Evaluation and management of non-alcoholic steatohepatitis

Abstract

1. IntroductionNon-alcoholic fatty liver disease (NAFLD) represents a spectrum of liver diseases characterized mainly by macrovesicular steatosis (Fig. 1) that occurs in the absence of alcohol consumption in amounts considered injurious to the liver. The hepatic histology can vary from isolated hepatic steatosis alone to steatohepatitis and are referred to as non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) respectively. In addition to predominantly macrovesicular steatosis, the diagnosis of steatohepatitis also requires the additional presence of varying combinations of findings including cytologic ballooning, Mallory's hyaline, scattered inflammation and pericellular fibrosis (Fig. 1) [[1]Contos M.J. Sanyal A.J. The clinicopathologic spectrum and management of nonalcoholic fatty liver disease.Adv Anat Pathol. 2002; 9: 37-51Crossref PubMed Scopus (63) Google Scholar]. These findings are indistinguishable from alcoholic liver disease and the distinction must be made clinically.A large body of literature clearly indicates that NAFLD is strongly associated with the metabolic syndrome. Early studies identified obesity and diabetes as the two major risk factors for the development of NAFLD [[2]Clark J.M. Brancati F.L. Diehl A.M. The prevalence and etiology of elevated aminotransferase levels in the United States.Am J Gastroenterol. 2003; 98: 960-967Crossref PubMed Scopus (1076) Google Scholar]. It is now known that hypertriglyceridemia and hypertension are also frequently present in subjects with NAFLD. The metabolic syndrome is characterized by a constellation of findings including obesity, diabetes, hypertension and hypertriglyceridemia, the principal risk factors for NAFLD (Table 1) [[3]Third Report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III) final report. Circulation 2002;106:3143–3421.Google Scholar]. The fundamental pathophysiologic process that connects these diverse conditions is insulin resistance [[4]Sanyal A.J. Campbell-Sargent C. Mirshahi F. Rizzo W.B. Contos M.J. Sterling R.K. et al.Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities.Gastroenterology. 2001; 120: 1183-1192Abstract Full Text Full Text PDF PubMed Scopus (1714) Google Scholar]. Insulin resistance is present in approximately 98% of individuals with NAFLD and over 80% of subjects with NAFLD meet minimal criteria for the metabolic syndrome [[5]Chitturi S. Farrell G.C. Etiopathogenesis of nonalcoholic steatohepatitis.Semin Liver Dis. 2001; 21: 27-41Crossref PubMed Scopus (592) Google Scholar]. Approximately 47 million individuals are estimated to have the metabolic syndrome in the US [[6]Ford E.S. Giles W.H. Dietz W.H. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey.JAMA. 2002; 287: 356-359Crossref PubMed Scopus (5712) Google Scholar]. Also, over 50% of the US population is overweight (body mass index (BMI) >25<29) or obese (BMI >29) [[7]Flegal K.M. Carroll M.D. Ogden C.L. Johnson C.L. Prevalence and trends in obesity among US adults, 1999–2000.JAMA. 2002; 288: 1723-1727Crossref PubMed Scopus (5333) Google Scholar]. There are thus millions of individuals at risk for development of NAFLD and approximately 12–15% of the population is estimated to have NAFL while 3–4% has NASH [[8]Haque M. Sanyal A.J. The metabolic abnormalities associated with non-alcoholic fatty liver disease.Best Pract Res Clin Gastroenterol. 2002; 16: 709-731Abstract Full Text PDF PubMed Scopus (120) Google Scholar].Table 1Diagnostic criteria for the metabolic syndrome: presence of 2 or more of the followingAbdominal obesity (waits circumference >102 cm for men and 88 cm for women)Triglycerides >250 mg/dlHDL <40 mg/dl for men or <50 mg/dl for womenBP ≥130/85Fasting blood glucose ≥110 mg/dlBased on adult treatment panel (ATP) III criteria [3]Third Report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III) final report. Circulation 2002;106:3143–3421.Google Scholar. Open table in a new tab 2. Is it necessary to make a precise diagnosis of non-alcoholic fatty liver disease (NAFLD)The precise diagnosis