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