Histologic evaluation of organ preservation injury and correlation with cold ischemia time in 13 intestinal grafts.

Lesions produced in the graft mucosa due to harvesting, storage, and implantation must be graduated to assess the subsequent protocolized biopsy specimens. The aim is to identify type and intensity of graft mucosal lesions observed immediately after implantation. Congestion, hemorrhage, microthrombi, neutrophilic infiltrates, shortening of villi, epithelial detachment, erosion, and crypt loss were separately evaluated by two pathologists in mucosal biopsy specimens from 13 grafts. Each change was assessed as normal, mild, moderate, or severe and by splintering the summation of points a global score was designed. Cold ischemia time was registered. Correlation between the pathologists' evaluations and between final preservation injury degree and cold ischemia time was determined using the "index of correlation rho (ρ)" (Spearman's test). The same changes were assessed in 19 biopsy specimens from day 2 to day 6 (3.6 ± 1.1) to determine their evolution. Congestion was found in 7 biopsy specimens, microthrombi in 2, hemorrhage in 4, neutrophils in 6, villous atrophy in 8, epithelial detachment in 9, erosions in 2 and/or crypt loss in 2. The maximum degree of preservation injury was expressed as intense congestion and hemorrhage associated with epithelial detachment and villous atrophy. The global preservation score was grade 3 in 2 cases, grade 2 in 5, grade 1 in 2, and grade 0 in 4. There was positive correlation (ρ = 0.915) in the evaluation between pathologists (P < .01), total agreement in 9 biopsy specimens, and partial agreement (only 1 point disagreement) in 4. Mean cold ischemia time was 327 ± 101 min. (135-480). There was positive correlation (ρ = 0.694) between preservation score and cold ischemia time (P < .01). In the follow-up biopsy procedures, histological injury decreased by at least one grade in every case. Additionally, karyorrhexis was observed in 3 grafts and very occasional apoptosis in 2 others. This scale achieves good reproducibility and allows graduate preservation injury in intestinal transplantation.

Histologic evaluation of post-implantation immediate C4d deposition in 13 intestinal grafts: correlation with cell-based crossmatching, cold ischemia time, and preservation injury.

C4d deposits are predictive of humoral rejection in kidney and heart transplantation. The aim of this study was to identify C4d deposit patterns in intestinal mucosa of the grafts on biopsy specimens obtained immediately after implantation and to detect if it could be a valuable tool to predict humoral or acute rejection. A second objective was to search for a statistically significant relationship between positive C4d deposition and other collected variables. Thirteen immediately post-transplantation mucosal graft biopsy specimens, formalin fixed, underwent immunohistochemical stain for C4d deposits. Diffuse intense staining of capillary endothelium was considered positive and absent, focal or weak stains as negative. Preservation injury grade and cold ischemia times were registered for each case. Donor-specific preformed antibodies were detected by complement dependent cytotoxicity serologic technique (crossmatching). Another 19 endoscopic follow-up biopsy specimens from days 2 to 6 were also evaluated. Statistical studies were made using the index of correlation ρ (Spearman's test). Diffuse intense C4d deposits were observed in 2 grafts, focal and weak in 5, and completely negative in 6. The mean cold ischemia time was 327 ± 101 minutes. Two cases showed diffuse positive deposits, 1 had a positive crossmatch and the cold ischemia time was 360 minutes whereas the other had not preformed antibodies and its cold ischemia time was 475 minutes. Humoral or acute rejection was not observed in follow-up mucosal biopsy specimens. There was no statistically significant relationship between the C4d deposition, cold ischemia time, crossmatching results, and preservation injury degree. In conclusion, C4d deposition was not a helpful tool for diagnosis of humoral rejection and prediction of acute rejection during the early post-transplantation period.

Influence of antiviral therapy in the long-term outcome of recurrent hepatitis C virus infection following liver transplantation.

