Download the liver

LIVER
THE THE
LIVER
Assessing the Silent Progress of Liver Disease
The liver is the second largest organ in the human body after skin and is the largest
internal organ.
The liver is first visible in a developing
embryo during the fourth week of pregnancy. As the fetus develops, the liver
divides into two sections, called the right
and left lobes. Ultimately, the right lobe
will be six times bigger than the left. By
the time a baby is born, the liver constitutes
about 5 percent of the baby's total weight.
The liver grows with the child and in adults
it weighs three to four pounds.
If you feel the right lower edge just under
your rib cage, you may detect a firm mass
that makes a solid sound when you give it a
good tap. That is your liver. It has the consistency of foam rubber when healthy. In a
child with liver disease, it is often firmer.
The liver, tucked under the diaphragm and ribs, extends across to the left side of the
body over the top edge of the stomach. The gall bladder and its ducts are just under the
right side of the liver.
The liver’s blood supply is unique; it comes from both the
heart and the digestive tract directly through a large blood
vessel called the portal vein.
Each of the two main lobes contain smaller units called
lobules. Most livers have 50,000 to 100,000 lobules that
consist of a vein surrounded by tiny liver cells, called
hepatocytes. These cells purify the blood, remove wastes,
toxins and poisons and store healthy nutrients for the
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body to use when needed.
The liver’s tasks are many. It converts sugar glucose into glycogen and stores it until the
body needs it. It also stores vitamins, minerals and iron until the body requires them.
Liver cells produce proteins and lipids or fatty substances that include triglycerides,
cholesterol and lipoproteins.
The liver makes bile acids that break down the fat in food. These bile acids are necessary for the body to absorb vitamins A, D and E, all of which are found in fat.
It removes chemicals, alcohol, toxins and medicine from the bloodstream and sends
them to the kidneys as urea to be excreted as urine or to the intestines to be excreted as
stool.
How the Liver Works
When food is eaten, the nutrients travel down the throat, into the stomach and then on to
the intestines. These organs break up and dissolve the food into small pieces that can be
absorbed into the bloodstream.
Most of these small particles travel from the intestines to the liver, which filters and
converts the food into nourishment that the bloodstream delivers to cells that need it.
The liver stores this nourishment and releases it throughout the day, as the body needs it.
The proteins, fats, enzymes and other chemicals the liver creates from nutrients are
critical to a person’s health.
For instance, the liver produces the proteins that are necessary for blood to clot. When
the liver cannot produce these clotting components, a person could bleed to death.
The liver also produces bilirubin, a reddish-yellow pigment formed by the breakdown of
hemoglobin in worn-out red blood cells. The blood carries this to the liver where it
combines with bile and is passed on to the duodenum to be excreted.
When the liver is damaged and it cannot screen out the reddish-yellow bilirubin in the
body, jaundice occurs and a person develops a yellowish color in the whites of their
eyes and in their skin.
The liver produces albumin, a protein found in blood, and cholesterol that is critical to
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the make-up of the outer membrane of cells.
When liver cells are damaged and cannot perform these functions, they release certain
enzymes into the blood. Doctors test for the presence of all of these enzymes and other
liver-related substances in the bloodstream to determine if the liver is damaged or
diseased.
When the Liver Is Diseased
Because the liver is so complex, it is susceptible to a wide variety of adverse effects
caused by an excess of alcohol or drugs, infections such as viral hepatitis, cancer and
other metabolic disorders.
But the liver is also resilient; it has a remarkable ability to regenerate itself following
injury or inflammation and it has nutrient reserves it can tap when it is damaged.
When a liver is under siege from viral hepatitis, its liver cells are damaged or destroyed.
This type of injury can initially be tolerated and resisted, due to the liver’s ability to
regenerate and compensate for the damage. This phase of liver disease is called compensated liver disease because the liver is able to continue all its functions.
When the liver begins to lose the battle, and it is not able to regenerate liver tissue and
its filtering and nutrient storing abilities are damaged by scar tissue, this end-stage of
liver disease is called decompensated liver disease, because the liver cannot compensate
for the ongoing damage.
During the early stages of chronic viral hepatitis, before a child’s immune system begins
to actively respond to the hepatitis virus and liver damage is just beginning, patients
usually feel no pain. This is why chronic viral hepatitis is called a “silent” disease – it
may cause no physical symptoms at all for decades, even though liver damage may be
occurring.
Once doctors discover that a viral hepatitis infection is present, they determine which
hepatitis viral antigens, antibodies and DNA or RNA levels are present to see how long
the infection has been present and whether the body is actively fighting it. If a child’s
immune system has not yet responded to the virus, they are considered to be in the
immune tolerant stage.
Next, doctors look for any visible signs of liver damage and they feel a child’s liver to
determine if it is enlarged, which could signal inflammation.
