Acute liver and renal failure during treatment with buprenorphine at therapeutic dose.

Buprenorphine is a semi-synthetic opioid derivative commonly used in the treatment of heroin addiction. Life-threatening complications have been described following overdoses while few cases of hepatotoxicity due to drug use at therapeutic doses have been recently described in hepatitis C virus carriers. In these cases, however, histological assessment was not exhaustive and no extra-hepatic organ failure was observed. We describe herein a case of acute liver and kidney failure in a patient with previously latent hepatitis C virus chronic infection following recommended doses of buprenorphine. Histology did not demonstrate any feature compatible with hepatitis C virus reactivation or liver cirrhosis and suspension of the treatment led to the resolution of both liver and kidney failure. Causality criteria fulfillment indicates a high probability of buprenorphine-induced liver toxicity. No signs of pre-existant kidney impairment or of pre- or post-renal causes were observed. Since buprenorphine is metabolized through cytochrome P450 3A4, we genotyped six genetic polymorphisms previously described in poor metabolizers but could not confirm these pharmacogenetic bases in this case. In conclusion, we surmise that buprenorphine at suggested doses can induce liver and kidney failure in susceptible individuals, possibly through direct mitochondrial toxicity.

Spontaneous hypoglycemia in patients with cystic fibrosis.

OBJECTIVE: Diabetes frequently complicates cystic fibrosis (CF) without fasting hyperglycemia or despite spontaneous hypoglycemia (anecdotally ascribed to malnutrition), whose prevalence, clinical meaning, and relationship with glucose tolerance and clinical/nutritional status were not previously investigated. The relationship of CF genotype with insulin secretion control is also unclear. DESIGN AND METHODS: A total of 129 CF patients without stable diabetes received 188 oral glucose tolerance tests. Distribution of fasting plasma glucose (FPG), glucose, insulin and C-peptide responses, clinical/nutritional variables, and their relationships were analyzed. RESULTS: FPG < 60 mg/dl (3.3 mmo/l) was detected in 14% of studies and reactive hypoglycemia (PG < 50 mg/dl (2.8 mmo/l)) in 15%. OGTT-based diabetes frequency was similar in the lowest quartile (Q1) and Q2-3 for FPG (10 and 8%), with higher glucose increment and area under the curve in Q1. Insulin and C-peptide levels were similar among FPG quartiles. Class I cystic fibrosis transmembrane conductance regulator mutation carriers had higher insulin concentrations than class II, especially in Q1 for FPG. Age, sex, nutritional, and anthropometric parameters including fat and lean body mass were unrelated to FPG. Lower FPG was associated with more frequent hospitalization rates (P = 0.002) and lower Shwachman scores (P = 0.041). Steroids weaning was accurately evaluated but then excluded as a possible cause of hypoglycemia. CONCLUSIONS/INTERPRETATION: Fasting asymptomatic hypoglycemia is frequent and possibly related to inappropriate insulin secretion control in class I mutation carriers. Low FPG does not exclude impaired glucose tolerance (IGT) and diabetes in CF and reflects worse clinical status.

Ten-year combination treatment with colchicine and ursodeoxycholic acid for primary biliary cirrhosis: a double-blind, placebo-controlled trial on symptomatic patients.

