Hyperbilirubinemia: Causes, Symptoms, Prognosis, Diagnosis and Treatment

Bilirubin is a tetrapyrrole produced by the normal breakdown of heme. Most bilirubin occurs during the breakdown of hemoglobin.

The accumulation of bilirubin or its conjugates in body tissues produces jaundice , which is characterized by elevated levels of bilirubin in plasma and deposition of yellow bilirubin pigments in the skin, sclerotics, mucous membranes and other less visible tissues.

Because bilirubin is highly insoluble in water, it must become a soluble conjugate before it is eliminated from the body.

In the liver, uridine diphosphate (UDP) -glucuronyl transferase converts bilirubin into a mixture of monoglucuronides and diglucuronides, known as conjugated bilirubin, which is then secreted into the bile by an ATP-dependent transporter.

This process is highly efficient under normal conditions, so the concentrations of unconjugated bilirubin in plasma remain low.

A large number of pathological states lead to the accumulation of bilirubin in the plasma. Diseases that increase the rate of bilirubin formation, such as hemolysis, or diseases that reduce the rate of bilirubin conjugation, such as Gilbert’s syndrome , produce unconjugated hyperbilirubinemia.

Diseases that reduce the rate of conjugated bilirubin secretion in the bile or the flow of bile to the intestine produce a mixed or predominantly conjugated hyperbilirubinemia due to the reflux of the plasma conjugates.

Elevated levels of conjugated bilirubin usually indicate hepatobiliary disease.

Laboratory tests for bilirubin typically involve cleavage in the presence of diazotized sulfanilic acid to generate a colored azodipyrrole that can be analyzed spectrophotometrically.

Due to its limited aqueous solubility, unconjugated bilirubin reacts slowly in the absence of an accelerator, such as ethanol, while conjugated bilirubin reacts rapidly.

Total bilirubin is measured in the presence of an accelerator, while bilirubin that reacts directly is measured without an accelerator.

Bilirubin that reacts indirectly is calculated by subtracting the bilirubin score that reacts directly from the total bilirubin score.

Although the concentration of bilirubin that reacts directly approximates the concentration of conjugated bilirubin in most cases, the 2 terms do not mean the same thing. Similarly, indirect bilirubin is not the same as unconjugated bilirubin.

Kidneys do not filter unconjugated bilirubin due to its avid binding to albumin. For this reason, the presence of bilirubin in the urine indicates the presence of conjugated hyperbilirubinemia.

Normal serum total bilirubin values ​​are typically 0.2-1 mg / dL (3.4-17.1 μmol / L), of which no more than 0.2 mg / dL (3.4 μmol / L) react directly.


Conjugated hyperbilirubinemia is the result of reduced secretion of conjugated bilirubin in bile, as occurs in patients with hepatitis, or of altered bile flow in the intestine, as in patients with biliary obstruction.

The formation of bile is sensitive to various hepatic lesions, including high levels of inflammatory cytokines, as can occur in patients with septic shock . High levels of conjugated bilirubin may secondarily elevate the level of unconjugated bilirubin.

Although the mechanism of this effect is not fully defined, a possible cause is the reduced hepatic clearance of unconjugated bilirubin resulting from competition with conjugated bilirubin for uptake or excretion.

In a literature review. They selected 17 studies that included 1692 neonates who met their selection criteria for the evaluation of the etiologies of conjugated hyperbilirubinemia.

Idiopathic neonatal hepatitis was the most frequent cause in childhood (26.0%) and extrahepatic biliary atresia (25.89%) and infection (11.4%) were the most commonly specified etiologies.

The selection criteria were observed as the following:

  • Prospective / retrospective case series or cohort study with at least 10 patients.
  • Consecutive babies who presented conjugated hyperbilirubinemia.
  • Patients who received an appropriate diagnostic evaluation for conjugated hyperbilirubinemia.
  • Specific diagnoses were not excluded in the studied cohort.


Data from the United States

Conjugated hyperbilirubinemia is a common abnormality among patients with significant liver or bile disease. It can also be observed in patients with systemic diseases, such as sepsis and cardiogenic shock .

Liver frequencies and biliary diseases that cause conjugated hyperbilirubinemia are described for each specific disease.

International Data

In certain less developed countries, parasitic diseases, such as clonorchiasis and ascariasis, usually produce biliary obstruction. Hemolytic diseases, such as malaria, can predispose patients to biliary obstruction through the formation of pigmented gallstones.

Differences Related to Race, Sex and Age in Incidence

The racial and sexual differences reflect those for the specific disease states that cause conjugated hyperbilirubinemia.

