Early predictors of antiviral treatment response in liver transplant recipients with recurrent hepatitis C genotype 1.

The success of current antiviral treatment for hepatitis C virus (HCV) recurrence in liver transplant (LT) recipients remains limited. We aimed at evaluating the value of IL28B genotype and early viral kinetics to predict response to standard treatment in the transplant setting. We retrospectively evaluated 104 LT recipients treated for HCV genotype 1 recurrence between 2001 and 2010. Baseline variables, including IL28B genotype, and early viral kinetics were compared among patients who did or did not achieve a sustained virological response (SVR). Logistic regression analyses of candidate variables were conducted to generate a reliable predictive model based on the minimum set of variables. Twenty-nine (28%) achieved an SVR. On multivariate analysis, the magnitude of HCV RNA decline at 4 weeks (OR: 3.74, 95% CI: 1.64-9.39; P = 0.003) and treatment compliance (OR: 35.27, 95% CI: 3.35-365.54; P = 0.003) were the only independent predictors of SVR. Favourable recipient IL28B genotype significantly correlates with virological response at week 4 (OR 3.23; 95% CI, 1.12-9.15; P = 0.03). By logistic regression analysis, a model including donor age, recipient rs12979860 genotype and viral load at 4 weeks showed the best predictive value for SVR with an area under the receiver operating curve of 0.861. Favourable recipient IL28B genotype strongly correlates with the viral response at week 4 which is the strongest predictor of response. The combination of recipient IL28B genotype and donor age with the week 4 response reliably estimates the probability of SVR early on-treatment and may facilitate therapeutic strategies incorporating new antiviral agents.

Lipoprotein lipase but not hormone-sensitive lipase activities achieve normality after surgically induced weight loss in morbidly obese patients.

BACKGROUND: Although bariatric surgery is currently the most common practice for inducing weight loss in morbidly obese patients (BMI>40 kg/m2), its effect on the lipid content of adipose tissue and its lipases (lipoprotein lipase [LPL] and hormone-sensitive lipase [HSL]) are controversial. METHODS: We analyzed LPL and HSL activities and lipid content from plasma as well as subcutaneous (SAT) and visceral (VAT) adipose tissue of 34 morbidly obese patients (MO) before and after (6 and 12 months) Roux-en-Y gastric bypass surgery and compare the values with those of normal weight (control) patients. RESULTS: LPL activity was significantly higher in MO (SAT=32.9+/-1.0 vs VAT=36.4+/-3.3 mU/g tissue; p<0.001) than in control subjects (SAT=8.2+/-1.4 vs VAT=6.8+/-1.0 mU/g tissue) in both adipose depots. HSL activity had similar values in both types of tissue (SAT=32.8+/-1.6 and VAT=32.9+/-1.6 mU/g) of MO. In the control group, we found similar results but with lower values (SAT=11.9+/-1.4 vs VAT=12.1+/-1.4 mU/g tissue). Twelve months after surgery, SAT LPL activity diminished (9.8+/-1.4 mU/g tissue, p<0.001 vs morbidly obese), while HSL (46.6+/-3.7 mU/g tissue) remained high. All lipids in tissue and plasma diminished after bariatric surgery except plasma nonesterified fatty acids, which maintained higher levels than controls (16+/-3 vs 9+/-0 mg/dL; p<0.001, respectively). CONCLUSIONS: When obese patients lose weight, they lose not only part of the lipid content of the cells but also the capacity to store triacylglycerides in SAT depots.

Ghrelin and apolipoprotein AIV levels show opposite trends to leptin levels during weight loss in morbidly obese patients.