of NAFLD and the distinction between hepatic steatosis and steatohepatitis requires a liver biopsy. Given the large number of afflicted subjects, the invasive nature of a liver biopsy and the lack of effective treatment, there is often a reluctance to pursue this diagnosis with vigour and many patients are left with a diagnosis of suspected NAFLD. The need to perform a biopsy and make these distinctions continue to generate controversy.There are three basic principles that determine the need and the aggressiveness with which one should try to evaluate any medical problem. First, one must consider the differential diagnosis and the potential possibilities that exist. Next, one must know the natural history of these conditions and consider which diagnoses, if missed, will have dire consequences for the individual patient. The answer to this question is linked to the critical final question: even if the diagnosis is made, is effective treatment available?Most subjects with NAFLD come to clinical attention due to the identification of elevated serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and/or alkaline phosphatase elevation (Alk Phos). One of the common diagnostic possibilities of viral hepatitis, hemochromatosis and autoimmune hepatitis are excluded, many patients are given the label of NAFLD. However, in studies of subjects with persistently elevated ALT values without an obvious explanation, NAFLD was found in only 70–80% of cases and 20–30% of subjects were found to have an alternate cause for their elevated liver enzymes [9Skelly M.M. James P.D. Ryder S.D. Findings on liver biopsy to investigate abnormal liver function tests in the absence of diagnostic serology.J Hepatol. 2001; 35: 195-199Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar, 10Mathiesen U.L. Franzen L.E. Fryden A. Foberg U. Bodemar G. The clinical significance of slightly to moderately increased liver transaminase values in asymptomatic patients.Scand J Gastroenterol. 1999; 34: 85-91Crossref PubMed Scopus (119) Google Scholar]. Of note, 5.9% of subjects had a normal liver despite a complete evaluation (Table 2).Table 2Final diagnosis of subjects with persistently abnormal LFTs after liver biopsy performedFinal diagnosisN (%), Total n=354Non-alcoholic steatohepatitis120 (34)Non-alcoholic fatty liver115 (32)Cryptogenic hepatitis32 (9)Drug-related liver disease27 (7.6)Normal liver21 (5.9)Alcoholic liver disease10 (2.8)Autoimmune hepatitis7 (1.9)Miscellaneous22 (6.3)Based on data from [9]Skelly M.M. James P.D. Ryder S.D. Findings on liver biopsy to investigate abnormal liver function tests in the absence of diagnostic serology.J Hepatol. 2001; 35: 195-199Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar. Open table in a new tab Given the generally excellent liver-related prognosis of isolated hepatic steatosis, this condition is often considered to be a medical curiosity and ignored as a clinically significant condition. It is however now clear that hepatic steatosis and insulin resistance have a ‘chicken and egg’ type relationship where each begets the other [[11]Choudhury J. Sanyal A.J. Insulin resistance and the pathogenesis of nonalcoholic fatty liver disease.Clin Liver Dis. 2004; 8: 575-594Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar]. Insulin resistance has been directly linked to the development of diabetes, hypertension and atherosclerosis which can all produce considerable morbidity and limit ones life [[12]De Fronzo R.A. Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease.Diab Care. 1991; 14: 173-194Crossref PubMed Scopus (4134) Google Scholar]. Thus, the general perception that NAFL is not a clinically significant entity is incorrect.Finally, the availability of effective therapy and its toxicity is an important consideration while deciding the aggressiveness with which to pursue a diagnosis of NAFLD. The lack of an established pharmacologic treatment for NAFLD has considerably reduced the enthusiasm for making a precise histologic diagnosis of NAFLD. Once effective therapy becomes available, if the treatment is highly effective