NONALCOHOLIC FATTY LIVER
Debra Hefner, DO
January 8, 2013
Nonalcoholic Fatty Liver Disease (NAFLD)-
Refers to the presence of hepatic steatosis
when no other causes for secondary hepatic fat
accumulation (i.e. heavy alcohol consumption)
NAFLD may progress to cirrhosis and is likely an
important cause of cryptogenic cirrhosis.
Nonalcoholic Fatty Liver Disease
NAFLD is subdivided into nonalcoholic fatty
liver(NAFL) and nonalcoholic steatohepatitis
In NAFL, hepatic steatosis is present without
evidence of significant inflammation, whereas in
NASH, hepatic steatosis is associated with hepatic
inflammation that may be histologically
indistinguishable from alcoholic steatohepatitis.
NONALCOHOLIC FATTY LIVER
Other terms that have been used to describe
NASH include :
Fatty liver hepatitis
Prevalence –NAFLD is seen worldwide and is the
most common liver disorder in Western
industrialized countries, where the major risk
factors for NAFLD, central obesity, Type 2 DM,
dyslipidemia, and metabolic are common.
In the US, studies report a prevalence of NAFLD of
Worldwide, NAFLD has a reported prevalence of 6-
In the US, the prevalence of NAFLD has been
increasing over time. This increase was
demonstrated in a comparison of 3 cycles of
the National Health and Nutrition Examination
Time Period: Prevalence of NAFLD:
Accounting for 47, 63 and 75% of chronic liver
disease during those time periods, respectively.
However, it should be noted that the definition of NAFLD used in
the study (elevated serum aminotransferase levels in the absence
of an alternative explanation) could lead to misclassification and
likely underestimated the true prevalence of NAFLD, since
patients with NAFLD may have normal serum aminotransferases.
Over the same three time periods, the study also noted
increases in the rates of other components of the
metabolic syndrome, including obesity, Type2 DM and
Obesity DM2 Systemic HTN
1988-1994 22 6 23
1999-2004 30 8 33
2005-2008 33 9 34
Most patients are diagnosed with NAFLD in their 40’s
Studies very with regards to sex distribution of
NAFLD, with some suggesting it is more common in
women and others suggesting it is more common in
Patients with NAFLD (particularly those with NASH)
often have one or more components of the
Insulin resistance or overt diabetes
ASSOCIATION WITH OTHER
The pathogenesis of NAFLD has not been fully
elucidated. The most widely supported theory
implicates insulin resistance as the key mechanism
leading to hepatic steatosis, and perhaps also to
Others have proposed that a “second hit”, or
additional oxidative injury, is required to manifest the
necroinflammatory component of steatohepatitis.
Hepatic iron, leptin, antioxidant deficiencies, and
intestinal bacteria have all been suggested as
potential oxidative stressors.
Most patients with NAFLD are asymptomatic,
although some patients with nonalcoholic
steatohepatitis (NASH) may c/o fatigue, malaise and
vague right upper abdominal discomfort.
Patients are more likely to come to attention because
laboratory testing revealed elevated liver
aminotransferases or hepatic steatosis was detected
incidentally on abdominal imaging.
Patients with NAFLD may have hepatomegaly on
physical examination due to fatty infiltration of the
In some patients, hepatomegaly is the presenting
sign of NAFLD. However, the reported prevalence
is highly variable.
Patients with NAFLD may have mild or moderate
elevations in the aspartate aminotransferase (AST) and
alanine aminotransferase (ALT), although normal
aminotransferase levels do not exclude NAFLD.
When elevated, the AST and ALT are typically 2 to 5
times the upper limit of normal, with an AST to ALT ratio
of less than one (unlike alcoholic fatty liver disease,
which typically has a ratio greater than two).
The degree of aminotransferase does not predict the
degree of hepatic inflammation or fibrosis.
The alkaline phosphatase may be elevated 2-3 times
the upper limit of normal.
Patients with NAFLD may have an elevated serum
ferritin concentration or transferrin saturation.
There is evidence that a serum ferritin greater than
1.5 times the upper limit of normal in patients with
NAFLD is associated with a higher nonalcoholic fatty
liver disease activity score (and thus, NASH) and
with advanced hepatic fibrosis.
In patients with NAFLD, these include increased
echogenicity on ultrasound, decreased hepatic
attenuation on computed tomography (CT) and
an increased fat signal on magnetic resonance
Diagnosis of NAFLD requires all of the
Demonstration of hepatic steatosis by
imaging or biopsy
Exclusion of significant alcohol consumption
Exclusion of other causes of hepatic steatosis
In those under going a radiologic evaluation,
radiologic findings are often sufficient to make the
diagnosis if other causes of hepatic steatosis have
While not indicated for the majority of patients, a
liver biopsy may be indicated if the diagnosis is not
clear or to assess the degree of hepatic injury.
