15
Practical approach to the diagnosis
and management of people with
fatty liver diseases

Jacob George & Geoffrey C. Farrell
Key learning points
1 In the appropriate metabolic setting, a primary diagnosis of non-alcoholic fatty liver disease (NAFLD)
can be made with relative ease.
2 A complete history (including family history of diabetes) and examination as well as tests to exclude viral
hepatitis are part of the initial evaluation of persons with suspected NAFLD.
3 Assessment for other features of the metabolic syndrome (e.g. hypertension, dyslipidaemia, central obes-
ity) is mandatory and helpful as a basis for practical management.
4 Criteria for the diagnosis of obesity and overweight are different across racial groups.
5 Lifestyle intervention with diet and increased physical activity is the cornerstone of management in
NAFLD/NASH.
6 Liver biopsy should be considered: (i) in those with warning signs of advanced liver disease; or (ii) in
those with clinical features associated with advanced hepatic fibrosis (diabetes, age 45 years, significant
overweight or obesity [body mass index 28 kg/m2 ]), particularly if liver tests have failed to normalize after
attempts at lifestyle adjustment.
7 Pharmacotherapy, particularly with insulin-sensitizing agents, show great promise but at present applica-
tion should be limited to clinical trials.
8 In patients with type 2 diabetes and NAFLD, insulin-sensitizing agents could be considered as first-line
drug therapy, although further weight gain may be an issue.
causes, the presence of insulin resistance may adversely
Abstract
in uence the progression of liver injury (Chapter 24).
The spectrum of non-alcoholic fatty liver diseases
A liver biopsy is the only method at present that can
(NAFLD) encompasses simple hepatic steatosis, steato-
distinguish simple steatosis from steatohepatitis. The
hepatitis and cirrhosis (Chapters 1 and 2). NAFLD is
latter represents a progressive form of liver injury that,
the hepatic manifestation of the insulin resistance or
in a proportion, may lead to advanced hepatic fibrosis.
metabolic syndrome (Chapter 5). Thus, in the appro-
The initial approach to the management of NAFLD is
priate setting, a primary diagnosis of NAFLD can be
to institute a programme of lifestyle intervention com-
made with relative ease on the basis of a history, physi-
prising weight-reduction strategies and enhanced
cal examination and a basic panel of biochemical
physical activity. The simultaneous identification and
assessments. In persons with liver disease from other
appropriate treatment of other components of the
181


FLDC15 13/9/04 9:57 AM Page 182
CHAPTER 15
metabolic syndrome is crucial to reduce hepatic as well
syndrome, a systemic disorder with many health im-
as cardiovascular morbidity and mortality. Failure to
plications for type 2 diabetes, heart and other vascular
normalize liver tests after a period of 3–6 months is an
disease, and as well as for cirrhosis. A complete meta-
indication to consider liver biopsy. To date, no univer-
bolic assessment and appropriate therapy of associated
sally accepted algorithms exist to identify persons
conditions is therefore an essential part of individual
with a high likelihood of having significant hepatic
patient care.
fibrosis and who may benefit from knowledge of their
histopathology. Among the published studies, obesity,
older age (over 45 years), the presence of type 2 dia-
Diagnosis of fatty liver disease
betes, or the presence of warning signs of cirrhosis
should prompt serious consideration for biopsy. In
For a more detailed account of the clinical features,
those with more advanced stages of disease confirmed
investigation and management of persons with NAFLD,
by biopsy, aggressive lifestyle intervention strategies
the reader is referred to Chapters 13 and 16. The focus
and enrolment in clinical trials of pharmacotherapy
of this chapter is a practical road map for clinicians
need to be considered.
caring for people with fatty liver disorders.
In the past, NAFLD has been primarily recognized
in those presenting with abnormal liver tests. It is likely
that this bias will continue because physicians are
Introduction
alerted by abnormal pathology results. However, it is
If current trends continue, primary care physicians and
now recognized that the full spectrum of NAFLD from
gastroenterologists will need to manage an increasing
steatosis to steatohepatitis, cirrhosis and liver-related
case-load of persons with NAFLD. Thus, an appreci-
morbidity can also occur in those with entirely ‘normal’
ation of the modes of clinical presentation, the optimal
liver enzymes by conventional criteria [1]. This raises
tools for diagnosis and therapeutic options is essential.
an important semantic and practical issue of ‘normal’
Given the near epidemic proportions of the problems
versus ‘reference ranges’ for liver biochemistry. Two
of diabetes, overnutrition and obesity in industrialized
recent publications have assessed the prevalence of
and developing nations, primary care physicians will
elevated aminotransferase (AT) levels in the cohort
also bear the brunt for case management. While drug
of subjects from the Third US National Health and
therapies may eventually have a role in management,
Nutrition Survey (NHANES III, 1988–94) (see also
lifestyle intervention is likely to be more feasible and
Chapter 3). In one report, the data set was evaluated in
cost effective for the more than 50% of the population
15 676 subjects aged 17 years and older and the preva-
of many countries who are already overweight or
lence of AT elevation (men: aspartate aminotransferase
obese, as well as specifically for the 10–20% of this
(AST) > 37 IU/L, alanine aminotransferase (ALT) >
group who have concomitant NAFLD/NASH. Thus,
40 IU/L; women: AST or ALT > 31 IU/L) was 7.9%.
up-grading of skills by gastroenterologists, hepatolo-
Aminotransferase elevations unrelated to alcohol con-
gists and specialist medical societies, of patients, the
sumption, hepatitis B and C or haemochromatosis
community and government is acentral issue for the pre-
(presumed NAFLD) occurred in 5.4% of the cohort
vention and control of NAFLD. The role of the special-
[2]. In contrast, when the data set was subanalysed
ist physician is likely to remain the identification and
including only the 8232 participants who had a fasting
management of patients with NASH as opposed to
morning examination, and using the cut-off of ALT >
benign forms of NAFLD (see Chapter 14), and particu-
43 IU/L as elevated, the prevalence of presumed NAFLD
larly those with advanced hepatic fibrosis. Some
after excluding other common causes was 2.8% [3].
patients with NASH may be suitable for pharma-
To add to the debate, a recent retrospective cohort
cotherapies as well as requiring follow-up for the
study from Milan assessed reference ranges for serum
development of liver-related morbidity and mortality.
