Approach to jaundice (unconjugated hyperbilirubinemia): Clinical sciences

Jaundice is yellow discoloration of the skin and mucous membranes caused by high levels of bilirubin in the serum, called hyperbilirubinemia.

More specifically, jaundice develops when total bilirubin exceeds 2 to 3 mg/dL. Bilirubin is produced as a result of red blood cell turn over. When heme is broken down, unconjugated or indirect bilirubin is released into the serum. It travels to the liver, where it is conjugated to glucuronic acid, and then the conjugated or direct bilirubin is released into the biliary tract. Conditions that cause elevations in either conjugated or unconjugated bilirubin can result in jaundice.

When approaching a patient with jaundice, first you should perform an ABCDE assessment to determine if your patient’s unstable or stable.

If your patient is unstable, stabilize their airway, breathing, and circulation before trying to identify the cause. Additionally, obtain IV access and put your patient on continuous vital sign monitoring.

Now, let’s go back to the ABCDE assessment and take a look at stable individuals.

In these patients, you should obtain a focused history and physical examination, and check labs, including CBC, AST, ALT, alkaline phosphatase or ALP, INR, and total and fractionated bilirubin. Fractionated bilirubin will distinguish between conjugated and unconjugated bilirubin and allow you to determine whether a conjugated or unconjugated hyperbilirubinemia is present.

If elevation in unconjugated bilirubin predominates, then the patient has unconjugated hyperbilirubinemia.

Unconjugated hyperbilirubinemia can be the result of excessive erythrocyte destruction, or hemolysis, decreased uptake of bilirubin by the liver; or problems with bilirubin conjugation by the liver.

Now to determine, which process is taking place, order some additional lab tests to assess for hemolysis, like CBC, haptoglobin, LDH and reticulocyte count.

If laboratory results show normocytic anemia and low haptoglobin, with high LDH and reticulocyte counts, then the patient has hemolytic anemia.

Conditions that cause hemolytic anemia include enzyme deficiencies, like G6PD deficiency; hemoglobinopathies, like sickle cell disease; mechanical causes, like the presence of an intravascular device; as well as immune mediated processes.

Now, to determine the cause of hemolytic anemia, order a peripheral blood smear. The appearance of red blood cells on the smear can help us determine what's going on.

If you find plasmodium parasites on the peripheral blood smear, consider malaria. History typically reveals headache, and fever, as well as time spent in a malaria-endemic area in the previous month.

Another infection that can present with hemolytic anemia is babesiosis, a tick borne disease endemic to the upper midwest and northeast United States. This can also be diagnosed with a peripheral smear, which will show protozoan parasites with a maltese cross appearance.

Now, let’s take a look at G6PD deficiency.

Going back to peripheral blood smear results, but now focusing on individuals that present with Heinz bodies and degmacytes or “bite cells”. These patients typically report that jaundice developed a week after taking a sulfa drug, like TMP-SMX, or an antimalarial, like quinine. In this case, suspect G6PD deficiency, which is an inherited enzyme disorder predisposing erythrocytes to oxidative injury.

In a person with G6PD deficiency, increased oxidative stress on red blood cells can be triggered by infection, certain medications, and even some foods, like fava beans. You can confirm the diagnosis with a G6PD assay, performed once hemolysis has resolved. Another less common, inherited enzyme deficiency causing hemolytic anemia is pyruvate kinase deficiency.

Alright, now let’s go back again to the results of the peripheral blood smear and focus on sickle-cell shaped erythrocytes.

These individuals usually are of African or mediterranean descent with a family history of anemia, and typically present with acute pain in the back, chest, or limbs.

In this case, consider Sickle cell disease, which is caused by an inherited hemoglobinopathy resulting in RBC sickling and early destruction. Hemoglobin electrophoresis can confirm the presence of hemoglobin S. Other inherited hemoglobinopathies associated with hemolytic anemia include alpha and beta thalassemias.

Ok, let’s go back to our peripheral blood smear, only this time the smear shows spherocytes.

Like the name suggests, spherocytes are round, or spherical erythrocytes, that lack central pallor, and have elevated MCHC or mean corpuscular hemoglobin concentration. They are formed when part of the RBC membrane is lost, which can happen due to an inherited disorder, like hereditary spherocytosis, or due to immune mediated processes, such as autoimmune hemolytic anemia, and hemolytic transfusion reactions.

To differentiate between these conditions, check a direct antiglobulin test, or DAT, also called Coombs test, which detects antibodies targeting the RBC membrane.

If DAT is negative and your patient has a family history of anemia; jaundice and splenomegaly on exam; consider hereditary spherocytosis, which is caused by an inherited defect of the RBC membrane.

Since the membrane defect is not immune-mediated, meaning there’s no antibodies involved, DAT testing will be negative. Other similar but less common inherited erythrocyte membrane defects include elliptocytosis and ovalocytosis, which are associated with elliptocytes and ovalocytes on peripheral blood smear.

However, if DAT is positive and a person reports fatigue and shortness of breath, they might have autoimmune hemolytic anemia or AIHA, which is characterized by autoantibodies that target and attack RBCs, and can be classified as warm or cold.

Warm AIHA is typically associated with IgG antibodies that are active at normal body temperatures, and is typically associated with diseases like lupus.

On the other hand, cold AIHA is typically associated with IgM antibodies that cause hemolysis upon exposure to cold temperatures, and can be associated with infections like mycoplasma or mononucleosis.

If DAT is positive and the patient develops fever, flank pain, or dark urine after receiving a blood transfusion, consider hemolytic transfusion reaction.