Hepatotoxicity of Antibiotics and Antifungals and Their Safe Use in Hepatic Impairment.

Idiosyncratic drug-induced liver injury (DILI) is a rare and unpredictable form of hepatotoxicity. While its clinical course is usually benign, cases leading to liver transplantation or death can occur. Based on modern prospective registries, antimicrobials including antibiotics and antifungals are frequently implicated as common causes. Amoxicillin-clavulanate ranks as the most common cause for DILI in the Western World. Although the absolute risk of hepatotoxicity of these agents is low, as their usage is quite high, it is not uncommon for practitioners to encounter liver injury following the initiation of antibiotic or antifungal therapy. In this review article, mechanisms of hepatoxicity are presented. The adverse hepatic effects of well-established antibiotic and antifungal agents are described, including their frequency, severity, and pattern of injury and their HLA risks. We also review the drug labeling and prescription guidance from regulatory bodies, with a focus on individuals with hepatic impairment.

Randomised clinical trial: a leucine-metformin-sildenafil combination (NS-0200) vs placebo in patients with non-alcoholic fatty liver disease.

BACKGROUND: Sirtuin 1 (Sirt1) is suppressed in non-alcoholic fatty liver disease (NAFLD), while its' stimulation or overexpression results in reduced disease severity in pre-clinical NAFLD models. Leucine allosterically activates Sirt1 and synergise with other Sirt/AMPK/NO pathway activators. We developed a triple combination of leucine, metformin and sildenafil (NS-0200), which was effective in a mouse model of non-alcoholic steatohepatitis (NASH). AIM: To report the results from a Phase 2, randomised clinical trial of of NS-0200 in 91 subjects with NAFLD (liver fat ≥15% by magnetic resonance imaging-proton-density fat fraction (MRI-PDFF)). METHODS: Subjects were randomised to placebo, low-dose (1.1 g leucine/0.5 g metformin/0.5 mg sildenafil) or high-dose NS-0200 (1.1 g leucine/0.5 g metformin/1.0 mg sildenafil) b.d. for 16 weeks; change in hepatic fat was assessed via MRI-PDFF, and lipid metabolism was assessed via changes in the lipidomic signature. Seventy subjects completed the trial and met a priori compliance criteria. Analyses were conducted on the full cohort and on those with alanine aminotransferase (ALT) values above median (50 U/L; n = 35). RESULTS: In the full cohort, active treatments did not separate from placebo. High dose NS-0200 reduced hepatic fat by 15.7% (relative change from baseline) in the high ALT group (P < 0.005) while low dose NS-0200 and placebo did not significantly change hepatic fat. Lipidomic analysis showed dose-responsive treatment effects in both overall and high ALT cohorts, with significant decreases in metabolically active lipids and up-regulation of fatty acid oxidation. CONCLUSION: These data support further evaluation of high-dose NS-0200 for treating NASH, especially in those with elevated ALT (NCT 02546609).

Clinical and metabolic effects associated with weight changes and obeticholic acid in non-alcoholic steatohepatitis.

BACKGROUND: In a 72-week, randomised controlled trial of obeticholic acid (OCA) in non-alcoholic steatohepatitis (NASH), OCA was superior to placebo in improving serum ALT levels and liver histology. OCA therapy also reduced weight. AIMS: Because weight loss by itself can improve histology, to perform a post hoc analysis of the effects of weight loss and OCA treatment in improving clinical and metabolic features of NASH. METHODS: The analysis was limited to the 200 patients with baseline and end-of-treatment liver biopsies. Weight loss was defined as a relative decline from baseline of 2% or more at treatment end. RESULTS: Weight loss occurred in 44% (45/102) of OCA and 32% (31/98) of placebo-treated patients (P = 0.08). The NAFLD Activity score (NAS) improved more in those with than without weight loss in both the OCA- (-2.4 vs -1.2, P<0.001) and placebo-treated patients (-1.2 vs -0.5, P = 0.03). ALT levels also improved in those with vs without weight loss in OCA- (-43 vs -34 U/L, P = 0.12) and placebo-treated patients (-29 vs -10 U/L, P = 0.02). However, among those who lost weight, OCA was associated with opposite effects from placebo on changes in alkaline phosphatase (+21 vs -12 U/L, P<0.001), total (+13 vs -14 mg/dL, P = 0.02) and LDL cholesterol (+18 vs -12 mg/dL, P = 0.01), and HbA1c (+0.1 vs -0.4%, P = 0.01). CONCLUSIONS: OCA leads to weight loss in up to 44% of patients with NASH, and OCA therapy and weight loss have additive benefits on serum aminotransferases and histology. However, favourable effects of weight loss on alkaline phosphatase, lipids and blood glucose seen in placebo-treated patients were absent or reversed on OCA treatment. These findings stress the importance of assessing concomitant metabolic effects of new therapies of NASH. Clinical trial number: NCT01265498.

