Nonalcoholic steatohepatitis: More than just being...
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Can J Gastroenterol Vol 16 No 5 May 2002 318 F atty liver (steatosis) is an excessive accumulation of lipids within hepatocytes, most commonly in the form of large droplets of triglyceride (macrovesicular fat). The oth- er form of fat accumulation, microvesicular steatosis with tiny fat droplets (such as fatty liver of pregnancy and Reyes syndrome), is quite rare and often rapidly fatal. In contrast, simple macrovesicular fatty liver was once considered quite benign and unimportant an incidental finding with an obscure pathogenesis. Long considered a rather innocuous entity associated with obesity and diabetes, this form of steatosis was thought to progress rarely to advanced liver disease, particularly when not associated with alcohol use (1-3). Over the past two decades, it has become apparent that some of these patients have (or develop) a wide spec- trum of lesions. Nonalcoholic fatty liver disease (NAFLD) is now recognized as a clinicopathological entity that extends beyond uncomplicated steatosis to steatohepatitis (fat plus inflammation, histologically resembling alcoholic hepatitis), steatonecrosis, advanced fibrosis, liver failure and, in some cases, hepatocellular carcinoma (2-7). In fact, nonalcoholic steatohepatitis (NASH) may frequently be a precursor of cryptogenic cirrhosis (8). NASH is probably the crucial stage in the progression of NAFLD to advanced liver disease. NASH is usually asymp- tomatic. Frequently, the only clues to its presence are smooth hepatomegaly and/or elevated transaminase levels (6,9). The alanine aminotransferase (ALT) level exceeds the aspartate aminotransferase (AST) level in most cases, unless cirrhosis has supervened. Ultrasonography may reveal only the bright appearance of the fatty liver. None of these findings is diagnostic. Of fundamental importance is the absence of excessive alcohol intake, which is best defined as more than 20 g/day for women or more than 30 g/day for men, although this may be difficult to confirm in practice (6). Hepatitis C and other liver diseases also must be excluded. Liver biopsy is necessary to distinguish NASH from sim- ple steatosis, to detect fibrosis or cirrhosis, and to exclude other forms of liver disease. Ludwig et al (10) coined the term, NASH and pointed out its histological similarity to alcoholic hepatitis. The minimum diagnostic requirements are macrovesicular fat and lobular inflammation. Stricter criteria include evidence of hepatic degeneration and/or fibrosis (11,12). Hepatocellular injury manifests as balloon- ing degeneration (fluid accumulates and causes hepatocytes to swell) or, less commonly, as acidophilic degeneration (Mallorys hyaline bodies) (9,12). A stronger definition would facilitate epidemiological and clinical investigations. The true prevalence of NASH is unknown because the need for liver biopsy inherently creates a selection bias. NASH has been found in up to 11% of liver biopsy speci- mens and 6% of autopsies (10,13,14). It occurs more fre- quently in obese women who have type II diabetes or hypertriglyceridemia (6). Although it is often not recog- Nonalcoholic steatohepatitis: More than just being fat Eldon A Shaffer MD FRCP Purity is obscurity. Ogden Nash EDITORIAL Correspondence: Dr Eldon A Shaffer, Division of Gastroenterology, Health Science Centre, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1. Telephone 403-210-9363, fax 403-210-9340, e-mail [email protected]
Transcript of Nonalcoholic steatohepatitis: More than just being...
Can J Gastroenterol Vol 16 No 5 May 2002318
Fatty liver (steatosis) is an excessive accumulation oflipids within hepatocytes, most commonly in the form of
large droplets of triglyceride (macrovesicular fat). The oth-er form of fat accumulation, microvesicular steatosis withtiny fat droplets (such as fatty liver of pregnancy and Reye�ssyndrome), is quite rare and often rapidly fatal. In contrast,simple macrovesicular fatty liver was once considered quitebenign and unimportant � an incidental finding with anobscure pathogenesis. Long considered a rather innocuousentity associated with obesity and diabetes, this form ofsteatosis was thought to progress rarely to advanced liverdisease, particularly when not associated with alcohol use(1-3). Over the past two decades, it has become apparentthat some of these patients have (or develop) a wide spec-trum of lesions. Nonalcoholic fatty liver disease (NAFLD)is now recognized as a clinicopathological entity thatextends beyond uncomplicated steatosis to steatohepatitis(fat plus inflammation, histologically resembling alcoholichepatitis), steatonecrosis, advanced fibrosis, liver failureand, in some cases, hepatocellular carcinoma (2-7). In fact,nonalcoholic steatohepatitis (NASH) may frequently be aprecursor of cryptogenic cirrhosis (8).
NASH is probably the crucial stage in the progression ofNAFLD to advanced liver disease. NASH is usually asymp-tomatic. Frequently, the only clues to its presence aresmooth hepatomegaly and/or elevated transaminase levels(6,9). The alanine aminotransferase (ALT) level exceeds
the aspartate aminotransferase (AST) level in most cases,unless cirrhosis has supervened. Ultrasonography mayreveal only the �bright� appearance of the fatty liver. Noneof these findings is diagnostic. Of fundamental importanceis the absence of excessive alcohol intake, which is bestdefined as more than 20 g/day for women or more than30 g/day for men, although this may be difficult to confirmin practice (6). Hepatitis C and other liver diseases alsomust be excluded.