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Another step they take is to draw a blood sample. When the liver and its cells are
injured, they release certain enzymes and other substances into the bloodstream. Doctors
examine a patient’s blood (serum) to see if there are any elevated or below normal levels
of liver enzymes, proteins and other compounds in the bloodstream. The term Liver
Function Tests or LFTs refers to tests that analyze how well the liver is functioning. The
term is also commonly used to refer to tests that measure liver enzymes, which can
indicate liver cell damage.
Here are some of the liver enzymes, clotting compounds and bile byproducts that
doctors evaluate to assess the health of a person’s liver.
Alanine Aminotransferase (ALT)
Liver cells produce the ALT enzyme. ALT levels increase when liver cells are damaged
or are dying. The higher the ALT levels, the more cell death or inflammation of the liver
is occurring. However, ALTs are not always good indications of how well the liver is
functioning; only a liver biopsy can reveal that.
ALT levels can remain low even when the liver is inflamed or is developing scar tissue,
or during a child’s immune tolerant stage of the disease.
Aspartate Aminotransferase (AST)
Like the ALT enzyme, AST is an enzyme produced by liver cells, but AST is also
produced by muscles and it can be elevated in conditions other than liver disease. For
example, AST is often elevated during a heart attack.
In many cases of liver inflammation, the ALT and AST levels are equally elevated. In
some conditions, such as alcoholic hepatitis, AST levels may be higher than ALT levels.
AST levels can be normal, yet there can be liver damage occurring. This test adds one
more perspective to the picture of liver disease.
Alkaline Phosphatase
Alkaline phosphatase is an enzyme produced in the bile ducts, intestines, kidney,
placenta and bone. This enzyme is measured to help doctors determine if a disease could
be concentrated in the bile duct or in the liver. When this enzyme level is high, and
when ALT and AST levels are fairly normal, there may be a problem in the bile duct,
such as an obstruction. Some bone disorders can also cause alkaline phosphatase levels
to rise.
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Gamma-Glutamyltranspeptidase (GGT)
This enzyme, like alkaline phosphatase, is produced in the bile ducts and may become
elevated when there is a bile duct disorder. Elevations in GGT and alkaline phosphatase
usually suggest bile duct disease. Measurement of GGT is an extremely sensitive test; it
can be elevated when there is any liver disease. Elevated GGT levels are also caused by
drugs (even when taken at prescribed levels) and they are often elevated in heavy drinkers, even when there is no liver disease.
Bilirubin
Doctors also measure bilirubin, the reddish-yellow pigment formed by the breakdown of
hemoglobin in worn-out red blood cells. Normally, the liver conjugates bilirubin and it
is excreted in bile and passes through the duodenum to be excreted.
Bilirubin levels in the blood can be elevated due to over-production, decreased uptake
by the liver, decreased conjugation, decreased secretion from the liver or blockage of the
bile ducts.
In cases of increased production, decreased liver uptake or decreased conjugation, the
unconjugated, or so-called indirect bilirubin, will be primarily elevated. In cases of
decreased secretion from the liver or bile duct obstruction, the conjugated, or so-called
direct bilirubin, will be primarily elevated. Many different liver diseases can cause
elevated bilirubin levels.
In the case of chronic liver disease, bilirubin levels are usually stable until a significant
amount of liver damage has occurred and cirrhosis is present. In acute liver disease, the
bilirubin is usually increased relative to the severity of the acute process.
In bile duct obstruction, or diseases of the bile duct, the alkaline phosphatase and GGT
levels are often elevated along with bilirubin.
Albumin
Albumin is the major protein that the liver synthesizes and secretes into the blood. Low
albumin levels indicate poor liver function. Albumin levels are usually normal in
chronic liver diseases until cirrhosis and significant liver damage occur. Albumin levels
are low when there is malnutrition and show increased losses with gastrointestinal and
kidney disease.
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Prothrombin Time (PT)
The prothrombin protein enables blood to clot. When bleeding occurs, prothrombin is
changed by a complex series of reactions into the insoluble protein thrombin.
When liver function is severely abnormal, the synthesis and secretion of clotting
proteins into the blood is decreased. The prothrombin time is a type of blood clotting
test performed in the laboratory and it is “prolonged” when the blood concentrations of
some of the clotting factors made by the liver are low.
In non-cholestatic chronic liver diseases, the prothrombin time is usually not elevated
until cirrhosis and significant liver damage occur. In cholestatic liver disease, patients
have a decreased ability to absorb vitamin K. This vitamin K deficency can lead to
prolonged prothrombin time. In acute liver diseases, the prothrombin time can be
prolonged and return to normal as the patient recovers.