In addition, liver biopsy is the only method currently
available to differentiate nonalcoholic fatty liver
(NAFL) from nonalcoholic steatohepatitis (NASH).
Which patients to biopsy:
There is no clear consensus about which patients
require a liver biopsy. Obtain a liver biopsy in
patients with suspected NAFLD if the diagnosis is
unclear after obtaining standard laboratory tests
and hepatic imaging, if there is evidence of
cirrhosis, if the patient wants to know if
inflammation or fibrosis is present or if the patient
is at risk for advanced fibrosis or cirrhosis.
Specifically, we obtain a biopsy if the patient:
Has peripheral stigmata of chronic liver disease (suggestive
Has splenomegaly (suggestive of cirrhosis)
Has cytopenias (suggestive of cirrhosis)
Has a serum ferritin>1.5times the upper limit of normal
(suggestive of NASH and advanced fibrosis)
Is >45years of age with associated obesity or diabetes
(increased risk of advanced fibrosis)
Which Patients to Biopsy?
Rule out other disorders:
Differentiating NAFLD from the other items in the
differential diagnosis begins with a thorough history
to identify potential causes such as significant alcohol
use, starvation, medication use and pregnancy-
related hepatic steatosis.
Alternative causes of hepatic steatosis that should be considered
in a patient with suspected NAFLD:
Alcoholic liver disease
Hepatitis C (particularly genotype 3)
Acute fatty liver of pregnancy
HELLP (hemolytic anemia, elevated liver enzymes, low platelet
Multiple therapies have been investigated for the
treatment of nonalcoholic fatty liver disease(NAFLD).
However, weight loss is the only therapy with
reasonable evidence suggesting it is beneficial and
Recommendations for patients with NAFL or NASH:
Weight loss for patients who are overweight or
obese. In addition to its other benefits, weight loss
has been associated with histologic improvement in
patients with NAFLD.
Options to promote weight loss include lifestyle
modifications and, for patients who are candidates,
A reasonable goal for many patients is to lose 1-
2lbs/week. More rapid weight reduction may be
associated with worsening of liver disease.
Histologic improvement has also been observed
after bariatric surgery.
Some of data is conflicted but when taken
collectively, these data suggest that bariatric
surgery is a promising approach in obese patients
However, given the potential for worsening
fibrosis in some patients following bariatric surgery,
patients should continue to have their liver function
Hepatitis A and B vaccinations should be given
to patients without serological evidence of
Additional vaccines recommended for patients
with chronic liver disease include pneumococcal
vaccination and standard immunizations
recommended for the population in general
(i.e. influenza, diptheria, tetanus boosters
Treatment of risk factors for cardiovascular
disease. Patients with NAFLD are at increased risk
for cardiovascular disease & often have multiple
cardiovascular disease risk factors. Mgmt
includes optimization of blood glucose control in
patients with DM2 and treatment of
hyperlipidemia. Statin therapy has been shown to
be safe in patients with NAFLD.
In general, the use of pharmacologic agents are not
recommended (i.e. Vitamin E, pioglitazone) solely for
the treatment of NAFLD. However, it is suggested
that Vitamin E at a dose of 400IU/day for patients
with advanced fibrosis on biopsy who do not have
DM or coronary artery disease. Limited evidence
supports a benefit with up to 800IU/day of Vitamin E
in patients w/out DM, but some observational studies
suggest a possible increase in all-cause mortality with
higher-dose Vitamin E (800IU/day).
Suggest that patients with NAFLD avoid all alcohol consumption.
Heavy alcohol use is associated with disease progression among
patients with NAFLD.
Suggest not using thiazolidinediones primarily for
the treatment of NASH.
Thiazolidinediones improve histologic parameters in
patients with NASH, but likely need to be used long-
term and their use has been associated with serious
adverse events, including heart failure.
Using a thiazolidinedione is reasonable in patients
who are candidates for thiazolidinedione treatment
for Type 2 DM.
Patients with NASH-related cirrhosis should undergo
screening for hepatocellular carcinoma
Recommend that patients with steatohepatitis on
biopsy be followed by a hepatologist.
Patients with nonalcoholic fatty liver without
steatohepatitis can often be followed by a primary
care physician, provided the diagnosis is clear.
However, if the patient develops significant
aminotransferase elevations (twice the upper limit
of normal) or evidence of cirrhosis, it is suggested
tat a referral to a hepatologist for further
evaluation & management.
WHEN TO REFER?