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BACKGROUND End-stage renal failure after successful liver transplantation (LTx) has been described in up to 5% of patients. Kidney transplantation (KTx) has been the treatment of choice in these cases. However, in recipients infected with hepatitis C virus (HCV), the augmentation of immunosuppression after KTx may result in an increased viral load. This, in turn, may adversely affect the liver allograft. METHOD The present study retrospectively examined the outcome in 17 patients (3 females and 14 males, mean age 51.1+/-11.3 years) who received KTx after LTx. The mean interval from LTx to KTx was 57.6+/-32.1 months. The mean follow-up was 41.7+/-20.5 months after KTx, and 99.6+/-37.7 months after LTx. Sixteen of the 17 patients received tacrolimus-based immunosuppression at the time of KTx. RESULTS During the follow-up period, one patient underwent combined liver and kidney retransplantation 3.7 years after KTx and 12.7 years after LTx. She subsequently died secondary to primary nonfunction. Four other patients died, two of lung cancer, one of pancreatitis/sepsis, and one of severe depression leading to noncompliance. A total of 29 episodes of biopsy-proven acute renal allograft rejection (1.7 episodes/ patient) were encountered and treated with steroids. Seven patients experienced a rise in liver function tests during the period of increased steroid dosage. Four patients received no treatment, and their liver function returned to baseline. The remaining three were treated with interferon. Overall 1- and 3-year actuarial patient and liver allograft survival was 88% and 71% (after renal transplantation); corresponding 1- and 3-year actuarial graft survival was 88% and 61%. Twelve patients are alive with normal liver function. One patient is on dialysis, because of renal allograft loss to noncompliance. CONCLUSION In this series, LTx recipients with HCV infection were able to undergo KTx with a reasonable degree of success. KTx should be offered for end-stage renal failure after LTx, even in the presence of HCV infection, to individuals with stable liver function and no signs of liver failure.

Acute liver failure has extremely high mortality without liver transplantation. We attempted to determine the value of abdominal CT scanning and liver biopsy in its management. A retrospective analysis of patients with acute liver failure was performed; demographic, clinical, radiologic and histopathologic features were noted. Over a period of 13 years, 177 patients were evaluated. The mean age was 39 years and 63% were females. The patients were divided into three groups. Fourteen percent survived with medical management (group I), 37% died (group II), and 49% had liver transplantation (group III). Most patients showed diffuse low density of the liver on CT scanning and the proportions were similar in the three groups. Moderate to large ascites was not present in group I but occurred in 31% of patients in group II and in 15% in group III. Mean hepatic volumes were similar in the three groups; however, 97% of the patients with a liver volume of less than 1000 ml either died or required liver transplantation. Liver biopsies among patients with spontaneous recovery (group I) were distinguished by the presence of regenerative changes and a hepatic parenchymal necrosis of less than 50%. These results suggest that in patients with acute liver failure a liver volume of less than 1000 ml and/or hepatic parenchymal necrosis of greater than 50% is indicative of a poor prognosis. This information may assist decision making in such patients, in particular, regarding the need for liver transplantation.

The colon had higher levels of baseline potential difference, short-circuit current, and resistance than the ileum during 6–48 h of ischemia. Colonic epithelial cells responded well to theophylline stimulation at 24 h of ischemia, while there was no ileal response. The colonic mucosa was histopathologically well preserved in UW solution for 48 h, and mucosal damage induced by reoxygenation was less than in the ileum. In conclusion, electrophysiologically and histopathologically, the colon is less susceptible to cold preservation damage than the ileum during storage with UW solution.

Background & Aims: The present organ shortage has brought into question the suitability of hepatitis C virus (HCV)-positive grafts. This study reviewed the outcome of such transplantations in our institution. Methods: Twenty-three HCV-positive patients who underwent orthotopic liver transplantation (OLT) for end-stage liver disease with HCV-positive grafts in 1992–1995 were studied. Only patients who survived more than 30 days were included in the analysis. Control group included 169 patients who underwent transplantation for HCV-related cirrhosis and received HCV-negative organs. Results: Patients who received HCV-infected organs had a cumulative survival rate of 89% and 72% at 1 and 5 years, respectively, vs. 88% and 73% for the control group (NS). There was no difference in graft survival, incidence of cirrhosis, mean hepatitis activity index score, fibrosis, or mean activity of serum transaminases. There was a trend toward lower incidence of recurrent hepatitis C in the study group compared with control (21% vs. 23% at 1 year and 47% vs. 64% at 5 years; NS). Patients in whom the donor strain became predominant after transplantation had significantly longer disease-free survival than patients who retained their own HCV strain ( P Conclusions: HCV-infected livers transplanted into HCV-infected recipients do not appear to convey a worse outcome in the initial years after OLT than HCV-negative grafts. GASTROENTEROLOGY 1999;117:149-153

Background: Because of the rarity of hilar cholangiocarcinoma, its prognostic risk factors have not been sufficiently analyzed. This retrospective study was undertaken to evaluate various pathologic risk factors which influenced survival after curative hepatic resection or transplantation. Methods: Between 1981 and 1996, 72 patients (43 males and 29 females) with hilar cholangiocarcinoma underwent hepatic resection (34 patients) or transplantation (38 patients) with curative intent. Medical records and pathologic specimens were reviewed to examine the various prognostic risk factors. Survival was calculated by the method of Kaplan-Meier using the log rank test with adjustment for the type of operation. Survival statistics were calculated first for each kind of treatment separately, and then combined for the calculation of the final significance value. Results: Survival rates for 1, 3, and 5 years after hepatic resection were 74%, 34%, and 9%, respectively, and those after transplantation were 60%, 32%, and 25%, respectively. Univariate analysis revealed that T-3, positive lymph nodes, positive surgical margins, and pTNM stage III and IV were statistically significant poor prognostic factors. Multivariate analysis revealed that pTNM stage 0, I, and II, negative lymph node, and negative surgical margins were statistically significant good prognostic factors. mFor the patients in pTNM stage 0–II with negative surgical margins, 1-, 3-, and 5-year survivals were 80%, 73%, and 73%, respectively. For patients in pTNM stage IV-A with negative lymph nodes and surgical margins, 1-, 3-, and 5-year survivals were 66%, 37%, and 37%, respectively. Conclusions: Satisfactory longterm survivals can be obtained by curative surgery for hilar cholangiocarcinoma either with hepatic resection or liver transplantation. Redefining pTNM stage III and IV-A is proposed to better define prognosis.

