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Approach to the Pathogenesis and
Treatment of Nonalcoholic
type 2 diabetes and obesity is unknown. Itis estimated that 75% of type 2 diabeticpatients present some form of nonalco- Nonalcoholic steatohepatitis (NASH) represents an advanced stage of fatty liver disease devel- holic fatty liver of different degrees. An oped in the absence of alcohol abuse. Its increasing prevalence in western countries, the diag- nostic difficulties by noninvasive tests, and the possibility of progression to advanced fibrosis and emia, as well as with clinical features of even cirrhosis make NASH a challenge for hepatologists. NASH is frequently associated with type insulin resistance, has frequently been re- 2 diabetes and the metabolic syndrome, and several genetic and acquired factors are involved inits pathogenesis. Insulin resistance plays a central role in the development of a steatotic liver, ported (4 –9). As far as obesity is re- which becomes vulnerable to additional injuries. Several cyclic mechanisms leading to self- enhancement of insulin resistance and hepatic accumulation of fat have been recently identified.
Excess intracellular fatty acids, oxidant stress, tumor necrosis factor-␣, and mitochondrial dys- function are causes of hepatocellular injury, thereby leading to disease progression and to the lean patients in a consecutive study (10), establishment of NASH. Intestinal bacterial overgrowth also plays a role, by increasing produc- tion of endogenous ethanol and proinflammatory cytokines. Therapeutic strategies aimed at modulating insulin resistance, normalizing lipoprotein metabolism, and downregulating inflam- matory mediators with probiotics have promising potential.
steatosis in obese patients is ϳ60%,whereas 20 –25% present NASH and Diabetes Care 27:2057–2066, 2004
Nonalcoholicsteatohepatitis(NASH) the U.S., with a suggested incidence of fortheStudyofLiverDiseasessingletopic
probably similar figures in Europe and Ja- asymptomatic patients are referred to the inflammation. In its initial phases, during levels obtained during routine evaluation apy. Because clinical signs and liver test gressing to established cirrhosis in some such as obesity, type 2 diabetes, and hy- making a specific diagnosis, histological filtrate, glycogen nuclei, and Mallory’s hy- testinal surgery, rapid weight loss in the liver biopsy may be required, in particu- aline (1). Because its adequate diagnosis obese, total parenteral nutrition, treat- lar, to differentiate between simple steato- liver, the prevalence of NASH is probably obesity or type 2 diabetes, high (at least two times that of normal) levels of alanine disease has been suggested to be the most aminotransferase (ALT) and triglycerides, ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● transferase/ALT ratio greater than unitymay justify performing a biopsy, since From the 1Liver Unit, University Hospital La Princesa, Autonomous University, Madrid, Spain; and the2Digestive Diseases Service, University Hospital, Valladolid, Spain.
prognostic information is greater in these Address correspondence and reprint requests to Ricardo Moreno-Otero, Unidad de Hepatologı´a (planta 3), Hospital Universitario de la Princesa, Diego de Leo´n 62, E-28006 Madrid, Spain. E-mail: Received for publication 24 October 2003 and accepted in revised form 29 April 2004.
J.M. and L.I.F.-S. contributed equally to this work.
Abbreviations: ALT, alanine aminotransferase; FFA, free fatty acid; IKK␤, I␬〉 kinase ␤; IRS, insulin
receptor substrate; LPS, lipopolysaccharide; NASH, nonalcoholic steatohepatitis; NF, nuclear factor; PPAR, PATHOGENIC
peroxisome proliferator–activated receptor; TGF, transforming growth factor; TNF, tumor necrosis factor.
A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion to Day et al. (14,18), the pathogenesis of 2004 by the American Diabetes Association.
DIABETES CARE, VOLUME 27, NUMBER 8, AUGUST 2004 Nonalcoholic steatohepatitis
Figure 1—Mechanisms leading to liver steatosis. Insulin resistance, occurring in response to a variety of genetic and acquired factors, is intimatelyassociated with the development of a steatotic liver. At least two mechanisms contribute to exacerbation of insulin resistance by cyclic self-perpetuation: 1) chronic activation of IKK, which plays a key role not only in the production of and response to proinflammatory cytokines, suchas TNF-, but also in the development of insulin resistance; and 2) the decreased clearance of insulin that occurs in the presence of a steatotic liver,thus creating a hyperinsulinemic medium that in turn enhances insulin resistance. Serine phosphorylation (rather than tyrosine phosphorylation) ofIRS-1 (which leads to disruption of insulin signaling) represents a central step in the stimulation of insulin resistance by a variety of factors. apoB,apolipoprotein B; JNK, c-Jun NH -terminal kinase; MTTP, microsomal triglyceride transfer protein. mainly a consequence of peripheral resis- resistance (25). This is caused by IKK␤- tance to insulin, whereby the transport of fatty acids from adipose tissue to the liver serine rather than in tyrosine) of insulin receptor substrate (IRS)-1, thus disrupt- ing the intracellular signaling triggered by stress, the fatty liver is in most cases par- represent the hepatic expression (20).