BACKGROUND: Although bariatric surgery is the most common procedure used to induce weight loss in morbidly obese patients, its effect on plasma satiety factors (leptin, ghrelin, and apolipoprotein (apo)-AIV) is controversial. The aim of this work was to analyze these parameters before and at different times after surgery. METHODS: Plasma was obtained from 34 patients before undergoing Roux-en-Y gastric bypass and during weight loss in the 12 months following surgery. RESULTS: Morbidly obese patients had significantly higher values (147%) of leptin than normal-weight (NW) persons, while their ghrelin levels were 46% less than NW. Apo-AIV levels had approximately the same value in both groups (obese and NW). During weight loss, leptin decreased by 75% and ghrelin increased by 78%. Both parameters reached values less than or near NW, respectively, at 1 year after surgery. During the first month after surgery, apo-AIV plasma levels decreased (47%) but later increased and finally returned to preoperative values. Apo-AIV levels were correlated negatively with leptin and positively with ghrelin. High-density lipoprotein (HDL) levels were positively correlated with those of ghrelin and apo-AIV. CONCLUSIONS: During weight loss, plasma leptin and ghrelin could be good markers of total fat decrease. Ghrelin could also indicate gastric mucous improvement, whereas apo-AIV could indicate the recovery of intestinal function. Changes produced in the HDL levels of morbidly obese patients during weight loss suggest a decreased risk of coronary disease.

Hepatitis B virus genotypes and G1896A precore mutation in 486 Spanish patients with acute and chronic HBV infection.

This study aims to determine the prevalence of hepatitis B virus (HBV) genotypes (A-F) and their association with the G1896A precore mutation in 486 patients positive for HBV surface antigen. Genotypes were determined by RFLP and precore mutation by real-time PCR. Genotypes D (48.1%) and A (39.5%) were the most common, followed by F (4.1%) and B, C and E (<1%). The A to D ratio (A:D) was 1.4 in HBeAg+ chronic hepatitis B (CHB), 0.6 in HBeAg- CHB and 1.4 in HBeAg- inactive carriers. Distribution of these genotypes was different between HBeAg+ CHB and HBeAg- CHB (P = 0.02), and between HBeAg- CHB and HBeAg- inactive carriers (P = 0.009). Genotype A was the most prevalent in HBeAg+ CHB with elevated alanine aminotransferase (ALT) (68.6%) and genotype D in HBeAg+ CHB with fluctuating ALT (60.7%). There was a difference in genotype prevalence between chronic and acute infection (P = 0.03). The precore mutant correlated with high levels of HBV-DNA in genotype d HBeAg- CHB. Genotype D is not as highly prevalent in Spanish patients as would be expected in a Mediterranean area. The unequal prevalence of genotypes between acute and chronic infection suggests that genotype A is associated with a higher tendency to cause chronic infection.

Early detection of nonresponse to interferon plus ribavirin combination treatment of chronic hepatitis C.

We have investigated the value of early hepatitis C virus (HCV) RNA decline (DeltaHCV RNA) to predict response to combination therapy in 66 chronic hepatitis C patients treated with IFN-alpha2b (3 MU thrice weekly) and ribavirin (800 mg daily) for 12 months [25 sustained responders (SR) and 41 nonresponders or relapsers (NR)]. Serum HCV RNA was retrospectively measured in samples obtained at baseline and 4, 8 and 12 weeks after treatment onset, using a commercially available quantitative RT-PCR assay. At 4 weeks, serum HCV RNA had decreased a mean of 2.6 +/- 0.8 logs among SR as compared with only 0.5 +/- 0.8 logs in NR (P < 0.001), and was already undetectable (< 600 IU/mL) in 12 (48%) of the SR but in none of the NR. At 8 weeks, HCV RNA was undetectable in 21 SR and in 2 NR and mean DeltaHCV RNA were 4.2 +/- 1.3 and 0.8 +/- 1.0 logs, respectively (P < 0.001). At week 12 all SR had undetectable HCV RNA as compared with only five NR (P < 0.001). Stepwise logistic regression analysis identified DeltaHCV RNA at 12 weeks as the strongest predictor of sustained response. Receiver operating characteristic (ROC) curves of DeltaHCV RNA for sustained response prediction identified sensitivity peaks with 100% negative predictive value corresponding to DeltaHCV RNA > 1 log at 4 weeks, > 2 logs at 8 weeks and > 3 logs at 12 weeks. Our results show that early changes in the HCV RNA level may reliably identify patients having no chance of a sustained virological response during the first 3 months of combination therapy, thus providing an excellent tool for optimizing antiviral treatment of chronic hepatitis C.

