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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 important 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, ranging from steatosis to NASH. NASH may be progressive and steatosis alone appears to be non-progressive. Only 15-20% of patients with NASH may progress to cirrhosis over one to two decades.
OUTLINE
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 CHRONIC LIVER DISEASE
Concurrence of histologic features of steatohepatitis with other forms of chronic liver disease.Brunt EM, Ramrakhiani S, Cordes BG, Neuschwander-Tetri BA, Janney CG, Bacon BR, Di Bisceglie AM.
Saint Louis University Liver Center Department of Pathology, Saint Louis University Health Sciences Center, St Louis, Missouri, USA.
Mod Pathol 2003 Jan;16(1):49-56 Abstract quote Steatohepatitis, of either alcoholic or nonalcoholic etiologies, is ultimately diagnosed by clinical-pathologic correlation and is characterized histologically by lesions that differ from the portal-based chronic inflammation and fibrosis of most other forms of chronic liver disease. With the increasing prevalence of steatohepatitis in our society, it is likely that some patients will have coexistent clinical and/or histopathologic findings of steatohepatitis concurrently with another form of liver disease.
The aim of this study was to document clinical and histologic findings in biopsies in an academic referral center. Ninety-three non-allograft liver biopsies with lesions of both steatohepatitis and another liver disease were retrospectively identified in 85 patients. The finding of coexisting disease represented 5.5% of all hepatitis C biopsies and 4.0% of other forms of chronic liver disease in the 34 month time period. Clinical chart review of patients with concurrent disease showed the following: Group 1, patients with hepatitis C (n = 54); Group 2, patients with hepatitis C and prior or current history of more than 80 g/d alcohol consumption (n = 20); Group 3, patients with other forms of chronic liver disease (n = 11). Groups 1 and 3 had <10 g/d alcohol use. Obesity (body mass index >30) was noted in 75%, 60%, and 33% respectively, while 94%, 87% and 100% of patients were considered overweight (body mass index > or = 25). Diabetes was reported in 35%, 25%, and 9%.
The concurrence of clinical and histologic features of steatohepatitis with another chronic liver disease may be a reflection of the frequency of steatohepatitis in the population at large.
DRUGS Amiodarone
Diltiazem
TamoxifenINSULIN RESISTANCE Syndrome X (Metabolic syndrome)
LipoatrophyLIPID METABOLISM DISORDERS Abetalipoproteinemia
HypobetalipoproteinemiaTOTAL 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 TESTSCHARACTERIZATION 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 VARIANTSCHARACTERIZATION GENERAL
Nonalcoholic Fatty liver disease: an underrecognized cause of cryptogenic cirrhosis.Clark JM, Diehl AM.
Departments of Medicine and Epidemiology, Johns Hopkins University, Baltimore, Md.
JAMA. 2003 Jun 11;289(22):3000-4. Abstract quote Cryptogenic cirrhosis is a common cause of liver-related morbidity and mortality in the United States.
Nonalcoholic fatty liver disease (NAFLD) is now recognized as the most common cause of cryptogenic cirrhosis. However, the diagnosis of cirrhosis in patients with NAFLD appears to be delayed compared with those with other chronic liver diseases and thus carries a higher mortality rate. This delay in diagnosis is illustrated in our case of a 53-year-old man who presented with hepatic hydrothorax and ascites, whose workup revealed cirrhosis due to NAFLD.
Although a diagnosis of presumed NAFLD can be made noninvasively, a definitive diagnosis requires a liver biopsy specimen. A biopsy specimen is also important for detecting histologically advanced disease, which may be clinically silent and undetected by aminotransferases or diagnostic imaging.
Although there are no proven treatments, recommendations for patients with NAFLD include avoidance of hepatotoxins and aggressive management of associated conditions, such as hypertriglyceridemia and type 2 diabetes mellitus.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.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL
- Fibrosis heterogeneity in nonalcoholic steatohepatitis and hepatitis C virus needle core biopsy specimens.
Goldstein NS, Hastah F, Galan MV, Gordon SC.
Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, MI.
Am J Clin Pathol. 2005 Mar;123(3):382-7. Abstract quote
We examined 46 nonalcoholic steatohepatitis (NASH) and 52 hepatitis C virus (HCV) biopsy specimens to determine the magnitude of fibrosis heterogeneity and minimum length for accurate fibrosis staging. Three fibrosis scores were recorded: lowest regional, highest regional, and most common overall. Mean specimen lengths were 1.6 and 1.8 cm in NASH and HCV, respectively (P = .283). Mean (highest minus lowest) fibrosis heterogeneity scores (highest regional fibrosis - lowest regional fibrosis) were 3.7 and 2.0 in NASH and HCV, respectively (P < .001). Of 36 NASH specimens longer than 1.0 cm, 31 (86%) had the highest regional fibrosis in the deepest sampled parenchyma.