binding of insulin to its receptor (25).
ticularly fragile and vulnerable to addi- The severity of insulin resistance has been tional insults, such as ethanol or bacterial shown to parallel the severity of fatty liver disease, with clinically overt type 2 diabe- first is increased hepatic oxidative stress.
elicited by oxidative stress and cytokines ␣) occurs. This leads to exacerbation of presence of diabetes has been suggested mal, and/or microsomal oxidation ofinsulin resistance, further oxidative to be useful for the identification of those factors (fat diets, lipopolysaccharide, eth- liver cells, resulting in an inflammatory severe liver fibrosis (16). These findings anol, and drugs) or genetic factors (␤- process, hepatocellular degeneration, and further support the notion that insulin re- particularly TNF-␣. This permits perpet- uation of the cycle, whereby TNF-␣ acti- vates IKK␤, which in turn induces TNF-␣ and inherited factors (22–24) (Fig. 1). A creased lipolysis and delivery of free fatty covery that chronic stimulation of I␬〉 several protein kinase C isoforms (1).
acids (FFAs) to the liver (Fig. 1). Insulin kinase ␤ (IKK␤), which promotes activa- resistance plays a primary role: it is the tion of nuclear factor (NF)-␬B (a tran- TNF-␣ in the development of insulin re- most specific finding in NASH, and it can scription factor involved in inflammatory DIABETES CARE, VOLUME 27, NUMBER 8, AUGUST 2004 Medina and Associates
sulin resistance in response to obesity in- show hypertriglyceridemia in both fasting duction (26). Notably, TNF-␣ expression tients. The apparent paradox of the corre- and postprandial situations, resulting in a in adipose tissue and liver is augmented in higher fat upload to the liver (29,42,43).
steatosis (in principle, leptin reduces fat These alterations in lipid metabolism also els correlate with insulin resistance (27).
sponsible for steatosis and oxidative stress to leptin actions or by a close relation be- in some liver diseases (28). Evidence ex- tween leptin levels and insulin resistance (4). In this respect, leptin inhibits insulin- patients is rich in unsaturated fat and cho- lesterol but poor in polyunsaturated fat, However, in a separate clinical study that tioned (TNF-␣, NF-␬B–mediated FFA ef- with that of healthy subjects. These levels fects), PPAR-␣–mediated inhibition by with a lower sensitivity to insulin, with these patients, and with other aspects of leptin/ml [n ϭ 26]; control group: 18 Ϯ 11 ng leptin/ml [n ϭ 20]; P ϭ 0.5) (38).
Furthermore, there was no correlation be- tance, the lipogenic effects of this hor- tween serum leptin and hepatic histology, serum transaminases, fasting insulin lev- resulting in the degradation of triglycer- els, or a measure of insulin resistance. Al- though these data suggest that leptin may does not progress, a minority of subjects into the blood flow (30). This situation is not be relevant in NASH, additional stud- similar to that observed in overweight pa- ies with larger cohorts of patients and an terindividual leptin levels and the absence indications that visceral and central adi- pose tissues play a more critical role than anism of cell death (45,46). Recent results obtained in a cohort of 264 prospectively and steatotic liver formation (4,19). The enrolled patients with nonalcoholic fatty liver disease indicate that insulin resis- the liver through the portal system for fat deleterious for the liver through a variety tance is a major, independent risk factor of mechanisms (1), including 1) de novo for advanced fibrosis, thus acting both as apoptosis; 2) resistance to insulin, by in- trophies— genetic diseases characterized terfering with intracellular phosphoryla- disease are not fully understood, although by absence of or insensitivity to leptin. In tion processes; and 3) lipid peroxidation.
these patients, adipose tissue is not devel- Under normal conditions, the liver is pre- vulnerable liver (Fig. 2). Furthermore, a the liver (thereby originating a secondary steatosis [32]), and peripheral resistance triglyceride formation, their oxidation, or to insulin occurs (22). Leptin is a hepato- clear peroxisome proliferator–activated Oxidative stress. Peripheral resistance
to insulin and high levels of leptin allow ulation. It precludes fat accumulation in role in these processes, by sensing excess nonadipose tissues by inhibiting lipogen- esis and potentiating lipolysis after exces- gram of their disposal (39). However, un- of the previously inhibited oxidation (14).
