Association of serum adipocytokines with hepatic steatosis and fibrosis in patients with chronic hepatitis C.

BACKGROUND: The pathogenic mechanisms of hepatic steatosis in hepatitis C (HCV) remain unclear. AIM: To assess the potential role of cytokines and adipokines in HCV-related steatosis and fibrosis. METHODS: We profiled several adipokines, cytokines, and related soluble molecules in 99 HCV patients and analyzed their potential associations with hepatic steatosis and fibrosis. RESULTS: Serum leptin and IL-1RA were significantly higher in HCV genotype 1 as compared to genotype 3. On the other hand, serum resistin, IL-8, IL-1B and sIL-6R, were significantly higher in HCV genotype 3. No differences were observed for adiponectin, visfatin, IL-6 and TNF-α. Regardless of HCV genotype, steatosis could be predicted by a combination of IL-8, IL-6, and sIL-6R/IL-6. When analysis was repeated for each of the genotypes, the reliability of models improved. Regardless of HCV genotype, moderate to severe fibrosis (Metavir score >F2), was predicted by IL-8 and resistin levels. CONCLUSIONS: Analysis of adipocytokines associated with steatosis supports the hypothesis that steatogenic pathways differ in HCV genotype 3 from those infected with non-genotype 3 infections.

Long-term follow-up of patients with nonalcoholic fatty liver.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of conditions ranging from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH) convincingly. NASH is the only subtype of NAFLD that has been shown to progress relatively, although these findings were reported from studies with short follow-up periods. We assessed the long-term outcomes of a NAFLD cohort. METHODS: Patients with NAFLD established by biopsy were identified in databases and categorized as NASH or non-NASH. Mortality data and causes of death were obtained from National Death Index Plus. The nonparametric Kaplan-Meier method with log-rank test and multivariate analyses with a Cox proportional hazard model were used to compare different NAFLD subtypes and to identify independent predictors of overall and liver-related mortality. RESULTS: Of 173 NAFLD patients (age at biopsy, 50.2 +/- 14.5 y; 39.9% male; 80.8% Caucasian; 28.9% with type II diabetes), 72 (41.6%) had NASH and 101 (58.4%) had non-NASH NAFLD. Over the follow-up period, the most common causes of death were coronary artery disease, malignancy, and liver-related death. Although overall mortality did not differ between the NAFLD subtypes, liver-related mortality was higher in patients with NASH (P < .05). Independent predictors of liver-related mortality included histologic NASH, type II diabetes, older age at biopsy, lower albumin levels, and increased levels of alkaline phosphatase (P < .05). CONCLUSIONS: This long-term follow-up evaluation of NAFLD patients confirms that NASH patients have increased liver-related mortality compared with non-NASH patients. In addition, patients with NAFLD and type II diabetes are especially at risk for liver-related mortality.

Gene expression profile associated with superimposed non-alcoholic fatty liver disease and hepatic fibrosis in patients with chronic hepatitis C.

BACKGROUND: Hepatic steatosis occurs in 40-70% of patients chronically infected with hepatitis C virus [chronic hepatitis C (CH-C)]. Hepatic steatosis in CH-C is associated with progressive liver disease and a low response rate to antiviral therapy. AIM: Gene expression profiles were examined in CH-C patients with and without hepatic steatosis, non-alcoholic steatohepatitis (NASH) and fibrosis. METHODS: This study included 65 CH-C patients who were not receiving antiviral treatment. Total RNA was extracted from peripheral blood mononuclear cells, quantified and used for one-step reverse transcriptase-polymerase chain reaction to profile 153 mRNAs that were normalized with six 'housekeeping' genes and a reference RNA. Multiple regression and stepwise selection assessed differences in gene expression and the models' performances were evaluated. RESULTS: Models predicting the grade of hepatic steatosis in patients with CH-C genotype 3 involved two genes: SOCS1 and IFITM1, which progressively changed their expression level with the increasing grade of steatosis. On the other hand, models predicting hepatic steatosis in non-genotype 3 patients highlighted MIP-1 cytokine encoding genes: CCL3 and CCL4 as well as IFNAR and PRKRIR. Expression levels of PRKRIR and SMAD3 differentiated patients with and without superimposed NASH only in the non-genotype 3 cohort (area under the receiver operating characteristic curve=0.822, P-value 0.006]. Gene expression signatures related to hepatic fibrosis were not genotype specific. CONCLUSIONS: Gene expression might predict moderate to severe hepatic steatosis, NASH and fibrosis in patients with CH-C, providing potential insights into the pathogenesis of hepatic steatosis and fibrosis in these patients.

