Nonalcoholic fatty liver disease in type 2 diabetes mellitus

Kenneth Cusi
Diabetes Division, Department of Medicine, The
University of Texas Health Science Center at San
Antonio and the Audie L. Murphy Veterans
Administration Medical Center, Texas, USA
Correspondence to Kenneth Cusi, MD, FACP, FACE,
Professor of Medicine, The University of Texas H.S.C.
at San Antonio, Diabetes Division, Room 3.380S, 7703
Floyd Curl Drive, San Antonio, TX 78284-3900, USA
Tel: +1 210 567 6708; fax: +1 210 567 6554;
e-mail: cusi@uthscsa.edu
Current Opinion in Endocrinology, Diabetes &
Obesity 2009, 16:141149

Purpose of review
To increase awareness about the close interrelationship between nonalcoholic fatty liver
disease and type 2 diabetes mellitus, and of recent diagnostic and treatment advances
in the field.
Recent findings
The perception of nonalcoholic fatty liver disease as an uncommon and benign
condition is rapidly changing. Approximately 70% of persons with type 2 diabetes
mellitus have a fatty liver and the disease follows a more aggressive course with
necroinflammation and fibrosis (i.e. nonalcoholic steatohepatitis) in diabetes. New
evidence suggests that it is not steatosis per se but the development of lipotoxicityinduced mitochondrial dysfunction and activation of inflammatory pathways that leads to
progressive liver damage. Nonalcoholic steatohepatitis is a leading cause of end-stage
liver disease and contributes to cardiovascular disease in patients with type 2 diabetes
mellitus. Because nonalcoholic steatohepatitis may develop even in the presence of
normal liver transaminases, a liver biopsy is still necessary for a definitive diagnosis.
However, new imaging methods and plasma biomarkers are emerging as alternative
diagnostic tools. Lifestyle intervention is the gold standard for the management of
nonalcoholic steatohepatitis. Recent randomized controlled trials suggest
thiazolidiendiones are promising therapeutic agents.
Summary
Nonalcoholic steatohepatitis is a frequently overlooked and potentially severe
complication of type 2 diabetes mellitus. Patients may benefit from its early diagnosis
and treatment.
Keywords
insulin resistance, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis,
pioglitazone, rosiglitazone, steatosis, thiazolidiendiones, type 2 diabetes
Curr Opin Endocrinol Diabetes Obes 16:141149
2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
1752-296X

Introduction
Nonalcoholic fatty liver disease is a chronic liver condition
characterized by insulin resistance and hepatic fat accumulation, in the absence of other identifiable causes of
fat accumulation, such as alcohol abuse, viral hepatitis,
autoimmune hepatitis, alpha-1 antitrypsin deficiency,
medications like corticosteroids and estrogens, and other
conditions [1

]. Hepatic steatosis may range from a
benign indolent deposition of fat to severe lipotoxicityinduced steatohepatitis with necroinflammation [known as
nonalcoholic steatohepatitis (NASH)] (Table 1). NASH is
an overlooked complication of type 2 diabetes mellitus
(T2DM) that if missed may carry serious long-term consequences. NASH is frequently associated with fibrosis
and approximately 10% of patients develop cirrhosis. The
risk of hepatocellular carcinoma is also increased in
patients with T2DM and NASH [2
]. Diabetes, dyslipidemia, hypertension, and cardiovascular disease (CVD)
occur more frequently in individuals with NAFLD [3

].
1752-296X 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins

NAFLD may also be associated with a greater risk of renal

disease in patients with T2DM [4]. Health care costs have
been long suspected to be higher in NASH patients, a
finding recently confirmed in a large cohort of 4224 from
Western Germany [5].
Unfortunately, clinicians are frequently unaware that
patients with T2DM are uniquely prone to NASH
because the disease is associated with few symptoms,
there is a lack of sensitive noninvasive diagnostic tests,
and physicians usually just rely on liver transaminases to
diagnose liver disease. However, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) are normal in most patients with NASH. Another limiting diagnostic factor is that the distinction between benign
steatosis or active NASH can only be done by performing
a liver biopsy, a procedure that both patients and doctors
are reluctant to pursue. However, recent work has broadened our understanding of the disease and offered new
treatments, suggesting that it will not be long before
DOI:10.1097/MED.0b013e3283293015

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142 Diabetes and the endocrine pancreas I

Table 1 Clinical features of NAFLD and NASH

NAFLD: hepatic fat accumulation in the absence of other
identifiable causes
NASH: chronic necrosis, inflammation / fibrosis (NASH) with
progressive liver damage (occurs in 40% of patients with NAFLD)
Risk factors for NASH
Type 2 diabetes or IGT
Insulin resistance
Metabolic syndrome (central obesity, dyslipidemia, hypertension)
Ethnicity: more common in Hispanics, less in African-Americans
Few clinical and laboratory findings
Right upper quadrant discomfort; findings of cirrhosis in
advanced disease
Elevated plasma ALT>AST levels (but in the majority
they are normal)
ALT, alanine aminotransferase; AST, aspartate aminotransferase; IGT,
impaired glucose tolerance; NAFLD, nonalcoholic fatty liver disease;
NASH, nonalcoholic steatohepatitis.

screening for fatty liver disease, either noninvasively or in

selected cases with a liver biopsy, will be incorporated
into our routine evaluation of patients in the same way
that we currently do for other chronic complications of
diabetes.

Type 2 diabetes: a major risk factor for NASH

Using the gold-standard magnetic resonance and spectroscopy (MRS) technique for the noninvasive assessment of hepatic steatosis, the prevalence of NAFLD
(defined as liver fat >5%) has been estimated to be
34% in the USA or approximately 7080 million people
[6]. This prevalence is, however, believed to be much
higher in T2DM. In our laboratory, the prevalence of
NAFLD by MRS in 107 unselected patients with T2DM
was 76% [7], which is similar to recent studies from Italy
[8] and Brazil [9]. Of note, most diabetic patients had
normal liver transaminases [7]. A normal AST and ALT is
consistent with earlier studies suggesting that liver transaminases are frequently not increased even in the presence of advanced fibrosis and cirrhosis [1012]. This has
been confirmed recently in a large cohort of 458 Italian
patients with biopsy-proven NASH [13
]. In this study,
NASH was diagnosed in 59 and 74% of the patients with
normal and increased ALT, respectively. Diabetes was
the single most important predictor of NASH and fibrosis.
In only those with normal ALT, NASH was strongly
predicted by insulin resistance [odds ratio (OR) 1.97;
95% confidence interval (CI) 1.23.7]. Therefore, normal
ALT levels should not preclude the clinician from pursuing an histological diagnosis if the disease is suspected.
Considering that up to 40% of adults with NAFLD have
progressive liver damage [1

] and that the majority of
patients with cryptogenic cirrhosis are diabetic [14,15
], it
follows that NASH in T2DM must be frequently missed
until it is too late and end-stage liver disease develops.
In the largest (n 129) and longest follow-up (13.7  1.3
years) study of patients with NASH, Ekstedt et al. [16]

reported that survival was significantly reduced.

