LIVER LAB

ESSENTIALS
HANDBOOK

Amer Wahed, MD
Table of contents
Abbreviation list 3

Chapter 1: Liver function

Analyzing liver function 5
Introducing liver diseases 9
Taking an appropriate history 15
Performing a physical exam 19

Chapter 2: Liver function tests

Reviewing bilirubin physiology 24
Getting to know albumin physiology 28
Covering the liver function panel 30
Figuring out prothrombin time 34

Chapter 3: Patterns of abnormal liver function

Recognizing a hepatocellular pattern 37
Identifying a cholestatic pattern 41
Diagnosing isolated hyperbilirubinemia 44

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Abbreviation list
AAT – Alpha-1 antitrypsin

ALP – Alkaline phosphatase

ALT – Alanine aminotransferase

AMA – Antimitochondrial antibodies

AST – Aspartate aminotransferase

g / day – Grams per day

g / dL – Grams per deciliter

GGT – Gamma-glutamyl transpeptidase

GI – Gastrointestinal

INR – International normalized ratio

IV – Intravenous

LDH – Lactate dehydrogenase

mg / dL – Milligrams per deciliter

mmol / L – Millimoles per liter

PT – Prothrombin time

PTT – Partial thromboplastin time

UDP – Uridine 5’-diphospho-glucuronosyltransferase

U / L – Units per liter

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 Chapter 1

LIVER
FUNCTION

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Analyzing liver function
The liver is the largest internal organ in the body. It is involved in processing dietary
amino acids, carbohydrates, lipids, and vitamins. It also metabolizes cholesterol
and toxins, produces clotting factors, and stores glycogen. As well, the liver is the
principal site for the synthesis of all circulating proteins (except gamma globulins). 

Four biomarkers are routinely measured on a liver function panel:

1. Bilirubin

2. Liver enzymes

3. Prothrombin and partial thromboplastin time 

4. Albumin

Let’s look at each of these tests in a bit more detail. 

Bilirubin
Bilirubin is a waste product that is produced from the breakdown of red blood
cells. Heme (derived from the breakdown of hemoglobin) ultimately becomes
unconjugated bilirubin, which is a water-insoluble molecule that is bound to serum
albumin in the blood. 

Unconjugated bilirubin is taken up by the liver, where it is converted to conjugated

bilirubin. Conjugated bilirubin is water-soluble and can be excreted in bile. 

Figure 1.  Heme is a  waste product that is produced from the breakdown of red blood cells. It ultimately
becomes unconjugated bilirubin and is converted to conjugated bilirubin by the liver.

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Liver enzymes
Six liver enzymes are commonly measured in a liver function panel:

1. Alanine aminotransferase (ALT) 

2. Aspartate aminotransferase (AST)

3. Alkaline phosphatase (ALP)

4. Gamma-glutamyl transpeptidase (GGT)

5. 5’-nucleotidase

6. Lactate dehydrogenase (LDH) 

Figure 2. Liver enzymes that are commonly tested on a liver function panel include alanine aminotransferase
(ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT),
5’-nucleotidase, and lactate dehydrogenase (LDH).

Prothrombin and partial thromboplastin time 

The coagulation cascade is divided into the extrinsic, intrinsic, and common
pathways. Prothrombin time (PT) is one way of measuring how long it takes
a patient’s blood to form a clot. It is a common measurement included in a liver
function panel and assesses the integrity of the extrinsic and common coagulation
pathways. 

Partial thromboplastin time (PTT) is another coagulation test. It measures the

integrity of the intrinsic and common coagulation pathways.

Except for factor VIII, all blood clotting factors are produced in the liver—including
prothrombin (which is also called factor II). Therefore, when liver function is significantly
impaired (in the acute or chronic setting), clotting factor levels will be reduced. 

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Figure 3. The coagulation cascade consists of intrinsic, extrinsic, and common pathways. Prothrombin time
(PT) measures the integrity of the extrinsic and common pathways, while partial thromboplastin time (PTT)
measures the integrity of the intrinsic and common pathways.

Albumin 
Albumin is the most common protein found in the blood. It is used by the body for
growth and tissue repair. When liver function is impaired over a prolonged period,
albumin synthesis is also impaired, which results in low levels of albumin in the
blood. For this reason, hypoalbuminemia is a common finding in chronic (but not
acute) liver failure. 

Figure 4. Albumin is the most common protein found in the blood. It is used for growth and tissue repair, and
levels are low with chronic (but not acute) liver disease.

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What do these liver function tests tell us? 
Biomolecules such as ALT, AST, ALP, and bilirubin are markers of liver injury. So, a
change in their levels suggests a pathological process causing liver damage or injury. 

In contrast, albumin, bilirubin, PT, and PTT are markers of hepatocellular function.
This means that changes in these biomarkers suggest an altered or reduced function
of the liver cells. 

Table 1.  Abnormal levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline
phosphatase (ALP), and bilirubin may suggest a pathological process that is causing liver damage or injury.
Abnormal albumin, bilirubin, prothrombin time (PT), or partial thromboplastin time (PTT) levels may suggest
reduced or altered hepatocellular function.