INTRODUCTION: Severity of recurrent hepatitis C virus (HCV) infection in liver transplant recipients (LTR) is variable and the influence of different factors, including the administration of antiviral therapy in the long-term outcome is controversial. METHODS: We analyzed the outcome of a cohort of HCV-infected LTR who were transplanted in our institution. Patients were divided into 2 groups (severe and non-severe HCV disease) depending on the presence of a fibrosis score of F ≥ 2 in the Scheuer index and/or fibrosing cholestasic hepatitis (FCH) in a graft biopsy. Risk factors were studied using logistic regression analysis. Survival of patients was estimated using Kaplan-Meier plots. A total of 146 patients were followed for a mean of 58 months. RESULTS: Fifty-six (34%) patients developed severe HCV disease and showed shorter survival (P < 0.024). Donor age (odds ratio [OR]: 1.04; 95% confidence interval [CI]: 1.02-1.06) and pre-transplant viral load (VL) >10(6) UI/mL (OR: 3.5; 95% CI: 1.42-10.61) were the only factors associated with severe HCV infection. Over-immunosuppression (OR: 2.3; 95% CI: 1.2-4.41) was specifically associated with the development of FCH. Overall, patient survival in recipients who received a full course of anti-HCV therapy was higher than in patients who did not complete antiviral therapy (P = 0.004) or received no treatment (P = 0.007). Patients with non-severe HCV infection have a higher probability of receiving a full course of antiviral therapy (P = 0.033). CONCLUSION: In conclusion, donor age, pre-transplant VL, and over-immunosuppression were associated with the long-term development of severe HCV recurrence in liver grafts. Administration of a full course of antiviral therapy was associated with better survival.

Biological behavior due to cell proliferation markers of gastrointestinal stromal tumors.

BACKGROUND/AIMS: The mitotic index and tumor size are currently the main prognostic indicators of gastrointestinal stromal tumors (GIST). The purpose of this study is to investigate the expression of different immunohistochemical markers and their relation to mortality and relapse, and especially concerning high-risk tumors. METHODOLOGY: We did a retrospective study of 68 patients who underwent surgery from 1997 to 2007 with a diagnostic of gastrointestinal stromal tumor. RESULTS: The median follow-up period was 29 months. Relapse and mortality rates were 35.3% (24 cases) and 41.2% (28 cases), respectively. The mitotic index was related to p53 and the cellular proliferation index -Ki67- (p = 0.006 and p = 0.003, respectively). Considering both high and intermediate-risk neoplasms, a significant relation to Ki67 was obtained (p = 0.008). Relapse was related to the mitotic index (p = 0.032) and Ki67 (p = 0.024). Concerning mortality, statistically significant results were obtained with necrosis variables (p = 0.02), mitotic index (p = 0.013), p53 (p = 0.024) and Ki67 (p = 0.033). CONCLUSIONS: Ki67 could be considered a prognostic marker for both relapse and mortality. Concerning high risk GIST, the usefulness the p53 protein and Ki67 nuclear antigen markers was also evident concerning relapse and mortality.

Surgical management of hereditary colorectal cancer: surgery based on molecular analysis and family history.

The importance of colorectal cancer (CRC) is increasing. A proportion show a hereditary component, as in Lynch syndrome and Familial Adenomatous Polyposis, and a recently defined entity as well, namely, Familial Colorectal Cancer type X. The high probability to develop CRC in these groups may, at the time of recognition, change surgical management, including its timing or even the surgical technique. In some cases prophylactic surgery can play an important role. The possibility of using tools that allow recognition of the aforementioned syndromes, including microsatellite instability, immunohistochemistry for DNA mismatch repair system proteins, and especially their mutations, is on the basis of therapeutic strategies that differ from those employed in sporadic CRC cases.

Chronic intestinal pseudo-obstruction: a diagnosis to be considered.

Chronic intestinal pseudoobstruction (CIPO) is a rare entity characterized by recurrent clinical episodes of intestinal obstruction in which no mechanical cause is identified. There are multiple causes for this syndrome but two main groups can be distinguished: a) secondary to a systemic non-gastrointestinal disease; and b) primary or idiopathic originated from alterations in the components of the intestinal wall. The latter forms are the most uncommon and their diagnosis is generally difficult. In the present article, we describe nine patients with CIPO that were diagnosed in our center over the last six years. Four of them were diagnosed with primary or idiopathic form of CIPO and another four were clearly secondary to a systemic disease. The ninth case, which was initially diagnosed as secondary, is probably also a primary form of the disease. The number of patients diagnosed in our center, even thought small, makes us to hypothesize that the prevalence of CIPO is probably greater than is generally believed and that the reasons of its rarity are the incomplete understanding of its physiopathology and the difficulties to achieve a correct diagnosis.