Platelet Count
Platelets are the smallest of the blood cells (actually fragments of larger cells known as
megakaryocytes) that are involved in clotting. When the spleen becomes enlarged as a
result of portal hypertension due to decreased blood flow through the liver because of
scarring, platelets can accumulate in the enlarged spleen. In chronic liver diseases, the
platelet count usually falls only after cirrhosis has developed. The platelet count can be
abnormal in many conditions other than liver diseases.
Alpha Fetoprotein (AFP)
Though not part of a Liver Function Test, many doctors perform this test to measure
alpha fetoprotein (AFP) levels in children and adults with chronic hepatitis B and sometimes hepatitis C.
AFP, produced by the liver, is more commonly measured to diagnose or monitor fetal
distress or fetal abnormalities in pregnant women. But when chronic hepatitis or liver
disease is present, doctors measure the AFP levels in a blood sample because elevated
levels may signal liver tumors or cancer.
Often doctors perform an ultrasound and an AFP test every six months or more often in
high-risk patients, such as those with abnormal Liver Function Tests or those with confirmed cirrhosis in order to detect and treat liver cancer at is earliest (and most treatable)
stage.
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However, some doctors test AFP levels in young patients with chronic hepatitis B
annually, even if liver enzymes are normal and there is no indication of liver damage,
scarring or cirrhosis. They use this test because even when Liver Function Tests are
normal, cirrhosis and even cancerous tumors can form on the liver. Elevated AFP levels
may indicate the silent presence of tumors and cancer.
During the 1990s, researchers conducted AFP tests twice yearly on 14,529 adult patients
with hepatitis B and C and non-hepatitis-related cirrhosis. According to a report
presented to the 51st Annual Meeting of the American Association for the Study of Liver
Diseases in October 2000, a total of 4,339 of these patients were considered to be at risk
for cancer. Twice a year, their AFP levels were measured and they were examined with
ultrasounds.
The tests and ultrasounds identified liver cancers in 237 of the 4,339 patients. AFP
levels were elevated above 400 ng/ml in 29.6 percent of them.
“Alpha fetoprotein levels are obtained at least yearly in my patients with chronic hepatitis B so they can be compared to previous values (test results),” said Dr. Philip Rosenthal, director of the Pediatric Liver Transplant Program and Pediatric Hepatology at the
University of California, San Francisco. “Data have shown in patients with chronic
hepatitis B infection, a rise in AFP can signal a tumor and the need to investigate and
then resect (surgically remove) the tumor as early as possible to improve prognosis. I try
to get alpha fetoprotein levels at least yearly and ultrasound exams baseline and then
every one to two years if the insurance company will let me. If the AFP is rising, then a
repeat ultrasound should be obtained and compared to the previous studies as quickly as
possible.”
Dr. Maureen Jonas, a pediatric gastroenterologist specializing in hepatitis at Children’s
Hospital Boston, also performs annual AFP tests in children with chronic hepatitis B,
even when Liver Function Tests and liver enzymes are normal.
“I don't recommend annual AFP in cases of hepatitis C unless there is cirrhosis, and not
just abnormal ALT levels,” she said. Dr. Jonas’ AFP testing protocol is based on experience in adults. “It may be a bit aggressive for children, but I have no hard data on which
to base other recommendations.”
What Causes Elevated Liver Enzymes in People with Viral Hepatitis?
ASTs and ALTs are sensitive indicators of liver damage but higher-than-normal levels
of these liver enzymes should not be automatically equated with chronic or long-term
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liver disease. Sometimes the levels can be normal when damage is present, but are
usually elevated in acute injury.
Patients with acute viral hepatitis A, which is a short-term illness that rarely causes
permanent liver damage, may temporarily develop very high AST and ALT levels. But
most patients with acute viral hepatitis A recover fully without any residual liver
disease.
In contrast, children and adults with chronic hepatitis C infection may have only a mild
elevation in their AST and/or ALT levels. However, some of these patients may have
quietly developed liver disease, with scarring and even cirrhosis.
Many infants and young children infected with hepatitis B have normal ALT levels until
their immune systems recognize and attack the virus residing in the liver cells.
The highest levels of AST and ALT are found when numerous liver cells die. This
occurs in such conditions as acute viral hepatitis B, pronounced liver damage inflicted
by toxins as from an overdose of acetaminophen or prolonged collapse of the circulatory
system (shock) when the liver is deprived of fresh blood bringing oxygen and nutrients.
AST and ALT serum levels in these situations can range anywhere from 10 to 100 times
the upper limits of normal.
A host of medications can also cause abnormal liver enzyme levels, such as:
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Anti-seizure medications such as phenytoin, valproic acid, carbamazepine and phenobarbital.
Acetaminophen (such as Tylenol).
Antibiotics such as the tetracyclines, sulfonamides, isoniazid (INH), sulfamethoxazole, trimethoprim, nitrofurantoin, etc.
Cholesterol-lowering drugs such as the “statins” and niacin.
