Long-term outcomes of direct acting antivirals in post-transplant advanced hepatitis C virus recurrence and fibrosing cholestatic hepatitis.

Long-term functional outcomes of sofosbuvir-based antiviral treatment were evaluated in a cohort study involving 16 Italian centres within the international compassionate use programme for post-transplant hepatitis C virus (HCV) recurrence. Seventy-three patients with cirrhosis (n=52) or fibrosing cholestatic hepatitis (FCH, n=21) received 24-week sofosbuvir with ribavirin±pegylated interferon or interferon-free sofosbuvir-based regimen with daclatasvir/simeprevir+ribavirin. The patients were observed for a median time of 103 (82-112) weeks. Twelve of 73 (16.4%) died (10 non-FCH, 2 FCH) and two underwent re-LT. Sustained virological response was achieved in 46 of 66 (69.7%): 31 of 47 (66%) non-FCH and 15 of 19 (79%) FCH patients. All relapsers were successfully retreated. Comparing the data of baseline with last follow-up, MELD and Child-Turcotte-Pugh scores improved both in non-FCH (15.3±6.5 vs 10.5±3.8, P<.0001 and 8.4±2.1 vs 5.7±1.3, P<.0001, respectively) and FCH (17.3±5.9 vs 10.1±2.8, P=.001 and 8.2±1.6 vs 5.5±1, P=.001, respectively). Short-treatment mortality was higher in patients with baseline MELD≥25 than in those with MELD<25 (42.9% vs 4.8%, P=.011). Long-term mortality was 53.3% among patients with baseline MELD≥20 and 7.5% among those with MELD<20 (P<.0001). Among deceased patients 75% were Child-Turcotte-Pugh class C at baseline, while among survivors 83.9% were class A or B (P<.0001). Direct acting antivirals-based treatments for severe post-transplant hepatitis C recurrence, comprising fibrosing cholestatic hepatitis, significantly improve liver function, even without viral clearance and permit an excellent long-term survival. The setting of severe HCV recurrence may require the identification of "too-sick-to-treat patients" to avoid futile treatments.

Liver transplantation in patients aged 65 and over: a case-control study.

INTRODUCTION: The average age of patients undergoing liver transplantation (LT) is consistently increasing. The aim of this case-control study is to evaluate survival and outcome of patients ≥65 yr compared to younger patients undergoing LT. MATERIALS AND METHODS: From 10/00 to 4/08 we performed 330 primary LT, 31 (9.4%) of these were in patients aged 65-70. Following a case-control approach, we compared these patients with 31 patients aged between 41 and 64 yr and matched according to sex, LT indication, viral status, cadaveric/living donor, LT timing, and Model for End-Stage Liver Disease (MELD) score. RESULTS: There were no statistically significant differences in demographic and surgical donor characteristics. The mean MELD score was under 18 in both groups. Post-LT complications occurred with a similar incidence in the two groups. one-, three-, and five-yr survival was 83.9%, 80.6%, and 80.6%, respectively, for the elderly group, and 80.6%, 73.8%, and 73.8%, respectively, for the young group (p = 0.61). DISCUSSION: Patients aged between 65 and 70 with low MELD score who undergo LT have the same short- and middle-term survival expectancy, morbidity, and outcome quality as younger patients with the same indication and same pre-LT pathology severity, whatever they might be. Thus, chronological age alone should not deter LT workup in patients >65 and <70.

Human immunodeficiency virus and liver transplantation: our point of view.

