Non-alcoholic fatty liver disease

Journal of Gastroenterology and Hepatology (2002) 17 (Suppl.) S186 S190 QUADRENNIAL REVIEW Non-alcoholic fatty liver disease PAUL ANGULO AND KEITH D LINDOR Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, Minnesota, United States of America Abstract Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that affects a high proportion of the world s population. Insulin resistance and oxidative stress play a critical role in the pathogenesis of NAFLD. Clinical, biochemical and imaging studies are of value in the diagnostic evaluation of patients with NAFLD, but liver biopsy remains the most sensitive and specific means of providing important diagnostic and prognostic information. Simple steatosis has the best prognosis within the spectrum of NAFLD, but NAFLD has the potential to progress to steatohepatitis, fibrosis and even cirrhosis. No effective medical therapy is currently available for all patients with NAFLD. In patients with diabetes mellitus and hyperlipidemia, appropriate metabolic control is always recommended, but rarely effective in resolving the liver disease. Weight reduction, when achieved and sustained, may improve the liver disease, although the results with weight loss have been inconsistent. Pharmacological therapy aimed at the underlying liver disease holds promise. Several medications with different mechanisms of action and potential benefit are currently being evaluated in clinical trials. Liver transplantation is a lifeextending therapeutic alternative for patients with end-stage NAFLD, but NAFLD may recur after liver transplantation. 2002 Blackwell Science Asia Pty Ltd INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) is an increasingly recognized clinicopathological condition that may progress to end-stage liver disease. The pathological picture resembles alcohol-induced liver injury, but occurs in patients who deny alcohol abuse. Nonalcoholic fatty liver disease comprises a wide spectrum of liver damage ranging from simple, uncomplicated steatosis to steatohepatitis to advanced fibrosis and cirrhosis. Non-alcoholic steatohepatitis (NASH) represents a stage within the spectrum of NAFLD and it is defined histologically by the presence of steatosis along with necroinflammatory activity mostly of lobular distribution regardless of the presence of fibrosis or Mallory s hyaline. 1,2 Non-alcoholic fatty liver disease must be differentiated from the steatosis with or without hepatitis resulting from secondary causes such as drugs, hepatotoxins, gastrointestinal surgery and some metabolic/genetic conditions. The diagnosis of NAFLD also requires the exclusion of other liver diseases that may present with steatosis such as viral, autoimmune and metabolic/hereditary liver disease along with a thorough effort to exclude alcohol abuse.the clinical implications of NAFLD are derived mostly from its common occurence in the general population as well as its potential to progress to cirrhosis and liver failure. EPIDEMIOLOGIC FEATURES Obesity, type 2 (non-insulin dependent) diabetes mellitus and hyperlipidemia, alone or in combination, are comorbid conditions frequently associated with NAFLD. 3 There is a direct correlation between the degree of obesity and prevalence and severity of NAFLD. The prevalence of NAFLD increases by 4.6- fold in obese people. 4 With any degree of obesity, type 2 diabetes mellitus significantly increases the prevalence and severity of NAFLD. 5,6 Truncal obesity seems to be an important risk factor for NASH even in subjects with Correspondence: Dr KD Lindor, Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN, USA. Email: lindor.keith@mayo.edn

Non-alcoholic fatty liver disease S187 normal body mass index. 7 NAFLD may affect any age group and has been described in most racial groups. Most series characterize a NAFLD patient as a middleaged woman; but others have shown a significantly greater prevalence of NAFLD in males than females. 8 10 Furthermore, many patients who lack these associated risk factors are increasingly diagnosed with this condition: 29% of our 144 patients with liver biopsy-proven NASH were non-obese and non-diabetic and also had normal lipid profiles. 11 In a recent population-based study among patients who were found with fatty liver on an ultrasound survey, 16.4% had none of these comorbid conditions. 4 PREVALENCE NAFLD affects 10 24% of the general population from different countries. The prevalence of NAFLD, however, increases significantly to 57.5 74% 4,9 in obese individuals. NAFLD affects 2.6% of children 10 and this figure increases to 22.5 52.8% 12 in the obese child population. NAFLD is the cause of asymptomatic elevation of aminotransferases in 42 90% 14 of cases once other causes of liver disease are excluded and represents a common explanation for abnormal liver tests in blood donors. 15 In the USA, it has been estimated that steatosis affects over two-thirds of the obese population, whereas NASH is found in 19% of these obese individuals. 5,6 Similarly, about one-third of the USA population who suffer from type 2 diabetes mellitus have NAFLD. These figures, however, clearly underestimate the real prevalence of NAFLD, since many patients with this liver condition are non-obese and non-diabetic, and the disease is increasingly diagnosed in children and adolescents. Furthermore, it is possible that the prevalence of NASH in the USA and other developed countries has increased over the past 10 15 years paralleling the marked increment of obesity and diabetes that has occurred among all age groups. CLINICAL FEATURES Most patients with NAFLD have no symptoms or signs of liver disease at the time of diagnosis. A high proportion of patients with cryptogenic cirrhosis share many of the clinical and demographic features of patients with NAFLD. 