Nonalcoholic Fatty Liver Disease

Pouneh S. Mofrad, MD, Arun J. Sanyal, MD

Fatty disorders of the liver are defined by 2 major histologic patterns of steatosis
within hepatocytes. Microvesicular steatosis is characterized by the presence of
numerous small vesicles of fat that do not displace the nucleus (Figures 1, 2).
Macrovesicular steatosis is characterized by engorgement of the hepatocyte by a
large fat globule that displaces the nucleus.

(Enlarge Image)
Figure 1.
Two patterns of hepatic steatosis are recognized: (1) microvesicular steatosis: the
cytoplasm is replaced by bubbles of fat that do not displace the nucleus; and (2)
macrovesicular steatosis: the cytoplasm is replaced by a large bubble of fat that
displaces the nucleus to the edge of the cell.

From Sanyal AJ. Nonalcoholic steatohepatitis. Clinical Perspectives in
Gastroenterology. 2000;129(May/June). Copyright 2000; republished with
permission from Elsevier.

(Enlarge Image)
Figure 2.
Steatohepatitis is shown here. The histologic findings shown include
macrovesicular steatosis, cytologic ballooning, Mallory bodies, and scattered
lobular inflammation.
There are 2 principal lesions of fatty liver disease: a pure fatty liver alone and
steatohepatitis ( Table 1 ). When fatty liver occurs in an individual who does not
consume alcohol in quantities considered to be harmful to the liver, it is referred
to as nonalcoholic fatty liver disease (NAFLD).
[1]
This condition was originally
identified in morbidly obese individuals, especially after weight loss surgery, and
in women who were diabetic.
[2,3]
It is now known that NAFLD occurs in men as
well as in individuals who are not diabetic, and it is increasingly being recognized
as a major cause of liver disease.
The prevalence of NAFLD in the general population ranges from 13% to 15%.
These data have been obtained from a number of studies that have used varying
criteria for the diagnosis of NAFLD. Studies that have used histologic
characterization of the condition have all focused on specific patient populations
within a hospital environment and are therefore potentially subject to selection
and ascertainment bias.
[4-6]
However, population-based studies have used
sonographic methods to make a presumptive diagnosis of NAFLD.
[7-11]
The latter
studies are unable to distinguish between a fatty liver and steatohepatitis. Even
more important, sonography cannot effectively distinguish between a fatty liver
and other medical disorders of the liver.
Perhaps the studies least subject to selection bias are those of air crash victims
who have undergone autopsies. Despite the heterogeneity of study methodologies,
the overall prevalence of NAFLD in all investigations is similar, and ranges
between 13% and 18%. Studies of liver biopsies of unselected autopsies or living
donors for liver transplant indicate that the prevalence of steatohepatitis ranges
from 2% to 4%.
[12,13]
This condition can affect any age group, including about
2.6% of children and up to 52.8% of obese children. NAFLD was originally
believed to occur primarily in middle-aged obese women; however, more recent
studies have shown that it occurs with equal frequency in men.
[14]