Background: Although tacrolimus-based immunosuppression has made intestinal transplantation feasible, the risk of the requisite chronic high-dose treatment has inhibited the widespread use of these procedures. We have examined our 1990–1997 experience to determine whether immunomodulatory strategies to improve outlook could be added to drug treatment. Study Design: Ninety-eight consecutive patients (59 children, 39 adults) with a panoply of indications received 104 allografts under tacrolimus-based immunosuppression: intestine only (n = 37); liver and intestine (n = 50); or multivisceral (n = 17). Of the last 42 patients, 20 received unmodified adjunct donor bone marrow cells; the other 22 were contemporaneous control patients. Results: With a mean followup of 32 ± 26 months (range, 1–86 months), 12 recipients (3 intestine only, 9 composite grafts) are alive with good nutrition beyond the 5-year milestone. Forty-seven (48%) of the total group survive bearing grafts that provide full (91%) or partial (9%) nutrition. Actuarial patient survival at 1 and 5 years (72% and 48%, respectively) was similar with isolated intestinal and composite graft recipients, but the loss rate of grafts from rejection was highest with intestine alone. The best results were in patients between 2 and 18 years of age (68% at 5 years). Adjunct bone marrow did not significantly affect the incidence of graft rejection, B-cell lymphoma, or the rate or severity of graft-versus-host disease. Conclusions: These results demonstrate that longterm rehabilitation similar to that with the other kinds of organ allografts is achievable with all three kinds of intestinal transplant procedures, that the morbidity and mortality is still too high for their widespread application, and that the liver is significantly but marginally protective of concomitantly engrafted intestine. Although none of the endpoints were markedly altered by donor leukocyte augmentation (and chimerism) with bone marrow, establishment of the safety of this adjunct procedure opens the way to further immune modulation strategies that can be added to the augmentation protocol.

A study was conducted to assess the inter and intrarater agreement for the histopathologic features and diagnosis of chronic rejection (CR) and several other important causes of late liver allograft dysfunction. On two occasions, five pathologists, experienced with liver transplantation, reviewed a set of 49 slides representing a range of diagnoses, without knowledge of the clinical history or liver injury test results. The readings were correlated with the original histopathologic diagnosis, liver injury tests, and clinicopathologic follow-up. Assessment of biopsy adequacy (kappa = 0.69) and portal tract counts (kappa = 0.79) showed good to excellent intrarater agreement, whereas interrater agreement for these variables was moderate to good, respectively (kappa = 0.44 and 0.65). Likewise, the intrarater agreement for the diagnosis of CR (kappa = 0.68), hepatitis (kappa = 0.77), and obstructive cholangiopathy (kappa = 0.55) showed good to excellent agreement, whereas the interrater agreement for these same diagnoses ranged from fair to good (kappa = 0.58, 0.46, and 0.25, respectively). In 18 specimens, there was a near unanimous diagnosis of CR across both readings. These biopsies were obtained at a median of 7.1 months (range, 42 days to 4.9 years) after transplantation, and the average number of portal tracts was 8.4 (range, 4-15). Interestingly, only 13 of these 18 specimens showed bile duct loss in >50% of the portal triads; the remaining cases showed atrophy/pyknosis of the biliary epithelium in a majority of small bile ducts. Clinicopathologic correlation showed that these 18 biopsies were obtained from 16 grafts from 15 patients, 14 of whom ultimately required retransplantation or died of or with CR, whereas two of the grafts/patients recovered. A high rate of sensitivity (92%) and a somewhat lower, but acceptable, rate of specificity (71% to 80%) was found for the diagnosis of CR. Chronic rejection and other causes of late liver allograft dysfunction can be diagnosed reliably by a group of pathologists experienced with liver transplantation, and the diagnosis of CR correlates with clinical course and liver function abnormalities. Expanded criteria for the diagnosis of CR are presented, and potential problem areas for practicing pathologists are discussed.

Background: The aim of this study was to report the influence of hepatitis C virus (HCV) genotypes and HLA matches on the outcome of liver transplantation, hepatitis recurrence, and progression to cirrhosis after transplantation. Methods: HCV genotypes were determined from pretransplantation sera and/or liver explant tissues from 202 patients with HCV-related end-stage liver disease. One hundred fifty patients with known infecting genotype for whom posttransplantation biopsy specimens were available or who had normal results of liver injury tests constituted the group analyzed. Patients were followed up for up to 4.5 years. Hepatitis activity index scores at the time of disease recurrence were used to assess disease activity. Cirrhosis was diagnosed by using histological evidence. The number of HLA matches with respect to A, B, DR, and DQ loci was determined. Results: The rates of hepatitis recurrence were 25% and 75% at 1 year and 4 years, respectively; Kaplan-Meier survival analysis did not reveal significant differences between the infecting genotypes with respect to overall rates of survival or recurrence of hepatitis. At hepatitis recurrence, hepatitis activity index scores did not differ between the genotype groups. The distribution of infecting genotypes among the 7 patients who developed cirrhosis is reflective of pretransplantation distribution. Neither HLA site-specific nor total matches affected the rates of survival or disease recurrence. Conclusions: The infecting HCV genotype had no influence on the incidence or severity of recurrent hepatitis, rate of survival, or development of cirrhosis. HLA matching does not influence transplantation outcome for HCV-related disease.

Fibrolamellar hepatoma (FL-HCC) is an uncommon variant of hepatocellular carcinoma (HCC), distinguished by histo-pathological features suggesting greater differentiation than conventional HCC. However, the optimal treatment and the prognosis of FL-HCC have been controversial. Follow-up studies are available from 1 year to 27 years, after 41 patients with FL-HCC were treated with partial hepatectomy (PHx) (28 patients) or liver transplantation (13 patients). In this retrospective study, the effect on outcome was determined for the pTNM stage and other prognostic factors routinely recorded at the time of surgery. Cumulative survival at 1, 3, 5, and 10 years was 97.6%, 72.3%, 66.2%, and 47.4%. Tumor-free survival at these times was 80.3%, 49.4%, 33%, and 29.3%. The TNM stage was significantly associated with tumor-free survival. Patients with positive nodes had a shorter tumor-free survival than those with negative nodes (P < .015). Patient survival was most adversely affected by the presence of vascular invasion (P < .05). FL-HCC is an indolently growing tumor of the liver, which usually was diagnosed in our patients at a stage too advanced for effective surgical treatment of most conventional HCC. Nevertheless, long-term survival frequently was achieved with aggressive surgical treatment. When a subtotal hepatectomy could not be performed, total hepatectomy (THx) with liver transplantation was a valuable option.

Cancers of the biliary tract are uncommon but aggressive malignancies that pose difficult problems in diagnosis and management. Long-term survival with these cancers is limited by their propensity for local invasion, so that pathologic stage becomes a major prognostic factor, and by their ability to cause biliary obstruction and sepsis and interfere with hepatic function. In selected patients, surgical resection offers the possibility of cure, but effective palliation is often the principal goal of treatment. Radiologic and endoscopic modalities thus often play a major role in patient management.

