ee For More Information

Points to Remember American Liver Foundation
+ Nonalcoholic steatohepatitis 75 Maiden Lane, Suite 603
(NASH) is fat in the liver, with New York, NY 10038-4810
inflammation and damage. 24-hour helpline (7 days/week):
. . 1-800-465-4837 or 1-888-443-7222
* NASH occurs in people who drink Phone: 1-800-676-9340 or 212-668-1000
little or no alcohol and affects 2 to 5 Fax: 212-483-8179
percent of Americans, especially Email: info@liverfoundation.org
people who are middle-aged and Internet: www.liverfoundation.org,

overweight or obese.
¢ Nash can occur in children.

* People who have NASH may feel
well and may not know that they
have a liver disease.

« NASH can lead to cirrhosis, a condi-
tion in which the liver is permanently
damaged and cannot work properly.

+ Fatigue can occur at any stage of
NASH.

* Weight loss and weakness may begin
once the disease is advanced or cir-
rhosis is present.

« NASH may be suspected if blood
tests show high levels of liver
enzymes or if scans show fatty liver.

+ NASH is diagnosed by examining a
small piece of the liver taken through
a needle, a procedure called biopsy.

* People who have NASH should
reduce their weight, eat a balanced
diet, engage in physical activity,
and avoid alcohol and unnecessary
medications.

* There are no specific therapies for
NASH. Experimental therapies
being studied include antioxidants
and antidiabetes medications.

5 Nonalcoholic Steatohepatitis


Treatment

It is important to stress that there are cur-
rently no specific therapies for NASH. The
most important recommendations given to
persons with this disease are to

¢ reduce their weight (if obese or
overweight)

¢ follow a balanced and healthy diet
* increase physical activity

¢ avoid alcohol

¢ avoid unnecessary medications

These are standard recommendations, but
they can make a difference. They are also
helpful for other conditions, such as heart
disease, diabetes, and high cholesterol.

A major attempt should be made to lower
body weight into the healthy range. Weight
loss can improve liver tests in patients with
NASH and may reverse the disease to some
extent. Research at present is focusing on
how much weight loss improves the liver

in patients with NASH and whether this
improvement lasts over a period of time.

People with NASH often have other med-
ical conditions, such as diabetes, high blood
pressure, or elevated cholesterol. These
conditions should be treated with medica-
tion and adequately controlled; having
NASH or elevated liver enzymes should not
lead people to avoid treating these other
conditions.

Experimental approaches under evaluation
in patients with NASH include antioxi-
dants, such as vitamin E, selenium, and
betaine. These medications act by reducing
the oxidative stress that appears to increase
inside the liver in patients with NASH.
Whether these substances actually help
treat the disease is not known, but the
results of clinical trials should become
available in the next few years.

4 Nonalcoholic Steatohepatitis

Another experimental approach to treating
NASH is the use of newer antidiabetic
medications—even in persons without
diabetes. Most patients with NASH have
insulin resistance, meaning that the insulin
normally present in the bloodstream is less
effective for them in controlling blood glu-
cose and fatty acids in the blood than it is
for people who do not have NASH. The
newer antidiabetic medications make the
body more sensitive to insulin and may help
reduce liver injury in patients with NASH.
Studies of these medications—including
metformin, rosiglitazone, and pioglita-
zone—are being sponsored by the National
Institutes of Health and should answer the
question of whether these medications are
beneficial in NASH.

Hope Through Research

What is most needed in the management
of NASH is more research to better under-
stand the liver injury found in this disease.
When the pathways that lead to the injury
are fully known, safe and effective means
can be developed to reverse these pathways
and help patients with NASH. Recent
breakthroughs in mapping the human
genome and uncovering the individual
steps by which insulin and other hormones
regulate blood glucose and fat could pro-
vide the necessary clues.

The National Institute of Diabetes and
Digestive and Kidney Diseases funds the
NASH Clinical Research Network, which
comprises eight clinical centers located
throughout the United States and a coordi-
nating center at Johns Hopkins University.
The NASH network researches the nature
and underlying cause of NASH and con-
ducts clinical studies on prevention and
treatment. More information on the
NASH Clinical Research Network and

the locations of the clinical centers are
available at www.nashcrn.com.


National Digestive Diseases
Information Clearinghouse

2 Information Way

Bethesda, MD 20892-3570

Phone: 1-800-891-5389

Fax: 703-738-4929

Email: nddic@info.niddk.nih.gov
Internet: www.digestive.niddk.nih.gov

The National Digestive Diseases Information
Clearinghouse (NDDIC) is a service of the
National Institute of Diabetes and Digestive
and Kidney Diseases (NIDDK). The NIDDK
is part of the National Institutes of Health
under the U.S. Department of Health and
Human Services. Established in 1980, the
clearinghouse provides information about
digestive diseases to people with digestive
disorders and to their families, health care
professionals, and the public. NDDIC answers
inquiries, develops and distributes publications,
and works closely with professional and patient
organizations and Government agencies to
coordinate resources about digestive diseases.

Publications produced by the clearinghouse
are carefully reviewed by both NIDDK scien-
tists and outside experts. This fact sheet was
reviewed by Anna Mae Diehl, M.D., Johns
Hopkins University; and Brent Tetre, M.D.,
St. Louis University.