A pilot trial of fenofibrate for the treatment of non-alcoholic fatty liver disease.

BACKGROUND: Dyslipidaemia and insulin resistance are two important risk factors for non-alcoholic fatty liver disease. Both factors can improve with fenofibrate. AIMS: To evaluate the effect of fenofibrate on the clinical, analytical and histological evolution of patients with non-alcoholic fatty liver disease. SUBJECTS AND METHODS: Sixteen consecutive patients with biopsy-confirmed non-alcoholic fatty liver disease were treated with 200mg/day of fenofibrate for 48 weeks. A clinical and biochemical follow-up was done every 3 months. A new liver biopsy was performed in all patients at the end of therapy. RESULTS: All patients completed 48 weeks of therapy with fenofibrate, without adverse events. At the end of the study, a significant decrease in triglyceride, glucose, alkaline phosphatase and gamma-glutamyl transpeptidase and an increase of apolipoprotein A1 levels were found. Insulin levels and insulin resistance showed a trend to decrease. Moreover, a reduction in the proportion of patients with abnormal aminotransferase levels (>45IU/L) was observed (alanine aminotransferase: 93.7% vs. 62.5%, p=0.02; aspartate aminotransferase: 50% vs. 18.7%, p=0.02). The body mass index did not show any significant change, but the proportion of patients with metabolic syndrome decreased significantly (43.7% vs. 18.7%, p=0.04). A control biopsy after treatment revealed a decrease in the grade of hepatocellular ballooning degeneration (p=0.03), but the grade of steatosis, lobular inflammation, fibrosis or non-alcoholic fatty liver disease activity score did not change significantly. CONCLUSIONS: In patients with non-alcoholic fatty liver disease, treatment with fenofibrate is safe and improves metabolic syndrome, glucose and liver tests. However, its effects on liver histology are minimal.

[Epstein-Barr virus infection and acute cholestatic hepatitis]. / Infección por el virus de Epstein-Barr y hepatitis aguda colestásica.

Epstein-Barr virus (EBV) is a herpesvirus whose only reservoir host is the human. It is transmitted by oropharyngeal secretions. Primary EBV infection is usually asymptomatic, but sometimes it causes infectious mononucleosis with fever, lymphadenopathies, splenomegaly and pharyngitis. Acute infection is diagnosed by serology (heterophile or specific antibodies). Immunofluorescence and molecular biologic techniques may be used to demonstrate the presence of EBV in biopsy specimens. Mild and transient elevations of serum aminotransferases are common, thus liver biopsy is usually not necessary to confirm the diagnosis. Severe cholestasis is rare (5%). We describe a patient with cholestatic hepatitis and acute EBV infection with atypical lymphocytes and positive anti-VCA IgM. The patient had taken drugs (ibuprofen, paracetamol and valerian). The bad evolution of the patient, the history of exposure to drugs, and the few cases of cholestatic hepatitis due to EBV infection reported, led us to consider liver biopsy. Molecular biologic techniques confirmed the presence of EBV in liver tissue however histologic features did not exclude the toxic aetiology or the concomitant effect of drugs and EBV infection.

First Spanish series of intestinal transplantation in adult recipients.

BACKGROUND: short-bowel transplantation has experienced a substantial growth worldwide following improved results from the late 1990's on, and its coverage by Medicare. According to the International Registry (1985-2005), a total of 1,292 intestinal transplants for 1,210 patients in 65 hospitals across 20 countries have been carried out thus far. OBJECTIVE: to know short-term (6 months) results regarding patient and graft survival from the first Spanish series of intestinal transplants in adult recipients. MATERIAL AND METHODS: we present our experience in the assessment of 20 potential candidates to short-bowel transplantation between June 2004 and October 2005. Of these, 10 patients were rejected and 4 were transplanted, which makes up the sample of our study. RESULTS: to this date 5 transplants have been carried out in 4 patients (2 retransplants, 2 desmoid tumors, 1 short bowel syndrome after excision as a result of mesenteric ischemia). Upon study completion and after a mean follow-up of 180 days (range 90-190 days) all recipients are alive, and all grafts but one (75%) are fully operational, with complete digestive autonomy. All patients received induction with alemtuzumab except one, who received thymoglobulin; in all induction was initiated with no steroids. CONCLUSIONS: intestinal transplantation represents a therapeutic option that is applicable in our setting and valid for recipients with an indication who have no other feasible alternative to keep their intestinal failure under control.