Background Central venulitis denotes a histologic lesion of the allograft liver characterized by perivenular and subendothelial mononuclear inflammation of the terminal hepatic venules associated with varying degrees of perivenular hepatocyte dropout. Although this lesion has generally been considered a manifestation of acute rejection, some have suggested that it instead represents tacrolimus hepatotoxicity. Methods We therefore compared the clinicopathologic features of 30 episodes of isolated central venulitis with 22 episodes of combined central venulitis and typical portal acute rejection occurring in 27 patients. Nineteen of the patients received tacrolimus and eight received cyclosporine as primary immunosuppression. Results No significant differences were found between the two groups, except that isolated central venulitis more often displayed a mild inflammatory component (P=0.007) with small lymphocytes as the predominant cell type (P=0.002). None of the patients had tacrolimus or cyclosporine levels that exceeded the therapeutic range, and none had other clinical evidence of drug toxicity. Usual antirejection therapy was instituted in all but two episodes; response was evident in 93% (28 of 30) of the isolated central venulitis and 86% (19 of 22) of the central venulitis-portal acute rejection group, with histologic regression documented in all follow-up specimens (four and five, respectively). Due to persistent central venulitis, two cyclosporine patients were switched to tacrolimus, with prompt resolution. Conclusions These findings are inconsistent with the concept that central venulitis represents drug toxicity and indicate instead that it is a form of acute allograft rejection.

The applicability of liver transplantation for ALD remains limited because of ethical arguments and also because of the perception of poor outcome after transplantation. Patients with alcoholic cirrhosis are known to do as well as patients with nonalcoholic liver disease after receiving liver allografts; however, the outcome in patients with severe acute alcoholic hepatitis in this setting is unclear. We studied 9 liver transplant recipients in whom severe acute alcoholic hepatitis was retrospectively diagnosed; 8 had underlying cirrhosis, and 1 had advanced fibrosis. All had Maddrey's discriminant function > 32, and most had hepatic encephalopathy and hepatorenal syndrome. History regarding abstinence was unreliable in some patients. Episodes of acute cellular rejection responded quickly to therapy, and despite recidivism in some patients, long-term survival was comparable to that of patients receiving transplants with alcoholic cirrhosis alone and those with a milder degree of alcoholic hepatitis and cirrhosis. This study suggests that severe acute alcoholic hepatitis may not be an appropriate contraindication for liver transplantation.

Epithelioid hemangioendothelioma (EHE) is best considered a vascular neoplasm of intermediate malignancy. Although usually progressive, the clinical course is highly unpredictable. The present communication describes a case of extensive recurrent hepatic EHE, limited to the liver allograft and initially manifest as an insidious seeding of individual tumor cells in areas of perivenular inflammation associated with rejection. A detailed immunophenotypic characterization of this and a small series of EHE was carried out in an effort to highlight subtle disease recurrence and to gain possible insights into tumor biology associated with this intriguing disease. In a series of five cases of hepatic EHE, CD34 (QB-END/10) was found to be more sensitive than Factor VIII (F-VIII) for recognition of the disease, similar to previous reports. The former diffusely and distinctly stained both epithelioid and dendritic tumor cells, whereas staining for the latter was focal, indistinct, and showed a high background. Although the tumor cells were negative for some markers of dendritic or macrophage maturation, such as CD1a, S100 protein, Mac 387, CD68, and LN3, there was marked infiltration of hepatic EHE by factor XIIIa + (F-XIIIa), Mac 387+, CD68+, and LN3+ macrophages and dendrocytes, most of which were interpreted as reactive. The "reactive" macrophage and dendrocyte populations were present throughout the fibrotic stroma and intermingled with the epithelioid clusters of EHE. Interestingly, a small subset of tumor cells coexpressed CD34 or F-VIII and F-XIIIa, the last of which is normally restricted to cells of the monocyte/macrophage lineage and cytokine activated microvascular endothelium in vitro. The known association of F-XIIIa+ dendrocytes with granulation tissue, repair and fibrogenesis, and the modulation of F-XIIIa and F-VIII expression by inflammatory cytokines led us to speculate that EHE lesions may derive from primitive "reticuloenothelial" cells that can differentiate along endothelial and dendritic pathways. The EHE lesions may represent a neoplastic analogue of wound healing. Thus, the variability in F-VIII staining, the strong expression of CD34, the infiltration of EHE lesions with F-XIIIa+ dendrocytes, and the coexpression of CD34 and F-XIIIa on a subset of tumor cells may have an important biological basis.

BACKGROUND & AIMS: Intestinal transplantation is a developing therapeutic option for patients with irreversible intestinal failure or short bowel syndrome. The aim of this study was to delineate the histopathology of human intestinal allografts and to define the features of intestinal rejection. METHODS: The histological features of 3015 endoscopic biopsy specimens and 23 allograft specimens from 62 intestinal recipients were analyzed retrospectively and correlated with clinical findings. RESULTS: Acute allograft rejection was characterized by a varying combination of crypt injury, mucosal infiltration primarily by mononuclear cells (including blastic lymphocytes), and increased crypt cell apoptosis (more than 2 per 10 crypts). It represented a patchy, often ileal-centered process that could progress to mucosal ulceration; later episodes (more than 100 days posttransplant) tended to show lesser cellular infiltration and greater apoptosis than earlier episodes. Correlation with clinical rejection was good (false-positive rate of 9%; false-negative rate of 26%). Two resected specimens showed obliterative arteriopathy indicative of chronic rejection. In other specimens, preservation injury, cytomegalovirus infection, post-transplant lymphoproliferative disorder, and nonspecific features of active or past mucosal injury could be recognized. CONCLUSIONS: Mucosal biopsy specimens are a useful means of monitoring intestinal allografts. Based on features validated by clinical correlation, acute rejection can be identified reliably and can be differentiated from the other pathological processes affecting the intestinal allograft. (Gastroenterology 1996 Jun;110(6):1820-34)

During acute rejection (AR), * the endothelial targeting seen in the mucosal vessels of the intestinal allograft (IA) could impair the blood supply and response to luminal stimuli. To study the effect of AR in the perfusion and reactivity of the IA mucosa, we measured the mucosal blood flow in the ileum (IL) of 2 groups of control rats (Lewis and ACI) and in the native and grafted IL of syngeneic (ACI to ACI) and allogeneic (donor ACI to recipient Lewis) rats. Using reflectance spectrophotometry and laser-Doppler flowmetry, parameters of mucosal oxygen saturation (ISO 2 ), hemoglobin content (IHB), and blood flow (FLOW) were obtained at baseline and after saline and 50% dextrose (D50) stimulation. When compared to controls, the isograft IL had similar perfusion (ISO 2 , IHB, and FLOW). The allograft IL showed ischemia (similar ISO 2 , and lower ISO 2 and FLOW). In the allografts, the ISO 2 and FLOW were lower than in the isografts. In response to D50, the native IL of all groups showed an increased IHB and FLOW (hyperemia); the isografts showed an increase only in IHB (partial response) ; the allografts did not show any response at all. In summary, the mucosal perfusion in the rejecting allografts, but not in the isografts, showed ischemia. The response to D50 seen in the native ilea was only partial in the isografts and absent in the allografts. Because these changes occurred before the onset of mucosal ulcerations, we postulate that they could be used as early indicators of AR.