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Introducing liver diseases
Let’s review some of the most common liver diseases and gallbladder-related
diseases that can affect the liver: 

• Liver failure
• Hepatitis
• Cirrhosis
• Hepatocellular carcinoma 
• Nonalcoholic steatohepatitis 
• Hepatic encephalopathy 
• Wilson’s disease 
• Gilbert’s syndrome 
• Cholestasis
• Gallstones and cholecystitis 
• Cholangitis

Liver failure
Liver failure reflects a loss of liver function. Many pathological processes can lead to
liver failure, but 80–90% of liver parenchyma must be destroyed before liver failure
manifests clinically. 

Ascites is the buildup of fluid in the abdomen secondary to liver failure. The most
serious complication of ascites is spontaneous bacterial peritonitis, which is an
infection of the ascitic fluid. 

Figure 1.  Liver failure can cause ascites, a buildup of fluid in the abdomen, which can progress into
spontaneous bacterial peritonitis if the ascitic fluid becomes infected.

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Hepatitis
Hepatitis is an injury to the liver parenchyma, which is composed mainly of
hepatocytes. Hepatitis is associated with an influx of inflammatory cells into the liver. 

Hepatitis can be caused by a viral infection, autoimmune disease, or can be

secondary to drug (both legal and illegal) and alcohol use. 

Figure 2. Common causes of hepatitis include viral infection, autoimmune disease, drug use, and alcohol use. 

Cirrhosis
Cirrhosis refers to a progressive, fibrosing, nodular condition that disrupts the
normal architecture of the liver. Any chronic insult to the liver such as alcoholism,
drug use, or viral hepatitis can cause cirrhosis. 

Cirrhosis can result in portal hypertension, which is high blood pressure in the portal
vein. The most serious complication of portal hypertension is variceal bleeding
within the digestive tract.

Figure 3. Cirrhosis can occur as the result of any chronic insult to the liver such as alcoholism, drug use, or
viral hepatitis. 

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Hepatocellular carcinoma 
Hepatocellular carcinoma is a primary liver cancer. It often occurs in patients
who contracted hepatitis B or C and developed chronic cirrhosis which eventually
became cancerous.

Figure 4. Patient with hepatitis B or C may develop chronic cirrhosis which can progress into hepatocellular
carcinoma. 

Nonalcoholic steatohepatitis 
Nonalcoholic steatohepatitis is a term used to describe liver inflammation and
damage that is caused by an accumulation of fat in the liver. It is commonly
associated with obesity. This condition can also lead to cirrhosis and hepatocellular
carcinoma. 

Figure 5.  Nonalcoholic steatohepatitis can lead to liver cirrhosis which can progress into hepatocellular
carcinoma. 

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Hepatic encephalopathy 
Hepatic encephalopathy is a decline in brain function that occurs as a result of
severe liver disease. When the liver cannot adequately remove toxins, the buildup of
toxins causes brain damage. This may present as an altered level of consciousness
and neuromuscular disturbances such as a flapping tremor (known as asterixis).

Figure 6.  Symptoms of hepatic encephalopathy may include altered levels of consciousness and asterixis
(e.g., flapping tremor).

Wilson’s disease 
Wilson’s disease is a genetic disorder associated with excess copper buildup in the
brain and liver. 

Figure 7. Wilson’s disease is associated with excess copper accumulation in the brain and liver. 

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Gilbert’s syndrome 
Gilbert’s syndrome is a genetic disorder where the liver does not properly process
bilirubin which results in jaundice. 

Figure 8. Jaundice is a symptom of Gilbert’s syndrome, a genetic disorder involving the incomplete processing
of bilirubin. 

Cholestasis
Cholestasis is a condition where bile builds up in the liver and impairs liver function.
The buildup is due to impaired release from the liver cells (e.g., intrahepatic) or
obstruction of the flow through the hepatic or common bile ducts (e.g., extrahepatic). 

Figure 9. Cholestasis can be intrahepatic, where bile builds up in the liver due to impaired release from liver
cells, or extrahepatic, where the flow of bile is obstructed through the hepatic or common bile ducts. 

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Gallstones and cholecystitis
Gallstones are hardened deposits of bile that form in the gallbladder. They can
obstruct the bile ducts and the flow of bile. Cholecystitis is inflammation of the
gallbladder and is often due to gallstones blocking the cystic duct. 

Figure 10.  Gallstones can cause an obstruction of the bile ducts. This can lead to inflammation of the
gallbladder (e.g., cholecystitis), if the cystic duct becomes blocked. 

Cholangitis
Cholangitis is inflammation of the bile duct system, usually caused by a bacterial
infection. Cholangitis can occur because of an autoimmune disease (e.g., primary
sclerosing cholangitis or primary biliary cholangitis) or a gallstone obstructing the
bile ducts. 

Figure 11.  Inflammation of the bile duct system can be caused by primary sclerosing cholangitis, primary
biliary cholangitis, or a gallstone obstructing the bile ducts. 

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Taking an appropriate history
The initial evaluation of a patient should always start with an appropriate history. In
the history, we are looking for potential risk factors of liver disease:

• Exposure to hepatotoxins
• Viral hepatitis 
• Certain medical conditions
 
What are some common hepatotoxins?
Possible hepatotoxins include excessive alcohol intake, medications (prescribed
and over the counter ones including herbal remedies), and dietary supplements. As
well, be sure to ask the patient about possible exposure to hepatotoxins such as
mushrooms, and industrial agents such as vinyl chloride. 