Incidence of de novo nonmelanoma skin tumors after liver transplantation for alcoholic and nonalcoholic liver diseases.

INTRODUCTION: Skin tumors are the most common malignancies after orthotopic liver transplantation (OLT). They have been related to sunlight exposure, tobacco consumption, and immunosuppression. The aim of this study was to compare the incidence of de novo skin tumors (nonmelanoma) in patients who underwent liver transplantation for alcoholic cirrhosis versus nonalcoholic diseases. PATIENTS AND METHODS: Between April 1986 and July 2004, we performed 1000 OLT in a population of 888 recipients. This study was performed in a sample of 701 adult recipients who survived >2 months after transplantation: 276 patients (39.4%) underwent OLT for alcoholic cirrhosis (AC-group), and 425 (60.6%) for nonalcoholic disease (N-AC). The overall incidence of de novo skin tumors was 3.5% (25 tumors): 5.4% (15 tumors) in the AC-group and 2.4% (10 tumors) in the N-AC group (P = .027). Two patients developed two tumors. There were 19 men and 4 women, mean age at OLT of 54.4 +/- 6.8 years (range, 40 to 66 years). The mean time from OLT to tumor diagnosis was 66.1 +/- 51.4 months (range, 3 to 165 months): 56.4 +/- 44.4 months in the AC-group versus 80.6 +/- 59.8 months in the N-AC group (P = NS). Histologically, 17 tumors (68%) were basal cell carcinomas and eight tumors (32%) were squamous cell carcinomas (P = .128). Fourteen patients (60.8%) were smokers: 11 patients (84.6%) in the AC-group versus 3 patients (30%) in the N-AC group (P = .012). All the patients underwent tumor resection, with only one patient dying, because of lymph node invasion of the neck. CONCLUSION: There was a higher incidence of de novo skin tumors among patients who smoked who underwent OLT for alcoholic cirrhosis.

Pseudomyxoma peritonei: a clinicopathologic analysis and follow-up of 21 patients.

BACKGROUND/AIMS: Pseudomyxoma peritonei is an uncommon disease characterized by the presence of mucinous peritoneal implants associated with an abdominal neoplasm. Our objective is to consider the characteristics of this entity in our western Mediterranean urban population. METHODOLOGY: All cases diagnosed with pseudomyxoma peritonei by our hospital during a period of 16 years were reviewed. Data from their clinical records and the biopsy samples were analyzed. RESULTS: We found 21 cases of pseudomyxoma peritonei with a male/female ratio of 10/11 and a mean age of 59 years. The predominant presentation symptom was abdominal pain (17 cases, 6 of them with acute abdomen). The most frequent primary site of origin of the pseudomyxoma was the appendix (10 cases). The histologic diagnosis was malignant (associated with carcinoma) in 17 cases and indeterminate behavior in 4. The follow-up was available for 15 patients (mean follow-up of 41 months), while six patients have been lost. Nine patients have died during the follow-up and the other 6 patients are still alive after follow-up. CONCLUSIONS: Laparotomy is the main tool for diagnosing pseudomyxoma peritonei. The appendix is the most frequent primary site of origin of pseudomyxoma peritonei, followed by bowel; the latter being more important than previously described. In most cases the histology is malignant. The prognosis is bad with a mortality greater than 60% at 5 years.

Safe endoscopic resection of gangliocytic paraganglioma of the major duodenal papilla.

A case of gangliocytic paraganglioma of the papilla of Vater in a 76-year-old man with a history of recurrent obstructive jaundice is presented. This is the first case of gangliocytic paraganglioma of the major papilla successfully resected by endoscopic ampullectomy.

Tissue CA-19.9 content in colorectal adenomas and its value in the assessment of dysplasia.

