Differential diagnosis of jaundice
The differential diagnosis of jaundice can be quite tricky. So, we’ve decided to make
things clearer in this Chalk Talk episode.
Jaundice, also known as icterus, is defined as the yellowish discoloration of the skin,
sclerae, and mucous membranes due to the deposition of bilirubin, which is increased in hyperbilirubinemia.
Bilirubin occurs in two forms in serum: as indirect bilirubin, also termed unconjugated
bilirubin, and direct bilirubin, also called conjugated bilirubin. Accordingly, hyperbilirubinemia
can be divided into two types: unconjugated hyperbilirubinemia and conjugated hyperbilirubinemia.
If the hepatic capacity to conjugate the liver has been reached, indirect bilirubin accumulates.
It’s mainly caused by two types of disorders: hemolysis and dyserythropoiesis, which is
the defective development of red blood cells.
Defective conjugation of bilirubin by the liver also leads to increased indirect bilirubin
levels. An example is Gilbert syndrome, an inherited disorder in which the liver can’t
fully process bilirubin due to a decreased activity of the UDP-glucuronosyltransferase
enzyme. Now let's move on to conjugated hyperbilirubinemia.
As its name suggests, conjugated hyperbilirubinemia is associated with elevated direct serum bilirubin
levels. However, some conditions that also show a concurrent increase in indirect bilirubin.
Therefore, conjugated hyperbilirubinemia comprises all disorders with elevated direct serum bilirubin,
regardless of indirect bilirubin levels. A useful clinical differentiation is that in
conjugated hyperbilirubinemia, the urine dipstick test yields a positive bilirubin result, whereas
in unconjugated hyperbilirubinemia, the urine dipstick test is negative.
Conjugated hyperbilirubinemia can be further categorized into diseases associated with
damage to the hepatocytes, commonly known as liver cells. One example is acute hepatitis
caused by viruses, drugs, or toxins. Another common cause is liver cirrhosis that occurs
with end-stage liver disease. In such cases, levels of serum direct and indirect bilirubin
are elevated, as both conjugation and secretion are affected.
Biliary obstruction, also known as cholestasis, is a type of conjugated hyperbilirubinemia.
It can be caused by a gallstone or bile duct tumor.
In cholestasis, the liver is able to conjugate bilirubin; however, it can’t be excreted
into the bile. The result is an increase in direct bilirubin levels.
Jaundice can be differentiated into three types based on the cause and the location
of the pathology. These are prehepatic, intrahepatic, and extrahepatic. The diseases within each
group usually show similar laboratory findings.
However, there’s an important exception. Although Gilbert syndrome is the result of
a gene defect that’s apparent in hepatocytes, laboratory findings are similar to those of
other diseases with prehepatic jaundice. Let’s take a detailed look:
In prehepatic jaundice, the liver’s capacity to conjugate bilirubin has been reached, leading
to an increase in indirect bilirubin. In contrast to bile retention, total serum bilirubin levels
rarely exceed 10 milligrams per deciliter. In the case that levels are higher, a prehepatic
cause is rather unlikely.
In prehepatic jaundice, direct bilirubin levels are usually normal, as there’s no impaired
drainage.
The bilirubin analyzed in the urine dipstick represents direct bilirubin. In prehepatic
jaundice, the urine dipstick test is negative, because serum direct bilirubin levels aren’t
increased.
In contrast, urinary urobilinogen levels are elevated. So, how can this be explained? Although
the liver’s capacity to conjugate bilirubin has been reached, there’s an increase in
bilirubin conjugation, resulting in higher bilirubin excretion into the bile. As a result,
more urobilinogen is produced in the colon, which is reabsorbed. The result is an increase
in serum urobilinogen levels. A higher fraction of urobilinogen than usual is excreted into
the urine, which can be detected using the urine dipstick.
In prehepatic jaundice, hepatocytes and bile ducts aren’t involved. So, serum levels
of transaminases, alkaline phosphatase, and gamma-glutamyl transferase are normal, provided
there is no concomitant disease.
How is it possible to further differentiate between the two examples shown here?
In hemolysis, laboratory findings reveal low hemoglobin levels and often reduced levels
of haptoglobin. In addition, LDH levels are elevated as a result of cell damage, and there’s
a reactive increase in the reticulocyte count. Dyserythropoiesis is characterized by low
hemoglobin levels. In contrast to hemolysis, the reticulocyte count is low.
Gilbert syndrome is caused by decreased UDP-glucuronosyltransferase enzyme activity. Although the disease occurs
in the liver, laboratory findings suggest a prehepatic cause. So, Gilbert syndrome is
categorized into prehepatic jaundice because it represents a common differential diagnosis.
Classical laboratory findings are elevated indirect bilirubin, the absence of bilirubin
in urine, and normal serum transaminase levels. However, urine urobilinogen levels are decreased
in Gilbert syndrome.
So, how can this be explained? Bilirubin conjugation is impaired in Gilbert syndrome. A lower amount
of bilirubin reaches the colon, resulting in less urobilinogen produced. The result
is lower levels of urinary urobilinogen. However, this decrease can’t be detected using the
urine dipstick test because it provides only semiquantitative measurements.
