Background

Pathologists have long noted the finding of fatty changes within the liver. For many years, it was attributed to alcohlic consumption. However, with increasing studies, it was clear that there was an importnat group of conditions, unrelated to alcohol abuse, that also produced similar histologic changes. This condition was originally termed NASH for nonalcoholic steatohepatitis. Today, it is recognized that NASH forms one end of the spectrum of diseases causing fatty changes within the liver.

Outline

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/Immunohistochemistry/Electron Microscopy
Differential Diagnosis
Prognosis and Treatment
Commonly Used Terms

EPIDEMIOLOGY	CHARACTERIZATION
SYNONYMS	Nonalcoholic steatohepatitis (NASH)
INCIDENCE
Prevalence of fatty liver in a general population of Okinawa, Japan. Nomura H, Kashiwagi S, Hayashi J, Kajiyama W, Tani S, Goto M. First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.	Jpn J Med 1988 May;27(2):142-9 Abstract quote A total of 2,574 residents in Yaeyama District of Okinawa, Japan, were investigated using real time ultrasonography to determine the real prevalence of fatty liver in the general population and to define its associated factors. Overall prevalence of fatty liver was 14.0%. Prevalence of fatty liver in persons under 19 years old was only 1.2%, and increased with age to a maximum in persons 40-49 years of age and then decreased. For persons over 20 years old, obesity index and serum levels of triglyceride and total cholesterol were measured, and alcohol consumption was asked. Prevalence of fatty liver was significantly higher in drinkers than non-drinkers (p less than 0.01), and increased with alcohol consumption. Furthermore, in persons not suffering from obesity prevalence of fatty liver was significantly higher in drinkers than in non-drinkers (p less than 0.001). The results of logistic regression analysis indicated that obesity and elevated serum triglyceride level in both sexes, and alcohol in males were significant predictors of fatty liver. In conclusion, prevalence of fatty liver increased with age to a maximum in persons 40-49 years of age and overall was 14.0%. Obesity was the strongest associated factor in both sexes and in males alcohol was also a strong factor.
GEOGRAPHY
Non-alcoholic fatty liver disease in an area of southern Italy: main clinical, histological, and pathophysiological aspects. Loguercio C, De Girolamo V, de Sio I, Tuccillo C, Ascione A, Baldi F, Budillon G, Cimino L, Di Carlo A, Di Marino MP, Morisco F, Picciotto F, Terracciano L, Vecchione R, Verde V, Del Vecchio Blanco C. Gastroenterology School, Faculty of Medicine, 2nd University of Naples, Via Foria, 58, 80137 Naples, Italy.	J Hepatol 2001 Nov;35(5):568-74 Abstract quote BACKGROUND/AIMS: Studies on non-alcoholic fatty liver disease (NAFLD) have included chronic liver damage attributed to various causes. Our investigation was held to observe the main clinical, histological, and pathophysiological aspects of NAFLD in patients not exposed to any known cause of chronic liver disease. METHODS: We evaluated, in 84 in-patients (male/female, 66/18; median age, 36 years), the clinical and biochemical characteristics of NAFLD, and particularly its association with diabetes, dyslipidemia, hyperinsulinemia and/or with the increase of parameters of oxidative stress (blood levels of malonyldialdehyde, 4-hydroxynonenal and total plasma antioxidant capacity). RESULTS: Ninety percent of patients had an increased body mass index (BMI), 35% had dyslipidemia, 40% had sub-clinical diabetes (only 3% had overt diabetes), 60% had hyperinsulinemia, and more than 90% had enhanced levels of lipid peroxidation markers. In 48 patients who had consented to liver biopsy, we found: 14 with simple steatosis, 32 with steatohepatitis, and two with cirrhosis. CONCLUSIONS: Our data indicate that in our country, NAFLD may occur in young males with an increased BMI, with or without hyperinsulinemia, dyslipidemia and diabetes, generally associated with disorders of redox status, and that it may be differentiated from steatosis to steatohepatitis or cirrhosis only with a liver biopsy.

 

DISEASE ASSOCIATIONS	CHARACTERIZATION
DRUGS	Amiodarone Diltiazem Tamoxifen
INSULIN RESISTANCE	Syndrome X (Metabolic syndrome) Lipoatrophy
LIPID METABOLISM DISORDERS	Abetalipoproteinemia Hypobetalipoproteinemia
TOTAL PARENTERAL NUTRITION
TOXINS
WEIGHT LOSS, SEVERE	Jejuno-ileal bypass Gastric bypass

 

