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According to current estimates, there are 60,000 to 80,000 HIV and HCV coinfected individuals in Spain, and 5,000 to 10,000 HIV and HBV coinfected individuals. Among these patients, 10% to 15% have liver cirrhosis. Thus, end-stage liver disease is one of the major causes of death in our country. Liver transplantation is the only therapeutic option for these patients. Accumulated experience in North America and Europe in the last five years indicates that three-year survival in HIV-positive liver transplant recipients is similar to that of HIV-negative recipients. The selection criteria for HIV transplant candidates includes the following: no history of opportunistic infections, CD4 lymphocyte count higher than 100 cells/mm3, and HIV viral load suppressible with antiretroviral treatment. In Spain, where the majority of patients are former drug abusers, complete abstinence from heroin or cocaine use during two years is also required, with the possibility of the patient being in a methadone program. To date 26 hepatic transplants have been performed in the same number of patients, with only two deaths (7%) after a median follow-up of eight months (1-28). The main problems in the post-transplantation period in all the series has been recurrent HCV infection, which is the principle cause of post-transplantation mortality, and pharmacokinetic and pharmacodynamic interactions between the antiretroviral and immunosuppressive agents. There is little experience with pegylated interferon and ribavirin treatment in this population.

Background: Nucleoside analogues may induce mitochondrial toxicity, particularly didanosine. Ribavirin increases didanosine exposure, which might be clinically relevant when coadministered in HIV/HCV-coinfected patients., Objective: To evaluate, among 89 patients receiving highly active antiretroviral therapy (HAART) and therapy for chronic hepatitis C, clinically relevant mitochondrial toxicity in those treated with concomitant ribavirin and didanosine (n=35, 39%)., Methods: From January 2000 to July 2002 longitudinal analysis of the incidence and clinical course of didanosine-related hyperamylasaemia, pancreatitis, hyperlactataemia/lactic acidosis or neuropathy. Risk factors were evaluated using univariate and multivariate Cox's proportional hazards model., Results: Among 35 patients who received concomitant didanosine (400 mg/day in 86%) and ribavirin (> or = 10 mg/kg/day in 91%), 20 (57%) developed one or more adverse events after a mean of 87 days. Most frequent laboratory abnormalities were hyperamylasaemia (18 patients, 51%) and hyperlactataemia (eight patients, 23%). Acute pancreatitis and symptomatic hyperlactataemia developed in 10 (28%) and six (17%) patients, respectively. Two patients (6%) with pancreatitis and severe lactic acidosis died; the other patients recovered uneventfully despite continuation of anti-HCV therapy in 83% after didanosine withdrawal in 40%. In the Cox's model higher baseline amylase levels (HR: 1.04, 95% CI: 1.02-1.06, P=0.001) and three nucleoside reverse transcriptase inhibitor-based HAART (HR: 5.3, 95% CI: 1.73-16.24, P=0.003) were significantly associated to toxicity., Conclusions: The coadministration of didanosine and ribavirin should be avoided in HIV/HCV-coinfected patients, due to a high rate of clinically significant toxicity, particularly in triple nucleoside-based HAART. Amylase levels should be strictly monitored, especially if elevated at baseline.

Background: Hepatitis C virus (HCV) and HIV coinfection constitutes an important epidemiological and clinical problem. We evaluated the safety and efficacy of Pegylated interferon alpha2b (Peg-IFN) and a fixed dose of ribavirin in the treatment of chronic hepatitis C in HIV coinfection., Methods: Open, prospective study in HCV-HIV coinfected patients with persistently elevated alanine aminotransferase (ALT) levels and a liver biopsy showing either portal or bridging fibrosis. Therapy included Peg-IFN (50 micro g weekly) with ribavirin 800 mg for 48 weeks. The primary end point was sustained virological response (SVR). Univariate and multivariate analyses were performed to determine factors associated with response., Results: By intent-to-treat analysis, 11 of 35 patients (31%) reached SVR. SVR was significantly better for genotypes 2/3 than for genotype 1 (54% versus 21%; P < 0.05). By multivariate logistic regression analysis, only a non-1 genotype was an independent factor for SVR [odds ratio (OR), 6; 95% confidence interval (CI), 1.1-31.7; P < 0.005]. A decrease of at least 1.5 log10 HCV RNA at week 12 of therapy was highly predictive of SVR (OR, 49.9; 95% CI, 4.9-508.2; P < 0.001). Most patients developed adverse events, although only six patients (17%) discontinued treatment due to toxicity., Conclusions: The combination of low doses of Peg-IFN plus a fixed dose of ribavirin resulted in a rate of SVR similar to that obtained with higher doses of the drugs in HIV-infected patients and lower than those obtained in non-HIV patients. Response at week 12 may be useful to help guide therapy in HCV-HIV co-infected patients.