INTRODUCTION: Highly active antiretroviral therapy (HAART) has been able to improve the immune system function and survival of HIV patients with a consequent increase in the number of HIV patients affected by end-stage liver disease (ESLD). Between June 2003 and October 2006, 10 HIV-positive patients underwent liver transplantations in our center. METHODS: All patients were treated with HAART before transplantation; treatment was interrupted on transplantation day and was restarted once the patients' conditions stabilized. Five patients were hepatitis C virus (HCV)-positive, 3 were hepatitis B virus (HBV)-positive, and 2 were HBV-HCV coinfected. HIV viral load before transplantation was <50 copies/mL in all cases. CD4+ cell count before transplantation ranged between 144 and 530 c/microL. Immunosuppression was based on Cyclosporine (CyA) and steroid weaning for 8 patients, and on Tacrolimus and steroid weaning for 2 patients. RESULTS: Five patients were cytomegalovirus (CMV)-positive pp65 antigenemia posttransplantation, and 1 patient was EBV-positive; 2 patients had a coinfection with HHV6. Four patients suffered from a cholestatic HCV recurrent hepatitis treated with antiviral therapy (peginterferon and Ribavirin). Three patients died after transplantation. DISCUSSION: The outcome of liver transplantation in HIV patients was influenced by infections (HCV, CMV, and EBV) and Kaposi's Sarcoma. HCV recurrence was more aggressive, showing a faster progression in this patient population. Drug interaction between HAART and immunosuppressants occurs; longer follow-up and better experience may improve the management of these drug interactions.

Temporary porto-caval shunt utility during orthotopic liver transplantation.

INTRODUCTION: In liver transplantation (OLT) a porto-caval shunt is a well-defined technique practiced by many surgeons in several centers. METHODS: We considered 186 cadaveric OLT patients who underwent a cavo-cavostomy-type reconstruction; they were divided into two groups: those in whom we performed a porto-caval shunt (group A) and those in whose we did not (group B). We evaluated several variables: warm and total ischemia time, intraoperative blood and fresh frozen plasma transfusions, crystalloid and colloid requirements, blood loss, operative duration, hemodynamic intraoperative changes and diuresis, length of hospital stay, and creatinine values at days 1 and 2, and at discharge day. RESULTS: Total and warm ischemic time differed significantly between the two groups. Infusion of blood, fresh frozen plasma, colloid, and crystalloid did not significantly differ. Blood loss was lower, and intraoperative diuresis was not significantly increased in group A subjects. Postoperative hospitalizations were 16.5 and 17.8 days and operative times, 504 and 611 minutes in the two groups. Both cardiac index and ejection fraction values during the anhepatic phase were significantly greater among group A than group B patients. PAD at the two phases was greater in group B. The PAS was significantly different only at reperfusion time. Creatinine values were significantly different at discharge. Better survival was shown for group A patients over group B subjects. CONCLUSION: The results presented herein confirmed that a porto-caval shunt during OLT was a safe, useful expedient contributing to an improved hemodynamic status and a better time distribution in the various phases of liver transplantation.

Vertebral morphometry by X-ray absorptiometry before and after liver transplant: a cross-sectional study.

OBJECTIVES: To evaluate bone density and fracture prevalence in patients with end-stage liver diseases (ESLD) awaiting liver transplant and in orthotopic liver-transplant (OLTx) recipients by using dual energy X-ray absorptiometry. DESIGN: In a cross-sectional study 27 patients (16 males and 11 females, mean age 49.9 +/- 1.7 years) with ESLD, and 36 subjects (26 males and 10 females, mean age 50.5 +/- 1.6 years) who had undergone OLTx 1-70 months before, were recruited. METHODS: All patients underwent biochemical assessment of mineral metabolism. Bone density measurement of the spine and femur and morphometric X-ray absorptiometry (MXA) of the vertebrae were also obtained. RESULTS: Bone density was decreased in both groups as compared to the expected normal values. Spinal density did not differ between the two groups, while femoral bone mass was lower in OLTx than in ESLD patients (T-scores of: femoral neck -1.91 +/- 0.16 vs -1.12 +/- 0.22, P < 0.01; total femur -1.62 +/- 0.16 vs -0.94 +/- 0.23, P < 0.02). Bone alkaline phosphatase was the only independent predictor of femoral density (R2 = -0.21, P < 0.05). Symptomatic fractures were reported by 25% of OLTx and 15% of ESLD patients. MXA vertebral fractures were present in 28% of OLTx and 7.5% of ESLD (P < 0.05) patients. Most of these fractures had been asymptomatic. Total methylprednisolone intake was higher in patients with MXA vertebral fractures than in non-fractured patients (P < 0.05). CONCLUSIONS: Fragility fractures, especially of the spine, occur more frequently after liver transplantation, with corticosteroid treatment being the most important risk factor. Morphometric X-ray absorptiometry represents a useful technique for identifying vertebral fractures even in liver transplanted patients.