Decreased survival was due to cardiovascular and liverrelated causes, including end-stage liver disease (5.4%)
and hepatocellular carcinoma (2.3%). In a recent study in
children with NAFLD (mean age 13.4 years) 40% had
progression of fibrosis in a follow-up liver biopsy at
28 months [17]. This is of concern as the prevalence of
NAFLD is rapidly increasing in children and adolescents,
particularly in Hispanics [18]. Once again, it is likely that
NASH may develop early in life in an increasing number
of children and that the window of opportunity for
intervention is overlooked by many physicians.
As with adults, metabolic syndrome (MetS) is common in
children with NAFLD [19
,20] and is a strong predictor
of future NASH and fibrosis [1

]. In a recent large
analysis in 827 patients, advanced fibrosis was closely
related to obesity, insulin resistance, and diabetes [21
].
Obesity and T2DM share a metabolic soil that promotes
hepatocyte lipotoxicity: adipose tissue insulin resistance,
subclinical inflammation, hyperinsulinemia, and abnormal glucose metabolism [22]. Perseghin et al. [23]
recently reported an association between hepatic and
cardiac triglyceride accumulation, with a close correlation
between the development of NAFLD and abnormalities
in left ventricular energy metabolism. Of interest, treatment with pioglitazone reduces both hepatic and myocardial steatosis [24], suggesting that lipotoxicity is a
common metabolic abnormality to both tissues.

Recent developments in the diagnosis of

NASH
Nonalcoholic fatty liver disease is most commonly diagnosed by a combination of clinical, laboratory, and imaging studies (Table 1). Ultrasound is the most widely
used imaging tool, but its sensitivity is poor at low to
moderate degrees of steatosis and it decreases further
with increasing central adiposity [1

,25]. At present,
MRS is the most reliable imaging technique for hepatic
fat steatosis [6,26,27], having found in our hands a close
correlation with fat estimated from liver biopsies in
patients with NASH (K. Cusi, et al., unpublished). Unfortunately, no imaging technique can replace a liver biopsy
to confirm the diagnosis of NASH. A liver biopsy may be a
reasonable approach to diagnose NASH and stage the
disease in individuals who are at the highest risk of
disease progression such as in obesity, metabolic syndrome, and/or T2DM, if the information obtained will
prompt a more aggressive treatment approach.
There is an active search for more practical ways to study
the large numbers of patients with NAFLD and T2DM.
Efforts include the use of plasma biomarkers [28
30,31

] and imaging by transient elastography [32
,33].
A promising biomarker is the measurement of plasma

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Nonalcoholic fatty liver disease in type 2 diabetes mellitus Cusi 143

cytokeratin-18 fragments (marker of hepatocyte apoptosis), which has been reported to be increased in patients
with NASH compared to those with simple steatosis or
normal livers [34] and reduced with pioglitazone treatment in association with histological improvement. The
use of transient elastography has recently shown a good
correlation between liver stiffness by this imaging technique and fibrosis stage [35], including in pediatric populations [36

]. These approaches are promising but await
more definitive validation in larger and more diverse
populations.

tion, and extracellular release of fatty acids, including the

alteration of hepatic apoB-lipoprotein production and
microsomal triglyceride transfer protein (MTP) stability
[51,52]. These effects are mediated by a cross-talk
between the mammalian target of rapamycin (mTOR)
and NF-kB [51]. In contrast to these studies, blocking
VLDL secretion alone in a mouse model of hepatic
steatosis lacking MTP caused hepatic steatosis, but not
hepatic necroinflammation, NF-kB activation, or insulin
resistance [53]. Taken together, these studies highlight
the complex interplay between steatosis, hepatic insulin
resistance, and tissue damage in NASH.

NAFLD: role of adipose tissue insulin

resistance, fatty acids, and lipotoxicity

Liver steatosis may also be due to an altered composition

of hepatic fat. Recently, Puri et al. [54
] reported an
increased content of triacylglycerol (TAG), diacylglycerol
(DAG), and of free cholesterol in NASH patients. A
cholesterol-rich diet promotes steatohepatitis with activation of NF-kB signaling in hyperlipidemic mouse
models [55], and mitochondrial toxicity with outer mitochondrial membrane permeabilization, cytochrome c
release, caspase-3 activation, and hepatocellular death
from mitochondrial glutathione depletion induced by
free cholesterol [56]. However, more attention has been
recently placed on the toxic role of saturated FFA in the
development of NASH. Human hepatocytes incubated
with unsaturated fatty acids accumulate large amounts of
triglyceride without harm, but saturated fatty acids (i.e.
palmitate) readily cause endoplasmic reticulum stress
and apoptosis, as they are poorly incorporated into triglyceride [57]. Fatty acids impair insulin signaling and
activate proinflammatory serine/threonine kinases and
the Ikb/NF-kB pathway, promote the accumulation of
DAG, and enhance the expression of cytokines such as
TNF-a and IL-1b [22]. Unsaturated fatty acids prevent
palmitate-induced apoptosis by channeling palmitate
into less harmful triglyceride pools and away from apoptotic pathways [58]. Inhibition of acyl-coenzyme
A:diacylglycerol acyltransferase (DGAT) 2 (the enzyme
that catalyzes the final step in triglyceride synthesis) in
obese, diabetic db/db mice fed a methionine-cholinedeficient (MCD) diet reduces steatosis at the expense of
exacerbating oxidative stress, liver injury, and fibrosis
[40]. Therefore, it appears that the target of treatment
may not be steatosis per se but the prevention of saturated
fatty acid formation and lipotoxicity-induced mitochondrial damage. Saturated fatty acids induce mitochondrial
dysfunction and oxidative stress by mechanisms dependent on lysosomal disruption and activation of cathepsin
B [41]. As proof-of-concept it has been recently shown
that fatty acid-induced mitochondrial oxidative stress and
hepatocyte apoptosis could be prevented by glycyrrhizin,
the major bioactive component of licorice root extract, by
stabilizing lysosomal membranes and inhibiting cathepsin B activity [59]. We have found that it is the combination of elevated plasma FFA and insulin levels, as