and safe, one management option would be to provide that treatment to everyone with suspected NAFLD. On the other hand, if the treatment only worked for specific subsets of patients defined histologically or had toxicity associated with it, it will become imperative to establish the diagnosis with certainty before recommending such treatment.While the jury is still out on whether it is imperative to establish of NAFLD and distinguish between NAFL and NASH, the practicing clinician should take these factors into consideration and discuss the diagnostic possibilities, the potential consequences of both pursuing the diagnosis as well as missing an alternate diagnosis, and the potential management strategies with the patient. Based on the outcome of these discussions, a decision to either pursue diagnosis or make an empirical diagnosis can be made.3. EvaluationThere are three principal objectives of the evaluation of a subject with suspected NAFLD: (1) confirmation of the diagnosis, (2) evaluation of prognosis, and (3) evaluation of the status of other end-organs affected by the metabolic syndrome. These data are then integrated to develop a treatment plan that addresses both the underlying metabolic syndrome and the liver disease.3.1 Should high-risk populations be screened for the presence of NAFLD?The ideal conditions for screening for a disease include a high prevalence of the disease in the general population, the availability of screening tools with a high positive and negative predictive value and the availability of a specific, effective intervention. It is currently estimated that there are over 47 million individuals with the metabolic syndrome and that over 80% of such individuals have NAFLD [13Diehl A.M. Fatty liver, hypertension, and the metabolic syndrome.Gut. 2004; 53: 923-924Crossref PubMed Scopus (46) Google Scholar, 14Marchesini G. Bugianesi E. Forlani G. Cerrelli F. Lenzi M. Manini R. et al.Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome.Hepatology. 2003; 37: 917-923Crossref PubMed Scopus (2165) Google Scholar]. The prevalence of the condition in diabetes clinics is not as well characterized but is estimated to be about 25% [[15]Clark J.M. Diehl A.M. Hepatic steatosis and type 2 diabetes mellitus.Curr Diab Rep. 2002; 2: 210-215Crossref PubMed Scopus (94) Google Scholar]. While the prevalence of the condition is clearly quite high, the diagnostic accuracy of non-invasive diagnostic tools remains poor. Moreover, there is no established pharmacologic treatment of NAFLD yet. Thus, while it may be reasonable to look for and aggressively manage the metabolic syndrome, the data do not support the routine screening of asymptomatic individuals with the metabolic syndrome for NAFLD. However, if such patients have symptoms or signs of liver disease including abnormal ALT values, the treating physician should have a low threshold for starting an evaluation for NAFLD.3.2 Who to evaluate?The great majority (45–100%) of subjects with NAFLD are asymptomatic from a liver point of view [16Falck-Ytter Y. Younossi Z.M. Marchesini G. McCullough A.J. Clinical features and natural history of nonalcoholic steatosis syndromes.Semin Liver Dis. 2001; 21: 17-26Crossref PubMed Scopus (580) Google Scholar, 17Youssef W. McCullough A.J. Diabetes mellitus, obesity, and hepatic steatosis.Semin Gastrointest Dis. 2002; 13: 17-30PubMed Google Scholar]. Most such patients come to clinical attention when they are discovered to have abnormal ALT values. The three most common modes of presentation include the presence of an elevated ALT level when (a) performed for non-specific symptoms, (b) as part of a routine annual examination or (c) following the prescription of a cholesterol-lowering drug or another drug for which routine ALT monitoring is recommended. Approximately 7.9% of the US population has elevated ALT levels, of which 69% are not explained on the basis of viral hepatitis, iron overload or alcohol consumption [[2]Clark J.M. Brancati F.L. Diehl A.M. The prevalence and etiology of elevated aminotransferase levels in the United States.Am J Gastroenterol. 