconjugated bilirubin levels and a normal spleen. A computed tomography (CT) scan, bile tract MRI, or endoscopic ultrasonography may be done if there is concern about possible gallstones, while an ultrasound and stool tests may be done if there is concern about abnormalities of the pancreas.

There is no single test that can differentiate the underlying causes of hyperbilirubinemia. Your diagnosis is based on the results obtained from a combination of tests.

Treatment

The treatment of hyperbilirubinemia depends on the underlying cause and can include approaches such as discontinuing a toxic drug, surgery, or long-term therapy.

Sometimes, hyperbilirubinemia may not require specific treatment, such as in cases of acute viral hepatitis where symptoms will typically go away on their own as the infection resolves. The same applies to Gilbert's syndrome, which is not considered harmful and does not require treatment.

A few treatment approaches:

• If the condition is drug-induced, a change of medication can resolve the effects.
• In cases of obstructive hyperbilirubinemia, surgery (usually laparoscopic) may be needed to remove gallstones or other sources of obstruction.
• Severe liver or pancreatic diseases would require the care of a qualified hepatologist, with treatment options ranging from drug therapies to an organ transplant.

Neonatal hyperbilirubinemia may not require treatment if the jaundice is mild. For moderate to severe cases, treatment may involve light therapy (which changes the structure of bilirubin molecules in newborns), intravenous immunoglobulin (which prevents the rapid breakdown of red blood cells), or a blood transfusion.

While there are no home treatments that normalize hyperbilirubinemia, you can avoid placing additional stress on the liver by cutting out alcohol, red meat, processed foods, and refined sugar.

If you are experiencing any symptoms of liver impairment, speak with your healthcare provider before taking any medications.