BACKGROUND: Combined medical treatment may provide further benefit to primary biliary cirrhosis (PBC) patients administered ursodeoxycholic acid (UDCA). AIM: To evaluate the long-term effects of colchicine and UDCA in symptomatic PBC patients. PATIENTS/METHODS: We extended up to 10 years the double-blind treatment of 44 symptomatic PBC patients originally included in a 3-year multicentre study comparing UDCA and colchicine (U + C) versus UDCA and placebo (U + P). Outcome measures were death or liver transplantation; incidence of clinically relevant events; clinical and quantitative variables retaining prognostic information. RESULTS: Mean follow-up was 7 +/- 3 years. One patient was lost, three withdrew because of jaundice (U + P); two patients stopped colchicine but remained on UDCA. Eleven patients (two for liver-unrelated reasons, U + P) and six patients (U + C) died, three and two patients, respectively, were transplanted (incidence rate difference, five cases per 100 patient-years; 95% CI, -1 to 11). Hepatocellular carcinoma developed in one (U + P) and four (U + C) patients (difference, -2; CI, -5 to 1), portal hypertension complications in nine patients from each group (difference, 1; CI, -5 to 6). Trends of serum bilirubin, Mayo score, antipyrine clearance were similar among treatment groups. CONCLUSIONS: In cirrhotic PBC patients, colchicine does not offer additional benefits to UDCA. In this population, UDCA does not obviate disease progression.

Long-term beneficial effects in sustained responders to interferon-alfa therapy for chronic hepatitis C.

BACKGROUND/AIMS: Assessment of chronic hepatitis C outcome in sustained responders to interferon requires prolonged observation and close monitoring. We prospectively studied the impact of sustained response on histology and clinically relevant outcomes. METHODS: The 47 sustained responders (ten with cirrhosis) from two interferon trials involving 235 chronic hepatitis C patients (81 with cirrhosis) were included. Hepatitis C virus (HCV) RNA was assessed every 6 months, liver histological changes from baseline, 6-12 and 48-72 months after treatment discontinuation. RESULTS: The mean follow-up was 102 +/- 19 months. HCV RNA became undetectable in 36/47 responders. Four responders, who had remained viremic, later relapsed. The histology progressively improved in non-viremic and viremic patients, with a more marked improvement in the former (P = 0.0089), normalizing in 53 vs. 0% (P = 0.0220). No patient progressed to cirrhosis. One non-viremic cirrhotic patient developed a hepatocellular carcinoma. Non-responders from the two original trials had worse histological outcomes and those with cirrhosis had a higher rate of clinically relevant events compared with cirrhotics showing a sustained biochemical response (4.5 vs. 1.2 cases/100 person-years; CI for the difference, 0.3-6.3). CONCLUSIONS: Most sustained, virological responders without cirrhosis normalize liver histology in the long-term and are cured of the disease. Sustained responders remaining viremic still show histological improvement, albeit to a lesser extent.

Autoantibodies against nuclear pore complexes are associated with more active and severe liver disease in primary biliary cirrhosis.

BACKGROUND/AIMS: Antibodies against nuclear pore complexes (NPCs) have been detected in primary biliary cirrhosis (PBC), but their clinical relevance is still unsettled. METHODS: We tested sera from 171 consecutive PBC patients and 230 control subjects (149 with autoimmune or viral liver diseases, 28 with systemic lupus erythematosus, and 53 healthy) by immunoblotting for antibodies against purified human NPCs. RESULTS: Antibodies to NPCs were detected in 27% of the patients with PBC, were highly specific (97%), and were not associated with antimitochondrial antibodies. Their prevalence was higher in symptomatic patients (36 vs. 16%, P < 0.01) and was associated (P < 0.001) with more severe disease, as assessed by the presence of cirrhosis or its complications (13% prevalence in patients without cirrhosis, 31% in uncomplicated, and 54% in complicated cirrhosis), or by the application of the Mayo prognostic model (12% in the lowest, 21% in the median, 47% in the highest score tertile). Positive patients had higher levels of serum bilirubin (2.2 +/- 3.7 vs. 1.0 +/- 1.1 mg/dl, P < 0.01) and more marked inflammatory infiltrates on liver biopsy (P < 0.05). CONCLUSIONS: Autoantibodies to NPCs are more prevalent in PBC patients than in controls and are strongly associated with more active and severe disease.

Multicentre randomized placebo-controlled trial of ursodeoxycholic acid with or without colchicine in symptomatic primary biliary cirrhosis.