Outcome and hepatic hemodynamics in liver transplant patients with portal vein arterialization.

UNLABELLED: Few cases of successful portal vein arterialization in orthotopic and auxiliary liver transplantation have been reported. AIM: To evaluate the effect of portal vein arterialization on hepatic hemodynamics and long-term clinical outcome in three patients undergoing liver transplantation. METHODS: Two patients with extensive splanchnic venous thrombosis received an orthotopic liver transplant and one with fulminant hepatic failure received an auxiliary heterotopic graft. Portal vein arterialization was performed in all cases. RESULTS: One patient died 4 months after transplant and two are still alive. Auxiliary liver graft was removed 3 months post-transplant when complete native liver regeneration was achieved. Immediate post-transplant liver function was excellent in all cases. Only one patient developed encephalopathy and variceal bleeding owing to prehepatic portal hypertension secondary to arterioportal fistula 14 months after transplant. He was successfully treated by embolization of the hepatic artery. Hepatic hemodynamic measurements demonstrated a normal pressure gradient between wedged and free hepatic venous pressures in all cases. Liver biopsy showed acceptable graft architecture in two cases and microsteatosis in one. CONCLUSIONS: Liver transplantation with portal vein arterialization is an acceptable salvage alternative when insufficient portal venous flow to the graft is present. The double arterial supply does not imply changes in hepatic hemodynamics, at least in the early months post-transplant.

[Microbiological study of post mortem lung biopsy in pediatric patients]. / Estudio microbiológico de la biopsia pulmonar post mortem en pacientes pediátricos.

AIM: The aim of this study was to correlate the morphologic and microbiologic findings of the post mortem biopsies of a series of pediatric patients. MATERIAL AND METHODS: A complete morphologic study of all the organs of the patients included in the study was performed. In the pulmonary samples provided by the pathologist, the presence of aerobic and anaerobic microorganisms and fungi were determined. RESULTS: Ninety-three pulmonary biopsies corresponding to 77 dead patients (47 infants and 30 fetuses) were undertaken. Forty-five patients showed pulmonary histology of infectious processes. The concordance between the morphology and the microbiologic culture was of 66.2%. The microorganisms most frequently isolated were gram positive cocci (46.4%) followed by gram negative bacillus (30.4%). CONCLUSIONS: Although post mortem pulmonary tissue cultures should be interpreted with caution without first relating these with the morphologic findings and the clinical characteristics of the patient, a statistically significant agreement was observed between the anatomo-pathological study and the microbiologic findings.

Recurrent hepatitis C virus infection after liver transplantation: immunohistochemical assessment of the viral antigen.

BACKGROUND: The value of immunohistochemical methods to identify hepatitis C virus antigen (HCVAg) in liver tissue has not been established. We have evaluated the significance of HCVAg expression in livers of patients with transplants and recurrent hepatitis C virus (HCV) infection. METHODS: Forty-two liver biopsy specimens from 32 liver-transplant recipients with recurrent HCV infection were tested for HCVAg using fluorescein isothiocyanate-labeled polyclonal, polyreactive human immunoglobulin. Histologic assessment of liver and quantitation of HCV RNA in sera were carried out in specimens obtained simultaneously with biopsies. RESULTS: HCVAg was found in 33% of the liver specimens obtained during the first month after transplantation and in all liver specimens obtained between 1 and 18 months after transplantation. Amounts of the antigen were significantly greater in specimens obtained more than 1 month after transplantation. A statistically significant increase of the average HCV RNA level in serum was observed in samples tested after the first month after the transplantation, and some decrease in the HCV RNA level was found in those obtained between 6 and 18 months after transplantation. Larger amounts of HCVAg were observed in specimens corresponding to episodes of acute or chronic hepatitis than in those associated with minimal parenchymal evidence of rejection. CONCLUSIONS: OBSERVATIONS of HCVAg expression in liver biopsy specimens indicated that the presence of viral antigens in hepatocytes is a constant finding in specimens obtained 1 month or longer after transplantation. Although large amounts of HCVAg correlated with acute or chronic hepatitis, the nature of this association with the development of pathologic changes remains to be established.