Diabetic neuropathy: prevalence, concordance between clinical and electrophysiological testing and impact of risk factors.

UNLABELLED: The aim of this study was to assess the prevalence of various forms of diabetic neuropathy (DN), by clinical and electrophysiological tests, on 374 diabetic patients (66 with type 1 and 308 with type 2 diabetes mellitus) and the concordance between clinical and electroneurological alterations and relative risk factors impact. The overall prevalence of DN, according to the Saint Antonio Conference criteria, was 44.9% (28.88% somatic, 14.44% mixed and 1.60% autonomic) without statistical difference between type 2 and type 1 diabetes (46.43% and 37.88% respectively). In 32.24% of patients nerve conduction velocity (NCV) abnormalities were present together with clinical signs or symptoms of neuropathy, while 12.68% presented only signs and/or symptoms. In addition 9.36% of patients showed alterations of NCV in the absence of clinical signs or symptoms of neuropathy. The most frequent form was asymptomatic (30.21%), followed by symptomatic neuropathy (12.83%); rare was the severe neuropathy. Relative risk increased for diabetes duration > 20 years (p < 0.0001). IN CONCLUSION: 1) the Saint Antonio Consensus Conference criteria can be considered the most complete test for neuropathy diagnosis; 2) NCV alterations may not be concordant with signs-symptoms of neuropathy; 3) the duration of diabetes seems to be the most important risk factor.

Liver-kidney-transplantation in type 1 primary hyperoxaluria: description and comments on a case.

BACKGROUND: Primary hyperoxaluria leads to oxalosis, a systemic illness with fatal prognosis in uremic youngsters because of systemic complications. CASE REPORT: A 14-year old boy with primary type 1 hyperoxaluria who had a long-lasting history of nephrolithiasis and passed from normal renal function to end-stage renal disease within 7 months. MEASUREMENT of alanine: glyoxylate aminotransferase (AGT) catalytic activity in the liver biopsy disclosed very low activity which was not. responsive to pyridoxin., thus the patient entered onto a priority national waiting list for liver-kidney transplantation and a week later received a combined transplant. In order to increase body clearance of oxalate, the patient underwent medical treatment to increase urine oxalate solubility (sodium and potassium citrate oral therapy, magnesium supplementation and increase of diuresis) and intensive dialysis both before and after transplantation. COMMENT: The medical approach to the treatment of this rare illness is discussed. Since the major risk for the grafted kidney is related to the oxalate burden, i.e. oxalate deposition from the body deposits to the kidney that becomes irreversibly damaged, treatment consists of increasing the body clearance of oxalate both by increasing oxalate solubility in the urine and with intensive dialysis performed both before and after combined transplantation. To the same extent (by limiting body oxalate deposits), a relatively early (native GFR 20-25 ml/minute) transplantation is advisable.

University of Modena experience in HIV-positive patients undergoing liver transplantation.

INTRODUCTION: Highly effective antiretroviral therapy in the last decade has increased the survival rates of HIV-positive patients, yielding a greater number of HIV patients suffering from liver-related disease. Liver transplantation (LT) is the only curative treatment for end-stage liver disease (ESLD) associated or not with hepatocellular carcinoma (HCC). PATIENTS AND METHODS: From June 2003 to September 2010, 23 patients underwent cadaveric donor LT for ESLD at our institution. Inclusion criteria followed the Italian Protocol for LT in HIV-positive patients. Immunosuppressive regimens were based on cyclosporine or tacrolimus, eventually switched to Rapamycin. RESULTS: The median CD4 T-cell count was 275/mmc (range=119-924). All patients were affected by ESLD, which was associated with HCC in 14 cases. Ten patients were within the Milan criteria and four patients exceeded them but were within the San Francisco criteria. Conversion from calcineurin inhibitors (CNI) to rapamycin occurred in ten cases. Hepatitis C virus (HCV) recurrence occurred in 13/21 HCV-positive patients. Acute cellular rejection occurred in eight patients with one developing chronic cellular rejection. Overall patient and graft survivals at 80 months were 50% and 45% respectively. DISCUSSION: LT in HIV-positive patients is a feasible procedure, even if in our experience was burdened by a greater incidence of complications including HCV recurrence and infection compared with HIV-negative patients.