ALT levels in 6835 blood donors who were negative
This chapter presents a practical approach to dia-
for hepatitis B and C markers and HIV. Based on 3927
gnosis and management of fatty liver disorders. How-
persons who satisfied the criteria of normal body mass
ever, as emphasized thematically throughout the book,
index (BMI), normal serum cholesterol, triglyceride and
NAFLD is the hepatic manifestation of the metabolic
glucose levels and no concurrent medications, median
182


FLDC15 13/9/04 9:57 AM Page 183
DIAGNOSIS AND MANAGEMENT OF FATTY LIVER DISEASES
nostic pathways for the assessment of liver disease, it is
Table 15.1 Clinical presentations of patients with NAFLD.
now prudent that all persons presenting with any fea-
ture of the metabolic syndrome be assessed for fatty
1 Features of the metabolic syndrome*
liver disease as well as for other less classic features of
2 Abnormal liver biochemistry
the syndrome (as opposed to ‘definitional criteria’
3 Abnormal hepatic imaging suggestive of fatty infiltration
specified elsewhere in the book) (see Chapter 5); the lat-
4 Non-specific symptoms (fatigue, abdominal discomfort)
ter include hyperuricaemia, obstructive sleep apnoea
5 Upper gastrointestinal bleeding (portal hypertension),
and polycystic ovarian syndrome [9].
liver failure or liver cancer
In those presenting with abnormal liver biochemistry
or imaging suggestive of fatty liver disease, certain clues
* See Table 15.2.
in the history and physical examination should raise
serum ALT was 11 IU/L, while values were 6, 9, 15 and
the suspicion of metabolic liver disease (Table 15.3).
26 IU/L for the 5th, 25th, 75th and 95th percentiles,
Of particular importance, questioning regarding recent
respectively. Based on these data, healthy ranges for
increases in weight, lifestyle changes and of a family
serum ALT values, defined as those below the gender-
history of NAFLD or type 2 diabetes is mandatory in
specific 95th percentile, were 30 IU/L for men and
any patient assessed for abnormal liver biochemistry
19 IU/L for women [4]. Using the above revised cut-
or a ‘bright’ liver on ultrasound suggestive of NAFLD.
offs for ‘abnormal’ ALT, Ruhl and Everhart [3] found
In a recent study of 66 patients with NASH [5], 33 had
the prevalence of presumed NAFLD to be 12% for
abnormalities of glucose tolerance, while 13 of 33
men and 14% for women. Thus, reference ranges for
(39%) of the remainder had a family history of type 2
serum AT from many laboratories may not re ect the
diabetes in one or more first-degree relative. In another
expected ‘normal’ values in healthy adults. Physicians
report [10], 16 of 90 (18%) patients with NASH had
therefore need to be alerted to the possibility that sig-
a first-degree relative with the condition.
nificant liver injury may occur in subjects with NAFLD
Likewise, an acute phase elevation in serum ferritin
who have AT levels within the ‘reference’ range, but
that is not associated with increases in transferrin satu-
which are clearly outside the ‘normal’ range for healthy
ration is present in up to 40% of patients with NAFLD;
adults.
this common finding should therefore alert the physi-
With this caveat in mind, patients with NAFLD may
cian to the possible diagnosis of NASH [11–15].
present in one of five ways (Table 15.1). NAFLD is now
Similarly, in patients with non-replicative forms of viral
accepted as the hepatic manifestation of the metabolic
hepatitis, the presence of abnormal liver biochemistry
(or insulin resistance) syndrome (Table 15.2) [5–8]
and/or presence of ‘rubbery’ hepatomegaly should
(see also Chapter 5). Thus, while abnormal biochem-
alert the clinician to the presence of NAFLD rather
istry or imaging will alert the physician to follow diag-
than chronic viral hepatitis. Finally, it is increasingly
Table 15.2 Diagnostic criteria for the insulin resistance syndrome. Modified from the World Health Organization criteria [8].
Component
Definition
Diabetes mellitus, impaired glucose tolerance and/orinsulin resistance, together with two or more of the following:
Raised arterial blood pressure
140/90 mmHg, or documented use of antihypertensive therapy
Raised serum triglycerides
1.7 mmol/L
and/or low serum HDL-cholesterol
< 0.9 mmol/L for men; < 1.0 mmol/L for women
Central obesity
Waist : hip ratio > 0.90 (for men)
waist : hip ratio > 0.85 (for women)
or body mass index > 30 kg /m2
Microalbuminuria
Urinary albumin : creatinine ratio (20 mg /g)
or urinary albumin excretion rate (20 ｵg /min)
HDL, high-density lipoprotein.
183


FLDC15 13/9/04 9:57 AM Page 184
CHAPTER 15
‘bright’ liver on ultrasound may bring useful confirmat-
Table 15.3 Clinical clues to the diagnosis of NAFLD.
ory information in a person with suspected NAFLD.
However, it should be emphasized that the presence of
Unexplained abnormal liver tests with:
fat, fibrosis or elevated hepatic iron stores can have an
Recent weight gain, expanding waistline, change of lifestyle
identical sonographical appearance. The sensitivity of
(unemployment, retirement, disability)
sonography for the detection of hepatic fatty infiltra-
Type 2 diabetes or impaired glucose tolerance
tion in a recent study was 67%, specificity was 77% and
Family history of type 2 diabetes or NAFLD
the positive predictive value was 67% [19]. However,
Obesity (particularly central [visceral] obesity)
ultrasound had 100% sensitivity for the detection of
Dyslipidaemia (elevated triglyceride, low high-density
more extensive hepatic steatosis, as defined by 33% of
lipoprotein)
cells showing steatosis [20].
Other features of the insulin resistance syndrome or its
In NAFLD, presentation with symptomatic liver
complications: arterial hypertension, ischaemic heart
disease (ascites, variceal bleeding, encephalopathy,
disease, vascular disease
hepatocellular cancer) has been infrequent. The large
Raised serum ferritin with normal transferrin saturation
burden of NAFLD in industrialized nations [3], and the
Other liver diseases and the presence of ‘metabolic’ risk
fact that NASH-associated cirrhosis has an identical
factors
prognosis to cirrhosis from chronic hepatitis C [21]
Non-replicative forms of viral hepatitis B or C
(see also Chapter 3), suggests that there is significant
case ascertainment bias in attributing liver disease to
recognized that metabolic (fatty) liver disease may be
end-stage NAFLD.
associated with accelerated disease progression in
Recent reports indicate that in patients presenting
those with liver diseases from any aetiology, including
with cryptogenic or obesity-related cirrhosis, NAFLD is
alcoholic liver disease [16] and viral hepatitis [17,18].
likely to be the underlying aetiological cause in approx-
Hence, physicians should not be dissuaded from a
imately two-thirds of cases (see Chapter 14) [22,23].