Defects at multiple levels may tip the metabolic balance

towards hepatic fat accumulation: excessive substrate
supply to the liver (i.e. fatty acids, glucose); intrahepatic
mismatch between lipid synthesis and oxidation;
inadequate export to peripheral tissues; and a combination of the above. Many molecular defects at these
different steps have been described in NAFLD but
exceed the scope of this brief review [3742]. Among
the metabolic defects, chronic hyperinsulinemia and
hyperglycemia as observed in T2DM are of paramount
importance as they promote lipogenesis by upregulating
hepatic sterol regulatory element binding protein 1c
(SREBP1c) and carbohydrate regulatory element binding
protein (ChREBP) activity, respectively. High carbohydrate/fructose-based diets promote de novo lipogenesis
and activate harmful inflammatory pathways [i.e. c-jun
N-terminal kinase (JUN)-signaling pathway] with hepatocyte apoptosis [43]. Increased consumption of dietary
carbohydrates is common in patients with NAFLD and
has been recently associated with increased hepatic
mRNA expression of fructokinase, a key enzyme for
fructose metabolism, and in fatty acid synthase, an
important lipogenic enzyme [44]. Restriction of dietary
carbohydrates reduces hepatic fat [45] and elevated ALT
[46] in obese patients with NAFLD.
In T2DM excessive rates of lipolysis from insulin-resistant adipose tissue is also a driving force for the development of steatosis [22,47
,48]. Adipocytes account for
approximately 6070% of the free fatty acid (FFA) used
for hepatic triglyceride synthesis and very low-density
lipoprotein (VLDL) secretion [49]. Many factors that
regulate VLDL metabolism may promote steatosis.
For example, the activity of stearoyl-CoA desaturase 1
(SCD1), a rate-limiting enzyme in monounsaturated fatty
acid synthesis essential for the assembly of VLDL
particles, has been reported to be low in obese patients
with NAFLD [50]. Down-regulation of hepatic tumor
suppressor phosphatase and tensin homolog (PTEN) by
unsaturated fatty acids induces steatosis by impairing
insulin signaling and affecting incorporation, esterifica-

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144 Diabetes and the endocrine pancreas I

compared to either factor alone or hyperglycemia, that

causes the greatest degree of hepatic steatosis and mitochondrial dysfunction in rodents [60
], pointing to the
value of therapies that can reverse lipotoxicity for the
prevention of NASH.
From adipose tissue insulin resistance to NASH: the
failure to adapt to a lipotoxic environment

From the above, one may conceptually delineate several

steps in the development of NASH. Still, our data are
fragmented and arise largely from rodents given the
natural difficulties of accessing human liver tissue. One
must keep in mind that there are significant metabolic/
molecular differences between livers from humans and
rodents, and even between rodent species. With these
limitations in mind, Fig. 1 is an effort to organize our
current understanding of NAFLD and NASH in a schematic framework for hypothesis generation and future
testing. This is obviously subject to rapid change as new
information emerges. A prerequisite or first step for
NASH appears to be adipose tissue insulin resistance,
providing the necessary lipotoxic environment that
ensures ample substrate supply to the liver (i.e. high

FFA flux) and compensatory hyperinsulinemia that

stimulates lipogenesis. The second step towards NASH
is the development of hepatic steatosis and of a lipid pool
from where lipid-derived toxic metabolites may activate
inflammatory pathways. Dietary and genetic factors
[61,62
] may condition the metabolic adaptation of the
liver to this harmful environment, particularly of several
mitochondrial-related energy regulators, such as 50 AMPactivated protein kinase (AMPK), peroxisome proliferator-activated receptor-g coactivator (PGC)-1a, peroxisome proliferator-activated receptor- (PPAR)- g, PPARa, and others, such as adiponectin [63,64]. Plasma adiponectin levels are low in patients with T2DM with
NASH [26]. Administration of adiponectin to steatotic
mice dramatically alleviates hepatomegaly, fat accumulation, and inflammation by increasing carnitine palmitoyltransferase (CPT)-I activity and enhancing hepatic
fatty acid oxidation while inhibiting fatty acid synthesis
[65]. Zhou et al. [66] recently reported that in adiponectin
knockout mice impaired mitochondrial respiratory chain
(MRC) activity can be completely overturned by adiponectin replenishment, with reversal of steatosis, accumulation of lipid peroxidation products, and down-regulation

Figure 1 Proposed framework on the progression from adipose tissue insulin resistance to NAFLD and NASH

(1) Insulin-resistant adipose tissue: in the setting of metabolic syndrome and/or T2DM, elevated rates of lipolysis/plasma FFA from insulin-resistant
adipose tissue combined with hyperinsulinemia and hyperglycemia stimulate excessive hepatic triglyceride synthesis and the formation of toxic
saturated fatty acids; (2) Compensated steatosis: steatosis in turn may: exacerbate hepatic insulin resistance, stimulate VLDL secretion, and increase
mitochondrial beta-oxidation. If a new steady state is achieved, only benign steatosis and/or dyslipidemia (high triglyceride, low HDL-C) takes place;
(3) Steatohepatitis: if mitochondrial function cannot adapt to the increased FFA flux and respiratory oxidation collapses, lipid-derived toxic metabolites
activate inflammatory pathways and hepatocyte lipotoxicity with stimulation of chronic necrosis and inflammation; (4) Fibrosis: the magnitude of the
cross-talk between hepatocytes, macrophages, and HSCs determines the degree of the fibrogenic response and potential progression to cirrhosis. In
this setting, low plasma adiponectin levels are believed to promote steatosis and fibrosis by allowing unchecked triglyceride synthesis and activation of
HSCs, respectively. FFA, free fatty acid; HDL-C, high-density lipoprotein-C; HSC, hepatic stellate cell; NAFLD, nonalcoholic fatty liver disease; NASH,
nonalcoholic steatohepatitis; T2DM, type 2 diabetes mellitus. Adapted with permission [22].