Figure 1. Common hepatotoxins include excess alcohol, medications, supplements, mushrooms, and industrial
agents.

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Which patients are at risk for viral hepatitis?
Individuals at risk for viral hepatitis are those who use intravenous (IV) drugs,
have had blood transfusions (especially before 1992), have had sexual exposure to
affected individuals, have body piercings or tattoos, or a history of travel to areas
known to be endemic for hepatitis.

Figure 2. Risk factors for viral hepatitis include intravenous (IV) drug use, blood transfusions, sexual exposure
to affected individuals, piercings and tattoos, and travel to areas at high-risk for hepatitis. 

Which medical conditions are associated with

liver disease?
Certain medical conditions are associated with liver disease, so you should be aware
of these when taking the patient’s history. For example, a patient with right-sided
heart failure may develop congestive hepatopathy. 

In hemochromatosis, iron is deposited in tissue with resultant tissue and organ

damage. The main organs that are affected are the liver, pancreas, skin, joints, heart,
and gonads.  Individuals with hemochromatosis present with skin pigmentation,
arthritis, diabetes mellitus, and cardiomyopathy. 

Early-onset emphysema may be due to alpha-1 antitrypsin (AAT) deficiency, which

is also a cause of liver disease. 

As well, autoimmune thyroiditis may be a clue to concomitant autoimmune liver disease.

Pregnancy and inflammatory bowel disease may be associated with gallstones,
which can interfere with liver and gallbladder function. Inflammatory bowel disease
is also associated with primary sclerosing cholangitis. 

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Figure 3.  Medical conditions commonly associated with liver disease include right-sided heart failure,
hemochromatosis, alpha-1 antitrypsin (AAT) deficiency, autoimmune thyroiditis, gallstones, and primary
sclerosing cholangitis.

What are some common symptoms of liver disease?

When taking a patient history, ask about specific symptoms  that are commonly
associated with liver disease including jaundice, pruritus, gastrointestinal bleeding,
coagulopathy, increased abdominal girth, and mental status changes.  

Figure 4.  Common symptoms of liver disease include jaundice, pruritus, gastrointestinal (GI) bleeding,
coagulopathy, increased abdominal girth, and changes in mental status. 

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Early cirrhosis can manifest as anorexia, weight loss, weakness, fatigue, and
osteoporosis from inadequate vitamin D and calcium absorption. Decompensated
cirrhosis presents with ascites, spontaneous bacterial peritonitis, hepatic
encephalopathy, and variceal bleeding from portal hypertension. 

Table 1.  Symptoms of early cirrhosis include anorexia, weight loss, weakness, fatigue, and osteoporosis.
Symptoms of decompensated cirrhosis include ascites, spontaneous bacterial peritonitis, hepatic
encephalopathy, and variceal bleeding.

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Performing a physical exam
The physical examination of a patient may suggest the presence of liver disease
and point towards an underlying cause. There are 14 common signs of chronic liver
disease and cirrhosis that you may uncover during a physical exam: 

1. Jaundice

2. Clubbing 

3. Gynecomastia

4. Spider nevi

5. Testicular atrophy

6. Caput medusae

7. Palmar erythema

8. Dupuytren’s contracture

9. Muscle wasting

10. Raised jugular venous pressure

11. Parotid gland enlargement

12. Enlarged Virchow’s node

13. Hepatic encephalopathy signs 

14. Neurologic symptoms 

Now, let’s dive into each of these liver disease signs in a little more detail.

Common signs of chronic liver disease and cirrhosis

Jaundice
We may find jaundice when examining the patient’s physical appearance. Jaundice
is a yellow discoloration of the skin, mucous membranes, and sclera. This would
mean that the bilirubin level in the blood is high, at least 2 mg / dL or higher. 

Clubbing
Clubbing is another possible sign of chronic liver disease and cirrhosis. It involves a
physical deformation of the fingernails.

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Gynecomastia
Look for enlargement of breast tissue in males, also called gynecomastia.
Gynecomastia is seen in up to two-thirds of patients with cirrhosis. It is thought to
be due to the increased conversion of androgens to estradiol, which occurs in the
setting of liver disease. 

Spider nevi
Spider nevi, which are clusters of dilated blood vessels on the skin that consist of a
central arteriole surrounded by smaller vessels, are also a common sign of chronic
liver disease. Similar to gynecomastia, they are also due to an increase in estradiol
concentrations. 

Testicular atrophy
Also check your male patients for testicular atrophy, which may result from
decreased androgen levels. 

Caput medusae
You may also notice caput medusae (distended and engorged epigastric veins
visible on the abdomen) radiating from the umbilicus. These are often a sign of liver
disease. 

Palmar erythema
Palmar erythema is reddish skin on the palm of the hand, which is also due to an
increase in estradiol. 

Dupuytren’s contracture
Dupuytren’s contracture results from thickening and shortening of the palmar
fascia. This causes a flexion deformity of the fingers. While the cause is unknown,
its presence is often associated with alcoholism and cirrhosis. 

Muscle wasting
Muscle wasting may also be present and results from the inability of the liver to
metabolize proteins. If muscle wasting is present (especially temporal and proximal
muscle wasting), it suggests long-standing liver disease.

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Raised jugular venous pressure
Another common sign of chronic liver disease and cirrhosis that you may uncover
during a physical exam is raised jugular venous pressure. Raised jugular venous
pressure implies right-sided heart failure which may cause hepatic congestion. 