The most common risk factor associated with NAFLD is the presence of the
metabolic syndrome. The metabolic syndrome is defined by the presence of 3 or
more of the following criteria ( Table 2 )
[15]
: (1) increased waist circumference,
(2) hypertriglyceridemia, (3) hypertension, (4) high fasting glucose, and (5) a low
high-density lipoprotein (HDL) level. NAFLD is now recognized to be the hepatic
manifestation of the metabolic syndrome. Given the fact that approximately 47
million individuals in the United States have the metabolic syndrome,
[16]
NAFLD
represents a major health concern. Insulin resistance is the common
pathophysiologic denominator that links all of the various components of the
metabolic syndrome.
Of all of the individual clinical components of the metabolic syndrome, obesity
has the strongest association with NAFLD. Obesity is defined as a body mass
index (BMI) > 30 kg/m
2
.
[17]
The more obese the patient, the higher the risk of
having a fatty liver. Thirty percent of patients who are obese have fatty liver, and
up to 80% of morbidly obese patients (BMI > 35) have NAFLD.
[18,19]
Regardless
of BMI, patients with truncal obesity are at greater risk of fatty liver disease.
Other risk factors associated with NAFLD include type 2 diabetes, total parenteral
nutrition, jejunal-ileal bypass operations for weight loss, and use of certain
medications, including calcium-channel blockers and amiodarone ( Table 3 ).
Like most chronic liver diseases, in NAFLD there is a long period during which
an individual patient remains essentially asymptomatic. In asymptomatic
individuals, the diagnosis is often made when a radiologic test performed for
unrelated indications reveals evidence of a fatty liver. In other cases, a persistently
elevated alanine aminotransferase (ALT) level leads to a work-up that yields the
diagnosis. Another common modality of presentation is an elevated serum ALT
level that is noted after a cholesterol-lowering drug is started. Frequently, baseline
ALT levels are either already increased or are not available in such cases.
When symptoms occur, they are often relatively nonspecific (eg, fatigue and
vague right upper quadrant discomfort; Table 4 ). Fatigue is the most common
symptom associated with NAFLD. The degree of fatigue does not correlate with
the histologic stage of liver disease nor the degree of hepatic synthetic
dysfunction. In many instances, the presence of poorly controlled diabetes,
hypothyroidism, or sleep apnea contributes to the fatigue, and these symptoms
should be looked for and evaluated appropriately. Because hypertriglyceridemia
and obesity are risk factors for not only NAFLD but also gallstones, many patients
with NAFLD are also at risk of developing gallstones.
[20,21]
Patients with NAFLD
may also present with symptomatic cholelithiasis; when an ultrasound is
performed for these symptoms, a fatty liver may then be noted.
When the liver disease is more advanced, patients may develop symptoms
indicative of severe liver disease. These symptoms include increasing fatigue,
pruritus, edema, and jaundice. The development of variceal hemorrhage, ascites,
or encephalopathy indicates the presence of cirrhosis.
In patients with NAFLD who do not have advanced liver disease, the most
common sign on physical examination is hepatomegaly ( Table 4 ).
[1,14]
Some
patients may have evidence of chronic liver disease such as palmar erythema,
spider angioma, jaundice, and hepatic encephalopathy. As with other causes of
advanced liver disease, patients who develop cirrhosis due to NAFLD may have
stigmata of portal hypertension, such as ascites, anasarca, and varices. Some
NAFLD patients, particularly children, may also have acanthosis nigricans, which
has been associated with insulin-resistant states. NAFLD is also associated with
several disorders characterized by abnormal body fat distribution
(lipodystrophies). The body habitus of patients with suspected or proven NAFLD
should be carefully evaluated for the presence of lipodystrophies. When
suspected, such individuals should be referred for appropriate work-up for
confirmation.
The presence of an elevated ALT level is often the first clue in the diagnosis
of NAFLD. In the majority of patients, the serum ALT level is only increased
by 1-4 times the upper limits of normal. AST levels may also be minimally
elevated, but the AST:ALT ratio is usually < 1.
[22]
In individuals with
cirrhosis, the AST:ALT ratio may exceed 1, but is rarely, if ever, > 2. This is
a useful way to distinguish NAFLD from alcoholic liver disease, which is
often associated with an AST: ALT ratio > 2. The degree of serum ALT
elevation does not correlate with liver histology. ALT levels may also be
normal in patients with NAFLD. A normal serum ALT does not exclude the
possibility of underlying steatohepatitis or even cirrhosis.
Increased glucose levels and abnormal lipid profiles may also be found in these
patients, given that individuals with diabetes mellitus and hyperlipidemia are at
higher risk for developing NAFLD. In patients who develop cirrhosis, the serum
albumin and prothrombin time may be abnormal. Serum bilirubin may also be
elevated in patients with end-stage liver disease. Once portal hypertension and,
therefore, hypersplenism occur, platelet counts may be decreased.
Imaging studies ( Table 5 ) such as ultrasound (sonography) may provide the first
indication that patients have hepatic steatosis.
[23]

Sonography is the most commonly used modality for the diagnosis of a fatty liver.
The sonographic findings of fatty liver include increased echogenicity of the liver
parenchyma and blurring of the vascular margins (Figure 3).