The age distribution of people with conjugated hyperbilirubinemia reflects the age distribution of the underlying disease states.

This varies from the first month of life, as in cases of biliary atresia; up to half of life, as in cases of viral hepatitis or primary biliary cirrhosis ; and senescence, as in cases of gallstones and malignant tumors.


Unlike unconjugated bilirubin, conjugated bilirubin does not bind significantly to neural tissue and does not produce kernicterus or other forms of toxicity.

Green and discolored teeth have been reported as a late complication (late infancy) of prolonged conjugated hyperbilirubinemia in very low birth weight infants.

The morbidity and mortality associated with conjugated hyperbilirubinemia result from the underlying disease process.

In certain disease states, such as alcoholic hepatitis or primary biliary cirrhosis, bilirubin levels correlate strongly with, but do not contribute to, short-term mortality.

Liver enzymes are frequently monitored during hospitalization, and elevated serum bilirubin is a common finding. This hyperbilirubinemia is often caused by an underlying hematologic or hepatic disorder, but it can also be a benign finding.

The doctor must be able to identify the underlying cause when appropriate. Bilirubin is a normal byproduct of hemoglobin metabolism .

Unconjugated (indirect) bilirubin in plasma binds to albumin and is absorbed by the hepatocytes, where it is conjugated with glucuronic acid.

The conjugated (direct) bilirubin is secreted in the bile and excreted. Hyperbilirubinemia can be caused by conditions that lead mainly to unconjugated or mainly conjugated hyperbilirubinemia.

The jaundice , or yellowing of the skin, sclera and mucous membranes for bilirubin typically is clinically detectable once serum bilirubin increases above 2.5 milligrams / deciliter (mg / dL) and is often detectable first conjunctiva or under the tongue.

Hyperbilirubinemia is only dangerous in newborns, where it can cross the blood-brain barrier, deposit and cause encephalopathy (kernicterus) at levels of 20-25 mg / dl.

Life-threatening conditions that can occur with hyperbilirubinemia and jaundice include acute cholangitis, fulminant hepatic failure, massive hemolysis, and acute fatty liver of pregnancy.


Hyperbilirubinemia is not a disease as such, but rather a visible sign of an underlying disease process.

People with hyperbilirubinemia will have a yellow discoloration of the skin to varying degrees, and may also exhibit yellowing of the mucous membranes and the whites of the eyes.

However, depending on the underlying cause of Hyperbilirubinemia, people may experience different symptoms.

Some people may have very few, if any, symptoms, while others may experience more severe and pronounced symptoms. People with hyperbilirubinemia may experience any of the following signs and symptoms

  • Stool pale.
  • Dark colored urine.
  • Skin itch.
  • Nausea and vomiting.
  • Rectal bleeding.
  • Diarrhea.
  • Fever and chills.
  • Weakness.
  • Weightloss.
  • Loss of appetite
  • Confusion.
  • Abdominal pain.
  • Headache.
  • Swelling of the legs.
  • Swelling and distention of the abdomen due to the accumulation of fluid.

What is the differential diagnosis for this problem?

The differential diagnosis for hyperbilirubinemia is quite broad and includes liver causes, hematologic causes and inborn errors of metabolism.

It is important to note whether hyperbilirubinemia is an isolated laboratory abnormality, or if it is associated with other hepatic enzymes or laboratory hematologic abnormalities.

In newborns, isolated hyperbilirubinemia is often associated with congenital errors of bilirubin metabolism and includes:

  • Physiological jaundice (usually resolves on day 10).
  • Jaundice in breast milk (resolves if breast milk is interrupted).
  • Gilbert Syndrome (benign).
  • Dubin Johnson Syndrome (benign).
  • Crigler-Najjar syndrome, type I and type II. Crigler-Najjar syndrome can cause kernicterus, which must be treated.

In adults, the differential diagnosis of hyperbilirubinemia should include congenital errors of bilirubin metabolism (Gilbert syndrome, Dubin Johnson syndrome, Rotor syndrome and Crigler-Najjar syndrome) and acquired disorders of bilirubin metabolism.

Unconjugated (indirect) hyperbilirubinemia can be caused by overproduction, altered uptake by the liver, or conjugation abnormalities, which include:

The intrahepatic causes of conjugated (direct) hyperbilirubinemia include:

  • Hepatitis (viral, alcohol-induced, autoimmune, drug-induced).
  • The pregnancy.
  • Total parenteral nutrition.
  • Primary biliary cirrhosis .
  • Cholestasis induced by toxins / drugs.
  • Septicemia.