Parotid gland enlargement

Look for the presence of parotid gland enlargement. This is typically a feature of
alcoholic liver disease, but not cirrhosis in general.

Enlarged Virchow’s node

An enlarged left supraclavicular node (Virchow’s node) suggests an underlying
abdominal malignancy, such as stomach cancer, which could spread to the liver.

Hepatic encephalopathy signs

Features of hepatic encephalopathy may also be present in a patient with liver
disease. These include an altered level of consciousness and neuromuscular
disturbances such as a flapping tremor (e.g., asterixis).

Neurologic symptoms
Neurologic symptoms may also be seen in liver-associated diseases such as
Wilson’s disease. In this disease, there is copper deposition in the basal ganglia and
liver. Clinical features of Wilson’s disease include liver disease with parkinsonism.

Figure 1. Common signs of liver disease and cirrhosis that may be present during a physical examination. 

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How to perform a liver-focused abdominal exam 
Examination of the abdomen should be performed in all patients with potential liver
disease. There are three additional steps to perform when tailoring the abdominal
exam for liver disease:

1. Check liver size and consistency

2. Assess spleen size

3. Assess for ascites

Step 1: Check liver size and consistency

Liver size and consistency can be judged with palpation of the liver. A hard liver
may denote underlying hepatocellular carcinoma. A tender liver is seen with viral
hepatitis. A tender, acutely congested liver is due to right-sided heart failure.

Table 1. A hard liver upon palpation may be a sign of hepatocellular carcinoma, a tender liver is associated
with viral hepatitis, and a tender, acutely congested liver is associated with right-sided heart failure.

Step 2: Assess spleen size

The size of the spleen is also important to assess. Splenomegaly is a well-
established finding in cirrhosis and is due to portal hypertension.

Step 3: Assess for ascites

Make sure to look for the presence of ascites in your examination. Ascites is seen
in decompensated cirrhosis. Patients with ascites will typically have flank dullness
on examination. Patients may also have shifting dullness, which is a change in the
location of dullness to percussion when the patient is turned (due to movement of
the ascites). 

Return to table of contents.

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 Chapter 2

LIVER FUNCTION
TESTS

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Reviewing bilirubin physiology
A liver function panel always includes tests for bilirubin levels. Let’s review how
bilirubin is formed and eliminated from the body, and how it’s measured in a clinical
laboratory.

How is bilirubin formed and excreted? 

Bilirubin is a waste product produced by the breakdown of red blood cells. Bilirubin
is the end-product of heme metabolism; the liver is the site for bilirubin metabolism.

Hemoglobin is broken down into heme, which is converted to biliverdin, and finally
into unconjugated bilirubin (which is not water-soluble). In the bloodstream,
unconjugated bilirubin binds with serum proteins—most commonly albumin. The
unconjugated bilirubin is then taken up by the liver.

Figure 1. During the breakdown of hemoglobin, heme is released and converted into biliverdin. Biliverdin is
converted into unconjugated bilirubin, which is transported in the bloodstream by binding with albumin and
taken up by the liver. 

In the liver, the unconjugated bilirubin is bound to glucuronide by the enzyme uridine
5’-diphospho-glucuronosyltransferase (UDP) and becomes conjugated bilirubin.
Conjugated bilirubin is then excreted in bile. 

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Figure 2.  In the liver, unconjugated bilirubin binds to glucuronide by the enzyme uridine 5’-diphospho-
glucuronosyltransferase (UDP). The product is conjugated bilirubin, which can be excreted in bile. 

In the intestines, bacterial enzymes hydrolyze conjugated bilirubin to release free,

unconjugated bilirubin, which is reduced to urobilinogen. Urobilinogen, bound to
albumin, is then excreted in urine. 

Figure 3. In the intestines, conjugated bilirubin is hydrolyzed by bacterial enzymes to produce unconjugated
bilirubin and ultimately urobilinogen, which can be excreted in urine after binding to albumin. 

In the intestines, some urobilinogen is converted to stercobilinogen and excreted in

the stool. Thus, in normal urine, only urobilinogen is present; in normal stool, only
stercobilinogen is present.

Figure 4. Urobilinogen in the intestines can also be converted to stercobilinogen, which is then excreted in the stool.

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What happens to bilirubin with cholestatic
or obstructive jaundice?
Cholestatic or  obstructive  jaundice occurs when liver cells are unable to
transport bilirubin through the hepatic-bile capillary membrane because of damage
in the liver. Obstructive jaundice can also occur when transport through the biliary
tract is blocked because of anatomical obstructions such as gallstones or cancer.

In obstructive jaundice, conjugated bilirubin regurgitates into the blood. Because

it is water-soluble, bilirubin is excreted into the urine. This is called choluria, or the
presence of bile in the urine. 

As well, less conjugated bilirubin is taken up by the intestines in obstructive jaundice.

As a result, less stercobilinogen is found in the stool and the stool appears pale.

Table 1. Under normal conditions, only urobilinogen is present in the urine, and stercobilinogen is present in
the stool. With obstructive jaundice, conjugated bilirubin is present in the urine (also called choluria) and less
stercobilinogen is present in the stool, giving the stool a pale appearance. 