Aspergillosis is a potential, severe, and usually early complication of liver transplantation. New promising strategies, such as detecting Aspergillus antigenemia, have been used for the diagnosis of aspergillosis in immunosuppressed patients, but the impact in solid organ transplantation is not well known. A case-control study in 260 adults who underwent liver transplantation from January 1994 to June 2000 was performed. A case was defined as any liver transplant recipient with a proven or probable diagnosis of invasive aspergillosis. Controls were defined as a liver transplant recipient without aspergillosis infection with a survival longer than two months after transplantation. Clinical and analytical variables, including Aspergillus antigenemia, were compared. A special analysis was performed in patients in whom late aspergillosis developed (after day 100 posttransplantation). Among 260 patients, invasive aspergillosis developed in 15 (5.6%). Median time from transplantation to aspergillosis in 13 patients with sufficient data for analysis was 126 days (range, 22 to 1117). Seven (54%) developed the infection after day 100 posttransplantation. Thirty-eight patients were used as controls. Antigenemia was available in nine of 13 cases and in 33 of 38 controls. By multivariate analysis, retransplantation (OR, 29.9 [95% CI, 2.1 to 425.1]), dialysis requirements after transplantation (OR, 24.5 [95% CI, 1.25 to 354]), and the presence of Aspergillus antigenemia in serum at any time point after transplantation (OR, 50.0 [95% CI, 3.56 to 650]) were independently associated to aspergillosis. In the subgroup of patients that developed late aspergillosis, cytomegalovirus infection (OR, 6.7 [95% CI, 1.0 to 42.5]) was the only independent factor associated. Hepatic and renal dysfunction predispose to Aspergillus infection in liver transplant recipients. Cytomegalovirus infection and increased immunosuppression favor invasive aspergillosis during the late posttransplantation period. Aspergillus antigenemia seems to be a good predictor of invasive aspergillosis.

Unlabelled: Minimal hepatic encephalopathy is often present in patients with chronic liver disease. The aim of this work was to determine changes in the dynamics of sleep electroencephalogram (EEG) in cirrhotic patients without overt encephalopathy. Twenty such cirrhotic subjects included in the protocol of hepatic transplantation of our hospital were studied and compared with 20 age-matched healthy volunteers. Spectral analysis of all-night EEG was estimated by computing the fast-Fourier transform in 2-second epochs, and averaging every 60 seconds. Artifacts were off-line suppressed, sleep stages (stage 2, stage 3-4 and REM) were determined, and the EEG mean dominant frequency (MDF) was calculated in each of these stages. Results show that in cirrhotic patients, nocturnal MDF evolution discloses a clear alteration of the ultradian EEG frequency oscillations present in controls. Also, the mean value of MDF in REM episodes was larger in cirrhotics than the corresponding value in controls., Conclusions: 1) sleep EEG evidences the existence of minimal hepatic encephalopathy; 2) the spectral analysis of EEG in minimal hepatic encephalopathy showed that the changes of MDF during sleep are an early marker of cerebral dysfunction in cirrhotic patients.