diagnosis of NAFLD as an additional and modifiable
Further, in current practice, NASH-associated liver
liver disorder in persons with other forms of liver dis-
failure may present in the later decades (7th and 8th)
ease and the presence of metabolic risk factors (see
in individuals with other comorbid conditions, and is
Chapters 23 and 24).
therefore often overlooked. For instance, insulin resist-
The alcohol history must be carefully evaluated in
ance, diabetes and diabetic metabolic control can be
persons with abnormal liver biochemistry. This involves
significantly worsened by the presence of advanced
both repeated questioning of the index person, and
hepatic fibrosis or cirrhosis, which impairs insulin
also of close family members. For clinical research, sig-
clearance. In the future, it is likely that NAFLD-
nificant alcohol consumption needs to be excluded.
associated liver failure may present in earlier decades,
‘Significant’ consumption is variously defined as 140 g/
given the epidemics of obesity and diabetes affecting
week and 20 g/day in men and 10 g/day in women. In
young adults and children (see Chapter 19). Advocacy
clinical practice, it is likely that there is a large pro-
to improved physician and patient awareness of the
portion of individuals in whom liver disease may be
hepatic consequences of the metabolic syndrome is
caused by the combination of toxic levels of alcohol
therefore important.
consumption and metabolic fatty liver disease (see also
Patients with the earlier stages of NAFLD may
Chapter 2). In these persons, alcohol intake should be
present with non-specific symptoms (see Chapter 13)
reduced to the safe levels suggested above (or discon-
including fatigue and right upper quadrant pain. The
tinued completely if it is unlikely that self-control can
latter is usually a dull discomfort, sometimes compared
limit intake to safe levels), concomitant with other
to a toothache, and often associated with hepatic tend-
dietary approaches aimed at reducing insulin resistance.
erness so that the person does not feel comfortable
The importance of lifetime alcohol exposure (versus
lying on the right side. Rarely, more severe pain may be
recent levels of intake) is discussed in Chapter 24.
a clue to hepatic pathology. While fatigue is very com-
Abnormal imaging, typically a hyperechoic liver on
mon, a thorough psychosocial and medical history, as
an ultrasound performed for another indication, is often
well as a complete physical examination, is required
the first clue to the presence of NAFLD. Conversely, a
before attributing it to NAFLD. Other common dis-
184


FLDC15 13/9/04 9:57 AM Page 185
DIAGNOSIS AND MANAGEMENT OF FATTY LIVER DISEASES
orders (depression, anaemia, sleep disorders) need to
Table 15.4 Measuring components of adiposity. (After
be considered (see also Chapter 14). Unless liver fail-
World Health Organization [24] and International Diabetes
ure has supervened, the physical examination may be
Institute [25].)
normal or only reveal hepatomegaly; the texture of the
liver is firm but not hard (‘rubbery’), and this is occa-
Category Anthropometric criteria
sionally associated with some tenderness.
Overweight
White
BMI 25 kg /m2
Asian
BMI 23 kg /m2
When to diagnose NAFLD
Pacific Islander BMI 26 kg /m2
While conventionally considered a disease of exclusion,
Obese
it is important for physicians to consider a positive
White
BMI 30 kg /m2
diagnosis of NAFLD based on the history and physical
Asian
BMI 25 kg /m2
examination. Features of the metabolic syndrome in
Pacific Islander BMI 32 kg /m2
association with abnormal liver biochemistry and serum
lipids or a ‘bright’ liver on ultrasound are present in
Central obesity
the vast majority of patients. Often the major clue for
White
WC > 102 cm (men)
considering NAFLD as a diagnostic possibility is the
WC > 88 cm (women)
presence of overweight or obesity and, more import-
Asian
WC 90 cm (men)
antly, central obesity and a family history of diabetes.
WC 80 cm (women)
There is clear evidence that the risk of cardiovascular
Pacific Islander Not determined
morbidity and mortality in relation to anthropometric
variables differs across ethnic groups. Thus, given the
BMI, body mass index; WC, waist circumference.
enormous cross-cultural migrations that have taken
place to regions such as North America and Australia
with pointers in the clinical history or baseline bio-
in recent decades, physicians should be aware of ethno-
chemistry (e.g. a positive family history of Wilson’s dis-
specific cut-offs for anthropometric criteria (Table 15.4)
ease or marked elevations in AT levels), other tests may
(see also Chapter 18).
be indicated including tests for autoimmune liver dis-
Clearly, a discrete panel of laboratory tests needs to
ease, Wilson’s disease and coeliac disease (see Chapter
be considered in patients presumed to have NAFLD.
21). Where the clinical history, examination and base-
Diabetes should be excluded with a fasting blood
line biochemistry is suggestive of NAFLD, hepatic
glucose. Appropriate therapy must be instituted if this
imaging by ultrasound can be a useful and relatively
is present. Tests of insulin resistance (e.g. the homo-
inexpensive test that will show appearances consistent
eostasis model assessment (fasting glucose [mmol/L]
with steatosis in two-thirds of cases. However, hepatic
ﾗ fasting insulin [units]/22.5) or impaired glucose
imaging cannot distinguish steatosis from steatohep-
tolerance based on a glucose tolerance test, while not
atitis and cirrhosis.
routinely used in clinical practice, should be strongly
A significant conceptual advance in understanding
considered. This is because NAFLD is rarely if ever
the pathogenesis and progression of chronic liver dis-
present in the absence of insulin resistance (see
ease is the knowledge that liver disease of any aetiology
Chapter 5). Estimation of serum lipids and serology
can be significantly worsened by the presence of insulin
for viral hepatitis B and C is mandatory. In the Anglo-
resistance (NAFLD) [17,26,27]. From a clinical per-
Celtic population, consideration must also be given to
spective, therefore, the assessment of any form of liver
the performance of iron studies, as haemochromatosis
disease should include a consideration of modifiable
may occur in up to 1 in 300 of the population and may
metabolic cofactors, including obesity, insulin resistance,
present with non-specific symptoms. As indicated ear-
diabetes and features of the metabolic syndrome. Thus,
lier, serum ferritin is increased in approximately 40%,
it is incumbent on the physician treating an obese or
but haemochromatosis is easily excluded in most cases
diabetic patient with chronic hepatitis C or alcoholic
by the percentage iron saturation of transferrin,
liver disease to ensure control of diabetes and lifestyle
together with genetic testing (C282Y, H63D). In those
modification to improve central obesity, lipid disorders
185


FLDC15 13/9/04 9:57 AM Page 186
CHAPTER 15
and other features of the metabolic syndrome. Control
tion, careful monitoring, enrolment in clinical trials).
of these factors may contribute to reducing disease
Among the published studies, a few clinical features
progression separately to effective treatment of the
have consistently suggested an increased likelihood
underlying liver disease (see also Chapter 24).
of advanced stages of hepatic fibrosis. These are older
age, obesity and type 2 diabetes [15,30,32–34]. Less
consistent findings in those with advanced fibrosis
include an elevated ALT, hypertriglyceridaemia, hyper-
When to consider a liver biopsy
tension and female gender [11,30,33].The use of
While a liver biopsy can ultimately confirm a dia-
non-invasive markers to predict fibrotic severity of
gnosis of NAFLD and determine its severity, for the
NAFLD/NASH is considered in more detail in Chapter
vast majority of patients seen in the primary care set-
3, and has been updated (to June 2004) in Chapter 24.
ting, biopsy is not required for patient assessment
The issue of whether female gender predisposes
and the institution of appropriate management, at
to advanced hepatic fibrosis is particularly vexed.
least in the first instance.