BACKGROUND: occasionally, the risk of malignant transformation may be difficult to establish in adenomatous polyps due to the fact that they contain areas with variable grades of dysplasia. A measurement of tissue tumor markers may be useful to recognize these adenomas. OBJECTIVES: the aims of this study were: to established firstly the relationship between carbohydrate antigen 19.9 (CA-19.9) content in the colorectal mucosa and the characteristics of polyps, and secondly, the diagnostic value of the formers measurement. PATIENTS AND METHODS: tissue CA-19.9 concentration was measured in 155 colorectal samples obtained from 145 patients (21 normal mucosa; 113 adenomatous polyps; 21 adenocarcinoma). Cytosol CA-19.9 content was determined by enzyme-linked immunoadsorbant assay, and the measurement of this protein was achieved by quantitative assay. Tissue samples were also processed for histological examination. RESULTS: we demonstrated that CA-19.9 levels in adenomatous polyps and adenocarcinomas were significantly higher than in the normal mucosa. These levels varied significantly according to polyp size, histological type, and grade of dysplasia. CA-19.9 contents were higher in polyps with a high risk of malignant transformation than in those with a low risk of severe dysplasia. The cut-off value 214 U/mg of protein properly differentiated both types of risk. The area under the receiver operating characteristic (ROC) curves showed that cytosol CA-19.9 levels allow classifying polyps according to their histological features. CONCLUSIONS: we concluded that the measurement of CA-19.9 content in adenomatous polyps may be useful to classify these tumors and confirm the feasibility to separate adenomas into two groups: low and high risk of malignant change.

Focal hyperplastic hepatocellular nodules in hepatic venous outflow obstruction: a clinicopathological study of four patients and 24 nodules.

AIMS: In hepatic venous outflow obstruction (Budd-Chiari syndrome), focal hepatocellular nodules are occasionally discovered showing variable morphology. These could be interpreted either as neoplastic (adenoma), regenerative (large regenerative nodule) or reactive to abnormal vasculature (focal nodular hyperplasia). The aim of this study was to investigate their histogenesis and to determine their morphological characteristics in order to provide diagnostic criteria. MATERIAL AND METHODS: Twenty-four hepatocellular nodules were studied, which were found in three explanted livers and in one additional autopsied liver from four patients with Budd-Chiari syndrome. As controls, we employed three explanted livers without nodules from patients who also suffered from Budd-Chiari syndrome. We attempted to classify the nodules morphologically as either adenoma-like, large regenerative nodule or focal nodular hyperplasia-like, using criteria from the literature. RESULTS: Out of the four cases, we observed two nodules in each of two livers, five in the third one and up to 15 in the remaining one. The size of the nodules ranged from 4 to 25 mm. Eleven nodules could be categorized as large regenerative nodules (two of them with a central scar), seven as focal nodular hyperplasia-like and six as adenoma-like. Some large regenerative nodules showed proliferated arteries with muscular hyperplasia similar to that seen in focal nodular hyperplasia. In the individual livers we could find nodules of various categories. Patchy or diffuse monoacinar regeneration was seen in most cases (six out of seven cases) in the macroscopically non-nodular liver parenchyma. In addition, thrombotic obstruction of portal vein branches was present in all except one of the nodular cases, but in none of the controls. Thus, it appears that portal venous obstructions are frequently, but not invariably associated with the development of nodules. CONCLUSIONS: The hepatocellular nodules seen in livers from patients with Budd-Chiari syndrome share morphological characteristics with large regenerative nodules, focal nodular hyperplasia and hepatocellular adenomas. Their multiplicity, the existence of mixed lesions, the frequent hepatocellular regenerative background as well as the frequently associated portal venous obstructions suggest that these nodules are regenerative in nature and conditioned by an uneven blood perfusion throughout the liver. In their differential diagnosis, the clinicopathological context in which they occur is of paramount importance and should allow recognition that those resembling adenomas may not be true neoplasms.

Kaposi's visceral sarcoma in liver transplant recipients.

We report three cases of Kaposi's sarcoma after orthotopic liver transplantation performed for cirrhosis related to hepatitis C virus (one case), ethanol (one case), or both (one case). All patients displayed disease within the first year after liver transplantation, and only in one case was the diagnosis obtained before the patient died. All three patients were on tacrolimus-steroid therapy, and in one case mycophenolate mofetil was added to treat acute persistent rejection.

Autoimmune enteropathy in an adult with autoimmune multisystemic involvement.