Cardiovascular drugs such as amiodarone.
Anti-depressant drugs of the tricyclic type.
When liver enzyme abnormalities are drug-related, the enzymes usually normalize
within weeks or months of stopping the medications.
Stages of Liver Disease
When liver function and enzyme test results are abnormal, doctors will next want to find
out why. Once the cause is known, a doctor will determine if the liver is inflamed, if it
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has developed any fibrosis or scar tissue, if scarring in the liver has advanced to cirrhosis, or if the liver has become cancerous.
During the early stages of liver disease there are certain areas of the liver that may be
prone to inflammation and scarring, including the lobules and the area where the large
portal vein and its branches enter the liver, called the portal triad.
During the intermediate stages of liver disease, the fibrosis tissue or scarring expands
and “bridges” between portal areas. In the late stage of liver disease, the scarring is so
extensive that it expands to the central area of the liver and the liver changes its shape or
“architecture” due to the scarring and tissue regeneration attempts.
Doctors assign “grades” to the degree of inflammation and liver cell damage and they
identify “stages” of liver scarring and cirrhosis. These stages and grades are assessed as:
none, minimal, mild, moderate or severe.
Liver Fibrosis
When hepatitis viruses begin to replicate in the liver, the body’s immune system may
recognize the presence of this foreign entity or antigen and immediately mount a counter
attack, targeting the infected liver cells in which the virus has “set up shop” and begun
replicating.
In the case of hepatitis B, it is the body’s immune
system attack on the infected liver cells that causes
the inflammation and scarring in a liver—not the
virus.
When there is chronic or long-term hepatitis B, D
or C, the body’s battle with the virus can be prolonged, and the liver may form scar tissue, called
liver fibrosis, as it fights the virus-infected liver
cells over a period of many months or years.
A liver with moderate
scarring or fibrosis.
To date, there is no clear linear pattern that defines
the rate or the location within the liver where
fibrosis or scarring occur during chronic hepatitis infections. The rate of scarring varies
from individual to individual. If untreated, liver scarring can spread throughout all of the
liver’s lobes and impede the function of the liver. However, if treated in time, doctors
have recently discovered that scarring (fibrosis) is reversible. They are now closely
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studying how fibrosis occurs in the liver in an effort to develop effective anti-fibrotic
therapies.
Fibrosis by itself does not impair liver function until it becomes so extensive throughout
the liver that it forms nodules and the liver becomes cirrhotic.
How Scar Tissue Is Formed
A liver contains hepatocytes or liver cells, a porous lining, tissue macrophages called
Kupffer cells and stellate cells (formerly called Ito cells or lipocytes or fat-storing cells).
The stellate cells make up about 15 percent of the liver’s resident cells.
In a healthy liver, these stellate cells are “quiescent” or fairly inactive cells that store
vitamin A and perform a variety of functions in the liver, including maintaining the
liver’s membrane around different liver sections.
But when there is injury to the adjacent membrane or Kupffer cells, the stellate cells
become activated and begin to proliferate in response to the damage. They shed their
vitamin A and basically reconstitute themselves and begin producing fibrous material or
scar tissue.
The scar tissue created by the stellate cells accumulates and increasingly hinders liver
functions. During recovery from hepatitis and liver injury, researchers report the number
of “activated” stellate cells declines. Researchers suspect they either return to their quiescent stage or the activated stellate cells disappear. Meanwhile the integrity of the liver
is restored and the scar tissue may even disappear.
Cirrhosis
During severe viral hepatitis infections, when liver cells are dying and the liver is being
extensively scarred over a prolonged period of time, cirrhosis can develop. This is the
seventh leading cause of death in the United States, according to the National Institute
of Diabetes and Digestive and Kidney Diseases.
Because of the ongoing damage to the liver, scar tissue slowly replaces normal functioning liver tissue, progressively diminishing blood flow through the liver. As the normal
liver tissue and functions are lost, nutrients, hormones, drugs and poisons are no longer
synthesized and filtered by the liver. Production of vital proteins, clotting components
and other substances also declines.
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As more and more scarring occurs, a large area of the liver may become scarred and
only a very small amount of blood will be able to pass through.
As cirrhosis worsens and blood flow is increasingly
impeded, pressure in the blood vessels in the stomach
and lower throat increase, and there may be enlargement
of the spleen. This is known as portal hypertension.
Slower blood flow through the liver may increase pressure in the abdomen from fluid buildup. This condition
is called ascites.
Cirrhosis is severe scarring of
the liver. It can even change the
shape or architecture of the
liver.
Other symptoms, due to improper “cleansing” of blood
by the liver, may include itching or a lessened ability to
think clearly. A person can even lapse into a coma due
to accumulation of toxins in the blood.