Predictive factors of lack of response to antiviral therapy among in patients with recurrent hepatitis C after liver transplantation.

The current therapy for hepatitis C recurrence after liver transplantation OLT is based on interferon (IFN) and ribavirin (RBV) in monotherapy or combination. The rate of sustained virological response (SVR) varies between 10% and 45%. We have retrospectively analyzed factors that could predict SVR after antiviral therapy. We analyzed 42 patients who completed a cycle of therapy with natural or pegylated IFN plus RBV. There were 15 (35.7%) patients who obtained an SVR. The following factors were significantly associated with a lack of SVR: donor age >or=50 years (P = .046); donor body mass index (BMI) > 27 (P = .016); genotype 1 versus 2 to 3 (P = 0.010), aspartate transferase (AST) before therapy >or= 140 U/L (P = .046), alanine transferase before therapy >or= 280 U/L (P = .055), use of natural IFN versus pegylated IFN (P = .016). The only factors remaining after multivariate analysis were: donor BMI, AST before therapy and genotype. Our data confirmed that genotype 1 was associated with poorer outcomes; other additional parameters can influence the response to antiviral therapy.

Novel genetic mutation in apolipoprotein E2 homozygosis and its implication in organ donation: a case report.

Disorders in lipoprotein metabolism do not contraindicate liver procurement and transplantation (LT). In this circumstance, LT provides an intriguing opportunity to assess the in vivo contribution of the liver to the synthesis and degradation of genetically polymorphic plasma proteins. Apolipoprotein (APO) E exists with several common phenotypic differences due to gene polymorphism. Some authors have shown that the APOE phenotype of the recipient was virtually completely converted to that of the donor, providing evidence that >90% of plasma APOE arises from the liver. Homozygosis for APOE2 (E2-E2) is related to an increased incidence of type III hyperlipoproteinemia (HLP). Recently, some authors have identified 4 new APOE mutations that are strongly linked to a unique entity of renal lipidosis called lipoprotein glomerulopathy (LPG). At present, 65 cases of LPG have been reported worldwide, although most patients have been discovered in Japan and other East Asian countries. We have herein reported a case of LT in a patient with advanced hepatocarcinoma who received a liver from a caucasian donor affected by type III HLP due to homozygous E2-E2. The LPG was due to a novel genetic mutation in APOE. After the LT, the recipient, developed de novo severe lipid abnormalities despite good graft function. To our knowledge this is the first report of an LT using a graft from a non Asian donor with homozygous E2-E2 with the presence of a novel APOE mutation.

Liver transplantation utilizing grafts from donors with genitourinary cancer detected prior to liver implantation.

Expansion of the donor pool has led to reconsideration of selection criteria to obtain the largest number of grafts without compromising recipient outcomes. This reconsideration concerns the utilization of donors with malignancies. Herein we have analyzed the outcomes, survivals, and risks of cancer transmission among patients who received a liver transplant from a donor with a genitourinary malignancy. Six of 363 patients (1.5%) who underwent transplantation at our center received an organ from a donor with a genitourinary cancer which was detected prior to the surgical harvest. Donors affected by low-grade renal cell carcinoma (Fuhrman grade 1 or 2) or low-grade intraprostatic prostate carcinoma (Gleason score

Immunosuppressive switch to sirolimus in renal dysfunction after liver transplantation.