Liver biopsy is necessary to distinguish NASH from sim-ple steatosis, to detect fibrosis or cirrhosis, and to excludeother forms of liver disease. Ludwig et al (10) coined theterm, �NASH� and pointed out its histological similarity toalcoholic hepatitis. The minimum diagnostic requirementsare macrovesicular fat and lobular inflammation. Strictercriteria include evidence of hepatic degeneration and/orfibrosis (11,12). Hepatocellular injury manifests as balloon-ing degeneration (fluid accumulates and causes hepatocytesto swell) or, less commonly, as acidophilic degeneration(Mallory�s hyaline bodies) (9,12). A stronger definitionwould facilitate epidemiological and clinical investigations.
The true prevalence of NASH is unknown because theneed for liver biopsy inherently creates a selection bias.NASH has been found in up to 11% of liver biopsy speci-mens and 6% of autopsies (10,13,14). It occurs more fre-quently in obese women who have type II diabetes orhypertriglyceridemia (6). Although it is often not recog-
Nonalcoholic steatohepatitis:More than just being fat
Eldon A Shaffer MD FRCP
Purity is obscurity.Ogden Nash
EDITORIAL
Correspondence: Dr Eldon A Shaffer, Division of Gastroenterology, Health Science Centre, University of Calgary, 3330 Hospital Drive NW,Calgary, Alberta T2N 4N1. Telephone 403-210-9363, fax 403-210-9340, e-mail [email protected]
shaffer.qxd 14/05/02 2:11 PM Page 318
nized as a serious problem in patients with type II diabetes,chronic liver disease rivals cardiovascular disease as a causeof excess mortality in this population (15).
Obesity remains the most consistent association. Mostpatients with NASH (60% to 95% in most series) are eitheroverweight (body mass index [BMI] higher than 25 kg/m2)or obese (BMI higher than 30 kg/m2). They tend to have acentral (truncal or abdominal) distribution of fat (6,16).Fatty liver is a very common finding in obese persons, afflict-ing as many as 60% to 94% of those who are morbidly obese(17-19). Obesity, with its propensity to NASH, is a harbin-ger of fibrosis (3,13,20,21). NASH can also occur in non-obese men with normal blood glucose and lipid levels, butsuch persons seem to have milder histological findings anda better prognosis (22). Other risk factors for the progres-sion of liver disease in obese subjects include advanced age,diabetes mellitus, AST level higher than the ALT level,and histological evidence of inflammation and fibrosis (20,23).
In this issue of the Journal, Zamin and colleagues (pages303-307) evaluated the frequency of NASH in 912 obesepersons referred to their outpatient clinic in Brazil. Sixty-eight had elevated aminotransferase levels. To define theapparent effects of obesity alone, they excluded those withalcohol use, diabetes mellitus or markers of viral hepatitis.Liver biopsy in 29 of the 33 remaining patients (ie, 3% ofthe total) revealed NASH of a relatively mild degree; fourhad steatosis. This frequency is less than the 18.5% ofmarkedly obese individuals reported to have steatohepatitisin a Canadian autopsy series (13). The difference may reflectthe problems inherent in autopsy studies. In addition, theBrazilian team excluded 12 diabetic patients and includedonly subjects with aminotransferase alterations.
NASH also occurs in children (24). The increasingprevalence of obesity in this population is alarming. Over20% of adolescents are overweight (above the 85th per-centile of BMI), and 8% to 17% are obese (above the 95thpercentile of BMI) (25). The prognosis for NASH in chil-dren is unknown, but the long course of disease may even-tually culminate in fibrosis and cirrhosis. There is aworldwide epidemic of obesity, in both developed anddeveloping countries (26,27). In the United States, forexample, 59.4% of men and 50.7% of women are over-weight, as defined by a BMI higher than 25kg/m2 (28). Thislevel of adiposity is often associated with insulin resistance(29). Generally, as the frequency of obesity increases inadults, so will the prevalence of NAFLD. The risk ofNASH also extends to lean men and women, even if theydo not have diabetes or hyperlipidemia (7,22).
Insulin resistance is the unifying theme for all of theserisk factors, and can lead to NASH, independent of thepresence of diabetes mellitus or obesity (30,31). It occursbefore the development of cirrhosis, which itself can causehyperinsulinemia (32,33). NASH may be part of the so-called metabolic syndrome or syndrome X, which includesimpaired glucose tolerance, hyperlipidemia and hyperten-sion (33). Because of the central role of insulin resistance inthis cluster, the disorder is also known as the insulin resist-
ance syndrome. The visceral obesity in some apparentlylean men would explain their developing NASH, in associ-ation with the metabolic syndrome. The splanchnic fatmight supply the excess triglycerides that are then stored inthe steatotic liver. In patients with simple steatosis, theaccumulation of triglycerides in hepatocytes generallyreflects an imbalance between hepatic triglyceride synthesis(or input) and secretion (output). This result is simplesteatosis. Only a minority of persons with simple steatosisdevelop steatohepatitis and fibrosis (2,5).