The liver can compensate for a significant amount of damage, but eventually liver
function will decline markedly. When cirrhosis is severe, it is called decompensated
cirrhosis, because the liver can no longer “compensate” for the extensive scarring.
How Doctors Evaluate Cirrhosis
When doctors evaluate a person with cirrhosis, they “grade” the liver disease based on
how extensive the scarring is throughout the liver, what areas of the liver are scarred, if
there are any lesions and whether continual scarring and liver tissue regeneration have
altered the “architecture” or shape of the liver.
A liver biopsy that extracts liver cells through a needle usually examines just one area of
the liver for scar tissue and damaged liver cells. But cirrhosis varies in severity and
location.
When examining liver tissue, doctors look at the fibrous bands of scar tissue that
surround nodules of regenerating liver cells. Cirrhosis is described as micronodular if
the nodule diameter is less than 3 mm and macronodular if it is more than 3 mm.
Patients with severe cirrhosis risk liver failure and development of liver cancer, also
called hepatocellular carcinoma or HCC.
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Is Cirrhosis Reversible?
Historically, doctors viewed cirrhosis as a late and irreversible stage of liver disease.
Most of the cirrhotic patients that doctors treated were adults, mostly male, who were
alcoholic or injecting drug users or who had other health problems. In these men, cirrhosis was irreversible and death from liver disease was often inevitable.
Today, as doctors expand their experience with diseased livers and find effective drugs
to treat children who have no other coinfections or history of alcohol abuse, they are
beginning to suspect that cirrhotic livers may be more resilient then previously thought.
Cirrhosis may even be reversible once the infecting virus is vanquished or under control.
In an editorial in the Feb. 8, 2001 issue of The New England Journal of Medicine, the
journal’s editors wrote, “In many cases, patients with cirrhosis are asymptomatic, with
normal findings on physical examination, and the disorder is detected initially because
of elevated serum liver enzyme levels or a positive serologic test for hepatitis B or C
virus.
“Advances in the treatment of liver diseases have made it increasingly apparent that
medical treatment may be beneficial even for patients with advanced histologic changes,
including cirrhosis. Furthermore, in some cases fibrosis and even frank [clear] cirrhosis
have appeared to regress with treatment.”
Liver Cancer
Liver cancer is the second most common cancer in the world. It is most common in
Africa, Asia and Southern Europe. In the United States,
approximately three out of every 100,000 people will
develop liver cancer each year.
The hepatitis B and C viruses can sometimes cause
cancer because they change a liver cell’s DNA—the
genetic code that instructs the cell how to reproduce—
when they take over liver cells to replicate.
In the case of hepatitis B, on a molecular level, the X
gene protein in the virus is believed to play a role in
causing cancer and tumors, possibly through its interaction with the P53 tumor-suppressor gene.
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Cancerous tumors form in the
liver during liver cancer.
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Children and adults chronically infected with hepatitis B, C or D (a hepatitis B infection
is needed before hepatitis D is contracted) are at increased risk of liver cancer. Without
proper treatment, about 20 percent of patients who have cirrhosis will go on to develop
liver cancer. According to cancer studies, about 75 to 95 percent of patients who
develop liver cancer have had cirrhosis.
The symptoms of liver cancer can be similar to those of cirrhosis, including jaundice,
fatigue, drowsiness and weight loss. Patients frequently have abdominal pain and
abdominal masses. Liver cancer may also spread through the bloodstream, causing
cancer in other tissues and areas of the body.
If the cancer is small, it is often removed through surgery. Because the liver can regenerate, it's sometimes possible to remove a great deal of liver tissue without long-term ill
effects. But often, by the time liver cancer is identified and surgically removed, the
cancer is so widespread or systemic that it may recur in the liver after surgery.
How Doctors Diagnose Liver Disease
To prevent liver scarring, cirrhosis and liver cancer, doctors want to identify and track
liver disease in children and adults as early as possible.
In addition to identifying which hepatitis antigens and antibodies are present and measuring liver enzymes and looking for tumors through an AFP test, doctors have other
tools to monitor and diagnose liver disease.
Doctors look at a patient’s health history and they physically examine the patient to
check for a swollen liver or for any abnormalities.
They may also perform an “ultrasound” examination to check for swelling, scarring or
tumors in different areas of the liver. Also known as ultrasonic imaging, this test sends
sound pulses into the body. The returning echoes are collected and a picture is produced
from them.
An ultrasound examination of the liver measures the liver’s size and determines whether
the liver disease is more advanced than what blood tests might indicate. The ultrasound
can reveal abnormal texture, discrete lesions and cirrhosis.
Some doctors perform a baseline ultrasound on children, even when their Liver Function
Tests are normal, to have as a reference. Then, as years pass or if liver enzymes
increase, doctors have the original ultrasound to compare to future ultrasound
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examinations.