Currently, it is unclear if this represents case ascertain-
The aims of liver biopsy for persons suspected to
ment bias, the possibility that males with NAFLD die of
have NAFLD are threefold. First, a biopsy can confirm
other disorders, or as yet unknown factors. Until large
the histological diagnosis of fatty liver disease and
(more than 300 persons) validated cohort studies are
exclude other disorders. In a recent study of 36 asymp-
published, it seems prudent to consider liver biopsy in
tomatic patients with non-specific persistent liver test
subjects with suspected NAFLD who are 45 years of
abnormalities, the presumptive prebiopsy diagnosis
age or older, diabetic and significantly overweight or
was altered in 14% of cases and in uenced the
obese (BMI 28 kg /m2 for white people). The pres-
frequency of subsequent monitoring in 36% [28].
ence of additional features of the metabolic syndrome,
Likewise, biopsy may help in the diagnosis of surreptiti-
including hypertension and hypertriglyceridaemia,
ous alcohol abuse by demonstrating ‘ orid’ changes
should lower the threshold for considering liver biopsy
(see Chapter 2) [26].
in these individuals. In addition, certain features sug-
Secondly, liver biopsy is currently the only available
gestive of cirrhosis, irrespective of the presence of other
method to distinguish between simple steatosis and
criteria, should prompt consideration for early liver
steatohepatitis (see Chapter 2). As outlined in Chapters
biopsy. These include a hard liver edge, an AST : ALT
3, 13 and 14, this distinction is not simply a matter of
ratio > 1, a low platelet count or serum albumin and
semantics, as steatohepatitis can progress in a propor-
imaging findings suggesting portal hypertension (dilated
tion of individuals to advanced hepatic fibrosis, liver
portal vein, hepatofugal blood ow in portal vein,
failure and, rarely, liver cancer. Finally, a biopsy pro-
splenomegaly).
vides information on the stage of hepatic fibrosis in
While a liver biopsy is being considered in individuals
NASH, the most crucial determinant of long-term out-
who meet the above criteria, an equally important issue
comes (see Chapter 3). Such information is particu-
is the timing of the biopsy. Most experts in the field
larly important in the light of data indicating the
would consider it valuable to embark on or recom-
difficulty of clinical criteria to identify advanced fibro-
mend a 3– 6 month trial of lifestyle intervention in an
sis or compensated cirrhosis [21,29–31]. Thus, in a
attempt to normalize AT levels before proceeding to
recent study of 23 persons with NASH-associated cir-
liver biopsy, unless there are warning signs to suggest
rhosis, only 26% had an AST : ALT > 1 and four were
advanced hepatic fibrosis (Fig. 15.1). This view is
36 years of age or younger [21].
endorsed by the editors.
While there are several cogent reasons for consider-
ing liver biopsy in persons with presumed NAFLD/
NASH, it is neither feasible nor appropriate to biopsy
Management of NAFLD
all patients, except in the setting of a clinical research
agenda. To date, no universally accepted algorithms
At present there are no consensus guidelines for the
exist to identify patients who have a high likelihood
management of patients with NAFLD/ NASH. This
of deriving benefit from the information provided by
situation is likely to change over the coming decade
a liver biopsy (e.g. more aggressive lifestyle interven-
with improved understanding of the pathophysiology
186


FLDC15 13/9/04 9:57 AM Page 187
DIAGNOSIS AND MANAGEMENT OF FATTY LIVER DISEASES
Fig. 15.1 A practical approach to the diagnosis and stepwise therapy of non-alcoholic fatty liver diseases (NAFLD).
of NAFLD and the completion of evidence-based life-
Because insulin resistance is near universal in persons
style modification and pharmacotherapeutic trials
with NAFLD/ NASH, strategies to lower insulin resist-
for management of these disorders. In broad terms,
ance are a logical first step. Given the prevalence of
therapy should target:
NAFLD in industrialized and developing nations (see
1 Components of the metabolic syndrome
Chapters 3, 5 and 18), and the cost and potential
2 Steatohepatitis
untoward adverse effects of drug therapy (Chapter 16),
3 Advanced liver disease (screening for treatable com-
pharmacotherapy is likely to remain a second choice
plications of portal hypertension, e.g. large esophageal
for a disease that is, in large part, lifestyle based [37,38].
varices, gastric arterio-venous ectosia).
As cited in a recent editorial on diabetes prevention,
Patients with NAFLD are at risk of both liver-related
which could apply equally to persons with NAFLD,
and non-liver-related (particularly vascular) morbidity
three types of interventions are possible.
and mortality. In those with earlier fibrotic stages of
1 Interventions that limit fat accumulation in the body
NAFLD at diagnosis, non-liver disease-related disease
(the reduction of central obesity is associated with less
end-points are likely to predominate, while in those
insulin resistance; see Chapter 4)
with advanced hepatic fibrosis, liver disease-related end-
2 Strategies that uncouple obesity and insulin resist-
points are likely to have a major impact (see Chapters
ance (reducing insulin resistance and thereby preventing
3 and 14) [21–23,35,36]. Thus, a thorough assessment
or delaying -cell failure)
for individual components of the metabolic syndrome
3 Interventions that directly preserve -cell mass and/
and appropriate therapy of underlying diabetes, hyper-
or function, thereby preventing or delaying the metabolic
tension or dyslipidaemia is warranted.
consequences of diabetes [39].