Characteristics of perisinusoidal collagenization in liver cirrhosis: computer-assisted quantitative analysis.

OBJECTIVE: To determine the respective roles of septal fibrosis, necroinflammatory activity, iron deposition, steatosis, and patterns of nodular and septal remodeling in the collagenization of the perisinusoidal space in livers from patients undergoing transplantation for alcoholic or posthepatitis C cirrhosis and to ascertain whether perisinusoidal collagenization has clinical implications added to those of septal fibrosis. STUDY DESIGN: Sixty-six hepatectomy specimens from patients undergoing liver transplantation for cirrhosis were analyzed. Thirty-two alcoholic and 34 posthepatitis C cirrhoses were included. Picro Sirius-stained slides were examined with polarized light and the amount of perisinusoidal collagenization measured by computerized image analysis. Size distributions of septa and nodules were assessed by mathematical morphology methods. RESULTS: The septal and perisinusoidal fibrosis indices and Knodell and Pugh-Child scores showed significant differences between alcoholic and posthepatitis cirrhoses. Correlation between septal fibrosis and perisinusoidal collagenization was weak, though significant. Both variables correlated significantly with the clinical score. The correlation was negative between septal fibrosis or perisinusoidal collagenization and the Knodell score. CONCLUSION: Perisinusoidal collagenization was not a feature of all cases of cirrhosis, although it was more prominent in alcoholics. For the whole series, it significantly correlated with the clinical score, which increased significantly when high perisinusoidal collagenization was added to high septal fibrosis. No absolute dependence was found between perisinusoidal collagenization and septal fibrosis; percentage of slender fibrous septa and amount of iron deposition were other factors entered in the regression equation.

Fine needle aspiration cytology of undifferentiated (embryonal) sarcoma of the liver. A case report.

BACKGROUND: Undifferentiated (embryonal) sarcoma of the liver (UESL) is a rare malignant mesenchymal hepatic tumor with an incidence among liver tumors of 27.7%. It occurs predominantly in children under the age of 15. CASE: The cytologic findings in a case of UESL in fine needle aspiration biopsy material in a 12-year-old girl are described. The patient presented clinically with upper abdominal pain and a palpable mass in the right hepatic lobe. Cytologic features included a combination of polygonal and spindle cells. The polygonal cells were large, with round or lobulated nuclei, and occasionally multinucleated, with one or several nucleoli and variable cytoplasm with poorly defined borders. A few intracytoplasmic and extracytoplasmic eosinophil globules were observed. Histologic and immunohistochemical studies were performed, and staining for vimentin and alpha-1 antichemotrypsin was positive. CONCLUSION: It is important to recognize the cytologic features of this type of liver tumor since rapid diagnosis and initiation of early treatment may improve the poor prognosis of these neoplasms.

Treatment of experimental pneumonia due to penicillin-resistant Streptococcus pneumoniae in immunocompetent rats.