Pathologic assessment of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) represents one of the most common forms of liver disease and is considered the hepatic manifestation of the metabolic syndrome. Within the NAFLD spectrum, simple steatosis is considered benign, whereas non-alcoholic steatohepatitis (NASH) may progress to cirrhosis. The distinction can be made only by liver biopsy. There is not complete agreement on criteria for diagnosis or the features used for grading and staging lesions. This article reviews some of the studies dealing with the histopathology of NAFLD, with attempts to develop a standardized pathologic scoring system for NASH.

Pathology of inflammatory bowel disease.

Inflammatory bowel disease in childhood refers to ulcerative colitis, Crohn's disease, and colitis of an indeterminate type. Their gross and microscopic features are discussed along with the differential diagnosis from other childhood conditions associated with bloody diarrhea.

Interinstitutional variability and effect of tissue fixative on the interpretation of a Barrett cytokeratin 7/20 immunoreactivity pattern in Barrett esophagus.

A unique pattern of cytokeratin (CK) 7/20 immunostaining (diffuse staining with CK7 and surface and superficial crypt staining with CK20) has been reported to be useful in differentiating Barrett esophagus (BE) from intestinal metaplasia of the stomach. However, there are conflicting results regarding the prevalence of a BE CK7/20 staining pattern in BE between different studies. Therefore, this study was performed to determine the degree of variability in interpretation of a BE CK7/20 pattern and to determine the reasons for variability when present. Esophageal and gastric mucosal biopsies from 67 patients with BE and antral intestinal metaplasia at 2 institutions were immunostained for CK7/20. All cases were evaluated for the presence of a BE CK7/20 pattern by 2 gastrointestinal pathologists from each institution, and the degree of agreement between institutions was determined. To determine the effect of tissue fixation and staining methods on the pattern of CK7/20 staining, unstained slides were exchanged between institutions, stained separately by each institution, and reexamined by all pathologists. There was excellent agreement on the presence of a BE CK7/20 staining pattern between pathologists at the same institution but only moderate agreement between pathologists at different institutions (71% overall, kappa = 0.58). Among BE cases, a BE CK7/20 staining pattern was identified in 50 (96%) of 52 cases by Cleveland Clinic Foundation pathologists but only 35 (67%) of 52 cases by Brigham and Women's Hospital pathologists. The major source of disagreement related to the interpretation of weak or variable CK7 staining of deep intestinalized mucosa in BE biopsies that were fixed in Hollande, but not those that were fixed in formalin. After the creation of a new set of criteria for a positive BE CK7/20 staining pattern, which took into account the effects of Hollande's fixative, the degree of agreement between pathologists at each of the 2 institutions was excellent (100%, kappa value = 1.0). Therefore, the CK7/20 staining pattern is influenced by the type of fixative used. Only a moderate level of interobserver agreement among pathologists regarding a BE CK7/20 pattern can be achieved if one is not aware of these effects. Nevertheless, specific criteria for interpretation of CK7/20 staining can be successfully applied between institutions and need to be developed before use of this technique in clinical practice.

Pathologic features associated with fibrosis in nonalcoholic fatty liver disease.

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.

Analysis of both NM23-h1 and NM23-H2 expression identifies "at-risk" patients with colorectal cancer.

Metastasis is the manifestation most directly affecting survival for patients with colorectal carcinoma. Identification of high-risk markers for metastases would allow focused selection of patients for adjuvant chemotherapy. Reports of the relationship between the putative metastasis suppressor NM23 and metastasis and/or survival in colorectal cancer patients are conflicting. The purpose of this study was to separately assess expression of NM23-H1 and NM23-H2 in primary colon cancers and determine whether expression was associated with regional nodal disease and/or liver metastases. Four patient cohorts were selected on the basis of histopathological staging at primary surgery (lymph node status/liver metastasis): -/- (n = 46), +/- (n = 47), -/+ (n = 43), and +/+ (n = 46). Primary tumors were evaluated by semiquantitative immunohistochemical analysis of NM23-H1 and NM23-H2. NM23-H2 expression was not related to survival; however, there was a modest survival advantage with low expression of NM23-H1 (P = 0.027). NM23-H1 expression in the +/+ group was increased compared with the other groups (P < 0.001). The -/+ group had the lowest expression of NM23-H2 (P < 0.001). This analysis distinguishes two high-risk groups of colorectal cancer patients. Prior discrepancies regarding the usefulness of NM23 staining may be explained by the need to evaluate both serotypes in addition to standard histopathological analysis to identify specific "at-risk" groups.