187


FLDC15 13/9/04 9:57 AM Page 188
CHAPTER 15
Among these, three recent large studies indicate that
ical activity of moderate intensity (e.g. brisk walking at
lifestyle intervention with diet and exercise can reduce
least 5 days/week, 30 min per occasion, 150 min/week)
the risk of diabetes in high-risk subjects. Further, they
and a low-energy low-fat diet (less than 30% of energy
are at least as effective as drug therapy with metformin
intake). While the composition of dietary formula-
[40– 42]. Clearly, therefore, lifestyle intervention can
tions in relation to weight loss and NAFLD have not
reduce insulin resistance and we believe it should be
been examined, it would appear prudent to decrease
the first-line treatment of NAFLD/NASH.
saturated fats and to increase polyunsaturated fats
In light of the above cogent considerations of patho-
and antioxidants (particularly vitamin C), and to add
physiology, a recent review of the literature found
complex carbohydrates rich in fibre (e.g. 15 g/day),
that there are surprisingly few data to support or
fruit and vegetables [52]. Guidelines for appropriate
refute the recommendation for weight reduction as an
diets include the American Heart Association (AHA)
effective therapy [43]. Among 517 potentially relevant
heart-healthy diet [53] and for those with diabetes,
studies, only 15 met the inclusion criteria of report-
the American Diabetes Association (ADA) diet [54].
ing histology, serum AT levels or hepatic imaging in
Such interventions and public health promotion pro-
obese subjects who had undergone weight reduction.
grammes should ideally begin in childhood as this
Further, these 15 studies included only one random-
group represents the future burden of disease to the
ized and two randomized controlled trials, and only
community.
three included more than 50 persons [43]. Although,
all 15 studies reported improvement in liver outcomes
Surgical therapies for weight reduction
(histology, serum AT levels or hepatic imaging), in
one study hepatic histology worsened in those with
Absorptive or restrictive (gastric banding) procedures
weight loss that exceeded 1.6 kg/week [43,44]. This
are increasingly being used as therapy for weight reduc-
analysis infers that there is a great need for lifestyle
tion (see Chapters 16 and 20). Procedures such as
programmes in subjects with NAFLD which include
jejuno-ileal bypass are contraindicated in patients with
robust markers of liver disease progression, including
NAFLD/NASH; they may lead to worsening of liver
histology. The results then need to be correlated with
disease and hepatic decompensation. Procedures such
potential non-invasive markers, including AT levels,
as banding are probably safer [33], but significant safety
hepatic imaging and potential serum markers suggested
issues remain in those with NAFLD/NASH and hepatic
as fibrotic markers among persons with hepatitis C
fibrosis, because weight loss of up to 4.5 kg/month can
[45–47].
occur and this may be associated with worsening of
Until such evidence-based data are available, it seems
liver injury [43,44].
prudent to recommend a sustainable programme of diet
and exercise aimed at both weight loss and subsequent
Pharmacotherapy of NAFLD
weight maintenance and increased physical activity.
However, rapid weight loss, in excess of 1 kg /week,
Several small studies of pharmacotherapy in NASH
should be avoided [44]. In order to achieve these goals,
have been completed, and large-scale trials are under-
a multidisciplinary approach is essential. This could
way (see Chapters 16 ad 24). Application of pharma-
include a dietitian and/or a physical therapist [40–42,
cotherapy to NAFLD/NASH may need to be lifelong,
48,49]. Involvement of the family and personal sup-
thereby incurring a considerable cost to the commu-
ports of the index case are crucial for establishing long-
nity and a burden of adverse effects such as weight
lasting lifestyle change.
gain. Thus, a critical issue is the targeting of therapy to
Based on the National Heart Lung and Blood Institute
patients most likely to benefit in terms of liver-related
(NHLBI) and the National Institute of Diabetes and
disease end-points. At present, no algorithms have
Digestive and Kidney Diseases (NIDDK) expert panel
been prospectively validated for the identification of
guidelines, the initial target for weight loss should be
individuals at high risk for disease progression. Even if
10% of baseline weight within a period of 6 months
such a cohort could be identified, cirrhosis in NASH
(0.5–1 kg/week) [50]. This can be achieved through a
may be slowly progressive. Hence, to demonstrate cost
variety of strategies. Based on the Diabetes Prevention
efficacy (cost per quality year of life saved from liver
Programme (DPP) study [51], guidelines include phys-
disease-related morbidity or mortality), long-term
188


FLDC15 13/9/04 9:57 AM Page 189
DIAGNOSIS AND MANAGEMENT OF FATTY LIVER DISEASES
Table 15.5 Potential
Drug class Examples
pharmacotherapeutic agents for use in
NAFLD.
Weight loss drugs Orlistat, phentermine, sibutramine
Insulin-sensitizing medications
Biguanides Metformin
PPAR agonists Rosiglitazone, pioglitazone
PPAR / agonists Raraglitazone
PPAR agonists Clofibrate
Lipid-lowering agents
Triglyceride Gemfibrozil,* clofibrate, probucol*
HMG CoA reductase inhibitors Atorvastatin
Antioxidants Vitamin E, betaine, probucol, N-acetylcysteine
Other hepatoprotective drugs Ursodeoxycholic acid
* Not available in USA.
studies spanning decades may be required. Given the
clearly demonstrates that in women with impaired
scope of the epidemic of NAFLD, it is prudent for the
glucose tolerance (insulin resistance), diabetes incid-
clinician to evaluate any new drug treatment study in
ence in the treated group was approximately 55% lower
relation to whether institution of lifelong therapy is
than in placebo controls. Further, protection from dia-
likely to alter liver disease end-points, and the associ-
betes was closely related to the degree of reduction in
ated costs and potential detriments of such treatment.
endogenous insulin resistance, and persisted 8 months
There is a pressing need for clinical studies and consen-
after study medication was ceased. The results point
sus guidelines in this field.
to the efficacy of this class of compounds to reduce
A variety of therapeutic strategies have been attempted
insulin resistance, which is thought to underlie NAFLD.
in patients with NAFLD. These are categorized and
Three small studies of the use of this class of com-
discussed in detail in Chapter 16 and summarized
pounds have been reported [57,61–63] (and see
in Table 15.5. Of the agents studied, drugs that
Chapter 24). As expected, they showed improvements
effect weight loss such as orlistat, in addition to that
in serum AT levels, hepatic steatosis, in ammatory
obtained by diet and exercise, may be of benefit, at
scores, ballooning and zone 3 fibrosis. However,
least during the weight loss rather than weight main-
adverse effects were reported including elevations in
tenance phase of NAFLD/NASH therapy [55,56] (and
serum ALT and weight gain (67% of subjects). Thus,
see Chapter 24). Use of insulin-sensitizing agents hold
while PPAR agonists are likely to be of benefit to
the most promise; however, large-scale clinical trials
patients with NAFLD, their routine use is neither
are awaited and these agents cannot be recommended,
recommended nor licensed. If possible, patients with
particularly as they facilitate weight gain [57]. Of
NAFLD and significant hepatic fibrosis on biopsy
drugs in this class, metformin reduces hepatic lipid in
should be enrolled into clinical trials. In patients with
both animal and human studies [58,59]. It is cheap,
type 2 diabetes and NAFLD, these agents could be
has a long history of use in clinical practice, does not
considered as first-line pharmacotherapy, after lifestyle
cause hypoglycaemia even in non-diabetic persons
modification. However, even with the newer agents
and has an excellent safety profile in those without
(rosiglitazone, pioglitazone), physicians should remain
advanced liver or renal disease. It is not yet known
vigilant to the possibility of rare but sometimes serious
whether it affects progression of NAFLD.
hepatotoxicity such as occurred with troglitazone.