2003; 98: 960-967Crossref PubMed Scopus (1076) Google Scholar]. Such unexplained ALT elevation is strongly linked to features of the metabolic syndrome and are likely to represent underlying NAFLD. While many such individuals have obvious risk factors and meet minimal clinical criteria for the metabolic syndrome, some subjects may not be obese, diabetic or hypertensive [[18]Neuschwander-Tetri B.A. Bacon B.R. Nonalcoholic steatohepatitis.Med Clin North Am. 1996; 80: 1147-1166Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar]. Thus, the possibility of NAFLD should be considered in all instances of unexplained persistent ALT elevation. NAFLD may also be considered when an abdominal imaging study reveals findings suggestive of fatty liver disease.In other cases, the presence of NAFLD may come to light due to the presence of symptoms and signs of this condition. These are discussed below:3.2.1 Symptoms and signs of NAFLDThe most common symptoms that bring NAFLD patients to clinical attention include malaise, fatigue and right upper quadrant discomfort. The discomfort is often described as a non-descript vague discomfort rather than pain. Such symptoms often antedate the diagnosis of NAFLD in a third of patients [[18]Neuschwander-Tetri B.A. Bacon B.R. Nonalcoholic steatohepatitis.Med Clin North Am. 1996; 80: 1147-1166Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar] (Table 3).Table 3Common symptoms and signs of 400 subjects with NAFLD (Data from the NAFLD clinic at Virginia Commonwealth University, previously unpublished data)FeatureNAFL (n=75) (%)NASH (n=325) (%)Symptoms and signs Asymptomatic6055 Fatigue3045 Pruritus24 Right upper quadrant (RUQ) discomfort3032 Edema45 Hepatomegaly2228 Stigmata of chronic liver disease810 Obesity6560 Diabetes4550 Hypertension6065 Dyslipidemia6569Lab abnormalities (ULN)Mean±SDMean±SDAST (<75 IU/l)65±5576±66ALT (<75 IU/l)135±70148±78Alk Phos (<110 IU/l)132±21128±34Total bilirubin (<2 mg/dl)0.8±0.30.7±0.7Albumin (3.5–4.5 g/dl)3.8±0.43.7±1Prothrombin time (<11 s)10.9±0.611.1±0.6Proportion of cirrhotics016 Open table in a new tab Fatigue is often present in patients with NAFLD and is often the most debilitating aspect of the condition for the individual subject. Several clinical variations of the fatigue syndrome can be recognized (personal clinical observation). Most commonly, subjects complain of chronic malaise and a sensation of severe lethargy and sleepiness during the day. Upon direct questioning, many individuals with such complaints will admit to disturbed sleep patterns and waking up feeling tired. The spouse will often confirm that the patient snores and is very restless at night. It has been the experience of these authors that many of these subjects have underlying sleep-apnea syndrome and correction of this condition produces a dramatic improvement in energy levels. This type of fatigue does not correlate with the grade or stage of steatohepatitis.Other subjects wake up relatively rested but tire easily. This pattern is more often associated with those with more advanced disease. Some patients have mixed patterns of fatigue, which are often difficult to evaluate and manage. Approximately 25% of subjects with NAFLD also carry a diagnosis of chronic fatigue syndrome [[19]Haller D.L. Sargeant C. Luketic V.A. Sanyal A.J. A behavioral analysis of nonalcoholic fatty liver disease.Hepatology. 2003; 38: 233ACrossref Google Scholar]. Some patients complain of aching soreness in their muscles along with fatigue and about 20% of all subjects suffer from a chronic pain disorder. At our institution, 27% of subjects diagnosed with NAFLD were taking analgesics, including narcotics (7%), at the time of diagnosis [[19]Haller D.L. Sargeant C. Luketic V.A. Sanyal A.J. A behavioral analysis of nonalcoholic fatty liver disease.Hepatology. 2003; 38: 233ACrossref Google Scholar].Hepatomegaly is the most common physical finding in subjects with NAFLD [20Bacon B.R. Farahvash M.J. Janney C.G. Neuschwander-Tetri B.A. Nonalcoholic steatohepatitis: an expanded clinical entity.Gastroenterology. 