Liver granulomas have long been known to pose diagnostic problems for pathologists; however, their prevalence and associated etiologic factors have not been studied in liver transplant patients. We reviewed 3632 liver biopsy specimens from 563 patients at two institutions and identified 42 patients with posttransplant granulomas. A possible or probable etiologic factor was identified in 30 (71%) cases. Most were epithelioid granulomas and microgranulomas located in the parenchyma associated with hepatocyte necrosis (21 cases, 50%). Portal-based granulomas were associated with recurrent primary biliary cirrhosis (5 cases, 12%), acute cellular rejection (2 cases, 4.8%), and a foreign body-type reaction (1 case, 2.4%). One case was associated with tuberculosis (2.4%), 4 cases occurred in a fatty liver (9.5%), and 8 patients had liver granulomas but no other significant abnormality. The granulomas were most frequent in the first 7 months after transplantation when the patients were biopsied more often and underwent episodes of rejection or acute hepatitis. Portal-based granulomas in this period were usually associated with acute cellular rejection. After 7 months, the frequency of granulomas as well as the number of biopsies decreased and portal-based granulomas associated with recurrent primary biliary cirrhosis were most common (5 cases, 12%). Rare, late-appearing parenchymal granulomas were also seen (3 cases) and consisted of 1 lipogranuloma and 2 cases of epithelioid granuloma. The latter were thought, in 1 patient, to be associated with parenchymal hepatocyte necrosis; the others were of unknown etiology.

Objective. To assess the risk of serious liver disease in patients with rheumatoid arthritis (RA) taking methotrexate (MTX). Methods. We surveyed members of the American College of Rheumatology to determine previous use of MTX in the treatment of rheumatoid arthritis and to identify cases of cirrhosis and liver failure. Cases were confirmed by review of pathology specimens, findings from diagnostic testing, and clinical presentations. A case—control study was then conducted to ascertain prognostic factors. Case and control medical records were reviewed for information on MTX therapy as well as other possible determinants of serious liver disease. Results. Twenty-four cases of cirrhosis and liver failure were identified, giving a 5-year cumulative incidence of ˜ 1/1,000 treated patients. Six of the 24 patients had died: 4 died of the initial liver disease, 1 of hepatic complications of another illness, and 1 of unrelated causes. Two patients continue to have active liver disease. Late age at first use of MTX and duration of therapy with MTX were independent predictors of serious liver disease. Conclusion. Serious liver disease is an uncommon, age- and dose-related complication of low-dose MTX therapy for RA.

Four patients who underwent transplantation for hepatitis B virus-related liver disease developed rapidly progressive liver failure attributable to recurrent hepatitis B disease typified by hyperbilirubinemia and distinctive hepatocyte ballooning and progressive fibrosis consistent with recently reported fibrosing cholestatic hepatitis. Among these four patients, the mean interval from transplantation to redocumentation of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) was 5 months, to development of malaise and jaundice 6 months, to histological diagnosis 7 months, and to graft failure 8 months. The only patient who underwent retransplantation had accelerated recurrence of the same syndrome with biopsy documentation 1 month later and graft failure 2 months later. Distinctive histological features included confluent hepatocellular ballooning and progressive periportal fibrosis followed by lobular collapse over 4–6 weeks without significant inflammation. Immunohistochemical staining showed marked HBsAg and hepatitis B core antigen (HBcAg) immunoreactivity. The rapid development of cytolytic hepatocellular necrosis and lobular collapse with prominent HBcAg immunoreactivity without significant inflammation suggests a cytolytic rather than immune pathogenesis for this unique and devastating form of recurrent hepatitis B that might better be termed "fibrosing cytolytic hepatitis."

Background Microsatellite instability (MSI) and lymphocytic infiltrate (LI) in colon cancer are associated with less aggressive biological characteristics. Patients with stage II disease who are negative for MSI and LI have been found to have a less favorable prognosis. These patients may be candidates for more aggressive adjuvant therapy. Objective To evaluate the outcomes of patients with colon cancer treated with and without adjuvant chemotherapy on the basis of stage, MSI, and LI. Design Prospective evaluation of MSI and LI status with retrospective analysis of chemotherapy regimen. Setting Community hospital system. Patients A total of 167 patients with colon cancer. Intervention Definitive resection of colorectal cancer with or without chemotherapy. Main Outcome Measure Disease-free survival (DFS) with and without chemotherapy according to combined MSI and LI status. Results Data on MSI and LI status and chemotherapeutic regimens were available for 140 patients. The 5-year DFS was 50% for patients with stage II disease who underwent chemotherapy vs 76% for those who did not (P = .02). In the group negative for MSI and LI, 5-year DFS was 29% for those undergoing chemotherapy and 91% for those who did not (P = .001). Conclusions Forgoing adjuvant chemotherapy should be considered in patients with stage II colon cancer who are negative for MSI and LI. The MSI and LI status shows promise as a combined prognostic marker and may prove particularly useful in selecting patients with stage II disease for adjunctive therapy.

Background Adenovirus hepatitis in the allograft liver is an uncommon condition hitherto recognized only in pediatric patients. We describe two adult cases. Methods Clinical information was obtained by reviewing the medical records. The diagnosis of adenoviral infection was made by immunohistochemistry or culture. Results Both patients had received recent antirejection treatment and presented with fever, hepatic dysfunction, and progressive leukopenia. One patient had some viral inclusions resembling those described in herpes simplex infections. Adenovirus was cultured from the liver in both cases and from the lung in one case. Both patients were treated by decreasing the immunosuppression and intravenous acyclovir, but died. Conclusions Adenovirus infection should be considered when evaluating adult liver transplant patients with necrotizing lesions or microabscess formation at allograft biopsy. A review of the literature shows that most previously reported infections have led to graft loss or death, but occasional remissions of disease are also on record.

Background In this study, we determined the prevalence of hepatitis G virus (HGV) infection in end-stage hepatitis C virus (HCV)-related liver disease and examined the influence of HGV coinfection on the outcome of liver transplantation. Methods HGV was detected by reverse transcriptase-polymerase chain reaction and Southern blotting in sera drawn from 159 patients who were known to be HCV infected before transplantation. Patients were followed up for a mean of 28.4 months after transplantation. Results Forty-one (25.3%) patients were HGV positive and the prevalence of HGV infection was similar for different HCV genotypes. Both HGV-positive and -negative groups had similar survival, recurrence rates, inflammatory activity scores, and degree of fibrosis at the time of recurrence. Conclusion Infection with HGV is common in end-stage HCV-infected patients presenting for liver transplantation. It influences neither the outcome of liver transplantation nor the recurrence of hepatitis in the graft.