A model of pneumonia due to Streptococcus pneumoniae resistant to penicillin was developed in immunocompetent Wistar rats and was used to evaluate the efficacies of different doses of penicillin, cefotaxime, cefpirome, and vancomycin. Adult Wistar rats were challenged by intratracheal inoculation with 3 x 10(9) CFU of one strain of S. pneumoniae resistant to penicillin (MICs of penicillin, cefotaxime, cefpirome, and vancomycin, 2, 1, 0.5, and 0.5 microg/ml, respectively) suspended in brain heart broth supplemented with 0.7% agar. The rats experienced a fatal pneumonia, dying within 5 days and with peak mortality (70 to 80%) occurring 48 to 72 h after infection, and the bacterial counts in the lungs persisted from 8.87 +/- 0.3 log10 CFU/g of lung at 24 h of the infection to 9.1 +/- 0.3 log10 CFU/g at 72 h. Four hours after infection the animals were randomized into the following treatment groups: (i) control without treatment, (ii) penicillin G at 100,000 IU/kg of body weight every 2 h, (iii) penicillin G at 250,000 IU/kg every 2 h, (iv) cefotaxime at 100 mg/kg every 2 h, (v) cefpirome at 200 mg/kg every 2 h, and (vi) vancomycin at 50 mg/kg every 8 h. Two different protocols were used for the therapeutic efficacy studies: four doses of beta-lactams and one dose of vancomycin or eight doses of beta-lactams and two doses of vancomycin. Results of the therapy for experimental pneumonia caused by penicillin-resistant S. pneumoniae showed that initially, all the antimicrobial agents tested had similar efficacies, but when we prolonged the treatment, higher doses of penicillin, cefotaxime, and cefpirome were more effective than penicillin at lower doses in decreasing the residual bacterial titers in the lungs. Also, when we extended the treatment, vancomycin was more efficacious than penicillin at lower doses but was less efficacious than higher doses of penicillin or cefpirome. The model that we have developed is simple and amenable for inducing pneumonia in immunocompetent rats and could be used to explore the pathophysiology and to evaluate optimal therapy of this infection in the immunocompetent host.

Interferon vs. adenine arabinoside 5'-monophosphate in patients with anti-HBe-positive chronic hepatitis.

Anti-HBe-positive patients with precore mutants may have severe, progressive liver disease. Therapy with interferon has been effective, but relapses are frequent. To evaluate and compare two antiviral treatments, lymphoblastoid interferon (ly-IFN) and adenine arabinoside 5'-monophosphate (ARA-AMP), 20 patients with anti-HBe-positive chronic hepatitis (5 cirrhosis and 15 CAH) and viral replication (HBcAg in the liver and HBV DNA in serum) were treated. Patients were randomized into two groups: 11 patients received ARA-AMP, 5 mg/kg/day during 7 weeks, and 9 received human ly-IFN, 5,000,000 units, three times per week, during 4 months. Baseline clinical, biochemical and histological features were not significantly different between the two groups. At the end of therapy, 8 (89%) patients in the interferon group and 5 (45%) in the ARA-AMP group showed normal ALT levels and no HBV DNA in serum by a liquid hybridization assay (P < 0.05). At 1 year of follow-up, a persistent response was observed in 33% of ly-IFN patients and in 27% of ARA-AMP patients, a transient response in 56% and 18%, and nonresponse in 11% and 55%, respectively. HBV DNA remained detectable by polymerase chain reaction (PCR) in 19 of the 20 patients. Among the responders, an improvement in histological lesion and the disappearance of intrahepatic HBcAg were observed; in the nonresponders, histological lesion remained stable or worsened. In conclusion, the efficacy of interferon and ARA-AMP was similar in treating anti-HBe-positive chronic hepatitis. Although interferon treatment led to initial improvement in a larger number of patients, there was a much higher rate of relapses with this drug.

[Digestive cytomegalovirus disease in AIDS patients]. / Enfermedad digestiva por citomegalovirus en pacientes con sida.