In addition to these tests, physicians may order more specific liver tests such as an autoimmune test that can determine the specific cause of a liver disease. But to date, the best
vehicle for assessing the true condition of the liver is a liver biopsy.
When Is a Biopsy Recommended?
When to order a liver biopsy is an area of contention within the medical community,
especially when deciding whether to recommend a liver biopsy in a child.
Nearly all doctors agree that a liver biopsy should be routinely ordered when tests reveal
elevated liver enzymes over several months. The liver enzyme “elevation” that merits a
liver biopsy and treatment can range from 1.5 times to twice the levels that are normal
for a child of that age and weight.
But when liver enzymes are only slightly elevated—or when there are “flares” of elevated enzymes—doctors face a dilemma of when or whether to order a biopsy. They
must decide when the value of the information gained from the biopsy outweighs the
medical risks of the procedure itself.
At the crux of this dilemma is the fact that liver damage can occur, especially in children, without tests revealing any tell-tale signs of liver cell damage or scarring. A
child’s ALT or AST readings may be normal or near normal even when hepatitis viruses
are rapidly infecting liver cells and causing inflammation and scarring.
Because there is no linear correlation between liver enzyme levels and the amount of
liver damage, doctors cannot judge how much damage is occurring in the liver simply
by looking at blood tests.
In the case of hepatitis C, many doctors recommend a biopsy to obtain a timeline in the
natural history of an individual’s disease. A patient’s blood tests and ultrasounds can
remain normal until there is less than 20 percent of the liver functioning.
According to the American Digestive Health Foundation, about 30 percent of chronically infected patients with hepatitis C have persistently normal ALT levels.
“Liver Function Tests can be perfectly normal, and yet there can be significant fibrosis,
even cirrhosis,” said Dr. Philip Rosenthal. “Liver Function Tests are only as good as the
moment the [blood] is drawn. They cannot reflect previous evidence of inflammation
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and scarring. The tests alone do not determine the need for a liver biopsy.”
So what, other than abnormal tests, justifies a liver biopsy in a child? The general health
of the child, any coinfections, any other test results including the status of the virus’
antigens and antibodies, and a physical examination all contribute to the decision to
order a liver biopsy.
Why a Liver Biopsy?
Many of the uncertainties that surround the health of a chronically infected child’s liver
are dispelled when a liver biopsy is performed.
Many medical centers that are conducting clinical trials in the treatment of viral hepatitis
may also require liver biopsies in order to monitor and assess the therapy’s impact on
the liver. All treatment trials of interferon, lamivudine and combination interferon and
ribavirin have greatly relied on liver biopsies before and after treatment to assess the
effects of the drug therapy.
When undergoing treatment or participating in a clinical trial, a child may have one
biopsy before treatment begins and a second after treatment concludes to gauge the
effectiveness of the drug. Biopsies are generally not performed during the treatment
period because the liver may be changing rapidly in response to the treatment. Patients
who have undergone liver transplantation often require numerous liver biopsies in the
early weeks and months following the surgery to accurately diagnose if the new liver is
being rejected or whether other problems have developed.
A parent of a young child who underwent a liver biopsy observed, “I really do believe
the biopsy is tougher on parents than on the child. Assuming your child's liver is in
decent shape and blood clots properly, there is little risk if an experienced pediatric
gastroenterologist or hepatologist conducts the procedure.
“While the procedure scared my daughter, I really don’t think there was much pain
associated. When she got home, she was back to doing her own thing. And there is some
comfort in knowing the true status of your child's liver, and the biopsy is the only real
way to know this,” the mother added.
How Is a Sample of Liver Tissue Taken?
A liver biopsy is a diagnostic procedure used to obtain a small amount of liver tissue.
The doctor examines the liver cells under a microscope to assess the health of the liver
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and determine if there is inflammation, scarring, lesions or cirrhosis. This is the best tool
available for diagnosing the progression of liver disease.
The most common way a liver sample is obtained is by inserting a special biopsy needle
through a small incision into the liver to
retrieve liver tissue. This liver biopsy procedure is commonly used in the United States
when children and adults are in the early to
mid-stages of liver disease.
Why a Liver Biopsy?
When the liver is badly damaged, the blood
cannot clot properly and the risk of internal
bleeding increases. Also, when the liver’s
“architecture” or structure has been distorted
by scarring, risks associated with biopsies
increase. In these scenarios, doctors may
perform a laparoscopic biopsy or transvenous
biopsy to retrieve liver tissue samples.
Dr. Luis Balart, Chief of Gastroenterology at Lo uisiana State
University Health Sciences Center in
New Orleans, explained, “This is an
important parameter that must be
part of the evaluation process in
these individuals. Only a liver biopsy
can truly stage [diagnose] the disease
and be capable of forecasting with
any degree of certainty what the
future course may hold for a
particular patient. Just as important,
liver biopsy findings and staging can
provide a firm basis from which to
make a decision as to whether
treatment is warranted immediately
or if watchful waiting is an option.”