PATHOGENESIS	CHARACTERIZATION
INSULIN RESISTANCE
Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, McCullough AJ, Natale S, Forlani G, Melchionda N. Unit of Metabolic Diseases, Department of Internal Medicine and Gastroenterology, University of Bologna, Italy.	Diabetes 2001 Aug;50(8):1844-50 Abstract quote Insulin sensitivity (euglycemic clamp, insulin infusion rate: 40 mU. m(-2). min(-1)) was studied in 30 subjects with biopsy-proven nonalcoholic fatty liver disease (NAFLD), normal glucose tolerance, and a BMI <30 kg/m(2). Of those 30 subjects, 9 had pure fatty liver and 21 had evidence of steatohepatitis. In addition, 10 patients with type 2 diabetes under good metabolic control and 10 healthy subjects were studied. Most NAFLD patients had central fat accumulation, increased triglycerides and uric acid, and low HDL cholesterol, irrespective of BMI. Glucose disposal during the clamp was reduced by nearly 50% in NAFLD patients, as well as in patients with normal body weight, to an extent similar to that of the type 2 diabetic patients. Basal free fatty acids were increased, whereas insulin-mediated suppression of lipolysis was less effective (-69% in NAFLD vs. -84% in control subjects; P = 0.003). Postabsorptive hepatic glucose production (HGP), measured by [6,6-(2)H(2)]glucose, was normal. In response to insulin infusion, HGP decreased by only 63% of basal in NAFLD vs. 84% in control subjects (P = 0.002). Compared with type 2 diabetic patients, NAFLD patients were characterized by lower basal HGP, but with similarly reduced insulin-mediated suppression of HGP. There was laboratory evidence of iron overload in many NAFLD patients, but clinical, histological, and biochemical data (including insulin sensitivity) were not correlated with iron status. Four subjects were heterozygous for mutation His63Asp of the HFE gene of familiar hemochromatosis. We concluded that NAFLD, in the presence of normoglycemia and normal or moderately increased body weight, is characterized by clinical and laboratory data similar to those found in diabetes and obesity. NAFLD may be considered an additional feature of the metabolic syndrome, with specific hepatic insulin resistance.
KUPFFER CELLS
Kupffer cell aggregation and perivenular distribution in steatohepatitis. Lefkowitch JH, Haythe JH, Regent N. Departments of Pathology (JHL) and Medicine (JHH), College of Physicians and Surgeons, Columbia University.	Mod Pathol 2002 Jul;15(7):699-704 Abstract quote Cytokine release from inflammatory cells, endotoxin, lipid peroxidation, and generation of reactive oxygen species are among the factors currently thought to be important in the pathogenesis of alcoholic and nonalcoholic steatohepatitis (SH). To more fully evaluate the role of mononuclear inflammatory cells in SH, 11 needle liver biopsies showing SH were selected for immunohistochemical staining to analyze the type and distribution of mononuclear inflammatory cells, including T and B lymphocytes and Kupffer cells (using immunostains for CD3, CD4, CD8; CD20; and CD68, respectively). An additional seven biopsies showing normal or fatty liver were also selected for CD68 immunostaining. Immunohistochemistry showed mild to moderate (1+ to 2+) numbers of T cells, with equal representation of CD4 and CD8 cells. T cells were found in portal tracts and in regions of SH. B cells were only rarely present. CD68 staining of simple fatty liver and normal liver showed elongated, spindle-shaped Kupffer cells diffusely distributed along the sinusoids throughout the lobules. In contrast, in cases of SH, there was prominent enlargement and aggregation of Kupffer cells in perivenular regions. Scattered large vacuoles of fat that had appeared to be within hepatocytes on routine stain were found actually to be within Kupffer cells. These results support the concept that hepatic Kupffer cells are a major immune effector cell in the pathogenesis of steatohepatitis. A potential direct Kupffer cell role in hepatic lipid processing is also postulated.
OXYGEN CONSUMPTION, HEPATIC
Hepatic circulation and hepatic oxygen consumption in alcoholic and nonalcoholic fatty liver. Kasahara A, Hayashi N, Sasaki Y, Katayama K, Kono M, Yashima T, Fusamoto H, Sato N, Kamada T. First Department of Medicine, Osaka University Medical School, Japan.	Am J Gastroenterol 1988 Aug;83(8):846-9 Abstract quote The purpose of this study was to determine the differences in hepatic circulation and oxygen consumption in two groups: those with nonalcoholic obesity-related fatty live and those with alcoholic fatty liver. Although the histological degree of fatty infiltration was equal in the two groups, the delta Er569-650, as an index of the regional liver blood flow estimated by spectrophotometric method, was significantly lower in alcoholic fatty liver than in nonalcoholic fatty liver, and the in vivo hepatic oxygen consumption (VO2), also determined by hepatic reflectance spectrophotometry during peritoneoscopy, tended to be lower in alcoholic fatty liver than in nonalcoholic fatty liver. The oxygen saturation of hemoglobin in local liver blood (SO2) was, however, significantly higher in alcoholic fatty liver than in nonalcoholic fatty liver. These results suggest that an increase in oxygen extraction to maintain oxygen consumption, which was indicated by the lowering of the SO2, was not found in alcoholic fatty liver, in spite of a reduction of oxygen supply to the liver. It is concluded that the impairment of hepatic circulation and hepatic oxygen consumption was more serious in alcoholic fatty liver than in nonalcoholic fatty liver, possibly contributing to a different prognosis for the two forms of fatty liver.
TT VIRUS
Influence of TT virus on the histopathological features of nonalcoholic fatty liver disease. Tokita H, Murai S, Kamitsukasa H, Yagura M, Harada H, Hebisawa A, Takahashi M, Okamoto H. Department of Gastroenterology, National Tokyo Hospital, 204-0023, Tokyo, Japan	Hepatol Res 2001 Mar 26;19(3):197-211 Abstract quote The sera of 38 patients with nonalcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis (NASH), were tested for TT virus (TTV) DNA by polymerase chain reaction (PCR) using three different primer pairs (UTR PCR, N22 PCR and genotype-1 PCR), and various histological features of the liver biopsy specimens were compared among those who were positive or negative for TTV infection. By UTR PCR which detects all TTV genotypes, TTV DNA was detected in 37 (97%) of the 38 patients. In contrast, N22 PCR which detects primarily TTV genotypes 1-4, detected TTV DNA in 18 patients (47%). In the liver biopsy specimens, moderate to many acidophilic bodies, moderate to marked focal/spotty necrosis of hepatocytes and marked stellate, pericellular or perivenular fibrosis were observed significantly more frequently among those who were positive for TTV DNA by N22 PCR, than among those who were negative by N22 PCR. Twelve patients (32%) were positive for TTV genotype 1. Moderate to marked vacuolation of nuclei, moderate to many acidophilic bodies, and moderate to marked focal/spotty necrosis as well as marked stellate, pericellular or perivenular fibrosis were found significantly more frequently in the TTV genotype 1-positive group than in the TTV genotype 1-negative group. These results suggest that certain TTV genotypes including genotype 1 influence the necrosis and inflammation of hepatocytes and liver fibrosis in NAFLD patients.

