Approach to jaundice (conjugated hyperbilirubinemia): Clinical sciences

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Introduction0:00–0:54

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 patient0:54–1:20

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 patient1:20–1:54

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.

Approach to conjugated hyperbilirubinemia1:54–2:21

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.

Hepatocellular injury2:21–2:49

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.

Acute causes2:49–3:14

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.

Acute autoimmune hepatitis3:14–4:28

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.

Drug-induced liver injury4:28–5:05

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.

Ischemic hepatitis5:05–5:38

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.

Acute viral hepatitis5:38–7:11

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.

Chronic causes7:11–7:47

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.

Chronic autoimmune hepatitis7:47–8:31

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.

Hemochromatosis8:31–9:02

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.

Wilson Disease9:02–9:39

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.
Diagnostic tests include serum ceruloplasmin and 24-hour urine copper excretion. The serum ceruloplasmin will be low and urine copper excretion will be high in patients with Wilson disease.
Finally, keep in mind that cirrhosis, or end-stage liver disease, from any cause can present with jaundice and conjugated hyperbilirubinemia.

Cirrhosis9:39–10:11

History most commonly includes chronic viral or alcoholic hepatitis; while physical exam often reveals spider angiomas, ascites, and palmar erythema.
An abdominal ultrasound will show a small, nodular liver and may reveal ascites.Okay, let’s go back to our assessment of AST and ALT levels and their ratio.

Alcohol-induced hepatitis10:11–10:52

If the AST to ALT ratio is greater than 1.5, consider alcohol-induced hepatitis.A person with alcohol-induced hepatitis may present with fever and right-upper quadrant abdominal pain.
Also, They will have a history of heavy alcohol use. But, keep in mind that people with a history of heavy alcohol use can have liver injury from other causes, so other etiologies should always be considered before attributing liver injury to alcohol use.Now, let’s go all the way back to our assessment of AST, ALT, and alkaline phosphatase levels.

Extra / Intrahepatic obstruction10:52–11:37

If alkaline phosphatase elevation predominates, then cholestasis is present, which can be caused by extrahepatic or intrahepatic obstruction of the biliary tree.
The first step in evaluating a patient with conjugated hyperbilirubinemia due to cholestasis is to check an abdominal ultrasound or CT to look for extrahepatic obstruction, or obstruction originating outside of the liver.
Common causes of extrahepatic obstruction include choledocholithiasis and malignancy.If a patient presents with right upper quadrant pain, nausea and vomiting, and the abdominal ultrasound reveals a stone obstructing the common bile duct, then the patient has choledocholithiasis.

Choledocholithiasis and acute cholangitis11:37–12:53

In some cases, the stone itself may not be visible on ultrasound, but you will see dilatation of the common bile duct. If this is the case, you might need to order additional imaging with magnetic resonance cholangiopancreatography, or MRCP, to confirm the diagnosis.
Now, here's a high yield fact to keep in mind! One possible complication of choledocholithiasis is infection of the biliary tree, called acute cholangitis or ascending cholangitis.
Be sure to assess patients with common bile duct obstruction for signs and symptoms of infection, like Charcot Triad, which is fever, jaundice, and right upper quadrant abdominal pain, or Reynolds pentad, which also includes mental status changes and hypotension.
Acute cholangitis can be life-threatening, so it is a can’t miss diagnosis. On the flip side, if a patient presents with jaundice, unintentional weight loss, and abdominal pain, and abdominal ultrasound reveals a biliary or pancreatic mass, consider malignancy.

Malignancy12:53–13:50

Pancreatic tumors can compress and obstruct the bile duct externally. Other cancers, like cholangiocarcinoma, may grow within the biliary duct, causing obstruction internally.
A biopsy is usually needed to confirm the diagnosis.Ok, let's go back to the abdominal ultrasound.If the abdominal ultrasound does not show any signs of extrahepatic obstruction, you should consider intrahepatic obstruction as a cause of jaundice and conjugated hyperbilirubinemia.
This includes primary biliary cholangitis and primary sclerosing cholangitis.If an individual presents with fatigue and pruritus, and they have a history of autoimmune disease, such as Sjogren syndrome or Raynaud disease, consider primary biliary cholangitis.

Primary Biliary Cholangitis13:50–14:24

Check antinuclear and antimitochondrial antibodies. Primary biliary cholangitis is often associated with positivity for antinuclear antibodies, while antimitochondrial antibodies are diagnostic.
But if the diagnosis is unclear, a biopsy may be needed. Finally, if you are seeing a person with fatigue and pruritus, and they have an inflammatory bowel disease, like Crohn disease, consider primary sclerosing cholangitis or PSC.

Primary Sclerosing Cholangitis14:24–15:45

PSC can be diagnosed based on the appearance of the bile duct on imaging, so order an MRCP, which will reveal multifocal bile duct strictures alternating with normal or slightly dilated segments of duct, confirming the diagnosis of PSC.
Okay, now one last high yield fact to keep in mind! Let’s say you are evaluating a person with conjugated hyperbilirubinemia but AST, ALT and alkaline phosphatase levels are normal.
In this case you should consider rare inherited disorders that can cause benign elevations in conjugated bilirubin, which include Dubin-Johnson syndrome and Rotor syndrome.
These individuals have impaired movement of bilirubin from hepatocytes into the biliary tract, which results in mild conjugated hyperbilirubinemia.
These two conditions can be distinguished from one another by checking urinary coproporphyrin excretion, which will be normal in Dubin-Johnson syndrome, but elevated in Rotor syndrome.
Alright, as a quick recap… Conjugated hyperbilirubinemia can be caused by diseases that cause hepatocellular injury or by processes that obstruct the biliary tract.

Recap15:45–17:02

First assess the pattern of liver transaminase and alkaline phosphatase elevations. If liver transaminase elevations predominate, then you’re dealing with a hepatocellular pattern.
If AST and ALT are elevated in the thousands, consider acute autoimmune hepatitis, acute viral hepatitis, ischemic hepatitis, and drug-induced liver injury.
If a hepatocellular injury pattern is present, but AST and ALT are elevated to a lesser extent, consider chronic autoimmune hepatitis, hemochromatosis, Wilson disease, cirrhosis, and alcohol-induced hepatitis.
On the other hand, if alkaline phosphatase elevation predominates, consider extrahepatic causes of biliary tract obstruction, such as malignancy and choledocholithiasis; or intrahepatic causes like primary biliary cholangitis, and primary sclerosing cholangitis.