Peroxisome proliferator activator receptor (PPAR )
While insulin resistance appears to be essential for
agonists are potent insulin-sensitizing agents in clinical
NAFLD, oxidative stress has been demonstrated both
use for the last decade. The recently published Troglita-
in animal models [64– 66] and humans with NAFLD
zone in Prevention of Diabetes (TRIPOD) study [60]
[7,67–70]. It represents either the cause or consequence
189


FLDC15 13/9/04 9:57 AM Page 190
CHAPTER 15
of liver injury in NAFLD and may be an important
vention incorporating both diet and physical activity
determinant of disease progression and in ammatory
should be instituted for a trial period of 3–6 months.
recruitment [71]. Thus, antioxidants have been studied
In those with warning signs or predictors of advanced
in small cohorts with NAFLD. Vitamin E perhaps holds
liver disease, liver biopsy should be considered, par-
the most promise, but again, its routine use awaits
ticularly if liver tests fail to normalize. In those with
large-scale randomized studies (see Chapter 16). While
significant fibrosis, more intensive lifestyle interven-
this compound has no significant adverse effects and is
tion and pharmacotherapy can be considered. At this
cheap, the optimal regimen for clinical use is not known
time, the latter can only be endorsed in the setting
(studies have used 400 –1200 IU/day). These compounds
of clinical trials. After lifestyle intervention, insulin-
may have a role because of their low toxicity profile in
sensitizing agents should be considered as first-line
children with NAFLD (see Chapter 19).
therapy in those with type 2 diabetes and NAFLD/
NASH. An essential role for the physician in the
management of NAFLD/NASH remains the identifica-
Management of advanced liver disease in those
tion and appropriate treatment of individual compon-
with NAFLD
ents of the metabolic syndrome that may contribute
This is no different to that for patients with advanced
to hepatic as well as cardiovascular morbidity and
liver disease from other causes who develop ascites,
mortality.
encephalopathy or variceal bleeding. In those with
low platelet counts (less than 100 ﾗ 109 /mL) or other
evidence of portal hypertension (see above), endos-
References
copy should be considered and prophylactic -blocker
therapy instituted if large varices are evident. Hepato-
1 Mofrad P, Contos MJ, Haque M et al. Clinical and
cellular cancer does occur in subjects with NASH
histologic spectrum of non-alcoholic fatty liver disease
and cirrhosis, but the incidence in obese persons with
associated with normal ALT values. Hepatology 2003;
cirrhosis remains controversial [21,23,34]. Those with
37: 1286–92.
multiple risk factors (previous hepatitis B or C virus
2 Clark JM, Brancati FL, Diehl AM. The prevalence and
infection, alcohol, older men) may be at greatest risk.
etiology of elevated aminotransferase levels in the United
Primary liver tumours in the setting of NASH should
States. Am J Gastroenterol 2003; 98: 960–7.
be treated by the usual approaches. While patients
3 Ruhl CE, Everhart JE. Relation of elevated serum alanine
with NASH and hepatic decompensation need to be
aminotransferase activity with iron and antioxidant
considered for hepatic transplantation, the underlying
levels in the United States. Gastroenterology 2003; 124:
metabolic milieu favours recurrence in the trans-
1821–9.
4 Prati D, Taioli E, Zanella A et al. Updated definitions of
planted liver [72]. These matters are discussed in
healthy ranges for serum alanine aminotransferase levels.
Chapters 2 and 17.
Ann Intern Med 2002; 137: 1–10.
5 Chitturi S, Abeygunasekera S, Farrell GC et al. NASH
and insulin resistance: insulin hypersecretion and specific
Conclusions
association with the insulin resistance syndrome. Hepato-
logy 2002; 35: 373–9.
Hepatic steatosis and lipid-mediated liver injury may
6 Pagano G, Pacini G, Musso G et al. Non-alcoholic steato-
be primary (NAFLD) or, more commonly, given the
hepatitis, insulin resistance, and metabolic syndrome:
prevalence of obesity in our population, a contributing
further evidence for an etiologic association. Hepatology
factor to liver disease from other causes (e.g. alcoholic
2002; 35: 367–72.
7 Sanyal AJ, Campbell-Sargent C, Mirshahi F et al. Non-
liver disease, viral hepatitis). In both circumstances,
alcoholic steatohepatitis: association of insulin resistance
steatosis can cause or worsen liver disease. In the appro-
and mitochondrial abnormalities. Gastroenterology 2001;
priate metabolic setting, physicians need to consider
120: 1183–92.
NAFLD/NASH or comorbid steatosis in the setting
8 World Health Organization. Definition, diagnosis and
of dual liver disorders as a primary diagnosis. Once a
classification of diabetes and its complications. I. Diagnosis
diagnosis of probable NAFLD/ NASH has been made
and classification of diabetes. Geneva: World Health
on clinical and laboratory grounds, lifestyle inter-
Organization, 1999: 20–1.
190


FLDC15 13/9/04 9:57 AM Page 191
DIAGNOSIS AND MANAGEMENT OF FATTY LIVER DISEASES
24 World Health Organization. Obesity: Preventing and
9 Sir-Petermann T, Angel B, Maliqueo M et al. Prevalence
Managing the Global Epidemic. Geneva: World Health
of type II diabetes mellitus and insulin resistance in parents
Organization, 1998.
of women with polycystic ovary syndrome. Diabetologia
25 International Diabetes Institute. The Asia–Pacific Per-
2002; 45: 959– 64.
spective: Redefining Obesity and its Treatment. Health
10 Willner IR, Waters B, Patil SR et al. Ninety patients with
Communications Australia, 2000: 54.
non-alcoholic steatohepatitis: insulin resistance, familial
26 Naveau S, Giraud V, Borotto E et al. Excess weight risk
tendency, and severity of disease. Am J Gastroenterol
factor for alcoholic liver disease. Hepatology 1997; 25:
2001; 96: 2957–61.