Thin-layer Pap test vs. conventional Pap smear. Analysis of 400 split samples.

OBJECTIVE: To analyze our experience with 400 Thin-Prep (TP) split samples (Cytyc Corp., Boxborough, Massachusetts) as an initial assessment of this new technology's effect in our laboratory. STUDY DESIGN: Three gynecologic oncologists and two general gynecologists obtained the 400 split samples using a broom sampling device. Following conventional smear (CS) preparation, they rinsed the broom in Preservcyt solution (Cytyc) for subsequent TP processing. The paired samples were separated, independently analyzed and classified by the Bethesda System. All available follow-up surgical pathology material was reviewed and compared to the cytologic diagnoses. RESULTS: TP had significantly more abnormal results (22% vs. 16%, P = .007), including more atypical squamous cells of undetermined significance (ASCUS) (9.5% vs. 6.3% P = .07) and low grade squamous intraepithelial lesion (LSIL) (7.8% vs. 5.3%, P = .03). Both methods had 3.3% high grade squamous intraepithelial lesion (HSIL). For TP, ASCUS/squamous intraepithelial lesion (SIL) = 0.86 and for CS, ASCUS/SIL = 0.74. Ten TP SILs had a paired negative CS, including LSIL (nine cases) and HSIL (one case). Consensus review of these 10 TP slides confirmed the HSIL and four LSILs. No CS SILs had a paired negative TP. Only 36 (9%) cases had surgical pathology follow-up. The surgical specimens included 17 cervical intraepithelial neoplasia (CIN) 2 or above. The TP method had no false negatives, while the CS method had 3 false negatives among the 17 confirmed cases of CIN 2 or above. CONCLUSION: TP appears to be superior to CS for detecting SILs.

Impact of non-alcoholic fatty liver disease on chronic hepatitis B.

BACKGROUND: The impact of superimposed non-alcoholic fatty liver disease (NAFLD) is well established in patients with chronic hepatitis C (CH-C), but the impact in patients with chronic hepatitis B (CH-B) is less clear. AIM: This study aims to evaluate the prevalence of NAFLD in patients with CH-B and the association with viral and host factors, particularly in patients with metabolic syndrome (MS). DESIGN: Data from patients with CH-B was obtained from our databases. Patients with excessive alcohol use were excluded. Hepatitis B virus (HBV) genotyping by INNO-LIPA was available for some patients. The presence of MS was defined according to the Adult Treatment Panel III (ATP III). All biopsies were read by two hepatopathologists using Metavir, modified histologic activity index (MHAI), as well as a NAFLD pathologic protocol. Patients were classified as (1) those without NAFLD; (2) those with simple hepatic steatosis; (3) and those with superimposed non-alcoholic steatohepatitis (NASH). Factors associated with superimposed NAFLD, its subtypes, and hepatic fibrosis were also analysed. RESULTS: Subjects included 153 HBV patients [66% male, age 50.5+/-27.5 years, body mass index 24.7+/-3.7 kg/m(2), waist 83.2+/-10.9 cm; 8.5% Caucasian, 67% Asian, aspartate aminotransferase (AST) 63.2+/-88.2 IU/l, alanine aminotransferase (ALT) 98.6+/-164.6 IU/l, glucose 111.6+/-50.5 mg/dl, HBV-DNA 1.8 x 10(8)+/-1.9 x 10(6) copies/ml, 7% with MS, 13% with diabetes, 20% with arterial hypertension and 8.5% with dyslipidaemia]. Liver biopsy was available for 64 subjects [19% had superimposed NAFLD, 13% had superimposed NASH, 86% had some degree of fibrosis, and 39% had advanced fibrosis (Ishak >3)]. Patients with HBV and superimposed NASH were significantly older (55 vs. 42 years, P=0.008), more likely to have hypertension (63% vs. 15%, P=0.006) and dyslipidaemia (50% vs. 8%, P=0.006), and had a larger waist circumference (92 vs. 83 cm, P=0.03). The presence of fibrosis was associated with higher waist circumference (84 vs. 80 cm, P=0.03), higher HBV-DNA (1.9 x 10(8) vs. 5 x 10(6) copies/ml, P=0.005), and elevated ALT >40 IU/l (73.6% vs. 33.3%, P=0.02). CONCLUSIONS: The components of MS (obesity, hypertension, and dyslipidaemia) are associated with the presence of NASH in patients with CH-B. The presence of hepatic fibrosis seems to be associated with known host and viral factors as well as the presence of abdominal obesity.