 

LABORATORY/RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
RADIOLOGIC
LABORATORY MARKERS
HYPERTRIGLYCERIDEMIA
Hypertriglyceridemia and fatty liver: clinical diagnosis of fatty liver and lipoprotein profiles in hypertriglyceridemic patients with fatty liver. Osono Y, Nakajima K, Hata Y. Department of Geriatric Medicine, School of Medicine, Keio University, Japan.	J Atheroscler Thromb 1995;2 Suppl 1:S47-52 Abstract quote Fatty liver has prevailed by 14% in the healthy population of this country. The factors contributing genesis of fatty liver were gender (male), obesity, high alcohol consumption, glucose intolerance and hypertriglyceridemia. And hypertriglyceridemia seems to be the common underlying factor to all other causes. The mechanism for accumulation of triglycerides in the liver can be explained at least by increased HTGL activities and elevated apo A-II levels, a postulated co-factor of HTGL. An hypertriglyceridemic patients with fatty liver had the insulin resistance.
LIVER FUNCTION TESTING
The ratio of aspartate aminotransferase to alanine aminotransferase: potential value in differentiating nonalcoholic steatohepatitis from alcoholic liver disease. Sorbi D, Boynton J, Lindor KD. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA.	Am J Gastroenterol 1999 Apr;94(4):1018-22 Abstract quote OBJECTIVE: The ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT) is often greater than 2:1 in alcoholic hepatitis. The purpose of this study was to determine whether this ratio may be used to distinguish nonalcoholic steatohepatitis (NASH) from alcoholic liver disease. METHODS: Patients with NASH were matched with controls with alcoholic liver disease based on age, gender, and date of diagnosis. The diagnosis of alcoholic liver disease was based on exclusion of other causes and a significant history of alcohol consumption. The diagnosis of nonalcoholic steatohepatitis was based on exclusion of other causes of liver disease and a liver biopsy showing > 10% steatosis and inflammation. The two sided Student t test was used for statistical analysis. RESULTS: From 1990 to 1996, 70 patients with NASH were matched with 70 subjects with alcoholic liver disease. Patients with NASH had a mean AST to ALT ratio of 0.9 (range 0.3-2.8, median 0.7) and subjects with alcoholic liver disease a mean ratio of 2.6 (range 1.1-11.2, median 2.0). The mean AST levels were 66 U/L and 152 U/L, and the mean ALT levels 91 U/L and 70 U/L, in the nonalcoholic steatohepatitis and alcoholic liver disease groups, respectively. Although the absolute aminotransferase levels were significantly different in the two groups (p < 0.05), the greatest difference was observed in the AST to ALT ratio (p < 0.000001). Subset analysis of patients with NASH revealed mean AST to ALT ratios of 0.7, 0.9, and 1.4 for subjects with no fibrosis, mild fibrosis, or cirrhosis, respectively. The differences among these ratios were statistically significant (p < 0.05). CONCLUSIONS: The AST to ALT ratio appears to be a useful index for distinguishing nonalcoholic steatohepatitis from alcoholic liver disease. Although values < 1 suggest NASH, a ratio of > or = 2 is strongly suggestive of alcoholic liver disease.

 

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
The clinicopathologic spectrum and management of nonalcoholic Fatty liver disease. Contos MJ, Sanyal AJ. Department of Pathology and Division of Gastroenterology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, U.S.A.	Adv Anat Pathol 2002 Jan;9(1):37-51 Abstract quote SUMMARY: Nonalcoholic fatty liver disease (NAFD) comprises a spectrum of conditions characterized by the presence of predominantly macrovesicular fatty change in the liver and the absence of alcohol consumption in amounts considered detrimental to the liver. The histologic spectrum of NAFLD includes fatty liver alone or steatohepatitis (NASH). Nonalcoholic steatohepatitis is associated with increasing fibrosis is some cases and may progress to cirrhosis. Nonalcoholic fatty liver disease is often associated with insulin resistance. It is likely that there are one or more additional pathophysiologic defects in those with NASH, rendering them more susceptible to injury from oxidative stress. The clinical and histologic features of NASH are described, and an approach to the diagnosis and treatment of NAFLD is provided.
VARIANTS

 