AIM: To establish the efficacy of combination therapy with ursodeoxycholic acid (UDCA) and colchicine in patients with symptomatic primary biliary cirrhosis (PBC), defined by the presence of liver cirrhosis, pruritus or bilirubin exceeding 2 mg/mL. METHODS: A total of 90 patients were randomly assigned to ursodeoxycholic acid 500 mg/daily plus placebo (UDCA group, n=44), or ursodeoxycholic acid at the same dosage plus colchicine, 1 mg/daily (UDCA/C group, n=46). The two groups were comparable for age, sex, stage of disease, severity of pruritus, bilirubin, and Mayo score. All patients underwent clinical, ultrasonographic, and biochemical examinations at entry and then every 6 months up to 3 years of follow-up. Patients with cirrhosis underwent endoscopy every 12 months. In a sub-group of patients without cirrhosis, who consented, liver biopsy was repeated at the end of the study. RESULTS: The number of treatment failures (i.e. dead, orthotopic liver transplantation (OLT), complications of cirrhosis, doubling of bilirubin, untreatable pruritus) was 11 (25%) in the UDCA group and four (9%) in the UDCA/C group (P < 0.05). No significant differences were observed in terms of improvement of liver enzymes related to cholestasis and cytolysis and of amelioration of pruritus. The Mayo score values increased less above the baseline values at 24 and 36 month-intervals in the UDCA/C group than in the UDCA group. Histological evaluation at baseline and at the end of the study was available for 15 patients with pre-cirrhotic stage. A significant reduction in histological grading score was observed in patients from the UDCA/C group, whereas no changes in these histological scores were observed in the UDCA group. CONCLUSIONS: The addition of colchicine to ursodeoxycholic acid in patients with symptomatic primary biliary cirrhosis results in a small but significant reduction of disease progress.

Delayed intestinal visualization at hepatobiliary scintigraphy is associated with response to long-term treatment with ursodeoxycholic acid in patients with cystic fibrosis-associated liver disease.

BACKGROUND/AIMS: Abnormalities of biliary drainage have been documented at hepatobiliary scintigraphy in many but not all patients studied with cystic fibrosis-associated liver disease. Ursodeoxycholic acid was shown to be beneficial in this disease, mainly by improving biliary secretion. Therefore, patients with impaired biliary drainage are expected to obtain the greatest benefit from this treatment. METHODS: We evaluated the effects of long-term treatment with ursodeoxycholic acid in 36 patients with cystic fibrosis-associated liver disease, and compared the response in patients presenting a normal (n=18) or delayed time of intestinal visualization (n=18) at baseline hepatobiliary scintigraphy. RESULTS: The mean treatment duration was 58+/-26 (S.D.) months and 63+/-29 months in the groups with normal or delayed time of intestinal visualization, respectively. The time of intestinal visualization decreased (57+/-23%, p<0.001) from baseline in patients with initially abnormal values and became normal in four (22%). Treatment failure, i.e. lack of sustained normalization of serum liver enzymes or the occurrence of a clinically relevant adverse event, was more frequently observed in patients with a normal time of intestinal visualization at baseline (OR, 5.50; 95% CI, 1.32-22.7). When only clinically relevant adverse events were considered, they occurred in six of the latter patients (liver transplantation in one case, development of ultrasographic or endoscopic signs of portal hypertension in six cases), but in only one patient (development of portal hypertension) in the group with delayed time of intestinal visualization (OR, 10.82; 95% CI, 1.17-100.4). CONCLUSIONS: Delayed intestinal visualization at hepatobiliary scintigraphy in patients with cystic fibrosis-associated liver disease seems to predict a better response to ursodeoxycholic acid.

Pharmacokinetics of anticancer agents in patients with impaired liver function.