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How is bilirubin measured in the lab and what are
the normal levels? 
In the clinical laboratory, conjugated bilirubin is measured as direct bilirubin. If we
take the total bilirubin and subtract the direct bilirubin, it provides the concentration
of unconjugated bilirubin (also referred to as indirect bilirubin).

Figure 5. Indirect or unconjugated bilirubin can be calculated by subtracting direct (e.g., conjugated) bilirubin
from the total bilirubin. 

This concludes our review of bilirubin metabolism and how it’s measured in the
laboratory. For your reference, here are the normal values of bilirubin in adults:

Total bilirubin: 0.3–1.0 mg / dL or 5.1–17 mmol / L 

Direct bilirubin: 0.1–0.3 mg / dL or 1.0–5.1 mmol / L 

Indirect bilirubin: 0.2–0.7 mg / dL or 3.4–11.9 mmol / L  

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Getting to know albumin physiology
In addition to bilirubin, albumin is another mainstay on a typical liver function panel.
Let’s review how albumin is formed, its functions, and what serum albumin levels
can tell us about your patients’ health. 

Where is albumin formed and what does it do? 

Albumin is the most abundant circulating protein found in the plasma. It
represents  half of the total protein content in the plasma of a healthy patient.  A
normal plasma albumin concentration in a healthy patient is 3.5–5.0 g / dL.

Albumin is synthesized by liver hepatocytes, but very little albumin is stored in the
liver. It is rapidly excreted into the bloodstream at the rate of 10–15 g / day in people
with normally functioning livers.

In humans, serum albumin functions as a significant modulator of plasma oncotic

pressure and as a transporter of endogenous and exogenous ligands (e.g., drugs). 

Figure 1. Functions of serum albumin include the modulation of plasma oncotic pressure and the transportation
of endogenous and exogenous ligands. 

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What can serum albumin measurements tell us?
In clinical medicine, serum albumin measurements are a highly sensitive marker of
a patient’s nutritional status. Low albumin levels may indicate malnutrition, chronic
liver disease, or inflammatory disease. 

The half-life of albumin is approximately three weeks. When liver function is

impaired over a prolonged period, albumin synthesis is also impaired, which results
in low levels of albumin. For this reason, hypoalbuminemia is a common finding in
chronic liver disease. However, a significant reduction in serum albumin levels is not
observed in patients with acute liver failure. 

Figure 2.  Low serum albumin can indicate malnutrition, chronic liver disease (not acute), or inflammatory
disease.

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Covering the liver function panel
Several liver enzymes are commonly measured in blood serum, and each one has a
normal range in healthy patients.

Table 1. Liver enzymes that are commonly measured in blood serum, and their normal ranges. 

Now, let’s take a look at what we can learn from each of these liver enzymes. 

What can serum alanine aminotransferase and 

aspartate aminotransferase testing tell us?
The breakdown of hepatocytes results in the release of aminotransferases such
as alanine aminotransferase (ALT) and  aspartate aminotransferase (AST)  into the
blood. Therefore, elevated levels of these enzymes indicate liver injury. 

Alanine aminotransferase is a cytosolic enzyme only found in hepatocytes and is

specific to liver disease. Aspartate aminotransferase is a mitochondrial enzyme
in the liver, but it is also found in the heart, muscle, kidney, and brain. So, AST is
nonspecific to liver disease. 

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Figure 1. Elevated serum alanine aminotransferase (ALT) levels are specific to liver disease, whereas elevated
aspartate aminotransferase (AST) levels are nonspecific to liver disease. 

What can serum alkaline phosphatase testing

tell us?
Alkaline phosphatase (ALP) is present in the liver, bone, intestine, and placenta.
Production of ALP is increased during cholestasis, which is a decrease in bile flow
due to intrahepatic or extrahepatic causes. 

It is important to determine if the source of ALP is the liver or another organ. If

gamma-glutamyl transpeptidase (GGT) or 5’-nucleotidase levels are increased
alongside ALP, we can assume that the source of the ALP is the liver. 

Figure 2.  Elevated levels of gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), and
5’-nucleotidase indicate cholestasis that is caused by the liver. 

What can serum GGT testing tell us?

Gamma-glutamyl transpeptidase is a microsomal enzyme produced by the biliary
epithelium. Gamma-glutamyl transpeptidase is elevated in the liver, biliary tract,
and pancreas diseases as well as common bile duct obstruction. When seen in
conjunction with the transaminases (e.g., ALT and AST), GGT is also a marker of
alcohol abuse.  

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Figure 3.  Elevated gamma-glutamyl transpeptidase (GGT) may indicate a disease of the liver, biliary tract,
pancreas, or a common bile duct obstruction. Elevated serum levels of GGT, alkaline phosphatase (ALP), and
aspartate aminotransferase (AST) may indicate alcohol abuse.  

What can serum 5’-nucleotidase testing tell us?

The serum 5’-nucleotidase enzyme is derived from the plasma membranes of liver
cells. It is elevated in hepatobiliary diseases. 

In cholestatic conditions, ALP, GGT, and 5’-nucleotidase levels are all elevated. 

Figure 4. The enzyme 5’-nucleotidase is elevated with hepatobiliary diseases.

So, there you have it! Elevated liver enzymes, whether alone or in combination, can
provide information that helps clarify the clinical picture of your patient.