(Enlarge Image)
Figure 3.
A sonogram of a fatty liver showing increased echotexture compared with the
adjacent kidney (bright liver). This is not a specific finding for NAFLD.
Sonography is a sensitive but relatively nonspecific tool for the diagnosis of fatty
liver. A CT scan is more specific for the diagnosis of fatty liver and has
comparable sensitivity. However, CT scan is more costly than sonography. The
presence of a fatty liver decreases the hepatic image intensity (ie, makes it appear
darker on CT scan). When the spleen is more than 10 Hounsfield units brighter
than the liver, a fatty liver can be diagnosed with confidence. A fatty liver shows
enhancement of its image after intravenous contrast administration, but this is less
marked than the spleen. When the spleen is more than 20 Hounsfield units
brighter than the liver in a postcontrast CT scan, a fatty liver can be diagnosed. A
fatty liver may also be diagnosed with relatively high sensitivity and specificity by
gradient-echo MR pulse sequences. None of these imaging modalities, however,
can distinguish a fatty liver from steatohepatitis, as confirmed by a recent
study.
[24]
These modalities are also poor in terms of assessing the stage of liver
fibrosis. Therefore, imaging studies may help with diagnosing fatty infiltration of
the liver, but they do not help in distinguishing between fatty liver, steatohepatitis,
and steatohepatitis with fibrosis.
Liver biopsy remains the gold standard for the assessment of liver histology and is
therefore a key test used to establish the diagnosis of NAFLD. Before undergoing
the risk of liver biopsy, however, it must first be discussed with the patient
whether the results will provide benefit. In the absence of effective therapy, one
may argue that a liver biopsy will not change the management of the patient and is
therefore not indicated in routine clinical practice. Until an effective therapy exists
for NAFLD, the decision of whether to perform a liver biopsy will remain
controversial. However, at this time, those patients who are likely to be enrolled in
therapeutic trials for steatohepatitis should be characterized by liver biopsy prior
to enrollment. Also, a liver biopsy is essential if there is uncertainty concerning
the diagnosis. Finally, a liver biopsy represents the only accurate way to stage
fibrosis in the liver. Thus, the decision of whether to perform a liver biopsy in
routine practice should be guided by the information that will be provided by the
biopsy, and whether that information will be used to make management decisions.
The microscopic features of NAFLD may be indistinguishable from those of
alcoholic fatty liver disease. As in alcoholic liver disease, the major histologic
feature of NAFLD is predominantly macrovesicular hepatic steatosis ( Table 6 ).
Other findings include hepatocellular ballooning, Mallory bodies (Figure 4),
pericentral perisinusoidal fibrosis (Figure 5), and lobular and portal inflammation.
Glycogen nuclei are often seen in patients with NAFLD, but are not a specific
finding.

(Enlarge Image)
Figure 4.
Mallory body is shown within a ballooned hepatocyte.

(Enlarge Image)
Figure 5.
Pericellular fibrosis is shown (Masson's trichrome stain). The collagenous tissue
(shown in blue) surrounds individual hepatocytes, producing a chicken-wire
appearance.
Unlike other forms of chronic liver disease, no consensus currently exists
regarding the grading and staging of NAFLD. The grade indicates the activity of
the steatohepatic lesion, whereas the stage reflects the degree of fibrosis.
Although the interobserver variability is relatively low in terms of diagnosing
steatosis, cytologic ballooning, and perisinusoidal fibrosis, there is considerable
variability with regard to the assessment of inflammatory changes. A scoring
system has been proposed by Brunt and colleagues ( Table 7 )
[25]
in which
individual parameters indicative of necroinflammatory activity (eg, cytologic
ballooning, steatosis, and inflammation) are scored separately and then a
composite score is derived to indicate the grade of steatohepatitis. This approach
also includes a staging system to assess hepatic fibrosis, which includes an
assessment of perisinusoidal fibrosis, portal fibrosis, and bridging fibrosis.
Nonalcoholic steatohepatitis (NASH)/NAFLD can progress to cirrhosis (Figure
6). Once cirrhosis develops, the amount of steatosis decreases, and may even
disappear completely. Additionally, the amount of cytologic ballooning may
decrease.