This report reviews published information on the clinical pharmacokinetics of antitumour agents in patients with liver dysfunction, associated with primary liver disease or liver metastases. Information was available for anthracyclines and their related compounds, antimetabolites, cyclophosphamide, vinca alkaloids, taxanes and epipodophyllotoxins. Changes in the pharmacokinetic profile or metabolism in patients with mild or severe hepatobiliary dysfunction are described and the relationships between serum levels, parameters employed for measuring hepatic function and toxic or therapeutic effects are examined. Current knowledge of the pharmacokinetics of antineoplastic agents in liver disease is far from complete, mostly obtained in small numbers of non-homogeneous patients often presenting only moderate liver dysfunction, and empirical guidelines for dose assessment are still largely applied in clinical practice. Because of the complex pathophysiological mechanisms of liver insufficiency in cancer patients, there is still doubt whether endogenous markers are useful. Although caution in treating cancer patients with liver insufficiency is compulsory, for most compounds there seems no need to recommend dose reductions for moderate impairment. However, for the tubulin acting agents, vincristine, vinblastine and possibly for paclitaxel and docetaxel, there is strong evidence that dose adjustment is mandatory in order to avoid excessive neutropenia and neurotoxicity.

Clinical significance of hepatic HCV RNA in patients with chronic hepatitis C demonstrating long-term sustained response to interferon-alpha therapy.

Whether sustained biochemical response and absence of serum HCV RNA in the 6-12 months following suspension of interferon-alpha (IFN-alpha) therapy reflect definitive viral clearance in patients with chronic hepatitis C virus (HCV) infection is controversial. To obtain more information on this topic, HCV RNA was sought in both liver and serum samples of 25 long-term responders who were followed for a median period of 39 months (range 21-79) after discontinuation of IFN-alpha. Liver biopsy was undertaken before and 6 to 12 months after IFN-alpha withdrawal. Liver and serum HCV RNA were tested by a nested polymerase chain reaction. Twenty-two patients (88%) tested negative for both liver and serum HCV RNA, two patients had detectable HCV RNA in both liver and serum, and one patient showed persistent HCV RNA only in the liver. Post-treatment liver histology improved markedly in all patients, including those with viral persistence. During further follow-up, biochemical remission was maintained in all patients except one in whom both serum and liver specimens remained HCV RNA positive. The data indicate that the large majority of long-term responders test negative for HCV RNA in the liver, which suggests definitive eradication of HCV RNA infection.

Hepatitis C virus genotypes and risk of hepatocellular carcinoma in cirrhosis: a prospective study.

A prospective study was performed to establish whether infection with specific hepatitis C virus (HCV) genotypes was associated with an increased risk of development of hepatocellular carcinoma (HCC) in cirrhosis. A cohort of 163 consecutive hepatitis C virus antibody (anti-HCV)-positive cirrhotic patients was prospectively evaluated for the development of HCC at 6-month intervals by ultrasound (US) scan and alpha-fetoprotein (AFP) concentration. HCV genotypes were determined according to Okamoto. Risk factors associated with cancer development were analyzed by univariate and multivariate statistics. At enrollment, 101 patients (62%) were infected with type 1b, 48 (29.5%) were infected with type 2a/c, 2 (1.2%) were infected with type 3a, 1 (0.6%) was infected with type 1a, 3 (1.8%) had a mixed-type infection, and, in 8 patients (4.9%), genotype could not be assigned. After a 5- to 7-year follow-up (median, 68 months), HCC developed in 22 of the patients, 19 infected with type 1b and 3 with type 2a/c (P < .005). Moreover, HCC developed more frequently in males (P < .01), patients with excessive alcohol intake (P < .01), those over 60 years of age (P < .02), and in patients who did not receive interferon treatment (P < .02). Multivariate analysis showed that type 1b was the most important risk factor associated with tumor development (odds ratio 6.14, 1.77-21.37 95% confidence interval). Other independent risk factors were older age and male sex. Cirrhotic patients infected with HCV type 1b carry a significantly higher risk of developing HCC than patients infected by other HCV types. The latter may require a less intensive clinical surveillance for the early detection of neoplasia.