1994; 107: 1103-1109Abstract PubMed Scopus (1019) Google Scholar, 21Ludwig J. Viggiano T.R. McGill D.B. Oh B.J. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease.Mayo Clin Proc. 1980; 55: 434-438PubMed Google Scholar]. A minority of subjects have stigmata of chronic liver disease such as spider angiomata or palmar erythema. Jaundice and features of portal hypertension, i.e. ascites, variceal hemorrhage etc. are seen in a small minority of subjects who present with advanced liver disease [[22]Powell E.E. Cooksley W.G. Hanson R. Searle J. Halliday J.W. Powell L.W. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years.Hepatology. 1990; 11: 74-80Crossref PubMed Scopus (1315) Google Scholar].3.2.2 Other conditions commonly present in patients with NAFLDThe association of NAFLD with obesity, diabetes, hypertension and hypertriglyceridemia are well known. We have recently performed a detailed inventory of associated symptoms and conditions in a cohort of 61 subjects with NAFLD [[19]Haller D.L. Sargeant C. Luketic V.A. Sanyal A.J. A behavioral analysis of nonalcoholic fatty liver disease.Hepatology. 2003; 38: 233ACrossref Google Scholar]. In addition to confirming the classic associations with NAFLD, it was found that 26% of subjects had various allergies and 25% suffered from chronic depression while 10% carried a diagnosis of an anxiety disorder and over 50% of subjects were taking a psychotropic drug at the time of diagnosis. Whether these symptoms are unrelated or somehow related to NAFLD remain to be evaluated. Also, the prevalence of NAFLD in the general population of subjects with chronic pain or fatigue is unknown. One should however be aware NAFLD may also be present in subjects with chronic fatigue, fibromyalgia and depression.In summary, in those with risk factors for NAFLD, the presence of right upper quadrant discomfort, hepatomegaly or elevated liver enzymes should trigger an evaluation for NAFLD. Other subjects with persistently elevated liver enzymes, e.g. alanine aminotransferase (ALT) who do not have viral hepatitis, hemochromatosis, or other common liver diseases such as Wilson's disease etc. should also be evaluated for NAFLD.3.3 How to evaluate?A complete evaluation of a patient with NAFLD includes confirmation of the diagnosis, assessment of the etiology and delineation of the grade and stage of the disease. The diagnosis of NAFLD requires two steps: (1) to establish the presence of fatty liver disease, and (2) to establish the ‘non-alcoholic’ nature of the condition. Also, several other forms of chronic liver disease are extremely prevalent in the general population, e.g. hepatitis C and can often co-exist with NAFLD [[23]Clouston A.D. Powell E.E. Interaction of non-alcoholic fatty liver disease with other liver diseases.Best Pract Res Clin Gastroenterol. 2002; 16: 767-781Abstract Full Text PDF PubMed Scopus (52) Google Scholar]. It is therefore imperative that the initial evaluation include appropriate laboratory studies to exclude other common causes of liver disease.The gold-standard for the diagnosis of fatty liver disease is a liver biopsy. However, given the invasive nature, costs and risks of a liver biopsy, there is considerable interest in trying to make the diagnosis using non-invasive methods.3.3.1 Non-invasive methods for the diagnosis of NAFLDMost subjects with NAFLD are evaluated because of identification of abnormal liver enzyme values. In others, a starting point for the assessment of NAFLD is the presence of unexplained hepatomegaly or incidental findings of fatty liver disease on abdominal imaging studies. The diagnostic evaluation typically begins with assessment of the liver enzymes. Typically, NAFLD is associated with AST and ALT values under 250 IU/l and/or modest elevation of alkaline phosphatase. An ALT or AST value >300 IU/l should raise suspicion of alternate pathology. The alkaline phosphatase is increased in up to half of affected subjects [20Bacon B.R. Farahvash M.J. Janney C.G. Neuschwander-Tetri B.A. Nonalcoholic steatohepatitis: an expanded clinical entity.Gastroenterology. 