This publication is not copyrighted. The
clearinghouse encourages users of this fact
sheet to duplicate and distribute as many
copies as desired.

This fact sheet is also available at
www.digestive.niddk.nih.gov.

postin,

£ U.S. DEPARTMENT OF HEALTH

g AND HUMAN SERVICES

S National Institutes of Health
ean

NIH Publication No. 04-4921
January 2004


Nonalcoholic
Steatohepatitis

National Digestive Diseases Information Clearinghouse

Nonalcoholic steatohepatitis or NASH is

a common, often “silent” liver disease. It
resembles alcoholic liver disease, but occurs
in people who drink little or no alcohol.

Y

National ~
rata of The major feature in NASH is fat in the
Diabetes and liver, along with inflammation and damage.
a xldney Most people with NASH feel well and are
Diseases not aware that they have a liver problem.
NATIONAL Nevertheless, NASH can be severe and
INSTITUTES can lead to cirrhosis, in which the liver is

OF HEALTH

permanently damaged and scarred and
no longer able to work properly.

NASH affects 2 to 5 percent of Americans.
An additional 10 to 20 percent of Ameri-
cans have fat in their liver, but no inflam-
mation or liver damage, a condition called
“fatty liver.” Although having fat in the
liver is not normal, by itself it probably
causes little harm or permanent damage.

If fat is suspected based on blood test
results or scans of the liver, this problem
is called nonalcoholic fatty liver disease
(NAFLD). If a liver biopsy is performed
in this case, it will show that some people
have NASH while others have simple
fatty liver.

Both NASH and NAFLD are becoming
more common, possibly because of the
greater number of Americans with obesity.
In the past 10 years, the rate of obesity has
doubled in adults and tripled in children.
Obesity also contributes to diabetes and
high blood cholesterol, which can further
complicate the health of someone with
NASH. Diabetes and high blood choles-
terol are also becoming more common
among Americans.

Liver

Gallbladder

Cystic duct

Common bile duct

Duodenum

Common hepatic duct

Pancreas

Stomach

Pancreatic duct

U.S. Department
of Health and
Human Services

Biliary system



Diagnosis

NASH is usually first suspected in a person
who is found to have elevations in liver
tests that are included in routine blood test
panels, such as alanine aminotransferase
(ALT) or aspartate aminotransferase
(AST). When further evaluation shows no
apparent reason for liver disease (such as
medications, viral hepatitis, or excessive
use of alcohol) and when x rays or imaging
studies of the liver show fat, NASH is sus-
pected. The only means of proving a diag-
nosis of NASH and separating it from
simple fatty liver is a liver biopsy. For a
liver biopsy, a needle is inserted through
the skin to remove a small piece of the
liver. NASH is diagnosed when examina-
tion of the tissue under the microscope
shows fat along with inflammation and
damage to liver cells. If there is fat without
inflammation and damage, simple fatty

liver or NAFLD is diagnosed. An impor-
tant piece of information learned from the
biopsy is whether scar tissue has developed
in the liver. Currently, no blood tests or
scans can reliably provide this information.

Symptoms

NASH is usually a silent disease with few
or no symptoms. Patients generally feel
well in the early stages and only begin to
have symptoms—such as fatigue, weight
loss, and weakness—once the disease is
more advanced or cirrhosis develops. The
progression of NASH can take years, even
decades. The process can stop and, in
some cases, reverse on its own without
specific therapy. Or NASH can slowly
worsen, causing scarring or “fibrosis” to
appear and accumulate in the liver. As
fibrosis worsens, cirrhosis develops; the

A small, slender core of tissue is
removed with a biopsy needle and
looked at under the microscope.

Liver biopsy

2 Nonalcoholic Steatohepatitis



Fatty liver

Deposits of fat
cause liver
enlargement.

- y=
\

Liver fibrosis

Cirrhosis

Scar tissue forms. Scar tissue
More liver cell makes liver hard
injury occurs. and unable to

work properly.

Stages of liver damage

liver becomes seriously scarred, hardened,
and unable to function normally. Not every
person with NASH develops cirrhosis, but
once serious scarring or cirrhosis is present,
few treatments can halt the progression.

A person with cirrhosis experiences fluid
retention, muscle wasting, bleeding from
the intestines, and liver failure. Liver
transplantation is the only treatment for
advanced cirrhosis with liver failure, and
transplantation is increasingly performed
in people with NASH. NASH ranks as

one of the major causes of cirrhosis in
America, behind hepatitis C and alcoholic
liver disease.

Causes

Although NASH has become more com-
mon, its underlying cause is still not clear.
It most often occurs in persons who are
middle-aged and overweight or obese.

3 Nonalcoholic Steatohepatitis

Many patients with NASH have elevated
blood lipids, such as cholesterol and
triglycerides, and many have diabetes or
pre-diabetes, but not every obese person
or every patient with diabetes has NASH.
Furthermore, some patients with NASH
are not obese, do not have diabetes, and
have normal blood cholesterol and lipids.
NASH can occur without any apparent risk
factor and can even occur in children.
Thus, NASH is not simply obesity that
affects the liver.

While the underlying reason for the liver
injury that causes NASH is not known,
several factors are possible candidates:

¢ insulin resistance

¢ release of toxic inflammatory proteins
by fat cells (cytokines)

* oxidative stress (deterioration of cells)
inside liver cells