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Nonalcoholic fatty liver disease in type 2 diabetes mellitus Cusi 145

of uncoupling protein 2 (UCP2). The third step for

the progression from simple bland steatosis to active
necroinflammation depends on the ability of the liver to
adapt to longstanding triglyceride accumulation. Failure
would lead to FFA-induced lipotoxicity with mitochondrial dysfunction, endoplasmic reticulum stress, reactive
oxygen species (ROS) formation, and chronic necroinflammation. Fibrosis is the final or fourth step, involving
chronic activation of hepatic stellate cells in a yet poorly
understood cross-talk of Kupffer cells with hepatocytes
[38]. Of note, recent evidence indicates that adiponectin
inhibits effect hepatic stellate cell activation [67], highlighting a potential therapeutic target and the multiple
roles of this hormone in NASH.

Table 2 Clinical trials with pharmacological agents in NAFLD/

NASH
Intervention

Outcome

Ursodeoxycholic acid
Pentoxyphilline
Antioxidants (i.e. vitamin E or C)
Orlistat
Lipid-lowering agents: (statins,
fibrates, omega-3 FA)
Glucose-lowering agents
Metformin
Intensified insulin therapy (NAFLD)
Exenatide added to insulin (NAFLD)
Rosiglitazone
Pioglitazone

Not effective
Not effective
Not effective
Overall not effective
Overall not effective
Moderate efficacy
Moderate efficacy
Moderate efficacy
Moderate efficacy
Efficacy shown in
short-term studies

NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis.

Treatment of NAFLD
The current view of NAFLD as a serious condition with
potential for considerable morbidity and mortality has
stimulated the search for strategies ranging from lifestyle
changes to a variety of pharmacological interventions.

Most weight-loss studies in NAFLD/NASH are pilot

studies of short duration (212 months) and limited
success, reporting a decrease in hepatic steatosis and
liver transaminases, but with modest improvement in
necroinflammation or fibrosis [26,68,69
]. Reduction of
visceral fat may be a particularly important target, as
recent studies suggest a close relationship between visceral fat and hepatic steatosis [26,27], as well as with
inflammation, and even fibrosis [26,27,70].

obese, diabetic Otsuka Long-Evans Tokushima Fatty

(OLETF) rats, olmesartan reversed steatohepatitis and
fibrosis induced by a MCD diet. A modest effect on ALT
and/or fibrosis has been reported in recent small studies
with losartan [83], olmesartan [84,85], and telmisartan
[84,86], although no randomized controlled trials are
yet available. Inhibition of transforming growth factor
(TGF)-beta (which activates hepatic stellate cells)
appears as another interesting target. In obese diabetic
OLETF rats the anti-TGF-beta agent Tranilast or
N-(30 ,40 -dimethoxycinnamoyl)-anthranilic acid successfully prevented activation of hepatic stellate cells,
down-regulated the expression of TGF-beta and
TNF-a-dependent genes, and attenuated hepatic steatosis, inflammation, and fibrosis [87].

Bariatric surgery is gaining momentum for the treatment

of obesity associated with comorbidities such as T2DM
and NASH, with long-term reports of reduction in overall
mortality [71]. In NASH, results have been encouraging
in terms of histological improvement [72] and are not
associated with a paradoxical exacerbation of liver inflammation and fibrosis as reported in earlier series [73].

Statins have not been examined in large controlled prospective trials, but their use appears to be overall safe if
patients with NASH are closely followed [8890]. In
small uncontrolled trials modest or no benefit has been
reported with the use of other lipid-lowering agents such
as fibrates [91], omega-3 fatty acids [92], or probucol, a
lipid-lowering drug with antioxidant effects [93].

Pharmacological interventions in NAFLD and NASH

The shared metabolic abnormalities of T2DM and

NAFLD help explain the greater success in NASH of
agents used to treat diabetes. Metformin [94] improves
elevated AST/ALT and steatosis [95100] and to a lesser
extent inflammation [97,100]. However, not all studies
have seen a reduction in steatosis with metformin [101].
We have recently found that intensive insulin therapy
(basal and premeal rapid-acting insulin) in patients with
T2DM and NAFLD significantly reduces hepatic steatosis as assessed by MRS [102], and that the substitution
of premeal insulin for exenatide twice daily for 6 months
can further lower hepatic fat content [103].

Weight loss and lifestyle intervention

As listed in Table 2, a number of pharmacological interventions have been tried in NAFLD/NASH but with
overall limited benefit [1

]. Antioxidant agents may
arrest lipid peroxidation and cytoprotective agents
stabilize phospholipid membranes, but agents tried
unsuccessfully or with modest benefit so far include:
ursodeoxycholic acid [74,75], vitamin E (a tocopherol)
and C [7678], and pentoxifilline [79], among others.
Weight-loss agents such as orlistat have had no significant
benefit compared to weight loss alone [80,81]. Recent
interest in angiotensin receptor blockers (ARBs) arises
from their potential to modulate activated hepatic
stellate cells responsible for collagen synthesis and hepatic fibrosis. Kurita et al. [82] recently reported that in

However, thiazolidinediones (TZDs) have attracted the

most attention for the treatment of NASH [104
]. Early

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146 Diabetes and the endocrine pancreas I

Figure 2 Mean scores for inflammation, ballooning necrosis, steatosis, and fibrosis in liver biopsies before and after a hypocaloric
diet (S500 kcal/day) and pioglitazone or a hypocaloric diet and placebo in 55 patients with IGT or T2DM and NASH

IGT, impaired glucose tolerance; NASH, nonalcoholic steatohepatitis; T2DM, type 2 diabetes mellitus. Reproduced with permission from Belfort et al.
[26].

small pilot studies with TZDs met variable success

[78,105,106]. In the first randomized, double-blind,
placebo-controlled trial (RCT), we were able to show that
6 months of pioglitazone treatment improved glycemic
control, insulin sensitivity, systemic inflammation [plasma
C-reactive protein (hsCRP), TNF-a, and TGF-b, among
others], and liver histology in patients with NASH and
impaired glucose tolerance (IGT) or T2DM [26]. Treatment ameliorated adipose, hepatic, and muscle insulin
resistance and was associated with a significant approximately 50% decrease in necroinflammation (P < 0.002)
and a 37% reduction of fibrosis within the pioglitazonetreated group, although this did not reach statistical significance when compared with placebo (P 0.08) (Fig. 2).
These results generated considerable interest on the role
of TZDs in NASH [107,108]. Improvement in hepatocellular injury and fibrosis has been recently reported in
another controlled trial with pioglitazone [109
]. Importantly, there was no alteration in total body water volume or
water retention in our clinical trial when measured by three
different state-of-the-art techniques, suggesting that its
use is overall safe in this population in the absence of
preexisting heart failure [110].
In the first RCT with rosiglitazone in NASH, this TZD
also reduced plasma ALT levels and steatosis, but had no

significant effect on necrosis, inflammation, or fibrosis

[111
]. A preliminary report of the 2-year, open-label
follow-up of this trial has also been disappointing with
no significant benefit from rosiglitazone treatment [112].
The reasons for these discrepant results compared to
pioglitazone remain unclear, but may include intrinsic
pharmacological differences (i.e. as shown for their cardiovascular profile) or in the populations studied [104
].
Ongoing longer-term clinical trials with pioglitazone in
predominantly nondiabetic (PIVENS trial) or diabetic
(K. Cusi, et al., unpublished) patients will teach us more
about the long-term safety and efficacy of TZDs in NASH.