OBJECTIVE: Nephrotoxicity is a serious adverse effect after liver transplantation often related to calcineurin inhibitors (CNI) with a incidence of 18.1% at 5 years. Sirolimus (SRL) is a new immunosuppressive drug that was introduced into solid organ transplant management in 1999. Herein we have performed a retrospective review of patients who developed renal insufficiency owing to CNI therapy after orthotopic liver transplantation (OLT). MATERIALS AND METHODS: Thirty-one patients were switched to SRL monotherapy because of nephrotoxicity as evidenced by serum creatinine levels (SCr) > 1.8 mg/dL and estimated glomerular filtration rates (eGFR) < 45 mL/min/1.73 m(2). The dosage was adjusted to achieve trough levels between 8 and 10 ng/mL. RESULTS: The patients were followed for a mean of 52 months (range 2-88 months) after OLT. Mean follow-up after the switch was 27.5 months (range, 2-71.2 months). Immunosuppression was switched after a mean of 35.2 months (range, 0.2-43.4 months). Renal function was significantly improved, as shown by the improved SCr, urea, and eGFR after the switch. CONCLUSIONS: CNIs may be associated with significant nephrotoxicity and chronic kidney damage. Patients who develop renal dysfunction after OLT may be successfully treated by an early switch from CNIs to SRL, stopping the progression toward chronic renal damage and preserving allograft survival.

Clinical, ultrasonographic, and roentgenographic study in 134 asymptomatic gallstone carriers. Is oral ursodeoxycholic acid treatment worthwhile?

We investigated retrospectively the ultrasonographic and roentgenographic characteristics of the gallstones and the gallbladder in 134 symptom-free carriers and evaluated prospectively the outcome and side effects of 6 to 24 months' ursodeoxycholic acid (UDCA) therapy in 36 individuals with silent stones. Two-thirds of the 134 subjects had multiple stones, and 71-75% had stones less than 15 mm in diameter. Gallstone calcification was detected in 13%. A non-functioning gallbladder was observed in 19%, whereas gallbladder contraction was normal in 64 of 76 gallstone carriers. With regard to oral bile acid treatment, complete and partial dissolutions were achieved in 7 and 9 of 33 subjects, respectively (48.5%). Development of a non-functioning gallbladder occurred in 9%, and acquired gallstone calcification was seen in another 15%. We conclude that: i) the characteristics of the gallstones and the gallbladder are similar to those observed in symptomatic patients, and ii) UDCA therapy may be given in selected symptom-free carriers for no more than 6-12 months. Thereafter, it does not appear to be cost-effective.

The pharmacokinetics of H2 receptor blocking agents in compensated liver cirrhosis.

The bioavailability of oral and intravenous cimetidine and ranitidine was studied in patients with compensated liver cirrhosis. Single doses of 200 and 400 mg cimetidine were used for both administration routes, while ranitidine was administered in doses of 150 mg orally or 50 mg i.v. Plasma concentrations and urinary recovery were determined by the HPLC method. The pharmacokinetics of both of these drugs in the cirrhotic patients did not differ from those found in normal subjects. The two doses of cimetidine given i.v. gave rise to the same plasma concentrations, while after oral administration, 400 mg produced higher plasma concentrations than 200 mg. As to the pharmacokinetic parameters, neither cimetidine nor ranitidine administered i.v. offered any further advantages compared to the oral route. The urinary recovery of both cimetidine and ranitidine was higher after intravenous than after oral administration. It is concluded therefore that the pharmacokinetics of cimetidine and ranitidine is not altered in compensated liver cirrhosis.

Splenic impedance indices: a useful method to monitor patients after liver transplantation?