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL
Nonalcoholic fatty liver disease: assessment of variability in pathologic interpretations. Younossi ZM, Gramlich T, Liu YC, Matteoni C, Petrelli M, Goldblum J, Rybicki L, McCullough AJ. Department of Gastroenterology, The Cleveland Clinic Foundation, Ohio 44195, USA.	Mod Pathol 1998 Jun;11(6):560-5 Abstract quote The exact cause, prevalence, and rate of progression of nonalcoholic fatty liver disease (NAFLD) are unclear because of a lack of agreement on the pathologic features associated with the different types of NAFLD, their clinical syndromes, and because of a lack of accuracy in the interpretation of these pathologic features. Studies of NAFLD would be aided by a consistent and standardized approach to the interpretation of pathologic features. The aim of our study was to assess interobserver and intraobserver variation in the histologic abnormalities associated with NAFLD. We identified histologic features of NAFLD as reported in the literature, and we identified patients with the diagnosis of NAFLD through the databases of two large institutions. Histologic parameters were evaluated for each liver biopsy specimen by four hepatopathologists and twice by two of the four pathologists (blindly). Interobserver and intraobserver concordance among the pathologists was measured by kappa statistics. Nineteen histologic parameters compartmentalized into steatosis, inflammation, liver cell injury, and fibrosis were evaluated on 53 liver biopsy specimens. Significant, substantial, or moderate concordance was present in only six items: the extent of steatosis, sinusoidal location of fibrosis, perivenular fibrosis, grade of fibrosis, ballooning degeneration, and the presence of vacuolated nuclei. Substantial or moderate concordance also was seen for interobserver readings for location of steatosis and periportal injury. Parameters of inflammation were not scored as reliably as parameters of fibrosis and cell injury. We conclude that only some histologic features previously reported in NAFLD (especially those with substantial and moderate concordance for both interobserver and intraobserver interpretation) are interpreted uniformly by experienced pathologists. These histologic features might prove useful for the development of a standardized and reliable pathologic scoring system that includes the full histologic spectrum of NAFLD and its various clinical outcomes.
Nonalcoholic steatohepatitis: definition and pathology. Brunt EM. Department of Pathology, 4th Floor, Saint Louis University Hospital, 3635 Vista Ave., St. Louis, MO 63110, USA.	Semin Liver Dis 2001;21(1):3-16 Abstract quote Nonalcoholic steatohepatitis (NASH) is a significant form of chronic liver disease in adults and children. The natural history of NASH ranges from indolent to end-stage liver disease. Current studies are focusing on identification of histologic and/or clinical markers of progression. NASH may be an underlying cause of cryptogenic cirrhosis, and the lesions of NASH may recur in allograft livers. An expanding array of clinical conditions and pathogenetic mechanisms have been identified, but many cases remain "idiopathic"; lack of significant alcohol use is, by definition, common to all cases. Neither clinical evaluation nor laboratory values can ensure either the diagnosis or the exclusion of NASH, and liver biopsy interpretation continues to be considered the "gold standard" for diagnosis. The lesions in NASH are similar but not identical to those of alcoholic steatohepatitis; exact, specific histologic criteria for the diagnosis are currently under discussion. The lesions most commonly accepted for NASH include steatosis, hepatocyte ballooning degeneration, mild diffuse lobular mixed acute and chronic inflammation, and perivenular, perisinusoidal collagen deposition. Zone 3 accentuation may be detected. Mallory's hyaline, vacuolated nuclei in periportal hepatocytes, lobular lipogranulomas, and PAS-diastase-resistant Kupffer cells are common. In biopsy specimens from children, portal inflammation may be more prominent than in adults. Progression of fibrosis may result in bridging septa and cirrhosis. The lesions of steatohepatitis may be noted concurrently with other forms of chronic liver disease. A histological "grading and staging" system has been developed to reflect the unique features of steatohepatitis, gradations of severity and fibrosis, and to promote uniform reporting of the histopathology.
VARIANTS
HEPATITIS C
Chronic hepatitis C and superimposed nonalcoholic fatty liver disease. Ong JP, Younossi ZM, Speer C, Olano A, Gramlich T, Boparai N. Department of Gastroenterology and Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, Ohio, USA.	Liver 2001 Aug;21(4):266-71 Abstract quote BACKGROUND/AIMS: Hepatitis C and nonalcoholic fatty liver disease (NAFL) are the two most common forms of liver disease in the United States. Recently, obesity and its associated risk factors have been suggested to enhance HCV-related fibrosis. The aim of this study was to assess the impact of hepatic steatosis, steatohepatitis, and its associated risk factors on HCV-related fibrosis. METHODS: Patients with untreated, biopsy-proven, chronic hepatitis C (6/97-3/99) were included. Clinical and demographic data at the time of liver biopsy were obtained from chart review and verified by telephone survey. One hepatopathologist reviewed all pathologic specimens, using the modified histological activity index score and the Ishak staging for fibrosis and a NAFL pathologic protocol. RESULTS: One hundred and seventy patients with hepatitis C were included [age: 48.7+/-9.33 (years), body mass index (BMI): 28.1+/-5.7 (kg/m2) and type 2 diabetes mellitus (DM): 14%]. Of these, 77 (45.3%) had no or mild fibrosis and 93 (54.7%) had advanced fibrosis. Hepatic steatosis was seen in 90 (52.9%) patients. The grade of steatosis was associated with markers of obesity only. Age (p=0.002), type 2 DM (p=0.04), and superimposed steatohepatitis (p=0.047) were independently associated with advanced fibrosis. Superimposed nonalcoholic steatohepatitis (NASH) was seen in 17 (10%) patients. Patients with superimposed NASH were mostly obese (76.5%), males (62%) with 16% having type 2 diabetes and a BMI 33.8+/-7.12. CONCLUSION: In patients with chronic hepatitis C, type 2 DM and superimposed steatohepatitis are independently associated with advanced fibrosis.