Background: Microsatellite instability (MSI) may be a molecular marker of colorectal tumor biology. We sought to evaluate the incidence and significance of MSI in an unselected colorectal cancer population. Methods: Colorectal cancer cases from a community health system were prospectively evaluated for MSI and patient outcomes monitored. Results: Of 240 eligible, 140 underwent testing; 43 (31%) had high-frequency MSI (MSI-H). Those with MSI-H tumors presented with earlier disease stage (P = .014) and lymphocytic infiltration (P

Background: The suppressed production of nitric oxide (NO), associated with endothelial dysfunction, is thought to be a cause of ischemia and reperfusion injury of the liver. But findings of the salutary effects of NO enhancement on such injury have been conflicting. In this study, we tested our hypothesis that NO enhancement would attenuate ischemic liver injury. For this purpose, an NO precursor, L-arginine, and a novel NO donor, FK409, were applied to a 2-hour total hepatic vascular exclusion model in dogs. Study Design: L-arginine was administered IV at a dose of 100 mg/kg twice (n = 5), while 300 mg/kg twice of FK409 was infused continuously into the portal vein (n = 5). The drugs were given to the animals for 30 and 60 minutes before and after ischemia, respectively. Nontreated animals were used as the control (n = 10). Two-week survival, systemic and hepatic hemodynamics indices, liver function tests, energy metabolism, and histopathology were analyzed. Results: Both treatments comparably augmented hepatic tissue blood flow, decreased liver enzyme release, and increased high-energy phosphate restoration during the reperfusion period, all of which contributed to rescuing all of the treated animals from the 2-hour total hepatic ischemia. In contrast, ischemia caused 70% mortality in the control group. Histologically, structural abnormality and neutrophil infiltration were markedly attenuated by the treatments. Systemic hypotension was observed in the animals treated with FK409, however. Conclusions: Our data demonstrate that NO enhancement alleviates the liver injury caused by ischemia and reperfusion. The supplementation of L-arginine, rather than FK409, is considered more applicable to clinical use because of the absence of systemic adverse effects.

Objective To analyze a single center's 14-year experience with 62 consecutive patients with hilar (HCCA) and peripheral (PCCA) cholangiocarcinomas. Summary background data Long-term survival after surgical treatment of HCCA and PCCA has been poor. Methods From March 1981 until December 1994, 62 consecutive patients with HCCA (n = 28) and PCCA (n = 34) underwent surgical treatment. The operations were individualized and included local excision of the tumor and suprapancreatic bile duct, lymph node dissection, vascular reconstruction, and subtotal hepatectomy. Clinical and pathologic risk factors were examined for prognostic influence. Results Patients were followed for a median of 25 months (12-102 months). Postoperative morbidity and mortality (at 30 days) were 32% and 14%, respectively, for HCCA and 24% and 6% for PCCA. The survival rates for HCCA and PCCA were 79% (+/-8%) and 67% (+/-8%) at 1 year; 39% (+/-10%) and 40% (+/-9%) at 3 years; and 8% (+/-7%) and 35% (+/-10%) at 5 years, respectively. The median survival was 24 (+/-4) months for HCCA and 19 (+/-8) months for PCCA. The disease-free survival rates for HCCA and PCCA were 85% (+/-10%) and 77% (+/-9%) at 1 year; 18% (+/-11%) and 41% (+/-12%) at 3 years; and 18% (+/-11%) and 41% (+/-12%) at 5 years, respectively. Nearly 80% of these patients had TNM stage IV tumors. With HCCA, no risk factors were associated with patient survival. For PCCA, multiple tumors (relative risk [RR] = 3.5; 95% confidence interval [CI] = 1.2-10.5) and incomplete resection (RR = 8.3; 95% CI = 2.3-29.6) were independently associated with a worse prognosis. For HCCA, there was a trend for lower disease-free survival in females (p = 0.056; log rank test). For PCCA, tumor size >5 cm was the only factor associated with disease recurrence (p = 0.024; log rank test). Conclusions Even though rare, 5-year survival by resection can be achieved in both HCCA and PCCA, but new adjuvant treatments are clearly needed.

Large cell change (LCC), characterized by cellular enlargement, nuclear pleomorphism and hyperchromasia, and multinucleation of hepatocytes, is a common lesion in cirrhotic livers, but its nature, significance, and pathogenesis remain uncertain. Therefore, we assessed the prognostic value of LCC as a marker of subsequent hepatocellular carcinoma (HCC) through a case-control study that compared pretransplant liver biopsy specimens from 37 cirrhotic liver transplant recipients with HCC to specimens from a control group of recipients without HCC, matched for sex, age (+/-5 years), and cause of cirrhosis. LCC was identified in 16 (43%) of the study and 7 (19%) of the control group biopsy specimens. By matched-pair analysis, LCC conveyed a moderately increased risk of later HCC with an estimated odds ratio of 3.3 (95% CI, 1.2-15; P = .038). However, a pathology review of 45 HCCs showed adjoining LCC in only 12 (27%) and did not suggest a morphological transition or a histogenetic association between the two lesions. LCC hepatocytes displayed a low proliferative rate by Ki-67 or proliferating cell nuclear antigen immunostaining (labeling indices of 0.27 and 0.73) but showed a greater degree of apoptosis than normal hepatocytes (labeling indices of 1.9 and 0.23; P = .03) To reconcile these findings, we propose that LCC derives from derangements in the hepatocyte's normal process of polyploidization. Such derangements, possibly caused by chronic inflammation-induced DNA damage, could yield a population of enlarged liver cells with nuclear atypia and pleomorphism, frequent binuclearity, and minimal proliferation. According to this hypothesis, LCC would be a habitual feature of cirrhosis and a regular accompaniment of HCC but would not represent a direct malignant precursor.

Background: Recent publications have questioned the role of orthotopic liver transplantation (OLT) in treating advanced or unresectable peripheral cholangiocarcinoma (Ch-Ca). Study Design: We reviewed our experience with Ch-Ca to determine survival rates, recurrence patterns, and risk factors in 54 patients who underwent either hepatic resection or OLT between 1981 and 1994. Liver transplantation was performed in patients with unresectable tumors (n = 12) and in those with advanced cirrhosis (n = 8). There were 33 women (61%) and 21 men (39%), with a mean age of 54.3 years. The median followup period was 6.8 years. Prognostic risk factors were analyzed by univariate and multivariate analyses. Results: Mortality within 30 days was 7.4%. Overall patient and tumor-free survival rates were 64% and 57% at 1 year, 34% and 34% at 3 years, and 26% and 27% at 5 years after operation. Thirty-two patients (59.3%) experienced tumor recurrence. Univariate analysis revealed that multiple tumors, bilobar tumor distribution, regional lymph node involvement, presence of metastasis, positive surgical margins, and advanced pTNM stages were significant negative predictors of both tumor-free and patient survival. Multivariate analysis revealed that positive margins, multiple tumors, and lymph node involvement were independently associated with poor prognosis. When patients with these three negative predictors were excluded, the patient survivals at 1, 3, and 5 years were 74%, 64%, and 62%, respectively. Conclusions: Both hepatic resection and OLT are effective therapies for Ch-Ca when the tumor can be removed with adequate margins, the lesion is singular, and lymph nodes are not involved.