Shorter specimens were associated significantly with greater fibrosis heterogeneity in NASH (coefficient, -1.3; P < .001) but not in HCV (P = .901). NASH specimens longer than 1.6 cm had significantly lower mean heterogeneity scores than specimens 1.6 cm or shorter (1.2 vs 3.4; P = .012). In NASH, fibrosis heterogeneity can be substantial and is greater than in HCV, and parenchymal injury, fibrosis, and healing might vary in different regions of the liver.
The fibrosis stage in patients with NASH might not be assessed accurately in short specimens. Individual needle cores should be longer than 1.6 cm in NASH for accurate fibrosis staging.
- Nonalcoholic steatohepatitis: histologic features and clinical correlations with 30 blinded biopsy specimens.
Brunt EM, Neuschwander-Tetri BA, Oliver D, Wehmeier KR, Bacon BR.
Department of Pathology, Saint Louis University School of Medicine, St. Louis, Missouri 63110, USA.
Hum Pathol. 2004 Sep;35(9):1070-82. Abstract quote
Thirty overweight patients with clinically characterized and biopsy proven nonalcoholic steatohepatitis (NASH) were enrolled in a 48-week treatment trial with rosiglitazone, a peroxisome proliferator-activator receptor (PPAR)-gamma agonist that enhances insulin sensitivity.
Improvement in laboratory liver tests, insulin resistance and liver fat content were documented; blinded biopsy review demonstrated decreases in necroinflammatory activity or grade and in individual components of grade, and changes in the relationship of lobular and portal inflammation as well as in the nature of perisinusoidal fibrosis.
The current study identified correlations of histological features of the protocol entry biopsy specimens with contemporaneous laboratory and imaging tests. Significant correlations with histologically assessed steatosis were liver fat, evaluated by computed tomography (P = 0.001); mean HbA1C, a measure of glycemic control (P = 0.004); and QUICKI, a measure of insulin sensitivity (P = 0.05). Histologically determined grades of steatohepatitis (SH) correlated with HbA1C (P = 0.01), and a trend toward elevated fasting glucose levels was seen. No subject in the study was cirrhotic at entry; fibrosis scores of the 30 subjects did not significantly correlate with age, gender, body mass index, or clinical tests. All subjects underwent 3 biopsies (prior, entry, and posttreatment), and all had undergone a prior biopsy with diagnostic SH. By blinded analysis, 7 study entry biopsy specimens did not fulfill published strict criteria for SH. Laboratory results from these subjects included normal fasting glucose level and, compared with the 23 subjects with criteria for SH, lower mean alanine aminotransferase and aspartate aminotransferase levels (P = 0.02 for both), less insulin resistance (P = 0.03), and lower mean HbA1C (P = 0.001).
We conclude that biopsy findings determined by blinded analysis correlated with image-detected steatosis, laboratory markers of hepatic inflammation, insulin resistance, and long-term glycemia; the findings confirm the usefulness of strict histological criteria in the evaluation of NASH.
Pathologic features associated with fibrosis in nonalcoholic fatty liver disease.
Gramlich T, Kleiner DE, McCullough AJ, Matteoni CA, Boparai N, Younossi ZM.
Cleveland Clinic Foundation, OH, USA.
Hum Pathol. 2004 Feb;35(2):196-9 Abstract quote.
Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of clinicopatholologic conditions ranging from steatosis alone to nonalcoholic steatohepatitis (NASH), with varying risks for progression to cirrhosis. Although steatosis alone seems to be nonprogressive, some patients with NASH can progress.
This study focuses on the clinical and pathological characteristics of patients with NAFLD associated with the development of histological fibrosis. Patients with an established diagnosis of nonalcoholic fatty liver were identified through our NAFLD database containing extensive clinical, demographic, and laboratory data. Liver biopsy specimens were read blindly by one hepatopathologist using a 19-item pathological protocol and by another hepatopathologist using a second pathological protocol. Clinical and pathological data were matched to the presence of different types of histological fibrosis. Univariate and multivariate analyses helped determine all of the variables independently associated with histological fibrosis. Of 132 NAFLD patients, 21.2% had advanced fibrosis (septal/bridging fibrosis or well-established cirrhosis).
Sinusoidal fibrosis was present in 20.3% of patients, whereas perivenular fibrosis was seen in 17.2%. Ballooning degeneration and Mallory bodies were independently associated with both sinusoidal fibrosis and perivenular fibrosis. Aspartate aminotransferase/alanine aminotransferase ratio and ballooning degeneration were also independently associated with periportal-portal fibrosis.
We conclude that the presence of hepatocyte injury in NAFLD is associated with fibrosis. These pathological features can be used to establish the pathological criteria for diagnosis of the progressive form of NAFLD or NASH.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/
OTHERCHARACTERIZATION SPECIAL STAINS Trichome for Mallory's hyaline IMMUNOPEROXIDASE
Schuyler O. Sanderson, MD, and Thomas C. Smyrk, MDAm J Clin Pathol 2005;123:503-509 Abstract quote
Nonalcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) typically are indistinguishable histologically. The diagnosis relies on reporting of alcohol consumption. The metabolic syndrome involving insulin resistance is associated with nonalcoholic fatty liver disease (NAFLD). Protein tyrosine phosphatase 1B (PTP1B) negatively regulates the insulin receptor (IR). Increased PTP1B expression is seen in obesity and possibly is responsible for the insulin resistance seen in the metabolic syndrome.