BACKGROUND: In this paper we study the digestive manifestations of cytomegalovirus (CMV) in AIDS patients. Also, we evaluate the antiviral treatment and the necessity of maintenance therapy. METHODS: Retrospective review of medical charts of all patients with AIDS and digestive CMV disease diagnosed and followed-up since 1983 to december 1993. RESULTS: Of 720 AIDS patients, 96 presented a CMV disease. Among them, 30 patients (31%) complained digestive manifestations. These were 26 males and 4 females, mean age: 37.4 y-old. Risk factors for HIV were: 13 homosex and 12 intravenous drug abusers. Average of time between AIDS diagnosis and digestive CMV disease: 13.4 months. Fourteen patients had esophagitis, 9 proctocolitis, 3 hepatitis, 3 pancreatitis, 2 gastric ulcerations, one small bowel disease and other an oral ulceration. Two patients had a concomitant CMV chorioretinitis. CD4 lymphocytes were below 0.05 x 10(9)/l in 29 patients. Twenty-four patients received antiviral treatment during the acute disease period, with a clinical curation rate of 60%. Seven patients received maintenance therapy and remained free of CMV disease until death. Eleven patients didn't received maintenance treatment. Of them, one patient presented a digestive relapse and two developed a CMV chorioretinitis. Mortality in the first month from diagnosis was 23% and the median of survival time for patients who cured and initial episode of digestive CMV disease was 208 days, wether or not the patient received maintenance therapy or not. CONCLUSIONS: One third of ours patients with AIDS and CMV infection have a digestive disease. This CMV digestive disease appears in patients with a severe immunosuppression. Acute phase mortality was 23%. The median survival was 7 months, independently or receiving maintenance treatment or not.

Chronic delta hepatitis: is the prognosis worse when associated with hepatitis C virus and human immunodeficiency virus infections?

Eighty-six patients were followed for 6.5 years to study the epidemiological, virological, and histological course of chronic delta hepatitis and the relationship of this disease with HIV and HCV infection. Patients were classified into four groups according to simultaneous HCV and/or HIV infection: group 1, HDV infection (20 cases); group 2, HDV and HCV infection (11 cases); group 3, HDV and HIV infection (12 cases), and group 4, HDV, HCV, and HIV infection (43 cases). All but 14 patients were asymptomatic at presentation. Liver histology showed chronic active hepatitis in 53 cases and cirrhosis in 19 cases. During followup, 52 patients remained asymptomatic, 34 developed hepatic dysfunction, 28 died, and 1 received a liver transplant. Among the 28 patients who died, 4 had HDV infection; 3 HDV and HCV infection; 3 HDV and HIV infection; and 18 HDV, HCV, and HIV infection. Death was due to liver failure in 16 (57%), AIDS in 10 (36%), and was unrelated to liver disease in 2 (8%) cases. There results demonstrate that chronic delta hepatitis is a severe disease, especially among drug users with HIV and HCV infection. The high morbidity and mortality of chronic delta hepatitis justifies the use of antiviral therapy to modify the natural course of the disease.

Is hepatitis C virus recurrence a risk factor for chronic liver allograft rejection?

Several risk factors have been reported that may favour the development of chronic rejection. From October 1988 to December 1993, 97 liver transplants with survival of more than 3 months were included in the study. Fifty-two patients (54.1%) had chronic hepatitis C virus (HCV) infection before liver transplantation. Immunosuppression consisted of cyclosporine A and prednisone, whereas 14 patients received FK 506 and prednisone. Severe graft HCV reinfection was present in 32 patients (61.5%) after liver transplantation and chronic graft hepatitis C was found in 26 cases at the end of the study. Chronic rejection occurred in 8 of 97 allografts (8.25%); 5 presented chronic rejection and concomitant chronic graft hepatitis C. The incidence of chronic rejection in patients with HCV infection before liver transplantation (9.6%) did not differ when compared with the negative HCV patients (6.6%). However, when the 26 cases that developed graft dysfunction due to chronic hepatitis C after liver transplantation were considered, 5 presented chronic rejection, a significantly higher incidence than in the remaining patients (3 of 71) (Yates chi-square test: P < 0.05). In our experience, there appears to be a relationship between the development of chronic rejection and chronic hepatitis C in the graft after liver transplantation.

[Severe weight loss at the beginning of mesenteric panniculitis]. / Severa pérdida de peso en el debut de una paniculitis mesentérica.

We report a case of mesenteric panniculitis that presented with a severe lost of weight. We stress the difficulty that entails the diagnosis of this unusual entity, and also the excellent response to corticoid therapy in our patient. The clinical, pathological and therapeutic features of mesenteric panniculitis are reviewed.