Approach to jaundice (conjugated 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 conjugated bilirubin predominates, then the patient has a conjugated hyperbilirubinemia.

Conjugated hyperbilirubinemia can be the result of direct hepatocellular injury, which might occur in viral and alcohol-induced hepatitis; or from blockage of the biliary tract, also called cholestasis, which might occur in choledocholithiasis.

Now, to determine which process is taking place, assess the liver transaminase and alkaline phosphatase levels.

If AST and ALT elevations predominate, we call it a hepatocellular pattern. Many conditions can cause hepatocellular injury, and we can use the lab data we already have to narrow our diffetrential. First, assess the degree to which liver transaminases are elevated.

If AST and ALT are elevated over a thousand units per liter, consider acute causes of hepatocellular injury, most commonly acute autoimmune hepatitis, drug-induced liver injury, ischemic hepatitis, and acute viral hepatitis. In this case, you should review the patient’s history!

Consider acute autoimmune hepatitis in a biologically female patient with a history of autoimmune disease who has conjugated hyperbilirubinemia and elevated liver transaminases.

As a clinical pearl, when autoimmune hepatitis arises, it causes an acute pattern of transaminase elevation that can even go over a thousand units per liter, but as the condition progresses, transaminase levels decrease and reach a chronic pattern in the hundreds instead of the thousands. It’s also important to keep in mind that autoimmune hepatitis is more commonly chronic than acute.

Now, patients with acute autoimmune hepatitis can experience symptoms like generalized fatigue, abdominal discomfort, anorexia, and weight loss. Sometimes, it can even become fulminant!

Check for the presence of IgG antibodies like antinuclear, anti-smooth muscle, anti-liver cytosol, anti-liver as well as anti-kidney microsomal antibodies.

Positive autoantibodies are consistent with autoimmune hepatitis.

If you see a patient who reports recent use of acetaminophen, consider drug-induced liver injury. Many medications can cause liver injury, but acetaminophen is the most common in the US. Acetaminophen is a component of many over-the-counter medications, and individuals may inadvertently, or even purposefully, ingest toxic doses.

If acetaminophen use is reported or suspected, check serum acetaminophen levels because high serum acetaminophen concentration is consistent with drug-induced liver injury.

If history reveals an episode of shock or hemodynamic instability in the hours to days prior to the onset of AST and ALT elevations, consider ischemic hepatitis, also known as “shock liver.” This is when liver enzymes rise as a result of ischemic injury to the liver. In this case, you should check LDH levels, which usually have an early, rapid rise in ischemic hepatitis, helping support the diagnosis.

Finally, conjugated hyperbilirubinemia and extreme liver transaminase elevation in combination with history findings such as fever, myalgia, nausea, vomiting, right upper quadrant abdominal pain, and jaundice, are highly suggestive of acute viral hepatitis.

Check serologies for acute infection with hepatitis viruses A, B, and C, since hepatitis D and E are less common in the US. Positive serology confirms the diagnosis of acute viral hepatitis.

Now, here’s a high yield fact to keep in mind! These causes of acute hepatocellular injury may also lead to acute liver failure, which is an important cause of jaundice that can be diagnosed in patients with liver injury from any cause who do not have a history of chronic liver disease.

In particular, acetaminophen toxicity is the most common cause of acute liver failure in the US. Individuals with acute liver failure present with jaundice, elevated liver transaminases and conjugated bilirubin, indicating hepatocellular injury. Additionally, they will have impaired synthetic function of the liver, defined as having an INR greater than 1.5; and hepatic encephalopathy, which is typically associated with confusion, agitation, and the presence of asterixis.

Okay, let’s go back to our assessment of AST and ALT levels. Let’s go through cases where AST and ALT are elevated, but to a lesser degree, in the hundreds instead of the thousands.

This indicates a chronic cause of hepatocellular injury, and the ratio of AST to ALT can help us make a diagnosis. Now, if the AST to ALT ratio is less than 1.5, consider causes like autoimmune hepatitis, hemochromatosis, Wilson disease, and cirrhosis.

Consider chronic autoimmune hepatitis in a biologically female patient with a history of autoimmune disease who has conjugated hyperbilirubinemia and elevated liver transaminases. Patients with chronic autoimmune hepatitis can often be asymptomatic and identified during screening examinations, while some may experience symptoms like generalized fatigue.

Check for the presence of IgG antibodies like antinuclear, anti-smooth muscle, anti-liver cytosol, anti-liver as well as anti-kidney microsomal antibodies.

Positive autoantibodies are consistent with autoimmune hepatitis.

Now, let’s say your patient presents with fatigue, arthropathy, diabetes, a family history of hemochromatosis, and skin hyperpigmentation.

In this case, check serum iron and transferrin levels to evaluate for hemochromatosis.

If iron and transferrin levels are elevated, perform HFE gene testing, including C282Y and H63D variants, to confirm the diagnosis.

On the other hand, if an individual under 40 years of age presents with jaundice and neurologic or psychiatric symptoms, consider Wilson disease. The patient may have a family history of the condition, and physical exam may show Kayser-Fleischer rings, which are deposits of copper around the cornea.