We describe the case of a 58-year-old woman with autoimmune enteropathy associated with thyroiditis, gastritis, transitory neutropenia, sicca syndrome and severe axonal polyneuropathy of autoimmune origin. Enterocyte autoantibodies were not detected. However, predisposition to autoimmune disease was indicated by the presence of high titres of anti-gastric parietal cell, anti-thyroglobulin, anti-thyroid peroxidase and anti-neutrophil antibodies. CD4+ and CD8+ lymphocytes were equally distributed in the lamina propria of the small intestine, but CD8+ cells were highly represented among intraepithelial lymphocytes.

Long-term biliary complications after liver surgery leading to liver transplantation.

Chronic biliary obstruction with repeated bouts of cholangitis adversely affects quality of life and may lead to secondary biliary cirrhosis with liver failure. We reviewed our experience with chronic biliary complications after surgical treatment of various diseases that at the end needed a liver transplantation. Twelve patients with previous biliary surgery developed secondary biliary cholangitis, secondary biliary cirrhosis, or both. Seven had surgery for liver hydatid disease by Echinococcus granulosus, another four had complicated biliary surgery unrelated to hydatid disease, and one had a history of a traffic accident with liver trauma and hepatectomy with chronic biliary fistula. The repeated cholangitis attacks and in two cases of hydatid disease the development of biliary-bronchial fistulas made these patients' lives miserable. All had had previous surgical procedures that made the transplantation procedure more difficult. Nevertheless, patient survival and graft actuarial survival after liver replacement were 75.0% and 69.2%, respectively, at 5 years.

Liver transplantation and hepatitis C virus. Results in a Spanish center since 1989.

BACKGROUND/AIMS: Hepatitis C-related liver disease is the main indication for liver transplantation in many centers. Viral RNA remains after transplantation in almost 100% of the patients, and more recent reports show a graft hepatitis rate of about 90%. The progression of this hepatitis seems to be quicker than in the nontransplant setting. METHODOLOGY: From June 1989 to October 2000, 197 adult patients had 213 for HCV-related liver disease at our institution. Basal immunosuppression consisted of a triple therapy with cyclosporine, azathioprine and steroids, or dual therapy with tacrolimus and steroids. None of the patients was treated with antivirals after liver transplantation. RESULTS: Pure HCV-related cirrhosis was the indication for liver transplantation in 114 patients, another 14 with hepatocellular carcinoma, 8 associated metabolic diseases, 43 high alcohol intake, 4 hepatitis B, 5 cholestatic diseases, and 3 other diseases. Six patients out of the 197 transplanted in this period were already grafted before this time, and had their first retransplantation of the liver after 1989 (their first liver transplantation was done when HCV was not known). Sixteen additional retransplantation procedures were done in the period considered. Hepatitis was diagnosed in 84.3% of the grafts biopsied later than 90 days after liver transplantation (118/140), and in 92.9% if it was done after one year (92/99). Cirrhosis was diagnosed in 21 grafts at a mean time of 1004.7 days, 21.2% of the grafts biopsied after 1 year and 28.6% after 2 years. Nine grafts in 8 patients were diagnosed as fibrosing cholestatic hepatitis. Patient actuarial survival was 80.9%, 69.7%, 67.5% and 50.6% at 1, 3, 5 and 10 years. Liver failure and hepatoma recurrence were the cause of death in 42.4% of the patients. Actuarial graft survival was 75.2%, 64.9%, 63.5% and 48.6% at 1, 3, 5 and 10 years, and was significantly affected by Child stage (B vs. C, P = 0.004). When compared to 228 non-HCV- infected patients with chronic parenchymatous disease, these had an almost significantly better patient survival (P = 0.0577), but a nonsignificant difference in graft survival. Graft loss related to liver causes was 17.6% in HCV+ patients 14.6% in HCV- patients. Liver causes of death were 14.0% in HCV+ patients and 4.8% in HCV-patients (P = 0.002). CONCLUSIONS: HCV infected liver transplantation recipients present very often graft hepatitis, which may progress to advanced stages in a quite short interval. Mid-term patient and graft survival is comparable to those of non-HCV recipients, but causes of death related directly to liver disease are more common in HCV+. This makes one think that long-term prognosis (more than 10 or 15 years) will be worse in HCV patients.