Pegylated interferon alpha-2b, ribavirin and amantadine for chronic hepatitis C.

In an attempt to improve the efficacy of antiviral therapy for chronic hepatitis C, a three-drug combination of pegylated interferon alpha-2b, ribavirin, and amantadine has been suggested. Despite the initial enthusiasm, the role of amantadine in the treatment of chronic hepatitis C remains controversial. In a multi-center, open-label clinical trial, the potential efficacy and safety of this triple combination regimen were assessed. In this open-label pilot study, two separate patient populations with chronic hepatitis C and viremia were enrolled: treatment-naive and those who had failed a previous course of treatment. Patients were started on pegylated interferon alpha-2b at a dose of 1.5 microg/kg weekly with ribavirin, 1000-1200 mg/day, and amantadine, 200 mg/day, for 4 weeks, followed by pegylated interferon alpha-2b, 0.5 microg/kg weekly, ribavirin, 1000-1200 mg/day, and amantadine, 200 mg/day, for another 20 weeks. Patients with undetectable HCV RNA at week 24 continued this regimen for a total of 48 weeks and were followed for another 24 weeks. Patients with undetectable virus (<50 IU/mL) after 24 weeks of follow-up were considered to have SVR. Health-related quality of life and safety data were also collected. Sixty-nine treatment-naive and 99 nonresponder patients with chronic hepatitis C were enrolled in the study. Of all patients enrolled, 74% were male, aged 47.27+/-5.76 years; their body mass index (BMI) was 28.87+/-5.05 kg/m2, 79.4% were white, 85% had HCV genotypes 1 and 4, and 36% had cirrhosis. Their baseline HCV RNA was 689,242+/-698,030 IU/mL, with a baseline ALT of 107.25+/-79.08. Of the entire cohort, 35 (21%) discontinued early due to side effects or loss to follow-up. Significant anemia (hemoglobin, < 10 g/dL) occurred in 11% (19/168), while severe anemia (hemoglobin, <8.5 g/dL) occurred in 0.6% (1/168). In the treatment-naive group, sustained virologic response (SVR) was 34.3%, versus 19.4% for the group who had previously failed to respond to a course of treatment (P = 0.01). For both groups combined, virologic response after 24 weeks of therapy was 40.5%, with an end-of-treatment virologic response of 35.7% and a SVR of 26.2%. Patients with genotypes 1 and 4 had lower response rates than those with genotypes 2 and 3 (SVR, 21 vs. 46%; P = 0.001). Patients with advanced fibrosis (Metavir stages 3 and 4) tended to have lower response rates than those with minimal or mild fibrosis (Metavir stages 0-2) (SVR, 10 vs. 30%; P = 0.08). African-American patients with HCV had lower response rates than Caucasians or other ethnic groups (SVR, 4 vs. 29 vs. 20%; P = 0.04). Age, gender, and BMI did not affect SVR. The addition of amantadine to pegylated interferon alpha-2b and ribavirin does not seem to increase the efficicacy of this regimen.

Histologic changes in defunctioned rectums in patients with inflammatory bowel disease: a clinicopathologic study of 82 patients with long-term follow-up.