(Enlarge Image)
Figure 6.
Steatohepatitis with cirrhosis. A nodule of liver tissue is circumscribed by scar
tissue.

From Sanyal AJ. Nonalcoholic steatohepatitis. Clinical Perspectives in
Gastroenterology. 2000;130(May/June). Copyright 2000; republished with
permission from Elsevier.
As the lobular architecture becomes distorted by the remodeling of the liver
during transition to cirrhosis, it becomes increasingly difficult to assess
pericentral, perisinusoidal fibrosis. In other words, the key histologic features of
steatohepatitis either disappear or become difficult to assess once cirrhosis
develops. Many such cases are labeled as cryptogenic cirrhosis. In these settings,
the diagnosis can only be determined from the clinical profile of the patient and
the presence of risk factors for NAFLD.
The natural history of NAFLD has not been well defined. The existing literature is
almost entirely obtained in a retrospective manner, and is therefore subject to all
of the limitations of retrospective data. It is currently believed that there are
several histologic stages in the progression of NAFLD to cirrhosis. These
progressively include fatty liver alone, steatohepatitis, steatohepatitis with
fibrosis, and cirrhosis.
The earliest stage is a simple fatty liver alone. The concept of whether a fatty liver
progresses to steatohepatitis remains controversial. The current evidence indicates
that such progression does indeed occur, although the frequency with which it
does is likely low. Thus, the majority of patients with fatty liver alone have an
excellent prognosis. Over time, steatohepatitis may become associated with
increasing fibrosis. The pericentral, perisinusoidal fibrosis may extend to portal
tracts or other central veins forming central-central or central-portal bridges.
Portal-to-portal bridging fibrosis is unusual in NAFLD. Eventually, cirrhosis may
develop.
A retrospective study by Matteoni and colleagues
[26]
provides some assistance in
predicting the clinical course of patients with NAFLD. In this report, subjects with
NAFLD were grouped into 4 categories based on their liver histology as follows:
(1) fatty liver alone; (2) fat + lobular inflammation; (3) fat + ballooning
degeneration; and (4) fat + ballooning + Mallory's hyaline or fibrosis. Survival
among the patient groups over 18 years of follow-up were 33%, 30%, 26%, and
44%, respectively. Subjects in groups 3 and 4 had the highest number of liver-
related deaths, and liver-related diseases were the second most common cause of
death, with cancer being the number-one cause. Recent studies indicate that
NASH-related cirrhosis is associated with a higher likelihood of developing
hepatocellular carcinoma compared with cirrhosis associated with other causes.
[27]