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In a laparoscopic biopsy, the physician
inserts a special tube called a laparoscope
through an incision in the abdomen. The
laparoscope sends images of the liver to a
monitor. The physician watches the monitor and uses instruments within the laparoscope to retrieve tissue samples from one
or more parts of the liver. Physicians use
this type of biopsy when they need tissue
samples from specific parts of the liver.
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In a transvenous biopsy, a tube called a catheter that contains a biopsy needle is
inserted into a vein in the neck and guided to the liver. The needle then collects liver
tissue samples. Physicians use this procedure when patients have advanced liver
disease, including blood-clotting problems or fluid in the abdomen.
How a Liver Biopsy Is Performed
Most biopsies are performed in an out-patient hospital setting or with an overnight
hospital stay, especially for young children.
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Either the day before or the morning of the biopsy, the hospital lab or doctor’s office
staff will take a blood sample. Doctors will look at the blood sample to evaluate a
patient’s red and white blood cell count, platelets and prothrombin time, which indicate
whether a person is at increased risk of clotting problems and internal bleeding.
These tests are performed again shortly after the biopsy procedure and again the day
after the biopsy to test for any internal bleeding, especially in children.
Usually one week before the surgery, a patient must stop taking aspirin, ibuprofen and
any anticoagulants. A patient must not eat or drink anything for about eight hours before
the biopsy, which is often very difficult for young children.
Once in the hospital, if the patient is a child, he or she is sedated either through
conscious sedation or by being completely anaesthetized. This is a difficult time for
parents and children alike. Children will often have to be restrained and may cry while
being anaesthetized. Before the procedure, both the doctor and the anesthesiologist
should have met with parents to review the procedure.
If older teens are able to hold still during the procedure (they must also hold their breath
during the needle pass), just their skin and area under the skin where the needle will pass
quickly through is anaesthetized. Adults also usually receive a local anesthetic if they
can lie still and hold their breath during the procedure.
The physician and a radiologist will determine the best site, depth and angle of the
needle puncture by physical examination and through an ultrasound. The doctor may
actually draw an outline of the liver on the abdomen and then make an “X” where the
incision will be made and the needle inserted.
An ultrasound will usually be used during much of the biopsy procedure to guarantee
proper placement of the needle. Some doctors say an ultrasound-guided biopsy guarantees the best possible location for the biopsy and reduces risk of accidentally puncturing
the neighboring gall bladder or lung, especially in small children.
“I think today most liver biopsies should be ultrasound or CT-guided [using Computed
Tomography imaging or CAT] depending on the circumstances and the institution,” said
Dr. Philip Rosenthal. “In a normal anatomic liver, percussion and biopsy without guidance can be done. Personally, I like using ultrasound guidance. This is especially true in
a transplanted liver in which the normal anatomy has been changed, or if a piece of a
liver has been used for the transplant.”
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These liver cells, extracted during a
biopsy, are healthy.
These liver cells show
moderate scarring.
These liver cells show extended
scarring.
These liver cells show evidence of
cancerous growths or tumors.
Generally, doctors make only one “pass” with the thin needle to extract between two to
three inches of liver tissue. The risk of injury increases with the number of needle
“passes.”
The actual biopsy will take five seconds or less. The entire procedure generally takes
about 20 minutes.
According to reports, about half of adult patients who undergo a biopsy experience no
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pain after the procedure, while the other half report they experience a brief localized
pain that may spread to the right shoulder. Because children are generally sedated, there
are few reports of children experiencing pain shortly after the procedure. After the
biopsy, a dressing is placed over the small incision and the patient must lie on his or her
right side, to keep pressure on the incision site for three to four hours. During this time,
blood tests are performed again to make sure there is no internal bleeding and blood
pressure is taken frequently.
This post-biopsy period is often a difficult time for parents who must keep their restless
young children still. Videos are ideal distractions for older children. Younger children
usually require the constant presence of reassuring parents and favorite blankets and
animals.
Within a couple hours, the patient will be able to eat.
At home, the dressing will be able to be removed within a couple of days. Patients are
instructed to take it easy for the first week, and to apply some pressure to the side with
cushions or pillows as this aids healing, helps prevent bleeding and may make the
patient more comfortable. The doctor will have specific instructions.
For 14 days after the biopsy, patients should remain within one hour of a major hospital
and they should carry information to alert medical staff that they have recently had a
biopsy.
Following the biopsy, the doctor will call and meet with the family to review the results
and discuss the next treatment step.
Guidelines for Liver Biopsies in Children
According to a survey conducted by the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, the reported rates of major complications in
children who underwent liver biopsies over a 50-year period ranged from zero to 4.5
percent. The incidence of post-biopsy hemorrhage requiring transfusion ranged from
zero to 2.8 percent.