The derangement of sex hormone serum levels in cirrhotic patients is well-delineated, and increased levels of progesterone and estradiol have been associated to hyperventilation in cirrhotic patients. These hormones have a well-known role in the regulation of vascular tone. The aim of this study was to evaluate whether sex hormone levels contribute to pulmonary vasodilatation (PV) and gas exchange abnormalities in cirrhosis. Contrast transesophageal echocardiography, arterial blood gases, parameters of liver function, pulmonary function test, estradiol and progesterone levels were determined in 45 male cirrhotic patients. Nineteen of 45 patients (42.2%) presented PV. Hyperventilation (pressure arterial of CO2< or =35 mmHg) was correlated to progesterone levels (p<0.05) and pressure arterial of CO2 was high in patients with PV (p<0.005) and Child class B and C (p<0.01). Hypoxemia (pressure arterial of O2<80 mmHg) had inverse correlation with progesterone (p<0.05) and estradiol (p<0.05) levels and pressure arterial of O2 was low in patients with Child class B and C (p<0.05). PV was present in patients with high estradiol levels (p<0.05), high progesterone levels (p<0.005) and Pugh class B and C (p<0.05). Logistic regression analysis identified progesterone as the sole independent factor associated to PV (p<0.0005). Multivariate linear regression showed that PV was the sole independent factor related to both pressure arterial of CO2 (p<0.05) and pressure arterial of O2 (p<0.01) levels. PV was independently associated to gas exchange abnormalities in cirrhosis. Progesterone and estradiol were related with PV in cirrhotic patients.

We describe a case of glycogen storage disease type Ib in 32-year old male patient with poor metabolic control in spite of medical and nutritional management and the use of recombinant granulocyte stimulating factor. Because of this, liver transplantation was considered as a definitive treatment. We comment on the metabolic results of liver transplantation performed, with reversal of hypoglycemia, hyperuricemia, hypertriglyceridemia and cyclic neutropenia, all of which persist 4 years post-transplant. In view of this case, we believe that liver transplantation is a feasible option to consider in patients with type Ib glycogenosis as a definitive therapeutic procedure., (Copyright 2001 Harcourt Publishers Ltd.)

Patients with cirrhosis may fail to respond to anti-hepatitis B vaccine. An adequate response would be especially interesting when patients are on a liver transplant waiting list. Posttransplantation de novo hepatitis B has been well documented. One possible source is the grafting of organs from hepatitis B surface antigen (HBsAg)-negative, antibody to HBsAg (anti-HBs)-positive, antibody to hepatitis B core antigen-positive donors. The achievement of high titers of anti-HBs could be protective in this setting. We studied prospectively the response rate to recombinant hepatitis B vaccine (3 40-microg doses administered at 0, 1, and 2 months) in 62 patients with end-stage liver disease awaiting liver transplantation. Twenty-two patients showed antibody response (44%). A further 3 doses were administered in 15 of 28 nonresponders and were effective in 9 patients. Thus, the response rate reached 62% (31 of 50 patients completing 1 or 2 vaccination schedules before liver transplantation). Classic hepatitis B vaccination studies of patients with cirrhosis yield lower response rates. Vaccination with this double-dose schedule should be considered in such patients before liver transplantation.

Background: Liver granulomatosis is an occasional finding in posttransplant liver biopsies. Its diagnosis is made more difficult by the variety of conditions that can lead to it. In the nontransplant setting, the association of liver granulomatosis and hepatitis C virus (HCV) infection has occasionally been described., Methods: We describe the case of a patient with a liver transplantation for an HCV-associated cirrhosis who developed an alteration of liver tests. Granulomatosis was detected on the liver biopsy., Results: Other causes of granulomatosis were satisfactorily excluded. The development of the lesions coincided with a viral flare-up., Conclusion: We think that HCV can be listed among the possible causes of liver granulomas in the posttransplant setting and that it must be considered in the differential diagnosis of this condition.