Improvement in liver histology due to lifestyle modification is independently associated with improved kidney function in patients with non-alcoholic steatohepatitis.

BACKGROUND: Several recent studies have shown a strong association between non-alcoholic steatohepatitis (NASH) and chronic kidney disease. AIM: To examine the relationship between changes in liver histology and renal function in patients with NASH. METHODS: The present analysis represents a post hoc analysis of a recently published trial that included 261 patients with NASH who were treated with lifestyle modifications during 52 weeks. Kidney function was evaluated through Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rates (eGFR, mL/min/1.73 m2 ) overtime. We explored correlations between the kidney function and improvement in histological outcomes at 52 weeks. RESULTS: Interestingly, a one-stage reduction in fibrosis (r = 0.20, P < 0.01) and resolution of NASH (r = 0.17, P < 0.01) were significantly correlated with an improvement in the kidney function. The eGFR values significantly increased in patients with fibrosis improvement (+7.6 ± 6.5 mL/min/1.73 m2 ), compared to those without fibrosis improvement (-1.98 ± 6.4 mL/min/1.73 m2 ) (P < 0.01) at end of treatment (EOT). Likewise, NASH resolution was associated with an increase in eGFR compared with patients without NASH resolution (2.32 ± 7.8 mL/min/1.73 m2 vs. -1.04 ± 5.9 mL/min/1.73 m2 , P = 0.04) at EOT. After controlling for the confounders, the association between fibrosis improvement, NASH resolution and eGFR change remained significant (P < 0.05 for both). CONCLUSIONS: Improvement in liver histology due to lifestyle modification is independently associated with improved kidney function in NASH. As new drugs for NASH emerge, studies should address whether improvement in histology in response to pharmacotherapies yield the same improvement in kidney function as weight loss.

Randomised clinical study: GR-MD-02, a galectin-3 inhibitor, vs. placebo in patients having non-alcoholic steatohepatitis with advanced fibrosis.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) and resultant liver fibrosis is a major health problem without approved pharmacotherapy. Pre-clinical results of GR-MD-02, a galectin-3 inhibitor, suggested potential efficacy in NASH with advanced fibrosis/cirrhosis and prompted initiation of a clinical development programme in NASH with advanced fibrosis. AIM: To evaluate the safety, pharmacokinetics and exploratory pharmacodynamic markers of GR-MD-02 in subjects having NASH with bridging fibrosis. METHODS: The GT-020 study was a first-in-human, sequential dose-ranging, placebo controlled, double-blinded study with the primary objective to assess the safety, tolerability and dose limiting toxicity of GR-MD-02, in subjects with biopsy-proven NASH with advanced fibrosis (Brunt stage 3). The secondary objectives were to characterise first-dose and multiple-dose pharmacokinetic profiles and to evaluate changes in potential serum biomarkers and liver stiffness as assessed by FibroScan. RESULTS: GR-MD-02 single and three weekly repeated of 2, 4 and 8 mg/kg revealed no meaningful clinical differences in treatment emergent adverse events, vital signs, electrocardiographic findings or laboratory tests. Pharmokinetic parameters showed a dose-dependent relationship with evidence of drug accumulation following 8 mg/kg (~twofold). CONCLUSIONS: GR-MD-02 doses were in the upper range of the targeted therapeutic dose determined from pre-clinical data and were safe and well tolerated with evidence of a pharmacodynamic effect. These results provide support for a Phase 2 development programme in advanced fibrosis due to NASH.

A comprehensive assessment of environmental exposures among 1000 North American patients with primary sclerosing cholangitis, with and without inflammatory bowel disease.

BACKGROUND: The relationships between primary sclerosing cholangitis (PSC) and the environment are largely unknown. AIM: To validate associations reported in previous studies and to identify novel environmental exposures among PSC patients. METHODS: We performed a multicenter, case-control analysis utilising self-administered questionnaires. Responses between cases (n = 1000) and controls (n = 663) were compared using multivariable logistic regression adjusted for age and gender. The model was further stratified based on inflammatory bowel disease (IBD) status (with IBD n = 741 without IBD n = 259). RESULTS: Smoking was associated with PSC only when IBD was present (OR, 0.5; 95% CI 0.4-0.7) but not among those PSC patients without IBD (OR, 0.9; 95% CI 0.7-1.2). Compared to controls, women with PSC (irrespective of the presence of IBD) were less likely to have received hormone replacement therapy (HRT; OR, 0.5; 95% CI 0.4-0.7) and were more likely to have recurrent urinary tract infections (OR, 1.6; 95% CI 1.2-2.3). PSC patients regardless of gender or IBD status were less likely to eat fish (OR, 0.4; 95% CI 0.3-0.6) and grilled/barbecued meat (OR, 0.8; 95% CI 0.7-0.9). In contrast, PSC patients with and without IBD were more likely to consume steak/burgers that were more well done (OR, 1.3; 95% CI 1.2-1.5). CONCLUSIONS: IBD (rather than PSC) is associated with smoking. Women with PSC are more likely to have recurrent urinary tract infections and less likely to receive HRT. Dietary intake and methods of food preparation differ in PSC patients when compared to controls.