Splenic Doppler impedance indices are influenced, in portal hypertensive patients, by the resistance of the portal system. The aim of the study was to verify the usefulness of these indices in evaluating the presence of a pathological increase in portal resistance in patients with complications after liver transplantation. Splenic impedance indices have been evaluated in 46 patients before orthotopic liver transplantation (OLT), and 2 days, 1, 4, 8, and 12 to 18 months after transplantation. The results showed that spleen size slowly decreased after liver transplantation. From a baseline longitudinal diameter value of 18.0+/-3.6 cm (M+/-SD), the decrease was by 0%+/-3%, 8%+/-8%, 13%+/-9%, 15%+/-11%, and 14%+/-11% at 2 days and 1, 4, 8, and 12 to 18 months after liver transplantation. Splenic impedance indices-resistance index = (peak systolic - end diastolic) / peak systolic velocity; pulsatility index = (peak systolic - end diastolic) / mean velocity-which were increased before liver transplantation, showed a rapid decrease to normal values: resistance index: from 0.62+/-0.08 to 0.55+/-0.08 after 2 days, and to 0.49+/-0.09, 0.51+/-0.10, 0.54+/-0.10, 0.55+/-0.11 after 1, 4, 8, 12-18 months; pulsatility index: from 0.96+/-0.21 to 0.82+/-0.17 after 2 days, and to 0.69+/-0.19,0.72+/-0.21, 0.81+/-0.26, 0.84+/-0.26 after 1, 4, 8, and 12 to 18 months. Patients who had a good outcome, without any major complications, showed a clear and steady decrease in splenic impedance indices. On the contrary, patients who had complications affecting portal resistance (e.g., acute rejection, relapse of chronic hepatitis C virus-related hepatitis or cirrhosis, stenosis of portal anasthomosis, portal thrombosis), showed a lack of decrease, or, after an initial decrease, a subsequent re-increase in splenic impedance indices to pathological values. Splenic impedance indices measured in patients with complications were higher than those of patients without complications (P < .0004). Specificity and sensitivity of splenic impedance indices in the evaluation of the presence of complications increasing portal resistance were good. In conclusion, after OLT, splenic impedance indices could be useful aspecific parameters for identifying patients with complications that are able to affect or increase portal resistance.

Study on the Sternberg paradigm in cirrhotic patients without overt hepatic encephalopathy.

Memory dysfunction is reported in cirrhotics. The aim of this paper was to increase insight into memory function of cirrhotic patients without overt hepatic encephalopathy. Eighty-six consecutive cirrhotics without overt hepatic encephalopathy (aged 54+/-10 yr., mean+/-s.d.) and 28 controls (52+/-10 yr.) with comparable education level were enrolled. Seventeen patients were class A, 55 class B, 14 class C according to Child-Pugh classification; 29 had alcoholic cirrhosis. The presence of subclinical signs of central nervous system dysfunction were assessed by Number Connection Test (NCT) and quantified EEG analysis. Memory scanning was evaluated by reaction times (RTs) in the Sternberg paradigm. MANOVA analysis showed that RTs were higher (F1,99=11, p<0.01) and time outs (TOs) more frequent (F1,110=10, p<0.01) in cirrhotics than in controls, whereas button press errors (BPEs) did not differ significantly (F1,110=2, p=n.s.). In cirrhotics, an interaction Child-Pugh class x memory set size was found (F2,146=4, p<0.05), showing exceedingly delayed RTs with greater memory set size in class C patients. Patients with altered NCT had significantly prolonged RTs (F1,71=4, p<0.05) and more TOs (F1,82=11, p<0.01) than patients with normal NCT. Cirrhotics with altered EEG had significantly prolonged RTs (F2,70=6, p<0.01). RTs were found to be correlated to alpha relative power (r=-0.4, p<0.01) and theta relative power (r=0.4, p<0.01). In conclusion, cirrhotics without over encephalopathy, but with NCT or EEG alterations, perform a computerized digit recognition task more slowly and with higher TOs than cirrhotic patients with normal NCT or EEG. In severe liver insufficiency (class C cirrhotics) also an impairment of memory scanning was detected. Sternberg test performance correlates with NCT and quantitative EEG parameters.

Long-term persistence of low bone density in orthotopic liver transplantation.