Extrahepatic causes of conjugated hyperbilirubinemia include:

  • Gallstones (cholelithiasis / choledocholithiasis), stenosis .
  • Malignancy.
  • Primary sclerosing cholangitis.
  • Infection (cholangitis / cholecystitis).
  • Pancreatitis.

Each of these individual conditions will be analyzed in a separate review.

Gilbert syndrome is a hereditary condition present in 5-10% of Western European populations that causes a 70% decrease in the liver’s ability to conjugate bilirubin.

This results in intermittent episodes of unconjugated hyperbilirubinemia, often precipitated by fasting, infection, overexertion or medication.

Gilbert’s should only be diagnosed after excluding liver disease or hemolysis, and typically total bilirubin is <5mg / dL and conjugate <20% of the total fraction.

Approach / Diagnostic Method

There are several schemes available to help determine the etiology of hyperbilirubinemia:

  1. Classification based on age:
  • Causes of adults (with congenital and acquired subsets).
  • Pediatric causes
  1. Bilirubin processing based on conjugation:
  • Conjugated hyperbilirubinemia is observed with elevated direct bilirubin; Bile can be seen in the urinalysis.
  • The unconjugated hyperbilirubinemia is observed with elevated indirect bilirubin; Bile should not be seen in urinalysis.

Elevated direct bilirubin (conjugated hyperbilirubinemia) can be caused by several factors:

  • Intrahepatic cholestasis
  • Hepatocellular injury.
  • Extrahepatic cholestasis

Indirect elevated bilirubin (unconjugated hyperbilirubinemia) can be caused by several factors:

  • Increased production: hemolysis, resorption of bruises.
  • Impaired consumption: medications, portosystemic shunts, heart failure .
  • Deteriorated conjugation: Gilbert syndrome, Crigler-Najjar.
  1. Classification based on bilirubin processing based on location:
  • Prehepatic causes: hemolysis, resorption of hematoma.
  • Intrahepatic causes: can be broken down into conjugates and unconjugated.
    • Unconjugated : Gilbert syndrome.
    • Conjugates: intrahepatic cholestasis, hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, Dubin-Johnson syndrome, Rotor syndrome.
  • Post-hepatic causes : cholelithiasis, neoplasia and pancreatitis.

Important Historical Information

Physicians will want to ask about the patient’s age, associated symptoms such as fever, weight loss or abdominal pain, a history of jaundice or abdominal surgery, social history to determine any risk factors for hepatitis (including alcohol consumption and risk factors). viral risk).

Use of medications including herbs / supplements and family history, since each of these can help diagnose the underlying etiology of hyperbilirubinemia.

Maneuvers to Diagnose the Cause

The physical examination should look for signs of jaundice or underlying liver disease ( ascites , splenomegaly, angiomata spider, gynecomastia), but there is no pathognomonic physical examination to suggest the etiology of hyperbilirubinemia.

Tests to Diagnose the Cause

Hyperbilirubinemia will obviously be detected by an elevated level of bilirubin. Conjugated bilirubinemia is observed with elevated direct bilirubin; There may also be bilirubin in the urinalysis, since the conjugated bilirubin is soluble in water.

Unconjugated bilirubinemia is seen with elevated indirect bilirubin; the urine test will be negative for bilirubin. In predominantly unconjugated hyperbilirubinemia, hemolysis should be excluded with a peripheral blood smear, haptoglobin and lactate dehydrogenase.

In predominantly conjugated hyperbilirubinemia, liver enzymes should be obtained (aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transpeptidase and alkaline phosphatase), prothrombin time and albumin.

Additional tests, such as:

  • Pregnancy test.
  • Paracetamol level.
  • Serologies for hepatitis or autoimmune disorders.
  • Radiographic ultrasound tests generally first line, lower cost, lack of exposure to radiation and sensitivity to gallstones.
  • Computed tomography.
  • Magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography.
  • Liver biopsy awaiting the results of the initial tests and the suspected etiology.


The treatment for hyperbilirubinemia depends completely on the underlying cause. Once a diagnosis has been established, the appropriate course of treatment can be initiated. Certain patients will require hospitalization, while others may be treated as outpatients in the home.

  • In certain people with Hyperbilirubinemia, the treatment will consist of supportive care and can be managed at home. For example, most cases of mild viral hepatitis can be treated at home with a doctor’s attention and supervision (expectant management).
  • The cessation of alcohol is necessary in patients with cirrhosis, alcoholic hepatitis or acute pancreatitis secondary to alcohol consumption.
  • Hyperbilirubinemia caused by drugs / drugs / toxins requires the interruption of the offending agent. In cases of overdose of paracetamol (Tylenol) intentionally or not, the antidote N-acetylcysteine ​​(Mucomyst) may be necessary.