A second event or �hit� is necessary to produce inflam-mation and liver damage (34). A most attractive explana-tion for such injury invokes abnormal lipid peroxidationand oxidative stress (9,35). In this model, an increased gen-eration of reactive oxygen metabolites and carbon-centredfree radicals initiates the peroxidation of fatty acid sidechains in cell membranes and thus produces cell damage.As with alcohol-related liver disease, there is heightenedexpression of hepatic cytochrome P450 2E1 (CYP2E1).The end products of lipid peroxidation (eg, aldehyde prod-ucts) are capable of activating hepatic stellate cells (whichproduce collagen), causing hepatocyte degeneration (andcan form Mallory bodies) and upregulating proinflammato-ry cytokines and adhesion molecules. These effects lead toinflammation, cell injury and fibrosis � ie, NASH and itssequelae. Besides CYP2E1 induction, the high levels of fat-ty acids within the liver might provide another source ofoxidative stress through peroxisomal beta-oxidation, pro-ducing hydrogen peroxide. Hydrogen peroxide, in the pres-ence of free iron, is converted to highly reactive hydroxylradicals (9,34,36). Iron overload has been associated withboth steatosis and hepatic fibrosis. Once again, the com-mon denominator appears to be insulin resistance. Theimportance of liver iron to the pathogenesis of steatohep-atitis, however, has not been conclusively established.
Another candidate for this �second hit� is bacterial endo-toxin, because it induces the production of pro-inflammato-ry cytokines, such as tumour necrosis factor-alpha (TNF-α)(37). This concept evolved from efforts to explain thepropensity of obese patients undergoing jejunoileal bypasssurgery to develop NASH; the liver injury was mitigated bymetronidazole therapy. Such surgery promotes portal bac-teremia, while obesity apparently increases the sensitivity ofthe liver to endotoxin-induced damage. Indeed, some casesof NASH have bacterial overgrowth and increased serumTNF-α levels, even though the infected bypassed loop ofthe small intestine is not �leaky� and endotoxemia is notevident (38).
The story is approaching a full circle. TNF-α can induceinsulin resistance, through modulation of the tyrosinekinase activity of the insulin receptor, and is involved iniron regulation. Furthermore, because TNF-α is overex-pressed in adipose tissue, increased serum levels are foundwith obesity. Two polymorphisms in the TNF-α gene pro-moter, one at 308 (termed the TNF2 allele) and the otherat 238 (the TNFA allele), are associated with increasedexpression of this cytokine. The 238 TNF-α polymorphism
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is more prevalent in persons with NAFLD, perhaps repre-senting a genetic predisposition (39).
The trigger that sets off the liver injury in NASH is notknown with certainty. There are, however, therapeuticimplications to the presence of the common factors of obe-sity and insulin resistance (29). Even though weight lossseems to be an obvious benefit, there is little evidence thatit improves liver histology, and weight reduction is notori-ously difficult to maintain (40). Furthermore, any acuteweight reduction acts to lower hepatic levels of the endoge-nous antioxidant, glutathione, and is known to worsen theliver disease (35).
Several pharmacological interventions have been tried.Pilot studies with ursodeoxycholic acid have shown enoughpromise to warrant a well-designed, multicentred study, cur-rently underway. Ingestion of therapeutic dosages of antiox-idants such as vitamin E deserves further study (41), butsuch an approach merely addresses the effect rather thanthe cause. Lipid-lowering drugs are not consistently effec-tive for NASH, perhaps because they do not reverse insulinresistance (40). Aggressive control of diabetes with insulinor sulfonylureas, which actually aggravates the hyperin-sulinism, also has failed. More promising is the use of met-formin, which directly tackles the problem of insulinresistance and defective glucose production in type II dia-
betics, by blocking unnecessary hepatic gluconeogenesis.An alternative approach uses pharmacological ligands toactivate the peroxisomal proliferator-activated receptorgamma and thus enhance the sensitivity of peripheral tis-sues to insulin. In a preliminary study, one of this new classof drugs for treating type II diabetes, the thiazolidinediones,was found to decrease ALT levels but to produce only mildhistological improvement in NASH (42). Ironically, per-haps, the first generation of available thiazolidinedionescan cause mitochondrial liver damage. Dealing with such arelatively new and evolving entity as NASH obviouslyrequires well-designed clinical trials.
Despite our society�s obsession with the maintenance ofa low body weight, there is a galloping epidemic of obesity.With it comes NASH. NASH represents the critical stagein the spectrum of nonalcoholic fatty liver diseases. Theoverwhelming majority of individuals with simple steatosisdo not develop progressive liver disease. Rather, only a sub-set of patients with NASH is at risk for cirrhosis (2,4).NASH is thus a disease of emerging importance because ofits recently established high and increasing prevalence, aswell as the risk of progression to cirrhosis. The entity is nolonger unappreciated or obscure. Furthermore, NASH isnot truly �pure�, even though a common theme is obesity,diabetes and insulin resistance.
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