PURPOSE: Inflammation occurs in defunctioned rectums in patients without inflammatory bowel disease. Defunctioned rectums in patients with inflammatory bowel disease have additional histopathologic changes that can cause diagnostic confusion. The aim of this study was to ascertain whether histologic changes in defunctioned rectums had any association with original pathologic diagnosis in the colectomy specimen, duration of defunctionalization, or occurrence of Crohn's disease-like complications during follow-up. METHODS: In this retrospective study, we reviewed the patient records and reexamined histologically the defunctioned rectums and original colectomy specimens of 84 consecutive patients encountered between 1983 and 1986. RESULTS: All excised rectal specimens had ulcers and erosions, usually with prominent mucosal lymphoid aggregates, often with mucosal atrophy, diffuse mucin depletion, and marked mucosal architectural distortion. Transmural lymphoid aggregates were identified in 56 patients (67 percent) and were graded as moderate or marked in 35 (42 percent). Ten rectal specimens contained nonnecrotizing granulomas. The original pathologic diagnoses from the colectomy specimens were as follows: ulcerative colitis (n = 22), Crohn's disease (n = 19), indeterminate colitis (n = 41), adenocarcinoma (n = 1), and diverticular disease (n = 1). Only mild histologic changes were observed in rectal specimens from patients with diverticular disease and adenocarcinoma, and granulomas were identified more frequently in Crohn's disease patients. Otherwise, no feature in the defunctioned rectum was associated with the original diagnosis or duration of defunctionalization. Sixteen patients (19 percent) had late surgical complications suggestive of Crohn's disease (abscess, fistula, or subsequent biopsy specimen containing nonnecrotizing granulomas) after a median follow-up of 4.8 years. Five were patients categorized as having Crohn's disease with colectomy specimen, nine had indeterminate colitis, and two had ulcerative colitis. No histologic feature in the defunctioned rectum was associated with Crohn's disease-like complications. CONCLUSIONS: Granulomas in a defunctioned rectum were associated with an original diagnosis of Crohn's disease. Transmural lymphoid aggregates were common in defunctioned rectums in patients with inflammatory bowel disease and did not indicate Crohn's disease. Other histologic changes developed independently of diagnosis and duration of defunctionalization.

Nonalcoholic fatty liver disease in patients with type 2 diabetes.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is reported commonly in patients with type 2 diabetes mellitus (DM), which has been suggested as a risk factor for the progressive form of NAFLD, or nonalcoholic steatohepatitis. The aim of this study was to assess the outcome of patients with NAFLD and DM. METHODS: A cohort of patients with NAFLD was identified, and patients with other causes of liver disease (alcohol, medication, etc.) were excluded. Clinical, pathological, and mortality data were available for this cohort. Patients were categorized and compared according to the presence or absence of DM. RESULTS: Of 132 patients with NAFLD, 44 patients (33%) had an established diagnosis of DM. Patients with DM were older and had greater serum glucose and triglyceride levels and a greater aspartate aminotransferase-alanine aminotransferase ratio. Liver biopsy specimens from patients with DM showed more vacuolated nuclei and acidophilic bodies. Cirrhosis (histological or clinical) occurred in 25% of patients with DM (11 of 44 patients) and NAFLD compared with only 10.2% (9 of 88 patients) of patients without DM with NAFLD (P = 0.04). After adjusting for potential confounders (age, body mass index, and the presence of cirrhosis), both overall mortality (risk ratio [RR], 3.30; 95% confidence interval [CI], 1.76-6.18; P = 0.002) and mortality related to liver disease (RR, 22.83; 95% CI, 2.97-175.03; P = 0.003) were greater in diabetic patients with NAFLD. Markers of hepatic dysfunction (low albumin level, high total bilirubin level, and prolonged prothrombin time) were the only independent predictors of increased mortality. CONCLUSIONS: Patients with NAFLD and DM are at risk for the development of an aggressive outcome, such as cirrhosis and mortality. This study supports the potential role of insulin resistance in the development of poor clinical outcomes in patients with NAFLD.

Equivalent function, quality of life and pouch survival rates after ileal pouch-anal anastomosis for indeterminate and ulcerative colitis.