Conclusion
Nonalcoholic fatty liver disease is no longer considered a
benign condition in patients with T2DM. The possibility
of fatty liver disease should be entertained as a part of the
routine evaluation of patients with T2DM, in the same
way we search for microvascular complications and CVD.
Awareness by healthcare providers is essential for an early
diagnosis and timely implementation of lifestyle and
pharmacological interventions. A normal plasma ALT
or AST level should not mislead clinicians into dismissing
the possibility of fatty liver disease as transaminases in
most patients are not elevated. New laboratory and

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Nonalcoholic fatty liver disease in type 2 diabetes mellitus Cusi 147

imaging tests promise to make the diagnosis easier than at

the present time and minimize the need for a liver biopsy.
Thiazolidinediones are emerging as promising agents for
the treatment of NASH. However, more information is
needed about their long-term safety and efficacy before
the use of TZDs can be routinely recommended.

18

Schwimmer J, Pardee P, Lavine J, et al. Cardiovascular risk factors and the

metabolic syndrome in pediatric nonalcoholic fatty liver disease. Circulation
2008; 118:277283.
Highlights the early development of cardiovascular risk factors in children with
NAFLD.

19

20

References and recommended reading

Papers of particular interest, published within the annual period of review, have
been highlighted as:


of special interest


of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 194195).
Ali R, Cusi K. New diagnostic and treatment approaches in nonalcoholic fatty
liver disease (NAFLD). Ann Med 2009. [Epub ahead of print]. http://dx.doi.
org/10.1080/07853890802552437
Comprehensive overview of the risk factors for the development of NASH with
emphasis on future diagnostic and treatment approaches.

Targher G, Marra F, Marchesini G. Increased risk of cardiovascular disease in

nonalcoholic fatty liver disease: causal effect or epiphenomenon? Diabetologia 2008; 51:19471953.
Review assessing the cluster of cardiovascular risk factors associated with NAFLD
and the specific risk associated with the presence of fatty liver.

Harrison S, Oliver D, Arnold H, et al. Development and validation of a simple

NAFLD clinical scoring system for identifying patients without advanced
disease. Gut 2008; 57:14411447.
Valuable examination of risk factors in a large population of patients with NAFLD.
22

Cusi K. Evolving concepts in lipotoxicity. AASLD Postgraduate Course

2008; 2008:7284.

23

Perseghin G, Lattuada G, De Cobelli F, et al. Increased mediastinal fat and

impaired left ventricular energy metabolism in young men with newly found
fatty liver. Hepatology 2008; 47:5158.

24

Zib I, Jacob A, Lingvay I, et al. Effect of pioglitazone therapy on myocardial and

hepatic steatosis in insulin-treated patients with type 2 diabetes. J Investig
Med 55:ePub (electronic version); 2007.

25

Mehta SR, Thomas EL, Bell JD, et al. Noninvasive means of measuring
hepatic fat content. World J Gastroenterol 2008; 14:34763483.

26

Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006;
355:22972307.

27

Gastaldelli A, Cusi K, Pettiti M, et al. Relationship between hepatic/visceral

fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects.
Gastroenterology 2007; 133:496506.

28

Poynard T, Ratziu V, Charlotte F, et al., and the LIDO study group, and the
CYTOL study group. Diagnostic value of biochemical markers (NashTest) for
the prediction of non alcoholic steatohepatitis in patients with nonalcoholic
fatty liver disease. BMC Gastroenterol 2006; 6:34.

29

Ratziu V, Massard J, Charlotte F, et al., and the LIDO study group, and the
CYTOL study group. Diagnostic value of biochemical markers (FibroTestFibroSURE) for the prediction of liver fibrosis in patients with nonalcoholic
fatty liver disease. BMC Gastroenterol 2006; 6:6.

30

Angulo P, Hui J, Marchesini G, et al. The NAFLD fibrosis score: a noninvasive

system that identifies liver fibrosis in patients with NAFLD. Hepatology 2007;
45:846854.

3

Targher G, Chonchol M, Bertolini L, et al. Increased risk of CKD among type 2

diabetics with nonalcoholic fatty liver disease. J Am Soc Nephrol 2008;
19:15641570.

Baumeister SE, Volzke H, Marschall P, et al. Impact of fatty liver disease on

healthcare utilization and costs in a general population: a 5-year observation.
Gastroenterology 2008; 134:8594.

Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic

steatosis in an urban population in the United States: impact of ethnicity.
Hepatology 2004; 40:13871395.

Chen J, Mathew M, Finch J, Cusi K. The prevalence of NAFLD in T2DM is

highest among Hispanics and is closely related to hepatic and adipose tissue
insulin resistance [abstract]. Diabetes 2009; 58 (Suppl 1).

Targher G, Lorenzo B, Roberto P, et al. Prevalence of nonalcoholic fatty liver

disease and its association with cardiovascular disease among type 2
diabetic patients. Diabetes Care 2007; 30:12121218.

Leite N, Salles G, Araujo A, Villela-Nogueira C, Cardoso C. Prevalence and

associated factors of nonalcoholic fatty liver disease in patients with type-2
diabetes mellitus. Liver Int 2009; 29:113119.

10

Mofrad P. Clinical and histologic spectrum of nonalcoholic fatty liver

disease associated with normal ALT values. Hepatology 2003; 37:1286
1292.

11

Sorrentino P. Silent nonalcoholic fatty liver disease-a clinical-histological

study. J Hepatol 2004; 41:751757.

12

Amarapurkar D, Patel N. Clinical spectrum and natural history of nonalcoholic

steatohepatitis with normal alanine aminotransferase values. Trop Gastroenterol 2004; 25:130134.

Fracanzani A, Valenti L, Bugianesi E, et al. Risk of severe liver disease in

nonalcoholic fatty liver disease with normal aminotransferase levels: a role for
insulin resistance and diabetes. Hepatology 2008; 48:792798.
Valuable study in a large cohort of patients with NASH about the possibility of
significant liver disease in NASH even in the presence of normal liver transaminases.

