Christine G. Janney

Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions

OJECTIVE: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.

Nonalcoholic steatohepatitis: an expanded clinical entity.

BACKGROUND/AIMS In the past, nonalcoholic steatohepatitis has been described mostly in obese women with diabetes. The aim of this study was to describe a series of patients with nonalcoholic steatohepatitis with a different clinical profile. METHODS The clinical, biochemical, and histological features of 33 patients with nonalcoholic steatohepatitis seen from July 1990 to June 1993 were analyzed. RESULTS The mean age was 47 years. All patients were antibody to hepatitis C virus-negative. Nineteen of 33 (58%) were men, 20 of 33 (61%) were nonobese, 26 of 33 (79%) had normal glucose levels, and 26 of 33 (79%) had normal lipid levels. Fourteen of 33 (42%) had normal glucose and lipid levels and were not obese. Thirteen of 33 (39%) had pathological increases in fibrosis, 5 of whom had micronodular cirrhosis. Of these 13 with severe, progressive disease, 8 (62%) were women, 8 (62%) were obese, 4 (31%) were diabetic or had an elevated glucose level, and 3 (23%) had hyperlipidemia. Although serum iron studies (transferrin saturation and ferritin) were abnormal in 18 of 31 (58%), no patient had hemochromatosis. CONCLUSIONS Nonalcoholic steatohepatitis can be a severe, progressive liver disease leading to the development of cirrhosis. It should no longer be considered a disease predominantly seen in obese women with diabetes.

Concurrence of Histologic Features of Steatohepatitis with Other Forms of Chronic Liver Disease

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 ≥ 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.

Limited success of HCV antiviral therapy in United States veterans

OBJECTIVE:The treatment of hepatitis C virus (HCV) infection in United States veterans has become a major task for the Veterans Administration Healthcare System. Although the comprehensive diagnosis and treatment of HCV-infected patients has been mandated, little is known about the performance characteristics of HCV clinics and about the outcomes of antiviral therapy in this unique patient population.METHODS:We retrospectively examined clinic show rates, treatment eligibility, and the response to antiviral therapy in a dedicated HCV outpatient clinic in a large urban Veterans Affairs medical center.RESULTS:Our data demonstrate that few veterans—regardless of their age or ethnic background—pursue evaluation and treatment of their HCV infection by hepatologists. A minority of those patients who undergo a comprehensive clinic evaluation meet the standard eligibility criteria for antiviral therapy. The overall efficacy of antiviral treatment, as measured by the sustained virological response rate, is substantially lower than previously reported in randomized clinical trials. HCV-infected veterans are characterized by a unique combination of risk factors that are predictive of a poor response to antiviral therapy, including a preponderance of male gender, HCV genotype I, age > 40 yr, and histologically advanced degrees of liver disease.CONCLUSIONS:Our study demonstrates the limitations of outpatient HCV treatment initiatives in the United States veteran population, and suggests that the overall impact of current HCV treatment programs may be small.

Repetitive Self-Limited Acute Pancreatitis Induces Pancreatic Fibrogenesis in the Mouse

The role of repetitive acute injury in the pathogenesis of chronic pancreatitis remains unknown. To determine if repetitive injury induced by pancreatic hyperstimulation would reproduce the characteristic features of human chronic pancreatitis, acute reversible pancreatic injury was induced in mice by twice weekly cerulein treatment, 50 μg/kg/hr × 6 hr, for 10 weeks. Procollagen α1(I) mRNA was markedly increased by week 2. Sirius red staining of interstitial collagen demonstrated progressive accumulation of extracellular matrix surrounding acinar units and in interlobular spaces. Atrophy, transdifferentiation of acinar units to ductlike tubular complexes, and dilatation of intraacinar lumina also developed. Electron microscopy demonstrated the presence of stromal cells in areas of fibrosis with morphologic characteristics of pancreatic stellate cells. These findings demonstrate that, in a murine model, repetitive acute injury to the pancreas by hyperstimulation can reproduce the major morphological characteristics of human chronic pancreatitis.

