Inadequate dietary intake but not renal tubular acidosis is associated with bone demineralization in primary biliary cirrhosis.

BACKGROUND: Metabolic bone disease associated with primary biliary cirrhosis (PBC) is inadequately characterized. Renal tubular acidosis (RTA) may lead to bone loss through chronic mobilization of skeletal calcium salts to buffer increased acid load. AIM: To evaluate the prevalence of RTA in PBC and establish the relationships among bone mineral density (BMD), renal function and nutritional status. METHODS: We enrolled 69 female patients with compensated PBC and 35 control patients with chronic hepatitis C. RTA was searched in all patients, and 24-h dietary recalls were collected at enrolment. BMD was measured by dual-energy X-ray absorptiometry at the femur neck, lumbar spine and radius ultradistalis sites. RESULTS: No patients received a diagnosis of RTA. BMD values (Z-scores) showed only little deviation from normal population with no difference between PBC and controls. Osteopoenic PBC patients (T-score < 1) showed significantly lower daily phosphorus intake [median: 672 (288-1374) vs. 921 (253-1923) mg/day; P = 0.037], with a trend towards lower caloric intake than their nonosteopoenic counterparts. CONCLUSIONS: Renal tubular acidosis is uncommon in compensated PBC. Cholestasis is not associated with an increased risk of bone demineralization. Inadequate dietary intake may be a preventable factor contributing to bone loss in PBC.

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.

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 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.

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.

Ursodeoxycholic and tauro-ursodeoxycholic acids for the treatment of primary biliary cirrhosis: a pilot crossover study.

BACKGROUND: Results from animal studies and preliminary data from pilot studies in patients with primary biliary cirrhosis suggest that tauro-ursodeoxycholic acid has metabolic properties that may favour its long-term use as an alternative to ursodeoxycholic acid for patients with chronic cholestatic liver diseases. No direct comparison of tauro-ursodeoxycholic and ursodeoxycholic acids have yet been carried out in primary biliary cirrhosis. METHODS: The effects of ursodeoxycholic and tauro-ursodeoxycholic acids were compared in 23 patients with primary biliary cirrhosis according to a crossover design. Both drugs were administered at the daily dose of 500 mg. in a randomly assigned sequence for two 6-month periods separated by a 3-month wash-out period. RESULTS: Serum liver enzymes related to cholestasis and cytolysis consistently improved, as compared to baseline values, during the administration of both ursodeoxycholic and tauro-ursodeoxycholic acids, but no significant difference between these two bile acids was found. Both treatments were well tolerated and no patient complained of side effects. CONCLUSION: In the short-term, tauro-ursodeoxycholic acid appears to be safe and at least as effective as ursodeoxycholic acid for the treatment of primary biliary cirrhosis.

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.

Bile acid conjugation in early stage cholestatic liver disease before and during treatment with ursodeoxycholic acid.

The efficiency of bile acid conjugation before and during therapy with 600 mg/day of ursodeoxycholic acid was measured in seven adult patients with early chronic cholestatic liver disease (6 with primary biliary cirrhosis; 1 with primary sclerosing cholangitis). Duodenal bile samples were obtained by aspiration and the proportion of unconjugated bile acids was determined using lipophilic anion exchange chromatography to separate bile acid classes, followed by analysis of individual bile acids by gas chromatography-mass spectrometry. The proportion of conjugated bile acids was determined by high-performance liquid chromatography. Use of a (99m)Tc-HIDA recovery marker permitted the absolute mass of unconjugated bile acids in the gallbladder to be calculated. Unconjugated bile acids comprised 0.4% of total biliary bile acids before and 0.2% during ursodeoxycholic acid therapy, indicating highly efficient conjugation of bile acids. During therapy, percentage unconjugated ursodeoxycholic acid significantly increased from (mean +/- S.D.) 13 +/- 13% to 54 +/- 12%; P < 0.002. When the unconjugated and conjugated fractions of bile acids were compared, there was an enrichment in unconjugated fraction for cholic acid and ursodeoxycholic acid and a depletion for chenodeoxycholic acid both in basal condition and during ursodeoxycholic acid therapy, suggesting that hydrophilic bile acids were conjugated less efficiently. During therapy, the conjugation efficiency significantly increased for cholic acid and ursodeoxycholic acid. The pretreatment mass of total unconjugated bile acids in the gallbladder was (mean +/- S.D.) 4.4 +/- 3.2 mumol, and was not significantly changed by ursodeoxycholic acid therapy (6.2 +/- 3.5 mumol). However, ursodeoxycholic acid therapy caused a significant increase in the mass of unconjugated ursodeoxycholic acid. It is concluded that endogenous bile acids and exogenous ursodeoxycholic acid when given at the usual dose are efficiently conjugated in patients with early cholestatic liver disease. Despite showing increased biliary unconjugated ursodeoxycholic acid during its oral administration, our data do not lend support to the occurrence of hypercholeresis due to cholehepatic shunting of bile acids.