 

SPECIAL STAINS/IMMUNOPEROXIDASE/ OTHER	CHARACTERIZATION
SPECIAL STAINS	Trichome for Mallory's hyaline

 

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
ALCOHOLIC LIVER DISEASE
Alcohollike liver disease in nonalcoholics. A clinical and histologic comparison with alcohol-induced liver injury. Diehl AM, Goodman Z, Ishak KG. Department of Medicine, Veterans Administration Medical Center, Washington, D.C.	Gastroenterology 1988 Oct;95(4):1056-62 Abstract quote Individuals who deny alcohol consumption may develop liver injury that histologically resembles the liver injury found in alcoholic patients. To determine whether any clinical or histologic features distinguish alcoholic and nonalcoholic subjects with "alcohollike" liver injury, the clinical records and liver biopsy specimens of 68 alcoholic and 39 nonalcoholic patients with alcohollike injury on liver biopsy were compared. The clinical and biochemical features of the two groups differed significantly. Alcoholism was associated with more severe clinical and biochemical manifestations of liver disease. However, there was considerable overlap among histologic features of the two clinically defined groups. Based on histology alone, alcoholic and nonalcoholic patients were often indistinguishable. The observations suggest that the clinical differences between the alcoholic and non-alcoholic patients cannot be attributed to qualitative or quantitative differences in liver histology. On the other hand, histologic similarities between the two groups raise the possibility that a shared condition, perhaps nutritional or hormonal, is responsible for the histologic expression of alcohollike injury in both groups.

 