The study objective was to determine whether biopsy specimens with steatohepatitis could be classified accurately as alcoholic or nonalcoholic by immunohistochemical stains. We selected 241 cases of steatohepatitis, comprising 53 and 188 cases of alcoholic and NAFLD, respectively. Specimens were stained with PTP1B and IR (b subunit) and classified as NASH or ASH. The staining pattern predicted 60 cases of ASH and 181 cases of NASH.
Results correlated with clinical diagnoses in 70% and 88% of ASH and NASH cases, respectively (odds ratio, 16.6; 95% confidence interval, 8.2-35.4).
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.
GLYCOGENIC HEPATOPATHY
- Glycogenic Hepatopathy: An Underrecognized Hepatic Complication of Diabetes Mellitus.
Torbenson M, Chen YY, Brunt E, Cummings OW, Gottfried M, Jakate S, Liu YC, Yeh MM, Ferrell L.
*Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD daggerDepartment of Pathology, University of California San Francisco, San Francisco, CA double daggerSt. Louis University Liver Center, Department of Pathology, St. Louis University School of Medicine, St. Louis, MO section signDepartment of Pathology, Indiana University School of Medicine, Indianapolis, IN perpendicularDepartment of Pathology, Duke University Medical Center, Durham, NC paragraph signDepartment of Pathology, Rush University Medical Center, Chicago, IL musical sharpDepartment of Pathology, Case Western Reserve University, MetroHealth Medical Center, Cleveland, OH **Department of Pathology, University of Washington Medical Center, Seattle, WA.
Am J Surg Pathol. 2006 Apr;30(4):508-513. Abstract quote
Reported are the clinical and pathologic features of glycogenic hepatopathy, a pathologic overloading of hepatocytes with glycogen that is associated with poorly controlled diabetes mellitus.
Fourteen cases were studied by stains, including hematoxylin and eosin, trichrome, periodic acid-Schiff, and periodic acid-Schiff with diastase. Ultrastructural analysis was performed in 2 cases. Medical records were reviewed for clinical presentations, laboratory findings, and clinical outcomes. The individuals ranged from 8 to 25 years of age. All had type I diabetes mellitus with poor glycemic control. The clinical presentations included hepatomegaly, abdominal pain, and elevated transaminases (range, 50-1600 IU/L). The transaminases were dramatically elevated in 3 cases to greater than 10 times the upper limit of normal. All biopsies showed diffusely pale staining hepatocytes on hematoxylin and eosin stains, with excessive glycogen accumulation demonstrated by periodic acid-Schiff stains.
Ultrastructural examination revealed marked glycogen accumulation in the cytoplasm and nuclei. Most cases showed no evidence for fatty liver disease: steatosis was absent in 12 of 14 cases, simple steatosis was seen in 1 of 14 cases, and mild steatohepatitis was present in 1 of 14 cases. Mallory hyaline was absent in all cases, acidophil bodies were only rarely seen, and inflammation was absent or minimally present. Fibrosis was typically absent, with only 2 cases demonstrating focal mild fibrosis. Three patients had adequate follow-up and demonstrated improvement of liver enzyme levels with control of blood glucose.
We conclude that glycogenic hepatopathy can cause hepatomegaly and significant transaminase elevations in individuals with type I diabetes mellitus. The pathology is distinct from steatohepatitis.
STELLATE-CELL LIPIDOSIS
Stellate-cell lipidosis in liver biopsy specimens. Recognition and significance.Levine PH, Delgado Y, Theise ND, West AB.
Dept of Pathology, NYU Medical Center, TH-461, 560, First Ave, New York, NY 10016-6497, USA.
Am J Clin Pathol 2003 Feb;119(2):254-8 Abstract quote Hepatic stellate-cell lipidosis due to hypervitaminosis A can lead to cirrhosis, which can be averted by restricting vitamin A intake. Other causes, including the use of synthetic retinoids, have been postulated.
We studied the frequency and etiology of stellate-cell lipidosis in patients undergoing liver biopsy for reasons other than vitamin A abuse. Fourteen cases (1.1%) were identified retrospectively among 1,235 nontransplant liver biopsy specimens examined from January 1995 through December 1999.
Diagnostic criteria included the following: lipid-laden cells in the space of Disse; small, dark, crescent-shaped nuclei with inconspicuous nucleoli; and wispy cytoplasmic strands separating fat droplets. Patient details, reason for biopsy, and medication use were studied. Reasons for biopsy included hepatitis C (10 cases), abnormal liver enzyme levels (2 cases), methotrexate use (1 case), and alcohol abuse (1 case).
Hypervitaminosis A was not suspected clinically in the 5 patients who used oral vitamin A or 3 who used topical tretinoin (Retin-A). In 6 patients, no cause of stellate-cell lipidosis was discerned. Stellate-cell lipidosis should be reported to alert clinicians to a potentially preventable form of liver injury.
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