Tauroursodeoxycholic acid for the treatment of HCV-related chronic hepatitis: a multicenter placebo-controlled study.

BACKGROUND/AIMS: Tauroursodeoxycholic acid is a promising drug for the treatment of chronic cholestatic liver diseases since it has more favourable physicochemical and metabolic properties than ursodeoxycholic acid. Tauroursodeoxycholic acid may be of benefit also for necroinflammatory liver disease, especially for HCV-related chronic hepatitis in which bile duct damage and some degree of cholestasis are frequently seen at histology. METHODOLOGY: One hundred and fifty patients with chronic hepatitis were randomly assigned to receive tauroursodeoxycholic acid at daily doses of 500 mg or 750 mg, or a placebo for 6 months. RESULTS: A consistent decrease in aminotransferase serum levels was observed in patients treated with tauroursodeoxycholic acid compared with placebo (p<0.001) and a progressive improvement with time was also found (p<0.05; linear time effect). CONCLUSIONS: Tauroursodeoxycholic acid improves the biochemical expression of chronic hepatitis. Long-term studies with clinically relevant end-points are warranted.

[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.

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.

Hypercholesterolaemia is not associated with early atherosclerotic lesions in primary biliary cirrhosis.

BACKGROUND: Hypercholesterolaemia often occurs in primary biliary cirrhosis (PBC) as a result of chronic cholestasis, but whether these patients are exposed to greater cardiovascular risk is unknown. AIM: To establish whether hypercholesterolaemia is associated with subclinical atherosclerosis in PBC. PATIENTS: 103 consecutive patients with PBC (37 with total cholesterol > or =6.21 mmol/l) and 37 controls with hypercholesterolaemia, and 141 matched controls with normocholesterolaemia. METHODS: Ultrasound imaging of carotid artery to determine intima-media thickness (IMT) and stenosis. RESULTS: Controls with hypercholesterolaemia had higher IMT and prevalence of carotid stenosis compared with patients with hypercholesterolaemic PBC (mean (SD) 0.850 (0.292) mm v 0.616 (0.137) mm, p(c)<0.001; 43% v 19%, p(c) = 0.129) who, in turn, were similar to the 66 patients with normocholesterolaemic PBC (0.600 (0.136) mm; 5%). Compared with subjects with normocholesterolaemia, controls with hypercholesterolaemia, but not patients with hypercholesterolaemic PBC, had an increased risk of raised IMT (odds ratio (OR) 5.4, 95% confidence interval (CI) 2.5 to 11.9, p<0.001; and 0.7, 0.3 to 2.0, p = 0.543) or carotid stenosis (8.2, 3.4 to 20, p<0.001; and 2.5, 0.9 to 6.9, p = 0.075). In PBC, compared with younger patients without hypertension, the risk of increased IMT was OR (CI) 3.1 (0.6 to 17; p = 0.192) in patients with hypertension or old age, but not hypercholesterolaemia, and 4.6 (0.8 to 27; p = 0.096) in patients who also had hypercholesterolaemia. The corresponding figures for risk of stenosis were 3.6 (0.4 to 36; p = 0.277) and 15.8 (1.8 to 141; p = 0.014). CONCLUSIONS: Hypercholesterolaemia is not consistently associated with subclinical atherosclerosis in PBC, but should be treated if other risk factors for cardiovascular disease are also present. The search for factors that may protect patients with hypercholesterolaemic PBC against atherosclerosis should be encouraged.

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.

Failure of ursodeoxycholic acid to prevent a cholestatic episode in a patient with benign recurrent intrahepatic cholestasis: a study of bile acid metabolism.

Ursodeoxycholic acid was administered to a patient with benign recurrent intrahepatic cholestasis to prevent cholestatic episodes. A detailed study of bile acid metabolism in this patient was carried out in the anicteric and icteric phases before and after ursodeoxycholic acid (750 mg/day) administration. Urinary, biliary and serum bile acids were measured by gas chromatography-mass spectrometry and by high-performance liquid chromatography techniques. During the anicteric phase the daily urinary excretion and serum concentrations of bile acids were within normal ranges, indicating normal hepatic uptake and secretion of bile acids during the cholestasis-free period. Only slight qualitative differences from normal individuals were observed; the relative proportions of deoxycholic acid in the bile and serum were higher, and 12-oxo-lithocholic acid was the predominant urinary bile acid. During the icteric phase a marked increase in the urinary excretion of primary bile acids and C-1, C-2, C-4 and C-6 hydroxylated metabolites was found. Serum bile acid concentrations increased before the rise in bilirubin, suggesting an acute disturbance in bile acid transport at the onset of the cholestatic attack. After ursodeoxycholic acid administration in the anicteric phase, bile became enriched with the exogenous bile acid, but little qualitative change was found in the other metabolites present in the urine, serum or bile during the anicteric or icteric phases. Prolonged administration of ursodeoxycholic acid failed to prevent recurrence of a cholestatic episode, suggesting that in benign recurrent intrahepatic cholestasis, oral ursodeoxycholic acid may be of little benefit in the treatment or prevention of cholestasis despite marked enrichment of the bile acid pool with this hydrophilic bile acid.