1994; 107: 1103-1109Abstract PubMed Scopus (1019) Google Scholar, 21Ludwig J. Viggiano T.R. McGill D.B. Oh B.J. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease.Mayo Clin Proc. 1980; 55: 434-438PubMed Google Scholar]. The degree of abnormality is usually moderate and does not exceed 2–3 times the upper limit of normal values [24Matteoni C.A. Younossi Z.M. Gramlich T. Boparai N. Liu Y.C. McCullough A.J. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity.Gastroenterology. 1999; 116: 1413-1419Abstract Full Text Full Text PDF PubMed Scopus (2749) Google Scholar, 25Angulo P. Keach J.C. Batts K.P. Lindor K.D. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis.Hepatology. 1999; 30: 1356-1362Crossref PubMed Scopus (1398) Google Scholar]. Unfortunately, none of these tests are sensitive or specific enough to establish a diagnosis of NAFLD with great accuracy. It is currently unknown if the diagnostic value of abnormal AST, ALT and alkaline phosphatase are improved if the concomitant presence of other features of the metabolic syndrome are taken into consideration. Until such data are available, additional tests will be required to establish the diagnosis of NAFLD.There is considerable interest in being able to establish the presence of NAFLD non-invasively with a variety of imaging studies. Two-dimensional sonography, computerized tomography (CT) and magnetic resonance imaging (MRI) are the most studied methods that are also available at most medical centers. The sonographic features of NAFLD include increased hepatic parenchymal echotexture and vascular blurring [26Sanyal A.J. AGA technical review on nonalcoholic fatty liver disease.Gastroenterology. 2002; 123: 1705-1725Abstract Full Text Full Text PDF PubMed Scopus (899) Google Scholar, 27Yajima Y. Ohta K. Narui T. Abe R. Suzuki H. Ohtsuki M. Ultrasonographical diagnosis of fatty liver: significance of the liver-kidney contrast.Tohoku J Exp Med. 1983; 139: 43-50Crossref PubMed Scopus (153) Google Scholar, 28Fusamoto H. Suzuki K. Hayashi N. Sasaki Y. Kono M. Kasahara A. et al.Obesity and liver disease: evaluation of fatty infiltration of the liver using ultrasonic attenuation.J Nutr Sci Vitaminol (Tokyo). 1991; 37: S71-S77Crossref PubMed Scopus (19) Google Scholar] (Fig. 2). These findings are however also seen in those with any form of chronic liver disease and, although sensitive (85–95%), they are non-specific (positive predictive value 62%) [[29]Lee R.G. Nonalcoholic steatohepatitis: a study of 49 patients.Hum Pathol. 1989; 20: 594-598Abstract Full Text PDF PubMed Scopus (501) Google Scholar]. Also, the ability to detect fatty liver by sonography drops off markedly once the degree of hepatic steatosis decreases to 30% or less [[30]Saadeh S. Younossi Z.M. Remer E.M. Gramlich T. Ong J.P. Hurley M. et al.The utility of radiological imaging in nonalcoholic fatty liver disease.Gastroenterology. 2002; 123: 745-750Abstract Full Text Full Text PDF PubMed Scopus (1535) Google Scholar].Fig. 2This figure demonstrates hepatic sonographic features in subjects with NAFLD. These features include parenchymal echotexture and vascular blurring.View Large Image Figure ViewerDownload Hi-res image Download (PPT)CT imaging of the liver provides a more specific method for the non-invasive diagnosis of NAFLD (Fig. 3). Hepatic steatosis decreases the CT attenuation of the liver. When the hepatic parenchymal attenuation is 10 or more Hounsfield units lower than the spleen on a non-contrast-enhanced scan, a diagnosis of hepatic steatosis can be made. When intravenous contrast is administered, the hepatic enhancement lags behind the spleen and the liver-to-spleen attenuation differential exceeds 20 Hounsfield units [[31]Jacobs J.E. Birnbaum B.A. Shapiro M.A. Langlotz C.P. Slosman F. Rubesin S.E. et al.Diagnostic criteria for fatty infiltration of the liver on contrast-enhanced helical CT.AJR Am J Roentgenol. 1998; 171: 659-664Crossref PubMed Scopus (150) Google Scholar]. While these features allow hepatic steatosis to be defined with a 76% positive predictive value [[30]Saadeh S. Younossi Z.M. Remer E.M. Gramlich T. Ong J.P. Hurley M. et al.The utility of radiological imaging in nonalcoholic fatty liver disease.Gastroenterology. 