Background: Enhanced production of endothelin-1 (ET-1), vasoconstrictive 21 amino acids produced by endothelial cells during ischemia and after reperfusion of the liver, is known to cause sinusoidal constriction and microcirculatory disturbances, which lead to severe tissue damage. Using a 2-hour hepatic vascular exclusion model in dogs, we tested our hypothesis that neutralization of ET-1 by monoclonal anti-ET-1 and anti-ET-2 antibody (AwETN40) abates vascular dysfunction and ameliorates ischemia/reperfusion injury of the liver. Study Design: After skeletonization, the liver was made totally ischemic by cross-clamping the portal vein, the hepatic artery, and the vena cava (above and below the liver). Veno-venous bypass was used to decompress splanchnic and inferior systemic congestion. AwETN40, 5 mg/kg, was administered intravenously 10 minutes before ischemia (treatment group, n=5). Nontreated animals were used as controls (control group, n=10). Animal survival, hepatic tissue blood flow, liver function tests, total bile acid, high-energy phosphate, ET-1 levels, and liver histopathology were studied. Results: Treatment with AwETN40 improved 2-week animal survival from 30% to 100%. Hepatic tissue blood flow after reperfusion was significantly higher in the treatment group. The treatment significantly attenuated liver enzyme release, total bile acid, and changes in adenine nucleotides. Immunoreactive ET-1 levels in the hepatic venous blood of the control group showed a significant increase and remained high for up to 24 hours after reperfusion. Histopathologic alterations were significantly lessened in the treatment group. Conclusions: These results indicate that ET-1 is involved in ischemia/reperfusion injury of the liver, which can be ameliorated by the monoclonal anti-ET-1 and anti-ET-2 antibody AwETN40.

The distribution of hepatitis C virus (HCV) genotypes was studied in 202 anti-HCV-positive liver transplant candidates with end-stage liver disease. HCV sequences were successfully amplified from 185 patients: In the first 100, the genotype was determined by direct sequencing in the NS5 region, and in the remaining 85, type-specific primers were used for genotyping. Eighty-five patients (46.0%) were infected with type 1a HCV strains, 52 (28.1%) with type 1b, 14 (7.6%) with type 2b, 13 (7.0%) with type 4, 5 (2.7%) with type 3a, 2 (1.1%) with type 2a, and 1 (0.5%) with type 2c. Thirteen HCV-positive patients (7.0%) could not be genotyped. The relatively low prevalence of genotype 1b in this population of end-stage liver disease patients speaks against postulated higher pathogenicity of this genotype.

Although transjugular liver biopsy requires the availability of trained personnel, takes more time than percutaneous biopsy and is moderately expensive, it is a safe alternative technique for obtaining adequate liver tissue for diagnosis in special clinical situations. The usual indications for transjugular rather than percutaneous liver biopsy are (a) coagulation disorder (prothrombin time greater than 3 sec over control value and/or platelet count less than 60,000/cm3), (b) massive ascites and (c) desire to perform ancillary procedures, such as measurement of pressures or opacification of the hepatic veins and inferior vena cava. Less common indications for transjugular liver biopsy include failed percutaneous biopsy, massive obesity, small cirrhotic liver (increased risk and lower success rate) and suspected vascular tumor or peliosis hepatis. Results from several centers indicate that adequate or diagnostic liver tissue is obtained in 81% to 97% of cases. The typical length of the biopsy core ranges from 0.3 cm to 2.0 cm. Modification of the classic technique, particularly the adaptation of a Tru-Cut needle, shows promise in yielding longer cores of tissue with less fragmentation. Transjugular liver biopsy is performed with an acceptable complication rate that ranges 0% to 20%. The reported mortality of transjugular liver biopsy was 0 in three major centers and ranged from 0.1% to 0.5% in three other centers. Transjugular liver biopsy may be useful in obtaining diagnostic liver tissue not only in advanced chronic liver disease with coagulopathy, ascites or both, but also in patients with fulminant hepatic failure to better determine prognosis and the need for liver transplantation.

Background Microsatellite instability (MSI) is a genetic aberration associated with less aggressive tumor biology. Some tumors with MSI also have lymphocytic infiltrate (LI), which suggests a heightened immune response against the tumor. Objective To evaluate the combined prognostic significance of MSI and LI in a colon cancer population. Design Colon cancers were prospectively evaluated for MSI by assessing 11 satellite markers and were classified as MSI+ if 2 or more satellite markers displayed instability. Tumors were classified as LI+ if at least 5 lymphocytes were observed per 10 high-power fields. Setting Community hospital system. Patients Individuals undergoing definitive surgery for colon cancer. Main Outcome Measures Overall and disease-free survival were compared according to combined MSI and LI status. Results In 150 patients, tumors were classified as follows: 95 were MSI−/LI−, 9 were MSI−/LI+, 30 were MSI+/LI−, and 16 were MSI+/LI+. Median follow-up was 40.6 months. Five-year disease-free survival was 56.7% for patients with MSI−/LI− tumors and 88.9% for those with MSI+/LI+ tumors ( P = .01). Patients with MSI+/LI− and MSI−/LI+ tumors had 5-year survival of 75.4% and 75.0%, respectively. Conclusions Patients with colon cancer and MSI−/LI− tumors have worse disease-free survival rate regardless of stage at diagnosis. Patients exhibiting both MSI+ and LI+ tumors have more favorable disease-free survival rates. Both MSI and LI show promise as a combined prognostic marker and with further study may prove to be particularly useful in selecting patients with stage II disease for adjunctive therapy.

Verapamil, a calcium channel blocker, improves myocardial preservation during cold cardioplegia and protects against renal damage during periods of warm and cold ischemia. To determine if verapamil could prevent ischemic damage to livers during and after cold storage, harvested rat livers were flushed with either University of Wisconsin (UW) solution or UW solution with 25 mg/liter verapamil. Twenty rats were used in each group. After 24 hr of storage at 4 degrees C, livers were perfused with oxygenated blood through the portal veins for 2 hr at 37 degrees C and pH 7.4. Liver enzymes, electrolytes, and perfusate flow rate were determined at 30-min intervals. At 90 min of perfusion, the verapamil group of livers had less elevation of AST (110 +/- 17 IU/liter vs 172 +/- 25 IU/liter, P less than 0.05), ALT (115 +/- 21 IU/liter vs 210 +/- 34 IU/liter, P less than 0.05), and LDH (962 +/- 170 IU/liter vs 1452 +/- 253 IU/liter, NS). Verapamil livers produced more bile than controls (6.9 +/- 1.9 microliters/g vs 2.3 +/- 1.7 microliter/g, P less than 0.05) and maintained a higher portal flow rate throughout the perfusion. Both groups showed similar reduction in liver weights after storage (3.9 +/- 0.9% vs 2.8 +/- 0.7%) and required the same amount of bicarbonate for correction of acidosis during perfusion (2.6 +/- 0.2 mM vs 2.8 +/- 0.2 mM). Light microscopic exam after perfusion showed hepatocyte damage in 30% of control livers, but 0% of verapamil livers. We conclude that verapamil-treated rat livers showed less damage and better function upon reperfusion after 24 hr of cold storage. This agent may be clinically useful as an additive to the UW preservation solution for livers.