108–11.
11 Chitturi S, Weltman M, Farrell GC et al. HFE mutations,
27 Sanyal AJ, Contos MJ, Sterling RK et al. Non-alcoholic
hepatic iron, and fibrosis: ethnic-specific association of
fatty liver disease in patients with hepatitis C is associ-
NASH with C282Y but not with fibrotic severity. Hepato-
ated with features of the metabolic syndrome. Am J
logy 2002; 36: 142–9. Erratum in Hepatology 2002; 36:
Gastroenterol 2003; 98: 2064–71.
1307.
28 Sorbi D, McGill DB, Thistle JL et al. An assessment of
12 George DK, Goldwurm S, MacDonald GA et al. Increased
the role of liver biopsies in asymptomatic patients with
hepatic iron concentration in non-alcoholic steatohepatitis
chronic liver test abnormalities. Am J Gastroenterol 2000;
is associated with increased fibrosis. Gastroenterology
95: 3206–10.
1998; 114: 311–8.
29 Pinto HC, Baptista A, Camilo ME et al. Non-alcoholic
13 Bonkovsky HL, Jawaid Q, Tortorelli K et al. Non-alcoholic
steatohepatitis: clinicopathological comparison with alco-
steatohepatitis and iron: increased prevalence of muta-
holic hepatitis in ambulatory and hospitalized patients.
tions of the HFE gene in non-alcoholic steatohepatitis.
Dig Dis Sci 1996; 41: 172–9.
J Hepatol 1999; 31: 421–9.
30 Ratziu V, Giral P, Charlotte F et al. Liver fibrosis in over-
14 Younossi ZM, Gramlich T, Bacon BR et al. Hepatic iron
weight patients. Gastroenterology 2000; 118: 1117–23.
and nonalcoholic fatty liver disease. Hepatology 1999;
31 Loguercio C, De Girolamo V, de Sio I et al. Non-alcoholic
30: 847–50.
fatty liver disease in an area of southern Italy: main clinical,
15 Angulo P, Keach JC, Batts KP, Lindor KD. Independent
histological, and pathophysiological aspects. J Hepatol
predictors of liver fibrosis in patients with non-alcoholic
2001; 35: 568–74. Erratum in J Hepatol 2002; 36: 713.
steatohepatitis. Hepatology 1999; 30: 1356– 62.
32 Marceau P, Biron S, Hould FS et al. Liver pathology and the
16 Raynard B, Balian A, Fallik D et al. Risk factors of fibrosis
metabolic syndrome X in severe obesity. J Clin Endocrinol
in alcohol-induced liver disease. Hepatology 2002; 35:
Metab 1999; 84: 1513–7.
635– 8.
33 Dixon JB, Bhathal PS, O’Brien PE. Non-alcoholic fatty
17 Hui JM, Sud A, Farrell GC et al. Insulin resistance is asso-
liver disease: predictors of non-alcoholic steatohepatitis
ciated with chronic hepatitis C virus infection and fibrosis
and liver fibrosis in the severely obese. Gastroenterology
progression. Gastroenterology 2003; 125: 1695–704.
2001; 121: 91–100.
18 Gordon A, Mclean CA, Pederson JS, Bailey MJ, Roberts
34 Harrison SA, Hayashi P. Clinical factors associated with
SK. Steatosis in chronic hepatitis B and C: predictors,
fibrosis in 102 patients with non-alcoholic steatohepatitis.
distribution and effect on fibrosis. Hepatology 2003; 38:
Hepatology 2002; 36: 412A.
268A.
35 Matteoni CA, Younossi ZM, Gramlich T et al. Non-
19 Graif M, Yanuka M, Baraz M et al. Quantitative estimation
alcoholic fatty liver disease: a spectrum of clinical
of attenuation in ultrasound video images: correlation
and pathological severity. Gastroenterology 1999; 116:
with histology in diffuse liver disease. Invest Radiol2000;
1413–9.
35: 319–24.
36 Bugianesi E, Leone N, Vanni E et al. Expanding the natural
20 Saadeh S, Younossi ZM, Remer EM et al. The utility of
history of nonalcoholic steatohepatitis: from cryptogenic
radiological imaging in nonalcoholic fatty liver disease.
cirrhosis to hepatocellular carcinoma. Gastroenterology
Gastroenterology 2002; 123: 745–50.
2002; 123: 134– 40.
21 Hui JM, Kench JG, Chitturi S et al. Long-term outcomes
37 Farrell GC. Non-alcoholic steatohepatitis: what is it,
of cirrhosis in nonalcoholic steatohepatitis compared with
and why is it important in the Asia–Pacific region? J
hepatitis C. Hepatology 2003; 38: 420 –7.
Gastroenterol Hepatol 2003; 18: 124–38.
22 Caldwell SH, Oelsner DH, Iezzoni JC et al. Cryptogenic
38 Chitturi S, Farrell GC, George J. Non-alcoholic steato-
cirrhosis: clinical characterization and risk factors for
hepatitis in the Asia–Pacific region: future shock? J
underlying disease. Hepatology 1999; 29: 664–9.
Gastroenterol Hepatol 2004; 19: 368–74.
23 Ratziu V, Bonyhay L, Di Martino V et al. Survival, liver
39 Buchanan TA. Prevention of type 2 diabetes. Diabetes
failure, and hepatocellular carcinoma in obesity-related
Care 2003; 26: 1306–7.
cryptogenic cirrhosis. Hepatology 2002; 35: 1485–93.
191


FLDC15 13/9/04 9:57 AM Page 192
CHAPTER 15
40 Tuomilehto J, Lindstrom J, Eriksson JG et al. Finnish
of the American Diabetes Association, Veterans Health
Diabetes Prevention Study Group. Prevention of type 2
Administration, and American Association of Clinical
diabetes mellitus by changes in lifestyle among subjects
Endocrinologists. Clin Ther 2000; 22: 899–910; discus-
with impaired glucose tolerance. N Engl J Med 2001;
sion 898.
344: 1343–50.
55 Assy N, Svalb S, Hussein O. Orlistat (xenical) reverses
41 Knowler WC, Barrett-Connor E, Fowler SE et al. Dia-
fatty liver disease and improves hepatic fibrosis in obese
betes Prevention Program Research Group. Reduction in
patients with NASH. Hepatology 2001; 34: 251A.
the incidence of type 2 diabetes with lifestyle intervention
56 Harrison SA, Fincke C, Helinski D, Togerson S. Orlistat
or metformin. N Engl J Med 2002; 346: 393 –403.
treatment in obese, non-alcoholic steatohepatitis patients.