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Table 2. Summary of conditions associated with elevated levels of the liver enzymes alanine aminotransferase
(ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT),
and 5’-nucleotidase.

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Figuring out prothrombin time
Let’s dive into prothrombin time (PT) and partial thromboplastin time (PTT) tests
and discuss what PT can tell us about liver function. 

The coagulation pathway is made up of the extrinsic, intrinsic, and common

pathways. Prothrombin time is a coagulation test used to measure the integrity
of the extrinsic and common coagulation pathways. Partial thromboplastin time
measures the integrity of the intrinsic and common coagulation pathways. 

Figure 1.  The intrinsic, extrinsic, and common pathways of coagulation. Prothrombin time measures the
integrity of the extrinsic and common pathways, while partial thromboplastin time measures the integrity of
the intrinsic and common pathways.

What are the normal ranges for PTT and PT?

Partial thromboplastin time has a normal range of 25–37 seconds. As well,
prothrombin time is expressed in seconds or as a ratio called the international
normalized ratio (INR). Prothrombin time has a normal range of 9.4–12.5 seconds
or 0.9–1.1 INR.  

Table 1. Normal ranges for partial thromboplastin time (PTT) and prothrombin time (PT). 

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What does an abnormal PT tell us?
Prothrombin time involves the interactions of factors I (fibrinogen), II (prothrombin),
V, VII, and X. These factors are all synthesized by the liver. Remember, the common
coagulation pathway is measured by both PT and PTT, but the extrinsic pathway is
only measured by PT. So, if PT is abnormal and PTT is normal, we know the problem
lies with the extrinsic pathway. 

The clotting factors involved in the extrinsic pathway are factors III and VII. Factor
VII has the shortest half-life of all the clotting factors, which is 4–6 hours. Thus,
when the liver is injured and there is compromised liver function, factor VII levels
quickly fall. Within a short time after significant liver dysfunction, PT is prolonged
because the liver cannot make enough blood-clotting proteins. Consequently, it
takes longer for the blood to clot. 

So, if a patient has a normal PTT and an abnormal PT, we know that the abnormality
must lie with one of the extrinsic pathway factors (e.g., III or VII). Since factor III is one
of the reagents added when performing the PT test (and a factor III deficiency has
never been described), we can conclude that the patient has low levels of factor VII.

Low factor VII levels may be due to reduced factor synthesis or the presence of a
factor VII inhibitor (which is rare). Causes of reduced synthesis of factor VII include
congenital or genetic disorders, liver disease, and warfarin. Liver disease is usually
the culprit since congenital causes are rare and warfarin is easily ruled out. 

Figure 2. Causes of reduced factor VII synthesis include congenital disorders, liver disease, and warfarin use. 

As you can see, PT is an important test for assessing liver function. You can review
the coagulation pathways and learn how to interpret PT and PPT in more detail in
our Hematology and Coagulation Essentials course.

Return to table of contents.

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 Chapter 3

PATTERNS OF
ABNORMAL LIVER
FUNCTION

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Recognizing a hepatocellular pattern
An abnormality in a single liver function test provides us with limited diagnostic
information. But, if we can recognize a pattern of abnormality in our findings, it can
help us to determine the origin of the abnormality. Liver test abnormalities can be
divided into three patterns:

1. Hepatocellular (indicating hepatocellular disease)

2. Cholestatic (indicating intrahepatic or extrahepatic biliary obstruction) 

3. Isolated hyperbilirubinemia (indicating conjugated or unconjugated

hyperbilirubinemia)

Each of these may be acute (e.g., present for less than 6 weeks), subacute (e.g.,
present for 6 weeks–6 months), or chronic (e.g., present for more than 6 months). 

Figure 1. The three abnormal patterns that can be detected in liver function tests include the hepatocellular
pattern, cholestatic pattern, and isolated hyperbilirubinemia pattern, each of which can be acute, subacute, or
chronic in presentation. 

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How do you recognize a hepatocellular pattern?
Let’s discuss the hepatocellular pattern of liver test abnormalities. With the
hepatocellular pattern, serum aminotransferases, such as alanine aminotransferase
(ALT) and aspartate aminotransferase (AST), are significantly elevated. Alkaline
phosphatase (ALP) levels are mildly elevated (typically less than three times the
normal level), and serum bilirubin levels are also elevated. 

Tests for synthetic function, such as prothrombin time (PT) and albumin levels, may
also be abnormal. If they are abnormal, PT and albumin levels are typically decreased.

Table 1. Liver function testing abnormalities that are common with hepatocellular diseases.

Common causes of hepatocellular diseases include viral hepatitis, drug-induced

liver damage, and chronic liver disease. The most common chronic liver disease is
cirrhosis resulting from alcohol abuse or autoimmune hepatitis.

Figure 2.  A hepatocellular pattern on a liver testing panel could indicate viral hepatitis, drug-induced liver
damage, or chronic liver disease.

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What do relative levels of AST and ALT tell us in a
clinical setting? 
Let’s outline a few key points that may be clinically useful when it comes to
identifying a hepatocellular pattern on a liver function panel.