OBJECTIVE: To compare the function, complications, and quality of life after ileal pouch-anal anastomosis (IPAA) for patients with indeterminate colitis (IndC) and ulcerative colitis (UC). SUMMARY BACKGROUND DATA: Reports on the outcome of IPAA for IndC have been inconclusive because of the small numbers available for analysis. Concerns about functional outcome, infectious perineal complications, pouch loss and the development of Crohn's disease remain, while there is no data on the quality of life after IPAA for IndC. METHODS: One thousand nine hundred and eleven patients undergoing IPAA for Ind and UC from 1983 to 1999 were evaluated. IndC was confirmed by repeat pathologic evaluation in 115 patients. Functional outcome and quality of life were assessed prospectively for all office visits (IndC = 230; UC = 5388) using previously reported systems. Complications were evaluated retrospectively. RESULTS: Functional results and the incidence of anastomotic complications and major pouch fistulae were the same in UC and IndC patients. Although IndC patients were more likely to develop minor perineal fistulae, pelvic abscess, and Crohn's disease, the rate of pouch failure was 3.4%, identical to that of UC patients. There was no clinically significant difference in quality of life, or satisfaction with IPAA surgery. Patients were equally happy to recommend surgery to IndC or UC patients, but 3% fewer IndC would undergo the same surgery again for their disease. CONCLUSIONS: While functional outcome, quality of life, and pouch survival rates are equivalent after IPAA for IndC and UC, there is an increase in some complications and the late diagnosis of Crohn's disease. Over 93% of IndC patients would undergo the same procedure again, and 98% would recommend IPAA to others with IndC. Patients with IndC should not be precluded from having IPAA surgery.

Fluorescence in situ hybridization of cytologic specimens from Barrett's esophagus: a pilot feasibility study.

BACKGROUND: Endoscopic brush cytology is a promising surveillance technique for Barrett's esophagus. However, there is a need for ancillary biomarkers to increase the sensitivity of cytology and to allow identification of patients at increased risk for disease progression. The aims of this study were to evaluate the feasibility of fluorescence in situ hybridization of endoscopic brush cytology specimens and to determine if there are specific chromosomal changes in cytologic specimens from patients with cancer that are not present in patients without dysplasia. METHODS: Archival cytology slides from 16 patients with Barrett's esophagus were studied: 8 negative for dysplasia and 8 positive for adenocarcinoma. Fluorescence in situ hybridization was used to detect two alterations: HER-2 gene (17q11.2-q12) and 20q13.2 region amplification. OBSERVATIONS: For 7 of 8 adenocarcinoma cases, there was amplification/aneusomy of at least one of the two analyzed regions by fluorescence in situ hybridization. None of the samples negative for dysplasia were abnormal for either of the two genomic regions studied. CONCLUSIONS: Fluorescence in situ hybridization is feasible by using routine Barrett's esophagus cytologic specimens. Differences in genomic makeup can be detected in cells from patients negative for dysplasia and in those with adenocarcinoma.

Anal transitional zone cancer after restorative proctocolectomy and ileoanal anastomosis in familial adenomatous polyposis: report of two cases.

PURPOSE: Restorative proctocolectomy with ileal pouch-anal anastomosis is accepted as the surgical treatment of choice for many patients with familial adenomatous polyposis. The risk of cancer developing in the ileal pouch after this surgery is unknown. Cancer may arise from the ileal pouch after restorative proctocolectomy, but that arising from the anal transitional zone has not been documented in familial adenomatous polyposis. We report two cases of this cancer from the anal transitional zone in patients with familial adenomatous polyposis, with a review of the literature. METHODS: All patients with familial adenomatous polyposis treated with restorative proctocolectomy and ileal pouch-anal anastomosis in The Cleveland Clinic were included in the study. Patients whose surveillance biopsy of the anal transitional zone revealed invasive adenocarcinoma were studied. RESULTS: Among a total of 146 patients with familial adenomatous polyposis who underwent restorative proctocolectomy and ileal pouch-anal anastomosis from 1983 to 2001 in our institution, none developed cancer of the anal transitional zone at up to 18 years of follow-up. However, there were two patients, both of whom underwent surgery elsewhere but who were followed up here, who developed invasive adenocarcinoma of the anal transitional zone. In one of them, cancer was diagnosed three years after a double-stapled ileal pouch-anal anastomosis, whereas in the other, cancer occurred eight years after a straight ileoanal anastomosis with mucosectomy. CONCLUSIONS: Cancer may develop in the anal transitional zone after restorative proctocolectomy with ileal pouch-anal anastomosis for familial adenomatous polyposis. Long-term surveillance of the anal transitional zone needs to be emphasized.