We determined bone density and metabolism in 46 patients (35 males, 11 females) who had undergone liver transplantation 1-48 months previously. Twenty-one patients were then followed for the next 24 months. At each visit, blood and urine samples for bone and liver metabolism parameters, as well as spinal and femoral dual-energy X-ray absorptiometry (DXA) scans, were obtained. Basal spinal and femoral density was low (p < 0.001). Patients with pre-transplant cholestatic diseases had lower spinal density than all the other subjects (p <0.05) and the cumulative methylprednisolone intake was an independent negative predictor of total hip density (p < 0.02). At baseline, urinary hydroxyproline and N-telopeptide were at the upper normal level and decreased only after 24 months of follow-up (p < 0.05). During the first year of follow-up, femoral density decreased (p < 0.05) and a partial recovery was observed for both spine and femur after 24 months. After 12 months, femoral bone density was negatively associated with serum cyclosporin A levels (p < 0.005) and cumulative methylprednisolone intake (p < 0.05), while the percent decrease in spinal density after the first 12 months was negatively predicted by mean daily methylprednisolone intake (p < 0.05). In patients with pre-transplant cholestatic diseases, femoral and spinal density increased after the first (p < 0.05) and second year (p < 0.05), respectively. In patients with previous post-necrotic cirrhosis, femoral density decreased after 12 months (p<0.05) and was still lower than baseline after 24 months (p < 0.05). However, at the end of the study the cumulative percentage of femoral neck osteoporosis was 43%. In conclusion, an elevated prevalence of spinal and femoral osteoporosis is present even many years after liver transplantation, with immunosuppressive treatment and pre-transplant liver disease being the most important pathogenetic factors.

Effect of Silibinin on biliary lipid composition. Experimental and clinical study.

The effect of Silymarin, a natural flavonoid, on biliary lipid composition, was studied in rats and humans. Bile flow, biliary cholesterol, phospholipid and total bile salt concentrations were measured in 23 control rats and in 27 rats treated with Silibinin, the active component of Silymarin, at the dose of 100 mg/kg body weight i.p. (n = 21) or 50 mg/kg body weight i.p. (n = 6) for 7 days. Biliary cholesterol and phospholipid concentrations were significantly reduced after the higher Silibinin dose (60.9 and 72.9% of the control values), whereas bile flow and biliary total bile salt concentration were unchanged. After the lower Silibinin dose all parameters remained unchanged. Total liver cholesterol content was not affected by Silibinin. On the other hand, in vitro determination of rat liver microsomal 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity showed a significant dose-dependent inhibition by Silibinin (0.5-8 mg/kg). Biliary lipid composition was also assayed in four gallstone and in 15 cholecystectomized patients before and after Silymarin (420 mg per day for 30 days) or placebo administration. In both groups, biliary cholesterol concentrations were reduced after Silymarin treatment and the bile saturation index significantly decreased accordingly. These data suggest that Silibinin-induced reduction of biliary cholesterol concentration both in humans and in rats might be, at least in part, due to a decreased synthesis of liver cholesterol.

Effect of Silybin on biliary lipid composition in rats.

The authors studied the influence of Silybin in rats, administered i.p. for 7 days (daily dose of 100 mg/kg/b.w.) on the biliary lipid composition and on the maximal excretory rate of bile salts. Following this treatment, biliary cholesterol excretion was reduced, while the other lipids and bile flow were not significantly modified. After sodium cholate infusion (1.6 mumol/min/100 g b.w. i.v. for 80 minutes), the Tm of bile salts and bile flow remained unchanged in Silybin pretreated rats. The mechanism by which Silybin treatment reduces cholesterol excretion, is discussed.

Oral and intravenous pharmacokinetics of ranitidine in patients with liver cirrhosis.

The kinetics of p. o. (150 mg) and i.v. (50 mg) ranitidine was studied in nine healthy controls and in nine patients with compensated liver cirrhosis. Plasma concentrations and urinary recovery of unchanged drug were determined by high performance liquid chromatography. The pharmacokinetic data observed in the cirrhotic patients did not differ from those of controls after p.o. or i.v. administration. Moreover, oral bioavailability was similar in controls and cirrhotics. In conclusion, the pharmacokinetics of ranitidine is not altered in patients with compensated liver cirrhosis.