Histological evaluation of iron in liver biopsies: relationship to HFE mutations

OBJECTIVE:Hepatic iron overload is observed in many forms of chronic liver disease. Hereditary hemochromatosis (HH) results in hepatic iron overload and is associated with 2 missense mutations in the HFE gene. The aim of this study was to define the usefulness of the histological pattern of iron deposition in determining the probability of an iron-loaded patient having HFE-related iron overload.METHODS:This study assessed liver biopsies containing stainable iron from 103 patients with various liver diseases; clinical information included hepatic iron concentration and HFE genotype (C282Y, H63D). The biopsies were evaluated using a reproducible histological scoring system for iron deposition. Three separate components of histological iron deposition were recorded: 1) pattern (primarily hepatocellular with a zonal gradient, or reticuloendothelial without an obvious zonal gradient), 2) pattern score to denote the extent of iron within the acinus, and 3) quantitation grade of iron granules within affected hepatocytes.RESULTS:The predominantly hepatocellular pattern (HH pattern) was observed in 72 biopsies of which only 42 were from patients homozygous for the C282Y mutation, indicating that this pattern alone cannot be used as a surrogate marker for HH genotype. The predominantly reticuloendothelial pattern (non-HH pattern) was observed in the remaining 31 patients, none of whom was compound heterozygous or homozygous for the C282Y mutation (negative predictive value: 100%). Thus, the non-HH, reticuloendothelial pattern reliably predicts the absence of homozygosity for the C282Y mutation.CONCLUSIONS:The use of histological evaluation for iron deposition is simple, assists in expanding information communicated from histopathologic observations, and may be clinically useful in determining the necessity of further evaluation of HFE genotype in subjects with histological evidence of hepatic iron overload.

Hepatic lipid peroxidation in hereditary hemochromatosis and alcoholic liver injury

Studies in experimental animals have indicated that enhanced lipid peroxidation may play a role in the hepatic injury produced by iron overload or by excessive alcohol consumption. The aim of this study was to compare the formation of lipid peroxidation-derived aldehydes in the liver of patients with hereditary hemochromatosis (HH) and alcohol abuse. Liver biopsy specimens from 10 nondrinking patients with HH were evaluated. These patients were classified as having HH based on hepatic iron index or human leukocyte antigen identity with a known proband. All patients were homozygous for the Cys282Tyr mutation. In addition, 8 patients with alcoholic liver disease were examined, 2 of whom also had hemochromatosis. For comparison, 17 patients with liver diseases unrelated to iron overload or alcohol abuse were studied. Liver biopsy specimens were immunostained for protein adducts with malondialdehyde and 4-hydroxynonenal. Both malondialdehyde- and 4-hydroxynonenal-protein adducts were found from liver specimens of patients with HH and alcohol abuse in more abundant amounts than from patients in a control group. In alcoholics the adducts were primarily in zone 3, whereas in hemochromatosis staining had an acinar zone 1 predominance, which followed the localization of iron. The most abundant amounts of protein adducts were noted in patients with alcohol abuse plus iron overload. The data support the concept that both chronic alcohol use and iron overload induce hepatic lipid peroxidation. Through formation of reactive aldehydic products, excessive alcohol consumption and iron overload may have additive hepatotoxic effects.

Diagnosis and Management of Appendiceal Mucoceles

Preoperative diagnosis of appendiceal mucoceles is rare. If untreated, one type of mucoceles may rupture producing a potentially fatal entity known as pseudomyxoma peritonei. The importance of diagnosing appendiceal mucoceles is highlighted through a case presentation of a woman who had an incidental finding of mucinous cystadenoma of the appendix during colonoscopic evaluation for occult gastrointestinal bleeding. A detailed review of the medical literature regarding appendiceal mucoceles is presented, with emphasis on the pathologic, clinical, radiologic, and evolving endoscopic features. Surgical options and prognosis are discussed.

Original ContributionsNonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions

OJECTIVE: 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.

Hemostatic agent microporous polysaccharide hemospheres (MPH) does not affect healing or intact sinus mucosa.

Objectives/Hypothesis: Absorbable hemostatic agents are used routinely following sinus surgery. Recent studies suggest that current biomaterials, such as FloSeal Matrix Hemostatic Sealant (Fusion Medical Technologies, Mountain View, CA) may interfere with mucosal regeneration. This study was designed to evaluate the effects of Microporous Polysaccharide Hemospheres (MPH, Medafor, Inc., Minneapolis, MN), a novel rapidly‐absorbing hemostatic powder, on healing and intact sinus mucosa.