Approach to jaundice (unconjugated hyperbilirubinemia): Clinical sciences

Chapters:

Watch video only

Introduction0:00–0:51

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.

Unstable patient0:51–1:15

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.

Stable patient1:15–1:48

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.

Unconjugated hyperbilirubinemia1:48–2:17

Hemolytic anemia2:17–3:08

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.

Malaria3:08–3:45

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”.

G6PD deficiency3:45–4:51

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.

Sickle cell anemia4:51–5:27

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.

Spherocytes5:27–6:17

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.

Spherocytosis6:17–6:53

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.

Autoimmune hemolytic anemia6:53–7:37

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.

Hemolytic transfusion reaction7:37–8:17

Hemolytic transfusion reactions occur when a person who has preexisting antibodies against erythrocytes has foreign RBCs introduced to their immune system during blood transfusion.
Hemolytic transfusion reactions can be acute, that is occuring within 24 hours of transfusion, or delayed, occurring after 24 hours and up to 30 days later.
Now, let’s take a look at Schistocytes. Let’s say the blood smear shows schistocytes, also known as “helmet cells”, which are fragmented RBCs formed when normal erythrocytes are sheared, or mechanically damaged.

Schistocytes8:17–8:33

So, if your patient’s smear shows schistocytes and their history reveals a presence of an endovascular device, like a mechanical heart valve or ventricular assistance device, consider mechanical hemolytic anemia.

Mechanical hemolytic anemia8:33–8:58

In these patients, endovascular devices can fragment red blood cells as they pass by eventually destroying them and causing hemolysis.
On the other hand, if your patient has a CBC showing schistocytes and thrombocytopenia, consider a group of conditions called microangiopathic hemolytic anemia, or MAHA for short.

Microangiopathic hemolytic anemia8:58–10:39

Keep in mind that MAHA is not associated with an endovascular device. In MAHA, small blood vessels become partially occluded due to thrombosis, causing mechanical fragmentation as erythrocytes distort to pass through the narrowed lumen.
Many conditions are associated with MAHA, including HUS or hemolytic uremic syndrome, and TTP or thrombotic thrombocytopenic purpura, as well as DIC or disseminated intravascular coagulation, and HELLP syndrome, which stands for hemolysis, elevated liver enzymes, and low platelets.Now, here’s a clinical pearl to keep in mind!
Another cause of unconjugated hyperbilirubinemia due to increased bilirubin production is resorption of extravasated blood.
This can happen in patients after acute trauma, where resolution of extensive bruising or large hematomas causes unconjugated bilirubin levels to rise.Ok, let’s go back to our assessment of CBC, LDH, haptoglobin, and reticulocyte count.
If those labs are normal, then hemolysis is not present. So we need to consider other causes of unconjugated hyperbilirubinemia such as decreased hepatic uptake of bilirubin, like as a result of taking certain medications, or you see in patients with portosystemic shunts or congestive hepatopathy.Keep in mind that some medications can interfere with hepatic uptake of bilirubin.
So, if a person develops jaundice or unconjugated hyperbilirubinemia after starting a new medication, like rifampin or probenecid, consider iatrogenic unconjugated hyperbilirubinemia.

Medication effect (iatrogenic)10:39–11:08

If this is the case, stop the offending medication, and expect bilirubin levels to return to normal once the medication is stopped.
If a patient with known liver disease develops jaundice, and labs show an increase in unconjugated bilirubin, suspect portosystemic shunting, which is when vascular connections form that allow blood to bypass the liver.

Portosystemic shunt11:08–11:48

Portosystemic shunts can develop spontaneously, or they may be created surgically during a transjugular intrahepatic portosystemic shunt or TIPS procedure, which is performed to treat complications of portal hypertension.
When a portosystemic shunt is present, less unconjugated bilirubin makes it into the liver to be conjugated, resulting in unconjugated hyperbilirubinemia.
If an individual has right upper quadrant abdominal pain, and signs of right sided heart failure like lower extremity edema and hepatojugular reflux, consider congestive hepatopathy.

Congestive hepatopathy11:48–12:26

Labs will typically show mild liver transaminase elevation and mild unconjugated hyperbilirubinemia. If you suspect the diagnosis, order abdominal ultrasound and transthoracic echocardiogram.
Abdominal ultrasound will show a nodular liver, and a transthoracic echocardiogram, will show right ventricular dysfunction, which supports the diagnosis of congestive hepatopathy.
So far we’ve covered unconjugated hyperbilirubinemia caused by increased bilirubin production from hemolysis, and by decreased uptake of bilirubin by the liver.
Finally let's consider inherited conditions that can affect conjugation in the liver. Let’s say a person presents with episodic jaundice triggered by fasting, stress, or illness, but labs show only a mild unconjugated hyperbilirubinemia and normal liver transaminases.

Gilbert syndrome12:26–14:12

This person likely has Gilbert syndrome, which is a benign condition caused by UGT1A1 gene mutation, associated with an otherwise asymptomatic mild unconjugated hyperbilirubinemia.
Genetic testing for the mutation confirms the diagnosis. Here’s a high yield fact: The UGT1A1 gene codes for bilirubin uridine diphosphate glucuronosyltransferase.
The mutation responsible for Gilbert syndrome leaves affected individuals with about 20-30% capacity to conjugate circulating unconjugated bilirubin.
However, other more serious mutations of UGT1A1 leave affected individuals with even less conjugation capacity and much more serious disease manifestations, like in Crigler-Najjar syndrome, which has 2 variants, type I and type II.
Type I disease manifests in infancy with severe hyperbilirubinemia, jaundice, and neurologic impairment, while type II presents with less severe elevations in bilirubin, less severe jaundice, and neurologic impairment that manifests later in life.
Alright, as a quick recap… Jaundice from unconjugated hyperbilirubinemia can be caused by increased production of bilirubin; decreased hepatic uptake of bilirubin; or by problems with bilirubin conjugation.
The most common causes of increased bilirubin production include hemolysis, which can occur due to a wide range of conditions.

Review14:12–15:19

These include hemoglobinopathies, such as infections, like malaria, enzyme deficiencies, like G6PD deficiency, and sickle cell disease.Other important conditions include inherited disorders of the erythrocyte membrane like hereditary spherocytosis, autoimmune hemolytic anemia, hemolytic transfusion reactions, microangiopathic hemolytic anemia, as well as mechanical hemolytic anemia.
On the flip side, conditions that can interfere with bilirubin uptake by the liver include congestive hepatopathy, portosystemic shunts, and iatrogenic causes, such as medication effects.
Finally, unconjugated hyperbilirubinemia can occur due to impaired bilirubin conjugation, which is seen in inherited conditions such as Gilbert syndrome.
bilirubin uptake by the liver include congestive hepatopathy portosystemic shunts and iatrogenic causes such as medication effects Finally unconjugated hyperbilirubinemia can occur due to impaired bilirubin conjugation which is seen