The utility of radiological imaging in nonalcoholic fatty liver disease.

BACKGROUND & AIMS: This prospective study evaluates the role of radiological modalities in establishing the diagnosis of nonalcoholic steatohepatitis (NASH). METHODS: Consecutive patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD) were enrolled (2000-2001). Patients with other liver diseases and significant alcohol consumption (>20 g/day) were excluded. Clinicodemographic data were gathered at the time of liver biopsy. Each biopsy specimen was assessed by a hepatopathologist. Each patient underwent a limited abdominal ultrasonography (US), computerized tomography (CT), and magnetic resonance imaging (MRI). Films were interpreted by a radiologist who used a predetermined radiological protocol. Each radiological study was reread by the same radiologist and a second radiologist. RESULTS: Patients with NASH had greater aspartate aminotransferase levels (P = 0.03), greater ferritin levels (P = 0.05), more hepatocyte ballooning (P < 0.0001), and more fibrosis (P = 0.002). None of the radiological features distinguished between NASH and other types of NAFLD. No radiological modality detected the presence of hepatocyte ballooning, Mallory's hyaline, or fibrosis, which are important features in the diagnosis of NASH. The presence of >33% fat on liver biopsy was optimal for detecting steatosis on radiological imaging. CONCLUSIONS: Differences between NASH and nonprogressive NAFLD were not apparent with any radiological modality. Of the pathologic features important for establishing the diagnosis of NASH, only the severity of steatosis was reflected in these radiological modalities. Good intraobserver agreement was evident for each modality (US, CT, and MRI) that was superior to interobserver agreement.

Triple combination of interferon alpha-2b, ribavirin, and amantadine for treatment of chronic hepatitis C.

Retreatment of interferon-resistant chronic hepatitis C represents a significant clinical challenge. In an open-label, pilot study, the safety and efficacy of interferon alpha-2b, ribavirin, and amantadine were assessed. Twenty patients with chronic hepatitis C who had previously failed to respond to a course of interferon monotherapy followed by a course of combination therapy (10 patients received interferon alpha-2b [3 million units three times a week] plus ribavirin [800 mg/d] and 10 patients received interferon alpha-2b [3 million units three times a week] plus amantadine [200 mg/d]) were enrolled in this retreatment protocol. One month after discontinuation of their last regimen, patients started treatment with interferon alpha-2b (3 million units three times a week), ribavirin (1,000-1,200 mg/d), and amantadine (200 mg/d). Biochemical and virologic end points were monitored. Patients with hepatitis C virus (HCV) RNA levels of <100 copies/mL at the end of 24 weeks of therapy completed a 48-week course of interferon alpha-2b, ribavirin, and amantadine treatment. Of the enrolled subjects, 60% were male, 85% were white, 85% had HCV genotype 1, and 20% had histologic cirrhosis. The mean age +/- SD of the patients was 44.1 +/- 4.9 years, the mean baseline HCV RNA level +/- SD was 1,845,150 +/- 1,279,069 copies/mL, and the mean baseline alanine aminotransferase level +/- SD was 130 +/- 100 U/L. Five patients (25%) became HCV RNA negative (<100 copies/mL) after 24 weeks of treatment, with only three patients (15%) remaining HCV RNA negative at the end of 48 weeks of treatment. This end of treatment response was sustained 6 months after the discontinuation of treatment in only two patients (10%). In this interferon-resistant group, a treatment regimen of interferon alpha-2b, ribavirin, and amantadine was associated with only a 10% sustained viral eradication rate.

Cytokeratin expression patterns in noncardia, intestinal metaplasia-associated gastric adenocarcinoma: implication for the evaluation of intestinal metaplasia and tumors at the esophagogastric junction.