42 Pan XR, Li GW, Hu YH et al. Effects of diet and exercise
Hepatology 2002; 36: 406A.
in preventing NIDDM in people with impaired glucose
57 Neuschwander-Tetri BA, Brunt EM, Wehmeier KR,
tolerance. The Da Qing IGT and Diabetes Study. Diabetes
Oliver D, Bacon BR. Improved non-alcoholic steatohep-
Care 1997; 20: 537– 44.
atitis after 48 weeks of treatment with the PPAR-gamma
43 Wang RT, Koretz RL, Yee HF Jr. Is weight reduction an
ligand rosiglitazone. Hepatology 2003; 38: 1008–17.
effective therapy for non-alcoholic fatty liver? A system-
58 Lin HZ, Yang SQ, Chuckaree C et al. Metformin reverses
atic review. Am J Med 2003; 115: 554–9.
fatty liver disease in obese, leptin-deficient mice. Nat Med
44 Andersen T, Gluud C, Franzmann MB, Christoffersen P.
2000; 6: 998 –1003.
Hepatic effects of dietary weight loss in morbidly obese
59 Marchesini G, Brizi M, Bianchi G et al. Metformin in
subjects. J Hepatol 1991; 12: 224–9.
non-alcoholic steatohepatitis. Lancet 2001; 358: 893– 4.
45 Imbert-Bismut F, Ratziu V, Pieroni L et al. MULTIVIRC
60 Buchanan TA, Xiang AH, Peters RK et al. Preservation
Group. Biochemical markers of liver fibrosis in patients
of pancreatic beta-cell function and prevention of type 2
with hepatitis C virus infection: a prospective study. Lancet
diabetes by pharmacological treatment of insulin resist-
2001; 357: 1069–75.
ance in high-risk hispanic women. Diabetes 2002; 51:
46 Forns X, Ampurdanes S, Llovet JM et al. Identification of
2796– 803.
chronic hepatitis C patients without hepatic fibrosis by a
61 Neuschwander-Tetri BA, Brunt EM, Wehmeier KR
simple predictive model. Hepatology 2002; 36: 986–92.
et al. Interim results of a pilot study demonstrating the
47 Wai CT, Greenson JK, Fontana RJ et al. A simple non-
early effects of the PPAR ligand rosiglitazone on insulin
invasive index can predict both significant fibrosis and
sensitivity, aminotransferases, hepatic steatosis and body
cirrhosis in patients with chronic hepatitis C. Hepatology
weight in patients with non-alcoholic steatohepatitis.
2003; 38: 518–26.
J Hepatol 2003; 38: 434– 40.
48 Hickman IJ, Clouston AD, Macdonald GA et al. Effect of
62 Sanyal AJ, Contos MJ, Sargeant C et al. A randomised
weight reduction on liver histology and biochemistry in
controlled pilot study of pioglitazone and vitamin E versus
patients with chronic hepatitis C. Gut 2002; 51: 89 –94.
vitamin E for non-alcoholic steatohepatitis. Hepatology
49 Hickman IJ, Jonsson JR, Prins JB et al. Benefit of sustained
2002; 36: 382A.
weight loss and exercise in overweight patients with liver
63 Caldwell SH, Hespenheide EE, Redick JA et al. A pilot
disease: indicators for success. Hepatology 2003; 34: 504A.
study of a thiazolidinedione, troglitazone, in non-alcoholic
50 Anonymous. Executive summary of the clinical guide-
steatohepatitis. Am J Gastroenterol2001; 96: 519–25.
lines on the identification, evaluation and treatment of
64 Weltman MD, Farrell GC, Liddle C. Increased hepatocyte
overweight and obesity in adults. Arch Intern Med 1998;
CYP2E1 expression in a rat nutritional model of hepatic
158: 1855– 67.
steatosis with in ammation. Gastroenterology 1996; 111:
51 The Diabetes prevention program (DPP) research group.
1645–53.
The diabetes prevention program (DPP): description of
65 Leclercq IA, Farrell GC, Field J et al. CYP2E1 and CYP4A
lifestyle intervention. Diabetes Care 2002; 25: 2165–71.
as microsomal catalysts of lipid peroxides in murine
52 Musso G, Gambino R, De Michieli F et al. Dietary habits
nonalcoholic steatohepatitis. J Clin Invest 2000; 105:
and their relations to insulin resistance and postprandial
1067–75.
lipemia in non-alcoholic steatohepatitis. Hepatology 2003;
66 George J, Pera N, Phung N et al. Lipid peroxidation,
37: 909–16.
stellate cell activation and hepatic fibrogenesis in a rat
53 Kraus RM, Eckel RH, Howard B et al. AHA dietary
model of chronic steatohepatitis. J Hepatol 2003; 39:
guidelines: revision 2000. A statement for health care pro-
756 –64.
fessionals from the nutrition committee of the American
67 Weltman MD, Farrell GC, Hall P, Ingelman-Sundberg M,
Heart Association. Stroke 2000; 31: 2751– 66.
Liddle C. Hepatic cytochrome P450 2E1 is increased in
54 Clark MJ Jr, Sterrett JJ, Carson DS. Diabetes guidelines:
patients with non-alcoholic steatohepatitis. Hepatology
a summary and comparison of the recommendations
1998; 27: 128–33.
192


FLDC15 13/9/04 9:57 AM Page 193
DIAGNOSIS AND MANAGEMENT OF FATTY LIVER DISEASES
68 Chalasani N, Gorski JC, Asghar MS et al. Hepatic
70 Seki S, Kitada T, Yamada T et al. In situ detection of lipid
cytochrome P450 2E1 activity in non-diabetic patients
peroxidation and oxidative DNA damage in non-alcoholic
with non-alcoholic steatohepatitis. Hepatology 2003; 37:
fatty liver diseases. J Hepatol 2002; 37: 56– 62.
544 –50.
71 Ip E, Farrell, GC, Hall P et al. Administration of the potent
69 MacDonald GA, Bridle KR, Ward PJ et al. Lipid
PPAR against, Wy-14,643, reverses nutritional fibrosis
peroxidation in hepatic steatosis in humans is asso-
and steatohepatitis in mice. Hepatology 2004; 39: 1286–96.
ciated with hepatic fibrosis and occurs predominately in
72 Ong J, Younossi ZM, Reddy V et al. Cryptogenic cirrhosis
acinar zone 3. J Gastroenterol Hepatol 2001; 16: 599–
and posttransplantation non-alcoholic fatty liver disease
606.
[Abstract]. Liver Transpl 2001; 7: 797– 801.
193