The time course over which patients progress from one stage to the next remains
unknown. Additionally, the risk factors for progression are not well characterized.
However, cross-sectional studies suggest that increasing age, BMI, and the
presence of diabetes are associated with higher stages of fibrosis.
Improvement in liver histology has also been observed, mainly in patients with
minimal fibrosis. The latter occurs in obese patients who achieve slow but
significant weight loss. Conversely, rapid weight loss may promote progression of
the disease. Indeed, following severe and rapid weight loss, patients may present
with worsening liver failure. This phenomenon has been termed subacute NASH.
Therefore, when obese patients are placed on a weight loss program, the rate of
weight loss should be monitored and should ideally be between 1 and 2 lb/week.
As discussed above, gradual weight loss should be advocated in overweight
individuals.
[28]
Weight reduction by 10% or more has been associated with
normalization of elevated serum ALT levels and with a decrease in
hepatomegaly.
[29-31]
It should be reiterated that rapid weight loss may cause
progression of NAFLD. A heart-healthy diet, as recommended by the American
Heart Association and American Diabetes Association, appears to be a reasonable
recommendation in patients with NAFLD.
[32,33]
The effects of pharmacologic
agents used to induce weight loss (eg, orlistat) on liver histology are not well
known. The decision to use such agents or to proceed to bariatric surgery should
be dictated by the degree of obesity, the presence of other end-organ damage, and
the potential for severe hepatic decompensation due to surgery or rapid weight
loss, as dictated by National Heart, Lung, and Blood Institute guidelines for
weight management.
[28]

Patients with diabetes should have their disease controlled appropriately. The
impact of glycemic control and the type of antidiabetic therapy on liver histology
in patients with diabetes and NASH are not known. Because NAFLD is associated
with insulin resistance, it makes theoretical sense to use an insulin-sensitizing
agent in diabetic patients who also have NAFLD. The risks of hepatotoxicity
associated with these agents have not yet been well characterized in this
population and, if these agents are used, patients must be educated regarding the
potential risks of hepatotoxicity and monitored according to US Food and Drug
Administration guidelines.
Diabetic medications that have been shown to correct insulin resistance may
prove to be beneficial in treating patients with NAFLD, even in the absence of
overt diabetes, because most of these patients have underlying insulin resistance.
Metformin, a biguanide, has been shown to improve serum aminotransferase
levels in a recent study. The thiazolidinediones (eg, pioglitazone) act as
peroxisome proliferator-activated receptor (PPAR)-gamma agonists and improve
peripheral insulin sensitivity. A small study of patients treated with troglitazone
showed improvement in mean ALT levels and in hepatocellular inflammation.
Two small pilot studies of rosiglitazone and pioglitazone, published only in
abstract form, have also shown promising results.
[34,35]
However, there are no
definitive data regarding the use of these drugs in the treatment of NAFLD, and
the use of such agents should therefore be considered experimental at this time.
Several hepatoprotective drugs have also been used in patients with NAFLD (
Table 8 ). These agents include vitamin E, ursodeoxycholic acid, lecithin, beta-
carotene, taurine, selenium, and betaine. In a small study,
[36]
taurine was given to
obese children with fatty liver. The investigators reported a decrease in ALT
levels in these patients, leading to the conclusion that taurine has hepatoprotective
effects. However, this study, as well as most other studies, is limited by the lack
of histologic data.
Several large-scale trials using these agents are currently under way.
NAFLD is a common cause of chronic liver disease in North America; it is most often
associated with obesity. Other risk factors associated with NAFLD include diabetes, use
of specific drugs (eg, nucleoside analogs), jejunoileal bypass, severe rapid weight loss,
lipodystrophic syndromes, and use of total parenteral nutrition. The hepatic histology may
show either a fatty liver alone or steatohepatitis. Steatohepatitis may progress to cirrhosis
in some patients; this condition is characterized by a long asymptomatic period.
Hepatomegaly is the most common physical finding in patients with NAFLD. The serum
AST and ALT levels are often elevated to 1-4 times the upper limit of normal. The
AST:ALT ratio is usually < 1. Diagnosis depends on demonstration of appropriate
hepatic histology and absence of alcohol use in quantities known to be harmful to the
liver (20-30 g/day). A liver biopsy is usually required when the diagnosis is in doubt or if
the disease must be staged. Treatment involves optimization of weight status with the use
of diet and exercise. The impact of additional therapy for weight loss on the liver remains
to be defined. There is currently no established pharmacologic treatment of NAFLD,
although early pilot clinical trials with vitamin E, ursodeoxycholic acid, and insulin
sensitizers appear promising. Drugs with the potential for toxicity should not be used
outside of the context of a clinical trial at this time.