13

14

Maheshwari A, Paul JT. Cryptogenic cirrhosis and NAFLD: are they related?
Am J Gastroenterol 2006; 101:664668.

15 Caldwell S, Lee V. Cryptogenic cirrhosis. AASLD Postgraduate Course

2008; 2008:4857.
State-of-the-art review on cryptogenic cirrhosis and its frequent association with
obesity and T2DM.

Demircioglu F, Kocyigit A, Arslan N, et al. Intima-media thickness of carotid

artery and susceptibility to atherosclerosis in obese children with nonalcoholic fatty liver disease. J Pediatric Gastroenterol Nutr 2008; 47:6875.

21

1

2
Bugianesi E, Vanni E, Marchesini G. NASH and the risk of cirrhosis and


hepatocellular carcinoma in type 2 diabetes. Curr Diab Rep 2007; 7:175180.
Detailed review about the close relationship in patients with diabetes between
NASH, cirrhosis and hepatocellular carcinoma.

Schwimmer J. Definitive diagnosis and assessment of risk for nonalcoholic

fatty liver disease in children and adolescents. Semin Liver Dis 2007;
27:312318.

Wieckowska A, McCullough A, Feldstein A. Noninvasive diagnosis and

monitoring of nonalcoholic steatohepatitis: present and future. Hepatology
2007; 46:582589.
Excellent review on the current role and future potential of plasma biomarkers for
the management of NAFLD and NASH.

31

Friedrich-Rust M, Ong MF, Martens S, et al. Performance of transient

elastography for the staging of liver fibrosis: a meta-analysis. Gastroenterology 2008; 134:960974.
Comprehensive review on the role of this imaging technique from the available
literature.

32

33

Castera L, Forns X, Alberti A. Noninvasive evaluation of liver fibrosis using

transient elastography. J Hepatol 2008; 48:835847.

34

Wieckowska A, McCullough A, Feldstein A, et al. In vivo assessment of liver

cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty
liver disease. Hepatology 2006; 44:2733.

35

Yoneda M, Mawatari H, Fujita K, et al. Noninvasive assessment of liver fibrosis

by measurement of stiffness in patients with nonalcoholic fatty liver disease
(NAFLD). Digest Liver Dis 2008; 40:371378.

Nobili V, Vizzutti F, Arena U, et al. Accuracy and reproducibility of transient

elastography for the diagnosis of fibrosis in pediatric nonalcoholic steatohepatitis. Hepatology 2008; 48:442448.
The following (ref. [3742]) are all outstanding reviews by leaders in the field on
the mechanisms that lead to NAFLD and NASH

36

37

Pessayre D. Role of mitochondria in nonalcoholic fatty liver disease.

J Gastroenterol Hepatol 2007; 22:S20S27.

38

16

Ekstedt M, Franzen L, Mathiesen U, et al. Long-term follow-up of patients with

NAFLD and elevated liver enzymes. Hepatology 2006; 44:865873.

Elsharkawy A, Mann D. Nuclear factor-kappaB and the hepatic inflammationfibrosis-cancer axis. Hepatology 2007; 46:590597.

39

17

A-Kader H, Henderson J, Vanhoesen K, et al. Nonalcoholic fatty liver disease

in children: a single center experience. Clin Gastroenterol Hepatol 2008;
6:799802.

Greenfield V, Cheung O, Sanyal A. Recent advances in nonalcholic fatty liver

disease. Curr Opin Gastroenterol 2008; 24:320327.

40

Choi SS, Diehl AM. Hepatic triglyceride synthesis and nonalcoholic fatty liver
disease. Curr Opin Lipidol 2008; 19:295300.

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

148 Diabetes and the endocrine pancreas I

41

Li Z, Berk M, McIntyre TM, et al. The lysosomal-mitochondrial axis in free

fatty acid-induced hepatic lipotoxicity. Hepatology 2008; 47:1495
1503.

64

Tomita K, Oike Y, Teratani T, et al. Hepatic AdipoR2 signaling plays a

protective role against progression of nonalcoholic steatohepatitis in mice.
Hepatology 2008; 48:458473.

42

Marra F, Gastaldelli A, Svegliati Baroni G, et al. Molecular basis and

mechanisms of progression of nonalcoholic steatohepatitis. Trends Mol
Med 2008; 14:7281.

65

Xu A, Wang Y, Keshaw H, et al. The fat-derived hormone adiponectin

alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest
2003; 112:91100.

43

Wei Y, Wang D, Topczewski F, Pagliassotti M. Fructose-mediated stress

signaling in the liver: implications for hepatic insulin resistance. J Nutr
Biochem 2007; 18:19.

66

Zhou M, Xu A, Tam PK, et al. Mitochondrial dysfunction contributes to the

increased vulnerabilities of adiponectin knockout mice to liver injury. Hepatology 2008; 48:10871096.

44

Ouyang X, Cirillo P, Sautin Y, et al. Fructose consumption as a risk factor for

nonalcoholic fatty liver disease. J Hepatol 2008; 48:993999.

67

45

Tendler D, Lin S, Yancy WS Jr, et al. The effect of a low-carbohydrate,

ketogenic diet on nonalcoholic fatty liver disease: a pilot study. Digest Dis Sci
2007; 52:589593.

Ding X, Saxena NK, Lin S, et al. The roles of leptin and adiponectin: a novel
paradigm in adipocytokine regulation of liver fibrosis and stellate cell biology.
Am J Pathol 2005; 166:16551669.

68

Wang R, Koretz R, Yee H. Is weight reduction an effective therapy for

nonalcoholic fatty liver? A systematic review. Am J Med 2003; 115:554
559.

46

Ryan MC, Abbasi F, Lamendola C, et al. Serum alanine aminotransferase

levels decrease further with carbohydrate than fat restriction in insulinresistant adults. Diabetes Care 2007; 30:10751080.

47 Adiels M, Taskinen M-R, Boren J. Fatty liver, insulin resistance, and dyslipi

demia. Curr Diabetes Rep 2008; 8:6064.
Excellent review on the topic.

69 Harrison S, Day C. Benefits of lifestyle modification in NAFLD. Gut 2007;

56:17601769.
Excellent review on the topic.
70

van der Poorten D, Milner KL, Hui J, et al. Visceral fat: a key mediator of
steatohepatitis in metabolic liver disease. Hepatology 2008; 48:449457.