[Medico-biological and psychopathologic aspects of substance dependence]. / Aspetti medico-biologici e psicopatologici delle tossicodipendenze.

The paper examines the phenomenon of drug addiction from a bio-socio-pathological point of view. Neurophysiological advances in the field of drug addiction reveal the correlations between biology and behaviour, thus allowing the creation of numerous synergic strategies at different levels of intervention.

[Emergency psychiatric services in Torino. Presentation of the activities]. / Il servizio di urgenza psichiatrico a Torino. Presentazione della attività.

The paper reports on the emergency psychiatric Unit (EPU) that has been instituted in Turin. A period of transformation in the philosophy of psychiatric departments, has led, among other things, to the approval of a regional law that can be considered as a local interpretation, of national legislation. The EPU is an experimental model that codifies the emergency level of intervention to stand alongside existing emergency medical facilities, including first-aid stations. The purpose of this first investigation is to examine the number and type of calls studying the data obtained so far is a fundamental stage in our understanding of the "emergency" phenomenon and in the construction of other levels of intervention aimed to optimise available resources.

Effects of ursodeoxycholic acid and taurine on serum liver enzymes and bile acids in chronic hepatitis.

Hydrophobic bile acids have been shown to be hepatotoxic, whereas treatment with ursodeoxycholic acid, a hydrophilic bile acid, has improved liver function indices in patients with chronic liver disease. Taurine administration has also been suggested to be useful for chronic hepatitis, taurine-conjugated bile acids being more hydrophilic than glycine-conjugated bile acids. To determine if taurine and ursodeoxycholic acid are beneficial and if their effects are additive, a double-blind, randomized trial was designed comparing the effects of ursodeoxycholic acid, taurine, and a combination of the two on indices of liver injury in 24 patients with chronic hepatitis. They were assigned at random to two of the four following treatments: ursodeoxycholic acid (600 mg/day), taurine (1.5 g/day), ursodeoxycholic acid plus taurine (600 mg + 1.5 g/day) or placebo, given in two successive cycles of 2 mo each, according to a balanced incomplete-block design. Ursodeoxycholic acid became the predominant biliary bile acid when administered alone or in combination with taurine, and taurine conjugate levels increased during taurine administration. Ursodeoxycholic acid reduced aspartate aminotransferase (35%), alanine aminotransferase (33%), and gamma-glutamyl transpeptidase (41%), whereas taurine alone did not. The addition of taurine to ursodeoxycholic acid produced only minor changes in the effects of ursodeoxycholic acid alone. Results were confirmed by the administration of ursodeoxycholic acid, in a successive open phase of the study, to the entire patient population, which was large enough for different subsets of patients to be compared. Serum bile acids were measured at entry and during the open phase: primary bile acids did not change, whereas ursodeoxycholic acid levels increased from trace amounts to very high levels, especially in patients with more severe histological disease. It is concluded that ursodeoxycholic acid, but not taurine, improves enzymatic indices of liver injury in chronic hepatitis.

Serum 27-hydroxycholesterol in patients with primary biliary cirrhosis suggests alteration of cholesterol catabolism to bile acids via the acidic pathway.

Reduced cholesterol synthesis has been reported in patients with primary biliary cirrhosis but no data are available on changes in cholesterol catabolism induced by the disease. Serum levels of 7alpha-hydroxycholesterol and 27-hydroxycholesterol have been measured in 25 patients (either normocholesterolemic or hypercholesterolemic) with primary biliary cirrhosis and in control subjects. To evaluate cholesterol synthesis, serum levels of lathosterol were measured, and campesterol and sitosterol were considered to reflect intestinal absorption and biliary elimination of sterols. In normocholesterolemic patients with primary biliary cirrhosis, lathosterol was significantly lower than in normocholesterolemic controls (P < 0.05) whereas no difference was found between hypercholesterolemic patients and hypercholesterolemic controls. Serum concentrations of sitosterol were significantly higher in both normocholesterolemic and hypercholesterolemic patients with primary biliary cirrhosis as compared with the respective controls (P < 0.01). In patients with primary biliary cirrhosis, serum 7alpha-hydroxycholesterol was slightly higher than in controls. 27-Hydroxycholesterol was significantly higher in hypercholesterolemic compared to normocholesterolemic controls (P < 0.05) and a significant linear correlation (r = 0.771; P < 0.001) was found between 27-hydroxycholesterol and cholesterol. In contrast, in patients with primary biliary cirrhosis, high cholesterol concentrations were not associated with increased serum levels of 27-hydroxycholesterol. Our data confirm that in patients with primary biliary cirrhosis, cholesterol synthesis and biliary elimination of sterols are impaired and also suggest that both the feedback regulation of retained bile acids on cholesterol 7alpha-hydroxylase and the scavenger effect on elevated serum cholesterol by cholesterol 27-hydroxylase are deficient in these patients. acids via the acidic pathway.