2002; 123: 745-750Abstract Full Text Full Text PDF PubMed Scopus (1535) Google Scholar], they do not permit distinction between fatty liver and steatohepatitis. Also, the diagnostic sensitivity of the test depends on the severity of the steatosis and falls off when the steatosis is mild. CT imaging also does not provide any information on the stage of fibrosis in the liver unless features of portal hypertension are present. This only occurs in the presence of cirrhosis of the liver. Finally, it is worth remembering that CT scans are substantially more expensive than sonography.Fig. 3CT imaging of the liver in NAFLD. This figure demonstrates CT attenuation of the liver which is more prominent on non-contrast enhanced scan.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Magnetic resonance imaging (MRI) is even more sensitive than a CT scan for the assessment of hepatic steatosis. However, MRI also has many of the same limitations of CT imaging noted above. It is even more expensive than a CT scan and is not universally available. Given the modest increase in diagnostic accuracy and marked increase in cost with CT imaging and MRI, a hepatic sonogram is the most commonly used imaging modality to diagnose a fatty liver. However, it is important to note that none of these methods can diagnose steatohepatitis or accurately assess the stage of the disease.3.3.2 Role of a liver biopsy in the diagnosis of NAFLDA liver biopsy is the gold-standard for the diagnosis of NAFLD, separating those with a fatty liver alone from those with steatohepatitis and evaluation of the stage of hepatic fibrosis. Unfortunately, it requires an invasive liver biopsy, which is uncomfortable, expensive and occasionally causes severe morbidity and mortality. There is also no established, specific pharmacologic treatment for NASH at this time. Establishing a diagnosis of NASH versus NAFL does not therefore lead to specific treatment interventions in routine clinical practice. The invasive nature of a liver biopsy coupled with the lack of management options have led to a reluctance, on the part of many physicians, to perform a liver biopsy in cases of suspected NAFLD.In order for the practicing clinician to make intelligent decisions regarding who to biopsy and when to biopsy, one must consider the information to be obtained and how this will affect the individual undergoing the biopsy. It is important to remember that, in subjects with persistently abnormal ALT values and negative viral serologies, approximately 20–30% of subjects have an alternate diagnosis [32Sorbi D. McGill D.B. Thistle J.L. Therneau T.M. Henry J. Lindor K.D. An assessment of the role of liver biopsies in asymptomatic patients with chronic liver test abnormalities.Am J Gastroenterol. 2000; 95: 3206-3210Crossref PubMed Google Scholar, 33Caldwell S.H. Oelsner D.H. Iezzoni J.C. Hespenheide E.E. Battle E.H. Driscoll C.J. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease.Hepatology. 1999; 29: 664-669Crossref PubMed Scopus (953) Google Scholar]. The probability of having NAFLD is likely to be higher if other features of the metabolic syndrome are also present in such individuals. This however remains to be tested and proven. The clinical corollary is that individuals without risk factors for NAFLD are more likely to have an alternate cause for their abnormal liver enzymes. If the treating physician is interested in being able to identify such cases, they may consider selecting such individuals for liver biopsy to establish the diagnosis. In other cases, the need for a biopsy simply to make a diagnosis of NAFLD should be individualized. For example, demonstration of isolated hepatic steatosis may allow an individual to obtain life insurance.The second unique piece of information obtained from a liver biopsy is the distinction between hepatic steatosis and steatohepatitis. It is generally believed that steatohepatitis can progress to cirrhosis in 15–20% of individuals [[22]Powell E.E. Cooksley W.G. Hanson R. S