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSTIC FACTORS
GENERAL
The natural history of nonalcoholic fatty liver: a follow-up study. Teli MR, James OF, Burt AD, Bennett MK, Day CP. Department of Medicine, Medical School, University of Newcastle, Newcastle upon Tyne, United Kingdom.	Hepatology 1995 Dec;22(6):1714-9 Abstract quote Nonalcohol-induced fatty liver is widely believed to be a benign condition with little or no risk of disease progression. There have been occasional reports of progression to cirrhosis but none in the absence of preexisting fibrosis on the index biopsy specimen even when co-existing hepatitis was present (steatohepatitis). From our histological database (1978 to 1985), we identified 161 patients with fatty liver seen at our institution and traced the case notes of 156. One hundred five patients were initially excluded as having an alcohol-induced cause, and the remaining 51 either were seen in the clinic (37) or had died, in which cases copies of their death certificates were obtained (14). A further 7 patients were excluded after clinic attendance gave evidence of alcohol excess and another 4 after review of their initial biopsy showed the presence of fibrosis or steatohepatitis. The apparent cause of the steatosis in the 40 included patients with strictly nonalcohol-induced pure fatty liver was obesity in 12, diabetes in 4 (1 obese patient), and cachexia associated with extrahepatic malignancy in 6. Four of the remaining 19 had serological evidence of an autoimmune disorder, but none of these had any clinical or histological features of autoimmune liver disease. Nine patients had evidence of hyperlipidemia, 3 of whom were also obese. At a median follow-up of 11 years (7 to 16), 12 of 26 living patients had abnormal results of liver blood tests and had repeat liver biopsies performed. None had progressed to steatohepatitis or cirrhosis; 1 obese patient had developed mild fibrosis 9.8 years after her index biopsy.
Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Department of Gastroenterology, Cleveland, Ohio, USA.	Gastroenterology 1999 Jun;116(6):1413-9 Abstract quote BACKGROUND & AIMS: The spectrum of nonalcoholic fatty liver disease ranges from fatty liver alone to nonalcoholic steatohepatitis. Most previous studies have short follow-up and have not carefully delineated different histological types when determining clinical outcomes. The aim of this study was to compare clinical characteristics and outcomes of patients with different types of nonalcoholic fatty liver. METHODS: All liver biopsy specimens from 1979 to 1987 with fat accumulation were assessed for inflammation, ballooning degeneration, Mallory hyaline, and fibrosis. Biopsy specimens were also assessed for histological iron and hepatitis C RNA. Outcomes were cirrhosis, mortality, and liver-related mortality. RESULTS: Of 772 liver biopsy specimens, complete data were available in 132 patients. Fatty liver (type 1) did not differ from the other three types combined with respect to gender, race, age, or obesity. Cirrhosis was more common in the other types combined (22%) than fatty liver alone (4%; P CONCLUSIONS: The outcome of cirrhosis and liver-related death is not uniform across the spectrum of nonalcoholic fatty liver. These poor outcomes are more frequent in patients in whom biopsies show ballooning degeneration and Mallory hyaline or fibrosis.
Clinical features and natural history of nonalcoholic steatosis syndromes. Falck-Ytter Y, Younossi ZM, Marchesini G, McCullough AJ. Schwartz Center for Metabolism and Nutrition, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.	Semin Liver Dis 2001;21(1):17-26 Abstract quote Nonalcoholic steatohepatitis, along with other forms of nonalcoholic fatty liver disease, is a chronic liver disease that is attracting increasing significance. It is a clinicopathologic syndrome that was originally described in obese, diabetic females who denied alcohol use but in whom the hepatic histology was consistent with alcoholic hepatitis. This typical patient profile has been expanded and is now recognized to occur even in normal weight males without overt abnormalities in carbohydrate metabolism. Although originally believed to be a benign clinical entity, nonalcoholic steatohepatitis is now recognized as a cause of progressive fibrotic liver disease with adverse clinical sequelae. It is important to emphasize that nonalcoholic steatohepatitis is best considered one type of a larger spectrum of nonalcoholic fatty liver disease that is a consequence of insulin resistance and ranges from fat alone to fat plus inflammation, fat plus ballooning degeneration, and nonalcoholic steatohepatitis, the latter being the most serious form. As with any disease, the clinical importance of nonalcoholic steatohepatitis is related to its prevalence and natural history. Recent studies using different methodologies indicate that in the general population the prevalence of fatty liver and nonalcoholic steatohepatitis is approximately 20% and 3%, respectively. These prevalence rates are increased in certain subpopulations such as obesity and type II diabetes. Of greater concern is the recognition that cirrhosis and liver-related deaths occur in approximately 20% and 8% of these patients, respectively, over a 10-year period. Risk factors for these adverse clinical symptoms include patients older than the age of 45, the presence of diabetes or obesity, an aspartate aminotransferase/alanine aminotransferase ratio > 1 and hepatic histology. However, a number of important unresolved issues must be clarified before the true natural history of this disease can be fully understood.
Are there predictive factors of severe liver fibrosis in morbidly obese patients with non-alcoholic steatohepatitis? Crespo J, Fernandez-Gil P, Hernandez-Guerra M, Cayon A, Mayorga M, Dominguez-Diez A, Fernandez-Escalante JC, Pons-Romero F. Institute of Digestive Diseases, Universitary Hospital Marques de Valdecilla, School of Medicine, Santander, Spain.	Obes Surg 2001 Jun;11(3):254-7 Abstract quote BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a clinicopathological entity characterized by the presence of steatosis and lobular and/or portal inflammation with or without fibrosis. Patients with non-alcoholic fatty liver and fibrosis on liver biopsy have increased liver-related deaths. METHODS: 181 wedge liver biopsies, taken at the time of bariatric surgery from patients with a mean body mass index (BMI) of 47, were studied. In all cases, the liver biopsy was performed without knowledge of the patient's clinical and biochemical data, which were then examined with univariate and multivariate analysis. RESULTS: Diagnosis of NASH was established in 105 patients (91%); 74 patients (70%) showed mild steatosis, 20 (19%) had moderate inflammation and fibrosis, and 11 (10%) had steatosis with severe fibrosis. None of the liver biopsies showed cirrhosis. Age was the only independent predictor of moderate and severe fibrosis (p = 0.001). CONCLUSIONS: Since only age was a predictor of moderate or severe fibrosis, and no clinical or biochemical abnormalities detected slowly progressive hepatic fibrosis, liver biopsy is the only means of detecting progression to more advanced liver disease in a NASH patient.