If ALT and AST values are 8 times greater than the upper limit of the normal range, a
hepatocellular pattern of disease is more likely. If ALT and AST values are 25 times
greater than normal, the diagnosis is likely viral hepatitis or drug-induced liver
damage. However, if ALT and AST are 50 times greater than normal, it suggests
ischemic hepatic damage from insufficient blood flow secondary to shock or low
blood pressure. With nonalcoholic steatohepatitis, ALT and AST are less than 4
times the upper limit of normal. Lastly, an AST to ALT ratio that is greater than 2:1
suggests alcoholic liver disease.

Table 2. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) testing results and their implications.

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What should you do if you recognize this pattern
in your patients?
In individuals with hepatocellular patterns of liver function test abnormalities (e.g.,
significant elevation of ALT and AST), there are seven tests you should consider
running to help diagnose the cause:

1. Acetaminophen levels

2. Viral hepatitis serology

3. Toxicology screen

4. Autoimmune markers (if indicated) 

5. Antinuclear antibodies

6. Anti-smooth muscle antibodies

7. Anti-liver kidney microsomal type 1 antibodies

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Identifying a cholestatic pattern
Three abnormal patterns can be recognized when interpreting the results of a liver
testing panel. These include the hepatocellular pattern, the cholestatic pattern, and
the isolated hyperbilirubinemia pattern. Now, let’s focus on the cholestatic pattern.

How can I recognize a cholestatic pattern?

The cholestatic pattern of liver function test abnormalities indicates biliary
obstruction. The pattern occurs when there is a disproportionate elevation in alkaline
phosphatase (ALP) compared to alanine aminotransferase (ALT) and aspartate
aminotransferase (AST).

Serum bilirubin can also be elevated.  Tests for synthetic function, such as
prothrombin time (PT) and albumin, may be abnormal.  

Table 1. Liver function testing abnormalities that are common with the cholestatic pattern. 

What causes biliary obstruction?

Biliary obstruction or cholestasis can be due to intrahepatic or extrahepatic
obstruction. Causes of intrahepatic obstruction include primary sclerosing
cholangitis, primary biliary cholangitis, drugs (e.g., steroids or chlorpromazine),
toxins, and infiltrative diseases (e.g., tuberculosis, sarcoidosis, or lymphoma). On
the other hand, causes of extrahepatic obstruction include gallstones in the common
bile duct, tumors blocking the bile ducts, pancreatitis, and strictures.

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Figure 1. Intrahepatic obstruction can be caused by primary sclerosing cholangitis, primary biliary cholangitis,
medications, toxins, or infiltrative diseases. Extrahepatic obstruction can be caused by gallstones in the
common bile duct, tumors blocking the bile ducts, pancreatitis, or strictures.

How do you determine the possible cause of a

biliary obstruction?
There are four additional tests to consider when determining the cause of biliary
obstruction:

1. Further serum testing

2. Ultrasound

3. Magnetic resonance imaging (MRI) or x-ray

4. Biopsy

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Further serum testing
Biliary obstruction is characterized by elevated levels of ALP, typically three times
the normal level. Remember that there are three sources of alkaline phosphatase—
the liver, bone, and placenta. 

Whenever the source of elevated ALP is the liver, gamma-glutamyl transpeptidase

(GGT) levels are also raised. Thus, gamma-glutamyl transpeptidase can be tested if
there is a doubt about the source of the elevated ALP.  

In addition to elevated ALP, antimitochondrial antibody (AMA) levels are also raised
in primary biliary cholangitis.

Table 2.  With biliary obstruction, alkaline phosphatase (ALP) is typically elevated three times higher than
normal and gamma-glutamyl transpeptidase (GGT) is also elevated. With primary biliary cholangitis, ALP and
antimitochondrial antibody (AMA) levels are elevated.

Ultrasound
The next best test for determining the cause of biliary disease in individuals with
significantly elevated levels of ALP is imaging such as ultrasonography of the
abdomen. Gallstones in the common bile duct and pancreatic lesions are easily
diagnosed on ultrasound.

Magnetic resonance imaging or x-ray

Further testing by magnetic resonance cholangiopancreatography or endoscopic
retrograde cholangiopancreatography may be required to diagnose differential
causes of intrahepatic obstruction. 

Biopsy
Lastly, a liver biopsy may be required if the cause of the biliary obstruction remains
undetermined.

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Diagnosing isolated hyperbilirubinemia
When interpreting the results of a liver testing panel, hepatocellular, cholestatic, or
isolated hyperbilirubinemia patterns are all possible. Let’s take a closer look at the
isolated hyperbilirubinemia pattern. 

The hyperbilirubinemia pattern can be classified as unconjugated hyperbilirubinemia

or conjugated hyperbilirubinemia. First, let’s discuss unconjugated hyperbilirubinemia.

How can unconjugated bilirubin become elevated?

There are three categories of unconjugated hyperbilirubinemia:

1. Overproduction of bilirubin

2. Reduced uptake of bilirubin by the liver

3. Abnormal bilirubin conjugation 

Overproduction of bilirubin
The first category results from the overproduction of bilirubin. This is often caused
by hemolysis, dyserythropoiesis, or Wilson’s disease.

Figure 1. Bilirubin overproduction can be caused by hemolysis, dyserythropoiesis, or Wilson’s disease.

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Reduced uptake of bilirubin by the liver
The second category involves reduced uptake of bilirubin by the liver. This can occur
due to heart failure, portosystemic shunts, drugs (such as rifampin), or Gilbert’s
syndrome.