sive caloric intakes (33,34). Controversial following processes will take place: 1) the very-long-chain fatty acids is partly extra- expected increase in FFA sterification and triglyceride formation, but also 2) an in- crease in glycolysis and fatty acid synthe- sis, 3) an inhibition of oxidation (similarly particularly acyl-CoA, lead to PPAR-␣– tensity of liver steatosis in NASH, along (40), and 4) a reduced release of triglyc- mediated activation of the synthesis of en- with C-peptide (which reflects pancreatic insulin secretion) and age (36). However, mation of free oxygen radicals in a fat-rich DIABETES CARE, VOLUME 27, NUMBER 8, AUGUST 2004 Nonalcoholic steatohepatitis
growth (see below). TNF-␣ has several
modes of action: 1) it induces resistance to
insulin, thus producing increased levels
of FFAs; 2) it uncouples mitochondrial
respiration, thereby inducing oxygen rad-
ical formation, similarly to amiodarone
and perhexyline maleate (40); and 3) it
induces hepatocyte apoptosis and necro-
sis (62).
Genetic predisposition. NASH has
been suggested to have an inherited com-
ponent, involving genes related to 1) de-
termination of sensitivity to insulin
(22,63); 2) hepatic lipid storage, oxida-
tion, or release into the blood flow (64); 3)
obesity and its distribution (65,66); 4)
regulation of hepatic iron levels and oxi-
dative stress generation (67– 69); or 5) cy-
tokine synthesis (8,70,71).
Figure 2—Factors contributing to the development of NASH from a steatotic liver. Iron overload, Iron overload. Iron overload may play a
activation of CYP2E1, and induction of enzymes involved in FFA oxidation result in an increase in free oxygen radical production, which in turn induce lipidic peroxidation, leading to inhibition of mitochondrial respiration and NF-B–mediated TNF-synthesis. Bacterial endotoxin-stimulated TNF-synthesis also uncouples mitochondrial respiration. Both lipidic peroxidation and TNF-␣ liver disease (76) has been demonstrated.
are key triggering factors for NASH development. Iron catalyzes the transformation of hy-drogen peroxide into hydroxyl groups free oxygen radicals (49). The expression creased oxidative stress and lipidic per- tion uncoupling protein 2 is increased.
HFE gene and serum iron levels in the synthesis, but it also decreases ATP levels, thus making the cell more sensitive to in- prevalence of mutations in the HFE gene end products of oxidative stress activate sults (46,56,57) and facilitating hepato- along with elevated hepatic iron and more NF-␬B–mediated nitric oxide synthesis, c e l l u l a r a p o p t o s i s a n d n e c r o s i s .
leading to the formation of peroxynitrites tients (67,69), whereas others have failed (13). FFAs also increase the expression of to identify an excess of iron and its sup- tial of uncoupling protein 2 (59). Electron Fibrogenesis. Additional mechanisms
CYP2E1 is inhibited by insulin, its expres- sion levels are higher in case of peripheral crystaline inclusions in 10 –30% of hepa- tocellular mitochondria (6). Although the ingly, glucose and insulin potentiate its these inclusions are observed in patients synthesis. Hepatic stellate cell– derived since its promoter contains a binding site chondrial DNA alterations that affect re- for NF-␬B. Interaction of Fas ligand with Fas-expressing hepatocytes leads to their therefore represent a genetic basis deter- death through a process termed “fratri- TNF-. TNF-␣ also contributes to the
more advanced stages of fibrosis (36).
and Kupffer cells may be caused by 1) tive stress or directly by TNF-␣, it leads to alterations in electron transfer along the oxidative stress (61) or 2) endotoxemia resulting from intestinal bacterial over- DIABETES CARE, VOLUME 27, NUMBER 8, AUGUST 2004 Medina and Associates
considered to be involved in the etiology A clear link between intestinal bacterial 1. Correction of obesity with hypocaloric diets and physical exercise (94 –97).