During the first 24 months of the Oregon Liver Transplantation Program, which began in October 1988, 94 patients were formally evaluated and 47 adults underwent 54 liver transplantations. Thirty-four percent of patients were veterans. The recipient operation lasted a mean of 7.4 hours (range: 4 to 16 hours). Veno-venous bypass was used routinely at first but selectively later (7 of the last 26 cases), resulting in reduced operating time. Hepatic artery reconstruction was end-to-end anastomosis in 52 cases and iliac conduit in 2. No arterial thrombosis occurred. Biliary reconstruction was choledo-chocholedochostomy in 83% and choledochojejunostomy in 17%. Biliary complications occurred in 28%. Operative mortality was 2%, and 1-year actual survival was 80%. Patients with hepatitis B fared worse, with four of six dying at a mean of 7.6 months. Overall, the median hospital stay was 30 days. Patients surviving more than 3 months had a mean Karnofsky score of 82%. No significant difference in outcome was noted in patients receiving prophylactic OKT3 monoclonal antibody (used in 45%) versus conventional immunosuppressive therapy. Overall, allograft rejection occurred in 55% of patients. Retransplantation was required in seven patients, three for primary graft nonfunction, two for uncontrolled rejection during induction therapy with OKT3, and two for graft failure secondary to recurrent hepatitis B.

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 non-obese, 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.

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 non-obese, 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.

Nonalcoholic steatohepatitis (NASH) refers to an alcoholic hepatitis-like histologic pattern found in nonalcoholic patients. A review of 543 liver biopsies diagnosed as alcoholic hepatitis yielded 49 cases of NASH. The patients were commonly middle-aged women who were obese and often diabetic. NASH was usually discovered because of abnormal liver function tests or hepatomegaly noted during evaluation of other medical problems. Histologic examination revealed the same spectrum of changes found in alcoholic hepatitis, including cirrhosis in eight patients. Follow-up information was available for 39 patients after an average length of 3.8 years. Only one patient developed hepatic decompensation or died with liver failure or portal hypertension. Repeat histologic material was available for 13 patients after a mean 3.5 years of follow-up. Five patients showed progression of fibrosis, with cirrhosis developing in two, but the other eight patients demonstrated little morphologic change. These findings indicate that NASH is, in general, a clinically mild and biologically low-grade condition, but with the potential to progress and evolve into cirrhosis in some patients. The factors promoting progression are unclear.

The pathogenesis of liver disease in protoporphyria has been presumed to result from the hepatic deposition of protoporphyrin. To examine the effects of protoporphyrin on hepatic bile flow and histopathology, studies were performed employing an isolated, in situ, rat liver perfusion system. Rat livers in the control group were perfused with 0-80 μmol sodium taurocholate/h. Rat livers in the experimental group were perfused with sodium taurocholate and (a) sufficient quantities of protoporphyrin to produce maximal canalicular secretion and (b) perfusate protoporphyrin concentrations of 0.01, 0.1, and 1 μM. The administration of protoporphyrin sufficient to achieve maximal canalicular secretion was found to significantly reduce bile flow in rats infused with 0, 40, and 80 μmol sodium taurocholate/h. Linear regression analysis defined the relationship between bile flow and biliary bile acid secretion and showed that the bile acid-independent fraction of bile flow was reduced (P < 0.01). Bile acid-dependent flow was unaffected and there was no significant difference in biliary bile acid secretion rates between control and protoporphyrin-perfused livers. Perfusion of rat livers with varying concentrations of protoporphyrin demonstrated the reduction of bile flow was dose-related. Analysis of perfusate enzyme activity did not reveal abnormalities that could account for the cholestasis. Studies to evaluate the effect of protoporphyrin on regional hepatic hemodynamics were inconclusive. Histopathological studies of control and protoporphyrin-perfused rat livers did not show abnormalities on light microscopy. However, canalicular dilatation, distortion, and loss of microvilli were present in the protoporphyrin-perfused livers examined by transmission electron microscopy. Although ultraviolet microscopy showed diffuse fluorescence of the hepatocytes and canaliculi of protoporphyrin-perfused livers, the deposition of protoporphyrin in amorphous or crystalline forms was notably absent in studies with polarizing and transmission electron microscopy. These studies provide evidence that protoporphyrin has hepatotoxic properties that affect the canalicular secretory apparatus. The mechanism(s) responsible for the injury require further clarification.

To define the mucin secretion of Barrett's esophagus, 132 biopsy specimens from 37 patients were studied with histochemical stains for mucins. Columnar mucous cells contained largely neutral mucins, but scattered cells in over 70% of the biopsies also produced sialomucins and sulfomucins. Goblet cells contained sialomucins, sulfomucins, or both. The distribution and relative proportions of mucins varied considerably among biopsies and among patients. Barrett's esophagus histochemically represents a heterogeneous, partially differentiated epithelium analogous to incomplete intestinal metaplasia of gastric mucosa.

Twenty-nine patients with active rheumatoid arthritis receiving long-term oral weekly methotrexate (MTX) therapy were studied to determine the extent of their hepatic architectural changes. Liver biopsies (n = 101) were performed in all patients before the initiation of MTX therapy, after 2 years, and annually thereafter (mean duration of therapy 53 months). The hepatic histologic grade (5-point scale) in 25 patients increased (worsened) (mean +/- SEM change 0.84 +/- 1.02; P = 0.001). Fibrosis, confirmed by trichrome staining, developed in 14 of 27 patients (52%). A history of alcohol consumption prior to starting MTX correlated significantly with subsequent worsening of the liver biopsy grade (r = 0.55, P = 0.0054). Alcohol intake prior to study entry, elevated weight at MTX initiation, and dose and duration of MTX were significantly associated with the development of fibrosis. Elevations in serum aspartate aminotransferase levels at 29-53 months of therapy correlated with the increase in hepatic histologic grade at the 3-year biopsy (r = 0.50, P = 0.04) and 4-year biopsy (r = 0.58, P = 0.03). We conclude that long-term MTX therapy in rheumatoid arthritis patients results in a statistically significant worsening in hepatic histologic grade, with common development of mild fibrosis. We do not consider these changes to be clinically significant at present.

A 29-year-old woman with Behçet's syndrome developed a severe colitis that ultimately required colectomy. The colectomy specimen showed extensive mucosal ulceration with varying longitudinal, fissuring, and aphthoid configurations, usually occurring within a background of normal or focally inflamed mucosa, and associated with a lymphocytic vasculitis involving submucosal veins. A review of the literature reveals 29 additional cases of colitis complicating Behçet's syndrome. The colitis is characterized by multiple ulcers of diverse size, appearance, and depth of penetration involving any portion of the large bowel, occasionally with coexistent ileal or anal disease. Vasculitis may be the underlying process. Although it resembles other types of colitis, particularly Crohn's colitis, differences in clinical and pathologic features suggest that the colitis of Behçet's syndrome represents a distinct condition.