Clinical pharmacokinetics of therapeutic bile acids.

The pharmacokinetics of chenodeoxycholic and ursodeoxycholic acids are reviewed in this article. Chenodeoxycholic acid is well absorbed by the intestine, whereas the absorption of ursodeoxycholic acid is incomplete. They are extracted efficiently by the liver, conjugated with glycerine and taurine, secreted in bile, and then undergo enterohepatic circulation with the endogenous bile acids. Therapeutic bile acids are metabolised by intestinal bacteria to lithocholic acid which is mainly excreted with faeces. Since the large majority of bile acid is confined within the enterohepatic circulation (resulting in low serum concentrations) their volume of distribution is relatively high. Despite the high hepatic extraction, the clearance of therapeutic bile acids is relatively low because of the highly efficient enterohepatic recirculation. Elimination of therapeutic bile acids mainly occurs in the faeces either unmodified or after biotransformation. At present the main clinical indication for therapeutic bile acids is ursodeoxycholic acid treatment for chronic cholestatic liver disease. In these patients, ursodeoxycholic acid is efficiently absorbed but its hepatic uptake and biliary secretion are impaired, thus leading to reduced biliary enrichment and high serum concentrations of this exogenous bile acid. In patients with cystic fibrosis-associated liver disease, bile acid malabsorption also occurs, thus indicating the need for higher dosages. The volume of distribution and clearance of ursodeoxycholic acid reduced in the presence of liver disease. Also in this case, elimination mainly occurs with the faeces but, in the presence of severe cholestasis, renal clearance may become relevant. Sulphation or conjugation with glucose and N-acetylglucosamine facilitate urinary excretion.

Ursodiol in the long-term treatment of chronic hepatitis: a double-blind multicenter clinical trial.

Ursodeoxycholic acid (UDCA or ursodiol) administration has been associated with a reduction of serum liver enzymes in patients with chronic liver disease and with improvement of liver histology in patients with primary biliary cirrhosis. To establish the potential therapeutic efficacy of ursodiol in chronic hepatitis, serum biochemistry and liver histology were investigated in a multicenter, double-blind placebo controlled clinical trial. Sixty patients with non-cholestatic chronic active (mild or severe) hepatitis, mainly of viral (virus C) etiology and almost completely asymptomatic, were enrolled in 3 centers: 29 were assigned to receive placebo and 31 UDCA (600 mg/day) for 1 year. Demographic, biochemical, virological and histological features were balanced between the 2 groups at the entrance into the study. Fifty-six patients (34 males, 22 females; 19 with cirrhosis; 5 HBsAg-positive; 45 anti-HCV positive) were included in the final analysis. Compliance was checked by measuring UDCA levels at the 3 follow-up visits (3, 6 and 12 months). Liver biopsy was performed at the beginning and at the end of treatment and was evaluated blindly by our pathologist (F.C.). Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gammaglutamyltransferase (GGT) levels were significantly reduced by 25% from baseline values during treatment with ursodiol but not with placebo. The efficacy of UDCA in lowering serum AST and ALT was more pronounced in the presence of cirrhosis. The semiquantitative liver histological score used remained substantially unchanged after treatment and no differences between placebo and UDCA were found for portal or periportal necrosis or inflammation, intralobular degeneration, cholestasis or fibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Ursodeoxycholic acid therapy in cystic fibrosis-associated liver disease: a dose-response study.