BACKGROUND: Barrett esophagus (BE)/Barrett adenocarcinoma and distal gastric intestinal metaplasia (IM)/adenocarcinoma are similar histologically, but they differ in their clinical presentation, epidemiology, and pathogenesis. Differentiating BE from gastric IM and Barrett adenocarcinoma from gastric adenocarcinoma is difficult, especially when IM is short or tumors are large and involve both sides of the esophagogastric junction. Previously, the authors identified unique cytokeratin (CK) immunoreactivity patterns that were associated strongly with BE and Barrett adenocarcinoma. The specificity of CK7 and CK20 (CK7/20) expression patterns in patients with IM-associated gastric adenocarcinoma, which is distinct epidemiologically from BE/Barrett adenocarcinoma, has not been evaluated. The objective of the current study was to evaluate the CK7/20 expression patterns in noncardia, IM-associated gastric adenocarcinoma in a Chinese population with a low risk for BE and esophageal adenocarcinoma and a high risk for Helicobacter pylori infection and gastric carcinoma. METHODS: Endoscopic biopsy specimens of gastric IM and adjacent tumor from 50 consecutive patients with advanced noncardia gastric carcinoma were immunostained for CK7 and CK20. Clinical and endoscopic features and H. pylori status were documented. Two gastrointestinal pathologists, blinded to clinical and endoscopic data, independently assessed CK7/20 immunohistochemistry. RESULTS: H. pylori infection was present in 43 of 50 patients (86%). In the area of IM, patchy CK7 staining was seen in 9 patients (18%), and diffuse CK20 staining was seen in all 50 patients (100%). The BE CK7/20 pattern characterized by CK7 staining in superficial and deep glands and the CK20 staining in surface epithelium was not seen in any of the 50 patients. Only one patient (2%) demonstrated a CK7 positive/CK20 negative immunophenotype characteristic of Barrett adenocarcinoma. The remaining 49 patients (98%) showed non-Barrett adenocarcinoma patterns of CK7/20 staining, i.e., a CK7 positive/CK20 positive pattern was seen in 33 patients (66%), a CK7 negative/CK20 positive pattern was seen in 12 patients (24%), and a CK7 negative/CK20 negative pattern was seen in 4 patients (8%). CONCLUSIONS: In a patient population without risk factors for the development of BE/esophageal adenocarcinoma, the CK7/20 pattern characteristic of BE was not present in gastric IM adjacent to adenocarcinoma, and the CK7/20 pattern characteristic of Barrett adenocarcinoma also was extremely rare. These results support the hypothesis that, despite the presence of intestinalized mucosa in both disorders, BE/Barrett adenocarcinoma and gastric IM/adenocarcinoma are two distinct clinical entities with unique demographic, clinical, and CK immunophenotypic findings. These results may have application to the evaluation of patients with IM and adenocarcinoma arising at the esophagogastric junction.

p53 expression in low grade dysplasia in Barrett's esophagus: correlation with interobserver agreement and disease progression.

OBJECTIVES: The frequency of progression from low grade dysplasia (LGD) to high grade dysplasia/carcinoma (HGD/ CA) in Barrett's esophagus (BE) varies among studies. Current assessment is made more difficult because of pathologists' interobserver variability in diagnosing LGD. We recently conducted an interobserver study on LGD and reported a positive correlation between the extent of agreement among GI pathologists and progression of LGD. In the current study, we analyzed the immunohistochemical staining for p53 in patients diagnosed with LGD with known clinical outcome and interobserver agreement data. METHODS: Fixed, paraffin-embedded endoscopic biopsy specimens from 16 patients diagnosed with LGD in BE were immunostained for p53 (DO-7, Dako, Carpinteria, CA). Hematoxylin and eosin-stained and immunostained sections were examined in tandem to determine whether the LGD areas in question stained for p53. The p53 immunoreactivity was correlated with clinical progression and with the interobserver agreement among three GI pathologists. RESULTS: The overall mean follow-up was 23 months (range 2-84 months). LGD areas in seven of eight patients (88%) who progressed to HGD/CA stained positively for p53 compared to only two of eight nonprogressors (25%). A correlation with clinical progression was seen for p53 positivity (p = 0.017; log-rank test), and for either p53 positivity or complete agreement among three GI pathologists on LGD diagnosis (p = 0.014; log-rank test). The p53 staining demonstrated 88% sensitivity and 75% specificity for progression of LGD to HGD/CA. Adding complete interobserver agreement on LGD among three experienced GI pathologists to p53 positivity resulted in improved sensitivity with no change in specificity (100% and 75%, respectively). CONCLUSIONS: In conjunction with histological evaluation by GI pathologists for a diagnosis of LGD, immunohistochemical staining for p53 can be used as an adjunctive test, as it correlated with progression to HGD/CA in this series.