48

Korenblat KM, Fabbrini E, Mohammed BS, Klein S. Liver, muscle, and

adipose tissue insulin action is directly related to intrahepatic triglyceride
content in obese subjects. Gastroenterology 2008; 134:13691375.

71

Sjostrom L, Narbro K, Sjostrom CD, et al., the Swedish Obese Subjects S.

Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J
Med 2007; 357:741752.

49

Donnelly KL, Smith CI, Schwarzenberg SJ, et al. Sources of fatty acids stored
in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver
disease. J Clin Invest 2005; 115:13431351.

72

de Freitas AC, Campos AC, Coelho JC. The impact of bariatric surgery on
nonalcoholic fatty liver disease. Curr Opin Clin Nutr Metab Care 2008;
11:267274.

50

Stefan N, Peter A, Cegan A, et al. Low hepatic stearoyl-CoA desaturase 1

activity is associated with fatty liver and insulin resistance in obese humans.
Diabetologia 2008; 51:648656.

73

Luyckx FH, Desaive C, Thiry A, et al. Liver abnormalities in severely obese

subjects: effects of drastic weight loss after gastroplasty. Int J Obes Relat
Metab Disord 1998; 22:222226.

51

Vinciguerra M, Veyrat-Durebex C, Moukil MA, et al. PTEN down-regulation by

unsaturated fatty acids triggers hepatic steatosis via an NF-kappaBp65/
mTOR-dependent mechanism. Gastroenterology 2008; 134:268280.

74

Lindor KD, Kowdley KV, Heathcote EJ, et al. Ursodeoxycholic acid for
treatment of nonalcoholic steatohepatitis: results of a randomized trial.
Hepatology 2004; 39:770778.

52

Qiu W, Federico L, Naples M, et al. Phosphatase and tensin homolog (PTEN)

regulates hepatic lipogenesis, microsomal triglyceride transfer protein, and
the secretion of apolipoprotein B-containing lipoproteins. Hepatology 2008;
48:17991809.

75

Dufour JF, Oneta CM, Gonvers JJ, et al., and the Swiss Association for the
Study of the Liver. Randomized placebo-controlled trial of ursodeoxycholic
acid with vitamin E in nonalcoholic steatohepatitis. Clin Gastroenterol
Hepatol 2006; 4:15371543.

53

Minehira K, Young SG, Villanueva CJ, et al. Blocking VLDL secretion causes
hepatic steatosis but does not affect peripheral lipid stores or insulin
sensitivity in mice. J Lipid Res 2008; 49:20382044.

76

Harrison SA, Torgerson S, Hayashi P, et al. Vitamin E and vitamin C treatment

improves fibrosis in patients with nonalcoholic steatohepatitis [see comment]. Am J Gastroenterol 2003; 98:24852490.

54 Puri P, Baillie RA, Wiest MM, et al. A lipidomic analysis of nonalcoholic fatty


liver disease. Hepatology 2007; 46:10811090.
Provocative study on the role of different types of lipids in the development of
NASH using novel techniques in the field.

77

Sanyal AJ, Mofrad PS, Contos MJ, et al. A pilot study of vitamin E versus
vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis.
Clin Gastroenterol Hepatol 2004; 2:11071115.

78

Nobili V, Manco M, Devito R, et al. Lifestyle intervention and antioxidant

therapy in children with nonalcoholic fatty liver disease: a randomized,
controlled trial. Hepatology 2008; 48:119128.

55

Wouters K, van Gorp PJ, Bieghs V, et al. Dietary cholesterol, rather than liver
steatosis, leads to hepatic inflammation in hyperlipidemic mouse models of
nonalcoholic steatohepatitis. Hepatology 2008; 48:474486.

79

56

Mari M, Colell A, Morales A, et al. Mechanism of mitochondrial glutathionedependent hepatocellular susceptibility to TNF despite NF-kappaB activation. Gastroenterology 2008; 134:15071520.

Adams LA, Zein CO, Angulo P, Lindor KD. A pilot trial of pentoxifylline in
nonalcoholic steatohepatitis. Am J Gastroenterol 2004; 99:23652368.

80

Gentile C, Pagliassotti M. The endoplasmic reticulum as a potential therapeutic target in nonalcoholic fatty liver disease. Curr Opin Investig Drugs
2008; 9:10841088.

Zelber-Sagi S, Kessler A, Brazowsky E, et al. A double-blind randomized

placebo-controlled trial of orlistat for the treatment of nonalcoholic fatty liver
disease. Clin Gastroenterol Hepatol 2006; 4:639644.

81

Listenberger L, Han X, Lewis S, et al. Triglyceride accumulation protects

against fatty acid-induced lipotoxicity. Proc Natl Acad Sci U S A 2003;
100:30773082.

Harrison S, Fecht W, Brunt E, Neuschwander-Tetri B. Orlistat for overweight

subjects with nonalcoholic steatohepatitis: a randomized, prospective trial.
Hepatology 2009; 49:8086.

82

Wu X, Zhang L, Gurley E, et al. Prevention of free fatty acid-induced hepatic

lipotoxicity by 18 beta-glycyrrhetinic acid through lysosomal and mitochondrial pathways. Hepatology 2008; 47:19051915.

Kurita S, Takamura T, Ota T, et al. Olmesartan ameliorates a dietary rat model

of nonalcoholic steatohepatitis through its pleiotropic effects. Eur J Pharmacol 2008; 588:316324.

83

Yokohama S, Tokusashi Y, Nakamura K, et al. :. Inhibitory effect of angiotensin II receptor antagonist on hepatic stellate activation in nonalcoholic
steatohepatitis. World J Gastroenterol 2006; 12:322326.

84

Enjoji M, Kotoh K, Kato M, et al. Therapeutic effect of ARBs on insulin

resistance and liver injury in patients with NAFLD and chronic hepatitis C: a
pilot study. Int J Mol Med 2008; 22:521527.

85

Hirose A, Ono M, Saibara T, et al. Angiotensin II type 1 receptor blocker

inhibits fibrosis in rat nonalcoholic steatohepatitis. Hepatology 2007;
45:13751381.

62 Mark N, deAlwis W, Day C. Genes and nonalcoholic fatty liver disease. Curr


Diabetes Rep 2008; 8:156163.
Comprehensive review on the different genes reported to be involved in the
development of NAFLD.