Frequency of nonalcoholic steatohepatitis as a cause of advanced liver disease. Charlton M, Kasparova P, Weston S, Lindor K, Maor-Kendler Y, Wiesner RH, Rosen CB, Batts KP. Liver Transplant Unit, Mayo Clinic, Rochester, MN 55905, USA.	Liver Transpl 2001 Jul;7(7):608-14 Abstract quote Although nonalcoholic steatohepatitis (NASH) has generally been considered a benign condition, the increasing prevalence and severity of obesity has heightened concerns about the frequency with which NASH progresses to end-stage liver disease. The aim of this study is to determine the frequency, clinical features, and posttransplantation history of decompensated liver disease secondary to NASH. The frequency of NASH as a cause of end-stage liver disease was prospectively determined in patients evaluated for liver transplantation. NASH was considered to be the primary cause of liver disease in patients who had histological evidence of steatohepatitis and in whom chronic liver diseases other than NASH were excluded. Posttransplantation histological characteristics were also determined in patients with NASH and compared with those of patients with pretransplantation diagnoses of cholestatic liver diseases, alcoholic disease, and hepatitis C. Of 1,207 patients evaluated for liver transplantation during the study period, 31 patients (2.6%) had NASH as the primary cause of liver disease. In the same period, 546 liver transplantations were performed, 16 of which (2.9%) were for end-stage disease secondary to NASH. Posttransplantation steatosis was seen in 60% of transplant recipients with NASH versus 5% of those with cholestatic disease, 15% of those with alcoholic disease, and 15% of those with hepatitis C. Steatohepatitis recurred in 33% of transplant recipients with NASH, with progression to cirrhosis in 12.5%. NASH can progress to end-stage liver disease in a minority of affected patients and was the primary cause of liver disease in 2.9% of patients evaluated for liver transplantation at our center. Recurrence of steatosis and NASH is frequent and can be severe after liver transplantation.
Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Dixon JB, Bhathal PS, O'Brien PE. Monash University Department of Surgery, Alfred Hospital, Melbourne 3181, Victoria, Australia.	Gastroenterology 2001 Jul;121(1):91-100 Abstract quote BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is common in severely obese subjects and can progress to cirrhosis and liver failure. Predicting advanced or progressive disease may help in selecting patients for liver biopsy and assist the development of therapeutic options. METHODS: Liver biopsies were taken at laparoscopic obesity surgery in 105 consecutive patients. The clinical and biochemical variables were analyzed for correlation with specific histologic features. RESULTS: Twenty-six patients (25%) were found to have nonalcoholic steatohepatitis (NASH), and 11 (42%) of these had advanced fibrosis. A raised index of insulin resistance (odds ratio [OR] 9.3, 95% confidence interval [CI] 3.4-26), systemic hypertension (OR 5.2, 95% CI 2.0-13.5), and raised alanine aminotransferase (OR 8.6, 95% CI 3.1-23.5) were independent predictors of NASH. A combination of 2 or 3 of these predictors allows a sensitivity of 0.8 and specificity of 0.89 for NASH. Alcohol consumption was associated with a reduction in NASH (OR 0.35, 95% CI 0.12-1.00) and diabetes (OR 0.18, 95% CI 0.047-0.67). CONCLUSION: Insulin resistance and systemic hypertension, features of the metabolic syndrome, are independently associated with advanced forms of NAFLD. Moderate alcohol consumption seems to reduce the risk of NAFLD in the severely obese, possibly by reducing insulin resistance.
GRADING
Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Department of Pathology, Saint Louis University School of Medicine, Missouri 63110-0250, USA.	Am J Gastroenterol 1999 Sep;94(9):2467-74 Abstract quote OBJECTIVE: Steatohepatitis is a morphological pattern of liver injury that may be seen in alcoholic or nonalcoholic liver disease. This pattern may occur with obesity, diabetes, the use of certain drugs, or the cause may be idiopathic. The well-recognized histopathological features of nonalcoholic steatohepatitis (NASH) include hepatocellular steatosis and ballooning, mixed acute and chronic lobular inflammation, and zone 3 perisinusoidal fibrosis. Currently, there are no systems for grading necroinflammatory activity or for staging fibrosis as exist for various other forms of chronic liver disease. The purpose of this study was to develop such a grading and staging system and was based on review of liver biopsies from 51 patients with nonalcoholic steatohepatitis from Saint Louis University Health Sciences Center. METHODS: For determination of grade, 10 histological variables of activity were initially analyzed; an overall impression of mild, moderate, and severe was made and the variables considered to be most significant were used to develop the necroinflammatory grade. RESULTS: The histological lesions considered to be significant were: steatosis, ballooning, and intra-acinar and portal inflammation. A staging score was developed to reflect both location and extent of fibrosis. The fibrosis score was derived from the extent of zone 3 perisinusoidal fibrosis with possible additional portal/periportal fibrosis and architectural remodeling. Fibrosis stages are as follows: Stage 1, zone 3 perisinusoidal fibrosis; Stage 2, as above with portal fibrosis; Stage 3, as above with bridging fibrosis; and Stage 4, cirrhosis. CONCLUSION: We propose a grading and staging system that reflects the unique histological features of nonalcoholic steatohepatitis.
Mild-Grade 1
Moderate-Grade 2
Severe-Grade 3
STAGING	Am J Gastroenterol 1999 Sep;94(9):2467-74
Stage 1	Zone 3 perisinusoidal fibrosis
Stage 2	Zone 3 perisinusoidal fibrosis with focal or extensive periportal fibrosis
Stage 3	Zone 3 perisinusoidal fibrosis and portal fibrosis with bridging
Stage 4	Cirrhosis
TRANSPLANATION, RECURRENCE
Recurrence of nonalcoholic steatohepatitis following liver transplantation. Kim WR, Poterucha JJ, Porayko MK, Dickson ER, Steers JL, Wiesner RH. Division of Gastroenterology and Internal Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.	Transplantation 1996 Dec 27;62(12):1802-5 Abstract quote Patients with nonalcoholic steatohepatitis (NASH) may develop progressive liver dysfunction necessitating liver transplantation (OLT). We report the incidence of recurrent disease and outcome in patients undergoing OLT for NASH. Patients transplanted for NASH were identified according to pretransplant and explant liver histology. Patients with significant alcohol consumption were excluded. Medical records were reviewed to extract pre- and posttransplant data, including sequential body weight, biochemistry, and graft histology. Of 622 liver explants, eight patients had features consistent with NASH. All patients were female with a median age of 58. Seven patients were diagnosed with NASH preoperatively, including three who had undergone jejunoileal bypass. One patient was diagnosed as cryptogenic cirrhosis. At a median of 15 months following OLT, all of the eight patients were alive with no graft failure. Six patients developed persistent fatty infiltration in their graft, three of whom had accompanying hepatocellular degeneration, consistent with a diagnosis of recurrent NASH. In two patients, transition from mild steatosis to steatohepatitis and early fibrosis was observed over one to two years. The patients who did not develop recurrent steatosis had significant weight loss following transplantation, although the length of follow-up was relatively short. Patients undergoing OLT for NASH may develop recurrent steatosis shortly after transplantation, with possible progression to steatohepatitis and fibrosis. Although longer follow-up is necessary to determine the eventual prognosis related to the recurrent fat and fibrosis in the graft, patients with endstage liver disease due to NASH should be considered good candidates for OLT.