NASH has recently been established (81).
sions is not always precluded by measures Bacterial overgrowth has been detected in that target the etiological factors of NASH, NASH patients with breath tests with lac- tulose and D-xilose (82), as well as in some ternative treatments directed against spe- associated with obesity-related intestinal clinical trials with anti–TNF-␣ antibodies insulin, or oral antidiabetic agents. Si- protection of the liver from ethanol when intestinal bacterial overgrowth was inhib- Because bacterial overgrowth– derived li- hepatic exposure to bacterial lipopolysac- charide (LPS). Intestinal bacteria may in- (0.75–2 g/day for 3 months, followed by a crease hepatic oxidative stress by at least two mechanisms (81): 1) increased en- efficacious in reverting steatosis and, in dogenous ethanol production and 2) re- nism (86), with Kupffer cells (a cell type that plays a critical role in NASH) as the 4. Control of hyperlipemia with diet, or, main source of TNF-␣. Because TNF-␣ is a central mediator in the pathogenesis of has led to the proposal of probiotics as a mechanisms in this disorder (49). Further therapeutic strategy for this disorder. Pro- evidence that Kupffer cells are oversensi- ment of NASH at various levels: 1) tive in NASH, as well as in obesity, prob- ably because of leptin actions (87– 89).
such as TNF-␣; 2) alteration of the inflam- matory effects of pathogenic strains of in- cytokine signaling; 3) replacement of pathogenic strains of bacteria; and 4) im- obtained from leptin-deficient obese mice (ob/ob mice), regarded as a good experi- the liver to LPS and bacterial ethanol). Ev- fatty liver disease (103), as well as clinical strongly suggest that probiotics might be propose a protective role for low doses of uncontrolled clinical trial with NASH pa- alcohol, by reducing resistance to insulin and inhibiting TNF-␣ synthesis by mono- tion with choline is indicated to in-crease the synthesis of lecitin, THERAPEUTIC
6. In patients undergoing surgery to treat Several agents are included in this group, sit to help improve hepatic lesions.
therapeutic alternatives, as follows, are aimed at interfering with the risk factors DIABETES CARE, VOLUME 27, NUMBER 8, AUGUST 2004 Nonalcoholic steatohepatitis
formin statistically significantly improved mechanisms of action that justify its use that improve insulin sensitivity by bind- ing the PPAR-␥ class of nuclear transcrip- peptide levels (122). However, no signif- tion factors. Troglitazone led to a decrease patients (115), although no weight reduc- activity or fibrosis. Although larger stud- tion was observed. Nevertheless, troglita- have also shown some efficacy in improv-ing liver enzyme levels and histology Because iron deposits are associated with patients were treated with rosiglitazone, 4 mg twice daily for 48 weeks, reductions in 86 to 37 units/l) were already observed by lesions, delay their evolution, or even re- 24 weeks of treatment, along with the ex- plete normalization) in insulin sensitivity lestasis and alcoholic liver disease is based and an acceptable tolerance profile (117).
on its anti-steatotic, anti-inflammatory, anti-oxidant, and anti-fibrotic properties.
caused by improved insulin sensitivity or rhosis (123). However, some cases of dis- been tested in a pilot study with 18 non- graphic parameters of liver steatosis, in the absence of adverse effects (108).
␣-Tocoferol is effective in improving weeks resulted in normalization of ALT eliminating the dysfunctional loop, si- liver biochemistry and histological lesions levels in 72% of patients. Hepatic fat con- of NASH because of its actions as an anti- tent and size, as well as glucose and FFA sensitivity to insulin, were consistently TGF-␤, a cytokine involved in liver fibro- improved, as well as histological signs of factors such as excess intracellular fatty the treatment of alcoholic liver steatosis, tested as a therapy for NASH. In addition graphical signs (110). This drug restores bacterial overgrowth, and genetic predis- (119), metformin inhibits hepatic TNF-␣and several TNF-inducible responses, position. At present, therapeutic strate- which, as stated above, are likely to pro- therapeutic effects, along with the proven mote hepatic steatosis and necrosis.
efficacy in steatosis, may justify its indica- obese ob/ob leptin-deficient mice, met- formin reduced both hepatic steatosis and resistance, cytoprotective agents, antioxi- and antifibrogenic properties, with bene- ficial effects in alcoholic liver disease Acknowledgments — Financial support was
sulin sensitivity, and a decrease in liver obtained from a grant (C03/02) from the In- volume in 50% of patients (121). In a re- stituto de Salud Carlos III, Spain, SAF 2001- 1414 from Ministerio de Ciencia y Tecnologı´a, Spain (to R.M.O.), and a grant (02/3015) from Fondo de Investigaciones Sanitarias, Spain (to The authors are grateful to Brenda Ashley DIABETES CARE, VOLUME 27, NUMBER 8, AUGUST 2004 Medina and Associates
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