The optimal and safer interleukin-2 (IL-2) dose for treatment of chronic hepatitis C virus (HCV) infection has been studied in 33 HCV-RNA positive patients with chronic hepatitis C. Patients were randomly allocated to receive 5 days per week during 12 weeks IL-2 doses of: 0.9 MIU (n = 10), 1.8 MIU (n = 10), or 3.6 MIU (n = 13). After 12 weeks, responder patients stopped treatment, whereas nonresponders received 12 additional weeks of IL-2 at the next higher dose: 1.8, 3.6, or 5.4 MIU. As a whole, after the first 12 weeks of IL-2 alanine aminotransferase (ALT) levels significantly decreased (P < .001) with respect to the baseline values (140 +/- 63 vs. 70 +/- 30 IU/L). At the end of treatment (24 weeks), the mean ALT level (80 +/- 50 IU/L) continued significantly lower (P < .001) than the baseline one, and 24% of patients normalized ALT levels; according to dosage, ALT normalization was: 0% for 0.9 MIU, 25% for 1.8 MIU, 5% for 3.6 MIU, and 18% for 5.4 MIU. HCV-RNA levels decreased during treatment, but in none of the patients became undetectable. All patients had a local reaction at the injection site with induration, erythema, and swelling, which was dose-related. The dose of 5.4 MIU was poorly tolerated and was reduced to 3.6 MIU in 4 of 11 patients. No changes in hematological parameters were observed. At the end of follow-up (6 months) four of eight responder patients continued with normal ALT. In conclusion, IL-2 treatment for chronic hepatitis C induced a biochemical response in 8 of 33 (24%) patients at the end of therapy while at the end of follow-up, 4 of 33 (8%) patients remained with normal ALT. The dose of 1.8 MIU is well tolerated and seems to be the most efficacious.

Background/aims: Markers for hepatitis C virus are often detectable in patients suffering chronic hepatitis with liver-kidney microsomal type 1 antibodies. Several authors have suggested that two subsets of those patients can be defined: a) hepatitis C virus negative and b) hepatitis C virus positive. The aim of this work was to further analyze the possible genetic association, HLA class I and II, in these two groups of patients., Methods: HLA was analyzed in 49 patients. Class I was studied using a standard lymphocytotoxicity test and in class II a reverse hybridization-based test for DRB1 typing and PCR-SSO for DQB1 typing were used. Sixty healthy Spanish subjects and 39 chronic hepatitis C subjects without anti-LKM1 antibodies were used as control groups for the "a" and "b" subsets, respectively., Results: No significant association was found with class I specificities in either group. DQB1 typing showed a very significant increase of DQ2 in the "a" group (93.3% vs. 48%; RR = 15; Pc = 0.0025), and DRB1 typing from the "b" group revealed a high association with DR7 (82.3% vs. 43.6%; RR = 6; Pc = 0.0086)., Conclusions: Our studies revealed a strong association with DQ2 for the "a" group and for the first time an extremely high association with DR7 antigen for the "b" subset. Hence it is possible to establish a different genetic profile in these two patient groups.

A variety of immunological parameters has been serially examined in the blood of 12 patients with acute post-transfusion hepatitis non-A non-B (PTHNANB). Several alterations of these tests were transiently detected when comparing with healthy, extensively transfused subjects as well as with normal volunteers: 1. Low proportions of CD8+ T lymphocytes were observed at the disease onset, and these returned to normal after 1 month; 2. A diminution of the proliferative response of blood lymphocytes to mitogens was detected during the same period of time; 3. By the third month of disease, an enhanced spontaneous IgG secretion by cultured lymphocytes was found, and this observation was restricted to those patients who had not recovered. These alterations suggest that the immune system might be involved in the course of hepatitis C virus infection.

We have been interested in demonstrating the usefulness of the reverse endoscopic cholangiopancreatography, a technique already accepted in extrahepatic biliary pathology and the cholangiocarcinoma diagnosis. First of all we reviewed those cases diagnosed as cholangiocarcinoma using the REC and we found that only in 14 (60.9%) of a total of 23 cases the diagnosis was confirmed by surgery, resulting in a false positive ratio of 39.1%. In the second analysis of 22 patients who underwent surgery and whose surgical diagnosis was cholangiocarcinoma, we confirmed a correct presurgery diagnosis by REC in 14 (63.6%) with a false negative ratio of 36.3% which could be reduced to 26.3% after excluding the technically incorrect explorations or those in which only the pancreatic ductus was visualized. We conclude that cholangiocarcinoma diagnosis by REC has a high false positive or negative ratio, thus, treatment, specially non surgical, of a possibly malignant stenosis or obstruction of the bile duct can not only be based on choleangiopatic findings.