Development of nonalcoholic fatty liver disease after orthotopic liver transplantation for cryptogenic cirrhosis. Contos MJ, Cales W, Sterling RK, Luketic VA, Shiffman ML, Mills AS, Fisher RA, Ham J, Sanyal AJ. Department of Pathology, Division of Gastroenterology/Hepatology/Nutrition, Virginia Commonwealth University-Medical College of Virginia, Richmond, VA, USA.	Liver Transpl 2001 Apr;7(4):363-73 Abstract quote Many subjects with cryptogenic cirrhosis have underlying nonalcoholic steatohepatitis (NASH). The natural history of NASH-related cryptogenic cirrhosis after orthotopic liver transplantation (OLT) is not well defined. A primarily retrospective study of patients with the clinical histological phenotype of NASH-related cirrhosis undergoing OLT was performed. Data were compared with 2 sets of age- and weight-matched controls with (1) primary biliary cirrhosis or primary sclerosing cholangitis or (2) alcoholic liver disease. After OLT, all patients were managed by a standard immunosuppressive protocol. Liver biopsies were performed at 6 and 12 months after OLT and at 1- to 2-year intervals thereafter, as well as when liver enzyme levels were elevated enough to warrant diagnostic biopsy. Twenty-seven subjects with cryptogenic cirrhosis and a clinical histological phenotype of NASH and 3 patients with a long-standing diagnosis of NASH before OLT were included. The 30-day perioperative mortality was 1 in 30 patients. During a median follow-up of 3.5 +/- 2.7 years, 2 additional patients died of sepsis. There was a time-dependent increase in the risk for allograft steatosis that approached 100% by 5 years compared with only an approximately 25% incidence of steatosis in the control groups (P <.009, log-rank test). On multivariate analysis, only the cumulative steroid dose correlated with time to development of allograft steatosis. Three patients developed histological progression from hepatic steatosis to steatohepatitis. Of these, 1 patient developed progressive fibrosis. Four patients experienced at least 1 episode of acute cellular rejection; however, no patient developed chronic rejection or graft failure. In conclusion, nonalcoholic fatty liver disease occurs frequently after OLT in patients with the phenotype of NASH-related cirrhosis. Despite the frequent histological recurrence of disease, clinical outcomes are similar to those of other groups of patients undergoing OLT.
Lipoatrophic diabetes and end-stage liver disease secondary to nonalcoholic steatohepatitis with recurrence after liver transplantation. Cauble MS, Gilroy R, Sorrell MF, Mailliard ME, Sudan DL, Anderson JC, Wisecarver JL, Balakrishnan S, Larsen JL. Department of Internal Medicine, University of Nebraska Medical Center, Omaha 63198-3020, USA.	Transplantation 2001 Apr 15;71(7):892-5 Abstract quote BACKGROUND: Lipoatrophic diabetes is an insulin resistance syndrome characterized by the complete or partial lack of adipose tissue and disturbances in lipid and glucose metabolism. Nonalcoholic steatohepatitis (NASH) is a well-described change in liver pathology consisting of steatosis, hepatitis, and fibrosis that can be associated with lipoatrophic diabetes. RESULTS: This article describes the first reported case of lipoatrophic diabetes with NASH leading to liver failure and liver transplantation. Before transplantation, the patient required 600-700 U of insulin/day. After transplantation, a dramatic decline in her insulin requirements was observed, despite corticosteroids. Eighteen months after transplantation, her glycemic control worsened, and she developed recurrent NASH on serial liver biopsies. CONCLUSIONS: NASH associated with lipoatrophic diabetes can recur after liver transplantation, and in this case, was accompanied by increased insulin requirements. These results suggest that the development of NASH itself may contribute to the insulin resistance observed in lipoatrophic diabetes.
TREATMENT
GENERAL
Treatment of nonalcoholic fatty liver: present and emerging therapies. Angulo P, Lindor KD. Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA.	Semin Liver Dis 2001;21(1):81-8 Abstract quote Treatment of patients with nonalcoholic fatty liver has typically been focused on the management of associated conditions such as obesity, diabetes mellitus, and hyperlipidemia as well as discontinuation of potentially hepatotoxic drugs. Nonalcoholic fatty liver associated with obesity may resolve with weight reduction, although the benefits of weight loss have been inconsistent. Appropriate metabolic control for patients with diabetes mellitus or hyperlipidemia is always recommended but not always effective in reversing nonalcoholic fatty liver. Promising results of pilot studies evaluating ursodeoxycholic acid, gemfibrozil, betaine, N-acetylcysteine, and alpha-tocopherol suggest that these medications may be of potential benefit in the treatment of patients with nonalcoholic fatty liver. These medications, however, need first to be tested in well-controlled trials with clinically relevant end points and extended follow-up. A better understanding of the pathogenesis and natural history of this condition will help to identify the subset of patients with nonalcoholic fatty liver at risk of progressing to advanced liver disease and, hence, the subgroup of patients who should derive the most benefit from medical therapy. In this article, we review (1) the existing medical therapy for patients with nonalcoholic fatty liver, (2) the emerging data from clinical trials evaluating potentially useful medications, and (3) the potential therapeutic implications of recent studies on the pathogenesis of this liver disease.
URSODEOXYCHOLID ACID OR CLOFIBRATE
Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Laurin J, Lindor KD, Crippin JS, Gossard A, Gores GJ, Ludwig J, Rakela J, McGill DB. The Mayo Clinic and Foundation, Rochester, MN, USA.	Hepatology 1996 Jun;23(6):1464-7 Abstract quote Non-alcohol-induced steatohepatitis (NASH) is characterized by elevated serum aminotransferase activities with hepatic steatosis, inflammation, and occasionally fibrosis that may progress to cirrhosis. No established treatment exists for this potentially serious disorder. Our aim was to conduct a pilot study to evaluate the safety and estimate the efficacy of ursodeoxycholic acid (UDCA) and clofibrate in the treatment of NASH. Forty patients were diagnosed with NASH based on a compatible liver biopsy with other causes of liver disease, including alcohol abuse, excluded by history, serum tests, and use of ultrasound. Twenty-four patients received 13 to 15 mg/kg/d of UDCA for 12 months. Sixteen patients with hypertriglyceridemia were placed on clofibrate, 2 g/day for 12 months. Twenty-five women and 15 men entered the study. Six of 40 patients (15%) withdrew because of side effects. Four additional patients were withdrawn because of noncompliance; one of them later required liver transplantation. In the UDCA group, the decreases in mean serum levels of alkaline phosphatase, alanine transaminase (ALT), and gamma-glutamyl transpeptidase (GGT) as well as histological grade of steatosis were significant. Among the patients treated with clofibrate, no change from baseline was found in mean ALT, aspartate transaminase (AST), GGT, bilirubin, triglycerides, and cholesterol, or in histological grade of steatosis, inflammation, or fibrosis after 12 months of treatment as compared with entry. Alkaline phosphatase activities decreased significantly from baseline. Despite the known lipid-lowering effects of clofibrate, it did not appear to be of clinical benefit in the treatment of NASH in this 1-year pilot study. However, treatment of NASH with UDCA for 12 months resulted in significant improvement in alkaline phosphatase, ALT, GGT, and hepatic steatosis. The possible benefit of UDCA therapy should be further investigated in the context of a randomized, controlled trial.

Rosai J. Ackerman's Surgical Pathology. Eight Edition. Mosby 1996.
Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.
Adv Anat Pathol 2002;9:37-51

Liver

Last Updated 8/19/2002