To assess the histopathologic features of fundic gland polyps (FGP) of the stomach, 83 specimens from 25 patients were examined. In nine patients, FGP were associated with an inherited adenomatous polyposis syndrome; the other 16 patients had nonsyndromic FGP. FGP were microscopically characterized by the presence of fundic glands with variably disordered architecture, a feature not previously emphasized. Disordered architecture, found in 80 of 83 specimens (96%), comprised a spectrum of abnormalities, ranging from prominent glandular and cellular budding, found in 51 biopsies (61%), to irregular tortuous glands, noted in 61 biopsies (75%), to microcysts lined by fundic epithelium, seen in 72 biopsies (87%). The continuous range of these changes suggested that FGP arise through progressive formation and unfolding of secondary glandular buds, to result in cystic dilatation. No differences were found between syndromic and nonsyndromic FGP with respect to histologic features or mucin histochemistry, including presence of O-acylated sialomucins.

Upper gastrointestinal polyps have been considered an uncommon finding in patients with Gardner's syndrome and familial polyposis coli. Investigators from Japan, however, have recently reported finding gastric and duodenal polyps in a high percentage of Japanese patients with these conditions. We endoscopically examined 11 affected members of the originally described Gardner's syndrome kindred to determine if upper gastrointestinal polyps also occurred in patients with Gardner's syndrome living in the United States. Six of the patients were found to have numerous small polyps of the gastric fundus and body. Polyp histology in 5 of the 6 patients was consistent with fundic gland hyperplasia. Biopsy specimens from the remaining patient demonstrated normal mucosa only. Another patient with no fundic polyps had a single antral polyp that was an adenoma. Eight patients exhibited small polyps of the duodenum. Biopsy specimens were obtained in 7 of the 8. All polyps biopsied were adenomas. The terminal ileum was examined by endoscopy in 9 of the 11 study patients. All 9 had ileal polyps, but the polyps were adenomas in 6 patients and lymphoid aggregates in 3 patients. The results indicate that upper gastrointestinal polyps are a common pleiotropic manifestation of the genetic defect responsible for Gardner's syndrome.

Twenty-six patients receiving long-term oral methotrexate (MTX) therapy for rheumatoid arthritis (24 patients) or psoriasis (2 patients) were prospectively evaluated for alterations in liver morphology by light microscopy, electron microscopy, and immunofluorescence microscopy. Although only 4 MTX-treated patients had light microscopic evidence of mild fibrosis, all had evidence of collagen deposition in the space of Disse near Ito cells and changes in hepatocyte lysosomes on electron microscopy. These findings were absent from control livers. Fibrinogen, fibronectin, and type IV collagen were identified by immunofluorescence in both MTX-treated patients and controls. We conclude that long-term MTX therapy for rheumatoid arthritis is associated with alterations in hepatic ultrastructure, including collagen deposition in the space of Disse and changes in hepatocyte lysosomes.

To evaluate the consequences of dysplasia in Barrett's esophagus, six patients with esophageal mucosal biopsies showing dysplastic Barrett's mucosa in the absence of clinically evident esophageal carcinoma were identified and their clinicopathologic features reviewed. The patients, four men and two women, averaged 60 years and had long histories of gastroesophageal reflux. Four patients had high-grade dysplasia; two had low-grade. Dysplastic Barrett's mucosa appeared to arise most commonly from specialized-type Barrett's mucosa. After a mean follow-up of 29 months, four patients, all with high-grade dysplasia, had esophageal resections. Three of the four were found to have invasive adenocarcinoma, which extended through the esophageal wall in two patients. The fourth patient had a noninvasive adenomatous polyp ("Barrett's adenoma"), an infrequently described form of dysplasia in Barrett's esophagus. The two patients with low-grade dysplasia had developed no clinical indications of carcinoma. The results confirm that dysplastic Barrett's mucosa, particularly the high grade, is a morphologic marker for adenocarcinoma. Biopsy surveillance of patients with Barrett's esophagus is histologically feasible, but prospective studies are required to prove its effectiveness.

A patient with cirrhosis developed hemoperitoneum, lactic acidosis, and hyperphosphatemia in the absence of shock. At post-mortem examination occult multicentric hepatocellular carcinoma eroding the liver capsule was present. The case emphasizes the central role of the liver in lactic acidosis, indicates that hemoperitoneum may precipitate this complication, and documents the association of lactic acidosis and hyperphosphatemia.

The significance of marked eosinophilic infiltration in esophageal mucosal biopsy specimens was evaluated in 11 patients. The patients were generally young, with an average age of 14.6 years; all had diffuse intraepithelial eosinophilia in several biopsies. Ten patients (91%) had evidence for reflux esophagitis, which was associated with esophageal stricture in three of the six patients older than 1 year. Marked esophageal eosinophilia might therefore indicate prolonged or severe gastroesophageal reflux. One patient with peripheral eosinophilia, a history of asthma, and concurrent idiopathic eosinophilic gastroenteritis lacked evidence of reflux and represents a case of idiopathic esophagitis. Critical review of the literature establishes three additional cases. Idiopathic eosinophilic esophagitis is an unusual variant of idiopathic, but presumably allergic, eosinophilic infiltration of the gastrointestinal tract.

Three cases of the unusual esophageal adenoma are described. The patients included two men and one woman, with a mean age of 61 years, who presented with dysphagia or heartburn. Histologically, the esophageal adenomas were composed of dysplastic epithelium in a polypoid configuration, similar to adenomas elsewhere in the gastrointestinal tract. All three adenomas arose within Barrett’s esophagus (columnar epithelium-lined distal esophagus), and dysplastic Barrett’s mucosa was found in the adjacent mucosa of each case. Critical review of the literature identified three additional cases; similar clinicopathologic features were described. Esophageal adenomas are a complication of Barrett’s esophagus and are best considered as macroscopic variants of epithelial dysplasia rather than as isolated adenomatous polyps. As such, they likely represent premalignant lesions.

The majority of patients with Gardner's syndrome and familial polyposis coli develop duodenal adenomatous polyps. Duodenal cancer sometimes arises in this setting, but nonmalignant problems from duodenal polyps have not been described. This report presents a patient with Gardner's syndrome who developed hemorrhagic pancreatitis and was found to have a villous adenoma encasing the pancreatic duct at the duodenal papilla. The case is important because it suggests that patients with polyposis coli may be at risk for significant nonmalignant problems from duodenal polyps, particularly if polyps exhibit villous histology and occur at the duodenal papilla.

Eighteen consecutive asymptomatic patients with familial adenomatous polyposis (both familial polyposis coli and Gardener's syndrome) were studied over a 12-month period; side-viewing upper endoscopy and biopsy were used to assess the frequency of adenomatous polyps of the duodenal papilla. Nine of the 18 patients demonstrated adenomatous polyps of the papilla, varying in size and appearance from microadenomas in normal-appearing duodenal papillae (two) to a sessile polyp 3 cm in diameter. Two were tubulovillous adenomas (0.5 cm and 2 cm in diameter) and the remainder were tubular adenomas. Severe atypia and malignancy were not encountered. These findings reveal that adenomas of the duodenal papilla are common in individuals with familial adenomatous polyposis. Because of these findings and because of the known risk of periampullary adenocarcinomas and nonmalignant complications of polyps of the duodenal papilla in patients with familial adenomatous polyposis, upper gastrointestinal screening of such patients should include examination of the duodenal papilla with a side-viewing endoscope.