In contrast to hemolysis, urobilinogen levels aren’t elevated in Gilbert syndrome. Moreover,
the patient’s history provides an important clue to its presence: Episodes of mild jaundice
can be triggered by fasting or stress.
Let’s move on to intrahepatic jaundice. Hepatocyte damage leads to increased levels
of both direct and indirect bilirubin. In the hepatocyte, there is simultaneous uptake,
conjugation, and excretion of bilirubin, with impairment of all three processes in intrahepatic
jaundice. However, the rate-limiting step is the active transport of bilirubin from
the hepatocyte to the bile canaliculi. Therefore, the predominant feature in intrahepatic jaundice
is the reduced excretion of bilirubin, whereas conjugation is impaired to a lesser degree.
Direct bilirubin can re-exit the hepatocyte through blood vessels, resulting in increased
serum direct bilirubin levels. This intrahepatic cholestasis is present in many disorders.
Now let’s move on to urinary bilirubin. Because serum direct bilirubin levels are
elevated, there is an increase in the excretion of direct bilirubin in urine, which can be
detected in the urine dipstick test. The urine is dark, as bilirubin has a yellow-orange
color.
Urinary urobilinogen levels vary in intrahepatic jaundice. Urobilinogen levels are either normal
or increased. Elevated levels indicate that urobilinogen can’t be excreted by the liver
following resorption, resulting in more urobilinogen excreted into the urine. Depending on the
amount of bilirubin excreted via the gallbladder, the stool can have a pale, clay-color.
A characteristic of intrahepatic jaundice is a significant increase in serum transaminases,
which indicates hepatic cell damage, with levels exceeding 500 units per liter. In contrast,
serum levels of alkaline phosphatase and gamma-glutamyl transferase are rather mildly elevated. In
contrast to prehepatic and posthepatic jaundice, clinical findings indicate impaired liver
function. These are caused by bleeding disorders, hypoalbuminemia, and portal hypertension.
Now on to the final example. In extrahepatic jaundice, there is cholestasis, a condition
in which bile flow from the liver to the bowel is slowed or blocked. There’s a significant
elevation of serum direct bilirubin levels because bilirubin conjugation in the hepatocytes
isn’t impaired.
As a result of the blocked excretion of direct bilirubin, extrahepatic jaundice usually results
in the highest levels of serum bilirubin of the three main types of jaundice. Serum bilirubin
levels can increase to up to 30 milligrams per deciliter. Let’s use an example as a
comparison: In prehepatic jaundice, serum bilirubin levels rarely exceed 10 milligrams
per deciliter.
Direct bilirubin is excreted into the urine and not the gallbladder, resulting in high
levels of bilirubin in urine. In addition, the urine color is very dark. The stool is
often pale and clay-colored. Discolored stools occur as direct bilirubin doesn’t reach
the colon, so it’s not metabolized to stercobilin.
There’s also a decrease or absence of urobilinogen levels in urine, as the enterohepatic circulation
is impaired. This decrease in urobilinogen can’t be detected using the urine dipstick
test. However, the diagnosis of cholestasis is usually based on cholestatic enzymes and
imaging.
Hepatocytes aren’t directly affected in extrahepatic jaundice; therefore, transaminase
levels are normal or only moderately elevated in comparison to intrahepatic jaundice. Serum
transaminase levels are usually under 200 units per liter.
Alkaline phosphatase and gamma-glutamyl transferase, which are also termed cholestatic enzymes,
are often more than three times the upper reference value.
Alkaline phosphatase is an isoenzyme formed by many tissues and also by some tumors. It’s
found especially in bile ducts. In cholestasis, there’s increased alkaline phosphatase synthesis.
Therefore, it’s a classic indicator of biliary obstruction.
Gamma-glutamyl transferase levels are elevated in liver or biliary diseases, while the highest
levels occur in cholestasis. However, this enzyme is also sensitive to alcohol or drug-induced
liver damage, which induces enzyme activity. The presence of very dark urine and pale stools
also indicates an extrahepatic cause.
So, to sum up: Laboratory findings in extrahepatic jaundice characteristically show increased
serum direct bilirubin levels, significantly elevated serum alkaline phosphatase and gamma-glutamyl
transferase levels, and normal to mildly elevated serum transaminase levels. Also, an abdominal
ultrasound may show dilated extrahepatic bile ducts.
OK. As we’ve just mentioned, the causes of jaundice can be classified into three categories:
prehepatic, intrahepatic, and extrahepatic. This classification is based on serum indirect
and direct bilirubin levels as well as urine dipstick results. The complete blood count,
transaminases, and cholestatic enzymes are further important indicators of the cause
of jaundice.
However, as well as these laboratory parameters, the history and physical exam also provide
some vital clues. Does the patient have a condition affecting the hepatic or hematopoietic
system? Does the patient have a risk profile for viral hepatitis? How rapidly did jaundice
first appear, and what are the concomitant symptoms? Are there any changes to the patient’s
urine or stool?
What’s the size and consistency of the liver during the physical exam? Are there any cutaneous
signs of liver disease? Does the patient have petechiae suggesting a coagulation disorder?
In addition, you should also take note of whether the patient has ascites or if there
are signs or symptoms of encephalopathy, such as poor concentration and tremors.
Do you want to test your knowledge of jaundice? Then stay put for our quiz.