Other major complications in children, like in adults, have included internal bleeding,
bile leak if the gallbladder is nicked and ascitic fluid leak from the abdomen. Three
pediatric deaths were reported as a result of the procedure.
The Society examined liver biopsies in order to establish a recommendation on whether
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biopsies on children, who tend to be more high-risk than adults for this procedure,
should be conducted on an out-patient or in-patient hospital setting.
The Society decided that, “because of potentially increased risks, and the greater difficulty of detecting and managing shock, infants and children requiring liver biopsy
should not be compelled to have liver biopsy as outpatients.” However, the Society
agreed that an out-patient liver biopsy may be considered if, in the judgment of the
attending physician, certain conditions are met.
Young patients with underlying conditions such as active malignancy, AIDS, bone
marrow transplantation and ischemic liver disease are at significantly higher risk for a
complication or poor outcome following percutaneous liver biopsy, and generally are
not considered candidates for a liver biopsy in an out-patient setting, the group recommended.
The Society also stated that children who receive liver biopsies in an out-patient setting
should remain at the facility for at least six hours following the procedure for frequent
monitoring. This is the same recommendation made for adults by the American Gastroenterological Association.
According to studies in adults, severe complications occur in only 0.57 percent of
patients who undergo a liver biopsy. The risk of internal bleeding decreases, they found,
if the doctor who is conducting the biopsy uses ultrasound to guide the procedure,
according to an American Association for the Study of Liver Diseases report.
Preparing Children for Biopsies
Based on the age of the child, preparation and the constant presence of their parents can
help ease the liver biopsy experience.
According to experts, parents should try to explain the procedure in age-appropriate
ways, perhaps using a doll as a model. Stress the procedure is not a punishment, but a
way to make sure they are as healthy as possible.
Prepare yourself and your child for a period of fasting. His or her food and fluid will
probably be restricted for up to eight hours or more before the procedure. You must sign
an informed consent form giving permission for biopsy. Before the biopsy, blood
samples will be taken from your child to ensure his or her blood will clot properly.
Take the child’s favorite toys, blankets and other objects of comfort to the hospital to
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help them with the experience. Ask the doctor to describe in detail what will take place
when you arrive at the hospital with your child, so you both are prepared for the inevitable fasting period, blood tests, waiting, anesthetic, the biopsy itself and the recovery.
Be sure to bring toys or videos that your child will want during the post-operative
recovery period. Also ask about what food will be allowed during this recovery time.
Your child will be hungry and may want their favorite food.
How Liver Biopsies Are Evaluated
The Histologic Activity Index (HAI) or “Knodell Score” is the method many doctors
use to evaluate a liver sample. This is a standardized interpretation that has shown little
variation between “interpreting” doctors.
While some of the judgments in the HAI are subjective, the evaluation is straightforward and numeric “values” are assigned so a liver’s health can be accurately assessed
before and after treatment, or over a period of months or years.
Doctors use this standardized grading system to allow consistent comparison between
biopsies in the same patient that are performed and interpreted by different doctors and
for biopsies of large populations participating in clinical studies.
The test evaluates the liver specimen based on:
•
Degree of inflammation.
•
Evidence of “bridging” or growth of scar tissue.
•
Liver cell injury or death (necrosis) in different areas of the liver including the portal
area where the portal vein flows.
•
Change in the “architecture” or general shape of the liver.
•
The degree of fibrosis (scarring) that is present in the tissue sample.
In HAI results, “grade” refers to inflammation and “stage” refers to fibrosis or scarring.
These terms are universally accepted.
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These are the four features that are evaluated by the HAI and the range of their scores.
Zero indicates non-existent and high scores reflect severe indications:
•
Periportal and bridging necrosis – 0 to 10
•
Intralobular degeneration and necrosis – 0 to 4
•
Portal Inflammation – 0 to 4
•
Fibrosis (Scarring) – 0 to 4
All four scores are added and can range from 0 to 22. This final tally becomes a
patient’s HAI score and indicates the severity of the liver disease. (See Lab Test Results
section for more information.)
Portal inflammation refers to the inflammation of liver cells that surround the portal
tract. The portal tract is the area where the artery, vein and bile duct enter the liver.
Focal or lobular necrosis/inflammation refers to liver cell damage that exists between
the portal regions. Intralobular degeneration and necrosis refers to the cell damage that
extends across more than one liver lobule.
An individual’s HAI score serves as a baseline or reference point as doctors recommend
either a drug therapy or continued watchful waiting.
Doctors encourage patients and parents to focus less on numbers and more on the
description of scarring and the nomenclature such as bridging, nodules (which are signs
of cirrhosis) and widespread cirrhosis, which signify more advanced liver disease.
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