Previous studies from our groups have demonstrated improvements in biochemical markers of liver function when cystic fibrosis patients with associated liver disease were administered oral ursodeoxycholic acid. The magnitude of the response was somewhat less than that found when comparable doses (10 to 15 mg/kg body wt/day) of ursodeoxycholic acid are given to other liver disease patients; this may be explained by the bile acid malabsorption that is characteristic of the disease. For this reason a dose-response study was carried out in nine cystic fibrosis patients with liver disease to establish whether improved efficacy could be obtained with higher doses. Ursodeoxycholic acid in doses of 5, 10 and 15 mg/kg body wt/day was given orally for consecutive 2-mo periods in a replicated Latin-square design. After this, all patients received 20 mg/kg body wt/day. Liver function, individual serum bile acids and biliary bile acid composition were determined at entry and at the end of each treatment period. Our data demonstrate that the magnitude of the biochemical improvement in serum liver enzymes was significantly greater with higher doses of ursodeoxycholic acid; at 20 mg/kg body wt/day it was similar to that reported for patients with other liver diseases administered lower doses. Biliary ursodeoxycholic acid enrichment increased with increasing doses, attaining 42% +/- 6% of the total biliary bile acids with the highest dose. Fasting serum ursodeoxycholic acid concentrations increased during ursodeoxycholic acid administration but were variable and correlated poorly with the dose of ursodeoxycholic acid administered, whereas no correlation was found between serum ursodeoxycholic acid concentration and the proportion of ursodeoxycholic acid in bile.(ABSTRACT TRUNCATED AT 250 WORDS)

[Stress and the psychological profile of the cancer patient]. / Stress e profilo psicologico del paziente oncologico.

The results of a retrospective study on the personality traits of a patient with cancer are reported. The research was carried out on a group of cancer patients and on 2 control groups, one consisting of carriers of chronic non-tumoral disease, the other of patients with acute accidental pathology. Statistical processing of the data obtained has permitted the detection of interesting personological details in the 3 groups studied.

Effects of ursodeoxycholic acid therapy for liver disease associated with cystic fibrosis.

The hydrophilic bile acid ursodeoxycholic acid (UDCA) has recently been shown to improve indexes of liver function in adult patients with various liver diseases. The clinical and biochemical responses to UDCA administration (10 to 15 mg/kg body weight per day) were therefore investigated in nine patients with cystic fibrosis and evidence of liver disease. All patients were receiving pancreatic enzymes and taurine supplementation. Liver function tests were done and serum bile acid concentrations and biliary bile acid composition were determined before and during UDCA therapy; fat balance studies and fecal bile acid excretion were carried out before and 6 months after UDCA treatment. After 2 months of bile acid therapy, biliary bile acid composition was enriched in UDCA from approximately 5% before treatment to 25%, at the expense of cholic and chenodeoxycholic acids, thus making the pool more hydrophilic. This enrichment is lower than that reported for adults with chronic liver diseases. Serum concentrations of UDCA increased significantly but variably. UDCA became the predominant fecal bile acid excreted (12% to 67%), indicating a variable absorption of the administered bile acid. Liver function improved in all patients after 2 to 6 months of therapy, although the degree of improvement (aspartate aminotransferase, -34%; alanine aminotransferase, -41%; gamma-glutamyltranspeptidase, -41% alkaline phosphatase, -19%) was lower than that observed in adults with chronic liver diseases. Mean coefficient of fat absorption and growth rate were, on average, unaffected by UDCA therapy, although an improvement was noted for three patients with greater severity of steatorrhea. The study indicates that UDCA can be used safely in this patient population but that higher doses of UDCA may be of greater benefit in the treatment of the liver disease associated with cystic fibrosis.

Effects of taurine and ursodeoxycholic acid on liver function tests in patients with cystic fibrosis.

In 9 CF patients with clinical and biochemical evidence of liver disease, taurine (30 mg/kg/day) was administered one month before and during the successive treatment with ursodeoxycholic acid (10-15 mg/kg/day). Standard liver function tests were determined before and after each period of treatment. Taurine administration produced only inconsistent changes of liver function tests from baseline, whereas after the addition of ursodeoxycholic acid a substantial improvement in all abnormal indices was observed. The effects of longer period of treatment are currently investigated, with purpose of establishing their clinical impact and their relationship with changes in bile acid metabolism.