16 Thus, it is possible that unrecognized NAFLD has led to cirrhosis in a substantial proportion of patients that have been diagnosed with cirrhosis of obscure cause. Mild to moderate elevation of serum aminotransferases (ALT, AST) is the most common and often the only laboratory abnormality found in patients with NAFLD. The AST/ALT ratio is useful in differentiating NAFLD from alcoholic liver disease. 17 Most patients with NAFLD have an AST/ALT ratio of less than one, although the AST/ALT ratio increases as the liver disease progresses to cirrhosis, losing its diagnostic accuracy in the cirrhotic stage of NAFLD. 11 Hypoalbimunemia, elevated serum bilirubin and prolonged prothrombin time suggest advanced disease. Half of all patients with NASH have elevated serum ferritin levels whereas increased transferrin saturation is found in 6 11% of patients. Hepatic iron index and hepatic iron concentration, however, are usually in the normal range. The cross sectional imaging studies, ultrasonography and computed tomography, are useful in the diagnosis of fatty liver. Magnetic resonance imaging is useful for differentiating focal fatty infiltration or focal sparing from liver metastasis. LIVER HISTOLOGY Non-alcoholic fatty liver disease is histologically indistinguishable from the liver damage resulting from alcohol abuse. Liver biopsy features include steatosis, mixed inflammatory cell infiltration, hepatocyte ballooning and necrosis, glycogen nuclei, Mallory s hyaline and fibrosis. The presence of these histologic features, alone or in combination leads to a wide spectrum of non-alcoholic fatty liver disease. Steatosis, predominantly as large droplets or macrovesicular fat, as well as necroinfammatory injury, Mallory s hyaline and fibrosis are typically concentrated in acinar zone 3. The presence of fibrosis is a concerning histologic finding because it suggests a more advanced and severe liver injury. Fibrosis was found in 67% of patients with NAFLD at the time of diagnosis. 1,11,18 25 The pattern of fibrosis in NAFLD is a characteristic feature. Collagen is first laid down in the pericellular space around the central vein, and in the perisinusoidal region. Progressive injury in NAFLD results in portal fibrosis, central-portal and portal-portal septum formation and eventually cirrhosis. Severe hepatic fibrosis (septal/cirrhosis) is found in 25% 11,19 23,25 of patients at the time of diagnosis, whereas well-established cirrhosis is found in 14% of patients. 1,11,18 26 In patients with cirrhosis, the features of steatosis and necroinflammatory activity may no longer be present. There is not consensus on what are the minimal histologic features required for the diagnosis of NASH. However, the combination of steatosis, mixed mononuclear and/or polymorphonuclear cell infiltration, and hepatocyte ballooning and spotty necrosis are the most common lesions required for the histologic diagnosis of NASH. Most patients with NASH will show some degree of fibrosis, whereas Mallory s hyaline may or may not be present. PATHOGENESIS A net retention of lipids within hepatocytes, mostly in the form of triglycerides, is a prerequisite for the development of NASH. The primary metabolic abnormality leading to lipid accumulation (steatosis), however, is not well understood, but it could potentially result from insulin resistance and alterations in the uptake, synthesis, degradation or secretory pathways of hepatic lipid metabolism. Insulin resistance represents the most reproducible factor for the development of NAFLD. 27 29 The steatotic liver may then be vulnerable to further injury when challenged by additional insults. This has

S188 P Angulo and KD Lindor led investigators to presume that progression from simple, uncomplicated steatosis to steatohepatitis to advanced fibrosis results from two operating hits, 30 the first (mainly insulin resistance) leading to accumulation of fat within hepatocytes, and the second (mostly reactive oxygen species) leading to lipid peroxidation, cytokine production and Fas ligand induction. 31 Oxidative stress and lipid peroxidation are key factors in the development and progression from steatosis to more advanced stages of liver damage. Thus, the use of medications that improve insulin sensitivity and increase antioxidant chemical species may be of potential benefit in the treatment of patients with NASH. DIAGNOSIS The diagnosis of NAFLD is usually suspected in individuals found with asymptomatic elevation of aminotransferases, radiological findings of fatty liver or unexplained persistent hepatomegaly. The diagnosis of NASH implies a thorough effort to exclude alcohol abuse as the cause of liver disease. However, no clinical or biochemical abnormalities permit an accurate diagnosis of NAFLD. Although the AST/ALT ratio helps in differentiating alcoholic from non-alcoholic fatty liver disease, the clinical diagnosis and values of liver tests have a poor predictive value for making the diagnosis 32,33 and for differentiating simple steatosis from NASH. Imaging studies, although useful in determining the presence and amount of fatty infiltration of the liver, cannot be used to determine accurately the severity of liver damage. Hence, once other liver diseases have been excluded, the clinical suspicion of NAFLD can only be confirmed with a liver biopsy. It has been estimated in the general population that a daily