Figure 2. Reduced bilirubin uptake by the liver can be caused by heart failure, portosystemic shunts, certain
drugs such as rifampin, or Gilbert’s syndrome.

Abnormal bilirubin conjugation

The third category involves abnormalities in bilirubin conjugation. This can be
caused by Gilbert’s syndrome, Crigler-Najjar syndrome (a genetic disorder causing
high levels of unconjugated bilirubin), hyperthyroidism, advanced cirrhosis, or
maternal milk in neonates.

Figure 3.  Abnormal bilirubin conjugation can be caused by Gilbert’s syndrome, Crigler-Najjar syndrome,
hyperthyroidism, advanced cirrhosis, or maternal milk in neonates. 

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How do you diagnose unconjugated
hyperbilirubinemia? 
First, you’ll need to check the liver function tests. Liver disease and biliary disease
are ruled out if liver enzymes such as alanine aminotransferase (ALT), aspartate
aminotransferase (AST), and alkaline phosphatase (ALP) are normal.  

Table 1. Liver function testing abnormalities common with unconjugated hyperbilirubinemia.

What causes unconjugated hyperbilirubinemia?

Among the causes of unconjugated hyperbilirubinemia, there are three that are most
common:

1. Hemolytic anemia

2. Drugs

3. Gilbert’s syndrome 

Let’s take a closer look at these conditions. 

Hemolytic anemia 

Individuals with hemolytic anemia have low levels of hemoglobin, increased

reticulocyte count (also called polychromasia), and elevated levels of unconjugated
bilirubin. A peripheral blood smear examination may be useful for this diagnosis.

Figure 4.  Hemolytic anemia is associated with low hemoglobin levels, increased reticulocyte count, and
elevated unconjugated bilirubin levels. 

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Drugs
Drugs such as salicylates, sulphonamides, and rifampin can competitively bind
with albumin and result in unconjugated hyperbilirubinemia. Medication history is
necessary to rule out any drugs that can affect bilirubin uptake.

Figure 5. Certain medications can cause unconjugated hyperbilirubinemia including salicylates, sulphonamides,

and rifampin. 

Gilbert’s syndrome
Gilbert’s syndrome is a benign condition transmitted genetically as an autosomal
dominant trait. Patients with Gilbert’s syndrome have reduced uptake and decreased
conjugation of bilirubin in the liver. Patients may present with mild jaundice at times
of stress such as during infection with the influenza virus. 

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One test that is useful for detecting Gilbert’s syndrome is the calorie test. The
patient is put on a low-calorie diet for 48 hours and unconjugated bilirubin levels are
measured before and after the calorie restriction. Increased levels of unconjugated
bilirubin with a low-calorie diet is indicative of Gilbert’s syndrome. Genetic testing is
sometimes required to confirm the diagnosis.

Figure 6. Gilbert’s syndrome is associated with mild jaundice at times of stress or infection, a positive calorie
test, positive genetic testing (e.g., increased levels of unconjugated bilirubin with a low-calorie diet), and
elevated unconjugated bilirubin levels. 

How do we diagnose conjugated

hyperbilirubinemia?
Now, let’s look at conjugated hyperbilirubinemia. In conjugated hyperbilirubinemia,
conjugated and unconjugated bilirubin are both elevated. 

Table 2. Liver function testing abnormalities common with conjugated hyperbilirubinemia.

What causes conjugated hyperbilirubinemia?

Let’s discuss two possible causes of conjugated hyperbilirubinemia:

1. Cholestasis

2. Dubin-Johnson syndrome and Rotor’s syndrome

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Cholestasis
Conjugated hyperbilirubinemia is most often caused by decreased bile formation
or excretion associated with either intrahepatic or extrahepatic cholestasis.
Cholestasis is also characterized by elevated levels of ALP, typically three times that
of normal.

Figure 7.  Intrahepatic and extrahepatic cholestasis are both associated with elevated conjugated bilirubin,
elevated unconjugated bilirubin, and elevated alkaline phosphatase (ALP).

Dubin-Johnson syndrome and Rotor’s syndrome

Rarely, conjugated hyperbilirubinemia may result from congenital defects such as
Dubin-Johnson syndrome and Rotor’s syndrome, which are genetic syndromes
that cause defective canalicular excretion of bilirubin. In both Dubin-Johnson and
Rotor’s syndrome, levels of ALP as well as ALT and AST are all normal, which can
help point to the presence of these rare disorders. 

Figure 8. Both Dubin-Johnson syndrome and Rotor’s syndrome are associated with elevated conjugated and
unconjugated bilirubin levels along with normal alkaline phosphatase (ALP), alanine aminotransferase (ALT),
and aspartate aminotransferase (AST) levels. 

To conclude, let’s summarize the testing results we typically find with each condition
associated with unconjugated and conjugated hyperbilirubinemia. 

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Table 3. Summary of testing results typical with several conditions that are associated with unconjugated and
conjugated hyperbilirubinemia. 

Return to table of contents.

Become an expert at www.medmastery.com 50

APPENDIX

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Lok, ASF and McMahon, BJ. 2007. Chronic hepatitis B. Hepatology. 45: 507–539.
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Moussavian, SN, Becker, RC, Piepmeyer, JL, et al. 1985. Serum gamma-glutamyl
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van de Steeg, E, Stránecký, V, Hartmannová, H, et al. 2012. Complete OATP1B1 and

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