86

Jin H, Yamamoto N, Uchida K, et al. Telmisartan prevents hepatic fibrosis and

enzyme-altered lesions in liver cirrhosis rat induced by a choline-deficient
L-amino acid-defined diet. Biochem Biophys Res Commun 2007; 364:801
807.

Musso G, Gambino R, De Michieli F, et al. Adiponectin gene polymorphisms

modulate acute adiponectin response to dietary fat: possible pathogenetic
role in NASH. Hepatology 2008; 47:11671177.

87

Uno M, Kurita S, Misu H, et al. Tranilast, an antifibrogenic agent, ameliorates a

dietary rat model of nonalcoholic steatohepatitis. Hepatology 2008;
48:109118.

57

58

59

Wang S, Kamat A, Swamy A, et al. Hepatic steatosis is associated with

mitochondrial dysfunction in obese and diabetic rats [abstract]. Diabetes
2008; 55 (Suppl 1).
Study dissecting the role of FFA, glucose, and insulin in the induction of mitochondrial dysfunction in rodent models of NAFLD.

60

61

63

Greco D, Kotronen A, Westerbacka J, et al. Gene expression in human

NAFLD. Am J Physiol Gastrointest Liver Physiol 2008; 294:G1281G1287.

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Nonalcoholic fatty liver disease in type 2 diabetes mellitus Cusi 149

88

Liberopoulos EN, Athyros VG, Elisaf MS, Mikhailidis DP. Statins for nonalcoholic fatty liver disease: a new indication? Aliment Pharmacol Ther 2006;
24:698699.

102 Mathew M, Ali R, Kumar P, et al. Intensive insulin therapy reduces hepatic
steatosis and improves insulin secretion in T2DM [abstract]. Diabetes 2009;
58 (Suppl 1).

89

Argo K, Loria P, Caldwell S, Lonardo A. Statins in liver disease: a molehill, an

iceberg, or neither? Hepatology 2008; 48:662669.

90

Riley P, Sudarshi D, Johal M, et al. Weight loss, dietary advice and statin
therapy in nonalcoholic fatty liver disease: a retrospective study. Int J Clin
Pract 2008; 62:374381.

103 Mendoza C, Ali R, Mathew M, et al. Replacement of premeal insulin for

exenatide reduces hepatic steatosis and improves insulin secretion in
patients with T2DM [abstract]. Diabetes 2009; 58 (Suppl 1).
104 Cusi K. Thiazolidinediones for the treatment of nonalcoholic steatohepatitis


(NASH). Exp Rev Gastroenterol Hepatol 2009; (in press).
Comprehensive review on the mechanisms and potential role of TZDs for the
management of NASH.

91

Basaranoglu M, Acbay O, Sonsuz A. A controlled trial of gemfibrozil in the

treatment of patients with nonalcoholic steatohepatitis. J Hepatol 1999;
31:3841384.

92

Vega G, Chandalia M, Szczepaniak L, Grundy S. Effects of N-3 fatty acids on

hepatic triglyceride content in humans. J Investig Med 2008; 56:780785.

105 Caldwell SH, Hespenheide EE, Redick JA, et al. A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis. Am JGastroenterol
2001; 96:519525.

93

Merat S, Aduli M, Kazemi R, et al. Liver histology changes in nonalcoholic

steatohepatitis after one year of treatment with probucol. Digest Dis Sci
2008; 53:22462250.

106 Neuschwander-Tetri BA, Brunt EM, Kent R, et al. Improved nonalcoholic

steatohepatitis after 48 weeks of treatment with the PPAR-g ligand rosiglitazone. Hepatology 2003; 38:10081017.

94

Cusi K, DeFronzo R. Metformin: a review of its metabolic effects. Diabetes

Rev 1998; 6:89131.

95

Marchensini G, Bianchi G, Tomassetti S, et al. Metformin in nonalcoholic

steatohepatitis. Lancet 2001; 348:893894.

96

Uygun A, Kadayifci A, Isik A, et al. Metformin in the treatment of patients with

nonalcoholic steatohepatitis. Aliment Pharmacol Ther 2004; 19:537 544.

97

Bugianesi E, Gentilcore E, Manini R, et al. A randomized controlled trial of

metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver
disease. Am J Gastroenterol 2005; 100:10821090.

98

Lingvay I, Raskin P, Szczepaniak L. Effect of insulin-metformin combination

on hepatic steatosis in patients with type 2 diabetes. J Diabetes Complications 2007; 21:137142.

99

de Oliveira C, Stefano J, de Siqueira E, et al. Combination of N-acetylcysteine

and metformin improves histological steatosis and fibrosis in patients with
nonalcoholic steatohepatitis. Hepatol Res 2008; 38:159165.

107 Serfaty L. Pioglitazone: the beginning of a new era for NASH? J Hepatol
2007; 47:160162.
108 Lang L. Pioglitazone trial for NASH: results show promise. Gastroenterology
2007; 132:836838.
109 Aithal GP, Thomas JA, Kaye PV, et al. Randomized, placebo-controlled trial of


pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 2008; 135:11761184.
A 12-month RCT of pioglitazone in NASH showing a significant effect on metabolic
parameters, insulin sensitivity, and histological variables such as liver injury and
fibrosis.
110 Balas B, Belfort R, Harrison S, et al. Pioglitazone treatment increases whole
body fat but not total body water in patients with nonalcoholic steatohepatitis.
J Hepatol 2007; 47:565570.

100 Nobili V, Manco M, Ciampalini P, Alisi A, Devito R, Bugianesi E, Marcellini M,

Marchesini G. Metformin use in children with nonalcoholic fatty liver disease:
an open-label, 24-month, observational pilot study. Clin Therap 2008;
30:11681176.

111 Ratziu V, Giral P, Jacqueminet S, et al., Group TLS. Rosiglitazone for NASH:


one year results of the randomized placebo-controlled fatty liver improvement
with rosiglitazone therapy (FLIRT) trial. Gastroenterology 2008; 135:100
110.
A 12-month RCT of rosiglitazone in NASH showing a significant effect on liver
transaminases, insulin resistance, and steatosis.

101 Tiikkainen M, Hakkinen A-M, Korsheninnikova E, et al. Effects of rosiglitazone

and metformin on liver fat content, hepatic insulin resistance, insulin clearance, and gene expression in adipose tissue in patients with type 2 diabetes.
Diabetes 2004; 53:21692176.

112 Ratziu V, Charlotte F, Bernhard C, et al. Long-term efficacy of rosiglitazone in

NASH: results of the extension phase of the FLIRT-2 trial. Hepatology 2008;
48:803A.

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