dose of alcohol as low as 20 g in females and 30 g in males may be hepatotoxic. Thus, it may be reasonable to exclude alcohol abuse as the cause of the liver disease in patients who deny ingestion of these or greater doses of alcohol. ROLE OF LIVER BIOPSY Examination of a liver biopsy by an experienced pathologist is an essential diagnostic complement. However, given the lack of effective medical treatment for patients with NAFLD, there has been a reasonable hesitation to perform liver biopsy with the simple purpose of confirming the diagnosis. Nevertheless, liver biopsy remains not only the best diagnostic tool for confirming NAFLD, but also the most sensitive and specific means of providing important prognostic information. Some histologic features have been recognized as useful in determining the risk of progression to more advanced liver disease. The presence of cirrhosis on liver biopsy would dictate the need for periodic endoscopic surveillance for gastroesophageal varices, and possibly screening for liver cancer. Furthermore, liver biopsy is the best specific means of determining the effect of medical treatment given the uncertain correlation between improvement of liver tests or imaging studies with histologic damage. In patients with NAFLD, age older than 45 years, presence of obesity or type 2 diabetes mellitus and an AST/ALT ratio greater than one are noteworthy indicators of advanced liver fibrosis. 11 In the subgroup of patients with NASH who are overweight or obese; older age, higher BMI, and higher levels of ALT and triglycerides are also indicators of more advanced liver fibrosis. 25 These factors can help to identify the NASH patient expected to derive the most benefit from liver biopsy and enrollment into therapeutic trials. PROGNOSIS Prognosis in NAFLD is being defined, but it seems to be greatly determined by the severity of liver damage found on liver biopsy. Fifty-four out of 257 patients with non-alcoholic fatty liver reported in five different series 20 23,25 had subsequent liver biopsies performed during an average follow-up of 3.5 11 years. Of these patients, 28% had progression of liver damage; 59% remained essentially unchanged; whereas 13% showed resolution or improvement of liver injury. Progression from steatosis to steatohepatitis 8,34 to more advanced fibrosis 20,21,23,25 or cirrhosis 20 22,25 has been recognized in several cases. A total of 26 deaths occured during follow-up, two of them were liver-related including one patient who developed hepatocellular cancer. Thus, it is clear that some patients with non-alcoholic fatty liver follow a relatively benign course whereas, in some others, the disease progresses to cirrhosis and its complications. Patients with pure steatosis on liver biopsy seem to have the best prognosis within the spectrum of NAFLD, 23 whereas features of steatohepatitis or more advanced fibrosis are associated with a worse prognosis. 21,25,26 In one study, 25 progression of liver fibrosis occured only in patients with necroinflammation on liver biopsy. In another study, 26 liver-related deaths in patients with NAFLD were the second most common cause of death after a mean follow-up of 8.3 years and exceeded only by cancer-related deaths. There was a trend for more liver-related deaths among patients with NASH than in those without NASH; although this difference can also be explained by the significantly greater proportion of patients with cirrhosis among those with NASH. 26 MANAGEMENT OF ASSOCIATED CONDITIONS Treatment of patients with NAFLD has typically been focused on the management of associated conditions as well as discontinuation of potentially hepatotoxic drugs known to produce NAFLD. In patients with diabetes mellitus or hyperlipidemia, good metabolic control is always recommended, but rarely effective in reversing NAFLD. Improvement in serum levels of aminotransferases is almost universal in obese adults 9,34 37 and children 11,38,39 after weight reduction. The degree of

Non-alcoholic fatty liver disease S189 fatty infiltration usually improves with weight loss in most patients, although the degree of necroinflammation and fibrosis may worsen. 8,34,36,37,39,40 Hence, the improvement or normalization of serum aminotransferase levels and degree of fatty infiltration on imaging studies are poor indicators of worsening of liver damage that may occur during uncontrolled weight loss. Monitoring liver injury during treatment with weight reduction cannot be fully accomplished without careful analysis of the effects on liver histology. PHARMACOLOGIC THERAPY Because rapid weight loss may worsen NASH, use of medications that can directly reduce or reverse liver damage independent of weight loss is a reasonable alternative. Pharmacologic therapy may be of particular benefit for patients who do not lose weight or cannot maintain long-term weight reduction, as usually happens in most obese patients as well as for patients who lack risk factors or associated conditions such as those who are non-obese and non-diabetic. Pharmacological therapy directed specifically at the liver disease has only recently been evaluated in patients with NAFLD. 41 Encouraging results have been reported with pilot studies evaluating gemfibrozil, ursodeoxycholic acid, betaine, N-acetylcysteine, vitamin E (alphatocopherol) and insulin-sensitizer drugs (thiazolidinedione, metformin). These medications however, must be evaluated in carefully controlled clinical trials that must have enough power, extended follow up and include clinically relevant end points. 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