NASH resolution is associated with improvements in HDL and triglyceride levels but not improvement in LDL or non-HDL-C levels.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is associated with dyslipidemia and cardiovascular disease (CVD). AIM: To determine the relationship between resolution of NASH and dyslipidemia. METHODS: Individuals in the Pioglitazone vs. Vitamin E vs. Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) trial with paired liver biopsies and fasting lipid levels were included (N = 222). In the PIVENS trial individuals were randomised to pioglitazone 30 mg, vitamin E 800 IU or placebo for 96 weeks. Change in lipid levels at 96 weeks was compared between those with and without NASH resolution. RESULTS: Dyslipidemia at baseline was frequent, with low high-density lipoprotein (HDL) (<40 mg/dL in men or <50 mg/dL in women) in 63%, hypertriglyceridaemia (≥150 mg/dL) in 46%, hypercholesterolaemia (≥200 mg/dL) in 47% and triglycerides (TG)/HDL >5.0 in 25%. Low-density lipoprotein (LD) ≥160 mg/dL was found in 16% and elevated non-HDL cholesterol (non-HDL-C) (≥130 mg/dL) in 73%. HDL increased with NASH resolution but decreased in those without resolution (2.9 mg/dL vs. -2.5 mg/dL, P < 0.001). NASH resolution was associated with significant decreases in TG and TG/HDL ratio compared to those without resolution (TG: -21.1 vs. -2.3 mg/dL, P = 0.03 and TG/HDL: -0.7 vs. 0.1, P = 0.003). Non-HDL-C, LDL and cholesterol decreased over 96 weeks in both groups, but there was no significant difference between groups. Treatment group did not impact lipids. CONCLUSIONS: NASH resolution is associated with improvements in TG and HDL but not in other cardiovascular disease risk factors including LDL and non-HDL-C levels. Individuals with resolution of NASH may still be at increased risk of cardiovascular disease. ClinicalTrials.gov identifier: NCT00063622.

Comparative analysis of portal hepatic infiltrating leucocytes in acute drug-induced liver injury, idiopathic autoimmune and viral hepatitis.

Drug-induced liver injury (DILI) is often caused by innate and adaptive host immune responses. Characterization of inflammatory infiltrates in the liver may improve understanding of the underlying pathogenesis of DILI. This study aimed to enumerate and characterize leucocytes infiltrating liver tissue from subjects with acute DILI (n = 32) versus non-DILI causes of acute liver injury (n = 25). Immunostains for CD11b/CD4 (Kupffer and T helper cells), CD3/CD20 (T and B cells) and CD8/CD56 [T cytotoxic and natural killer (NK) cells] were evaluated in biopsies from subjects with acute DILI, either immunoallergic (IAD) or autoimmune (AID) and idiopathic autoimmune (AIH) and viral hepatitis (VH) and correlated with clinical and pathological features. All biopsies showed numerous CD8(+) T cells and macrophages. DILI cases had significantly fewer B lymphocytes than AIH and VH and significantly fewer NK cells than VH. Prominent plasma cells were unusual in IAD (three of 10 cases), but were associated strongly with AIH (eight of nine) and also observed in most with AID (six of nine). They were also found in five of 10 cases with VH. Liver biopsies from subjects with DILI were characterized by low counts of mature B cells and NK cells in portal triads in contrast to VH. NK cells were found only in cases of VH, whereas AIH and VH both showed higher counts of B cells than DILI. Plasma cells were associated most strongly with AIH and less so with AID, but were uncommon in IAD.

Serum proteomic profiling in patients with drug-induced liver injury.

BACKGROUND: Idiosyncratic drug-induced liver injury (DILI) is a complex disorder that is difficult to predict, diagnose and treat. AIM: To describe the global serum proteome of patients with DILI and controls. METHODS: A label-free, mass spectrometry-based quantitative proteomic approach was used to explore protein expression in serum samples from 74 DILI patients (collected within 14 days of DILI onset) and 40 controls. A longitudinal analysis was conducted in a subset of 21 DILI patients with available 6-month follow-up serum samples. RESULTS: Comparison of DILI patients based on pattern, severity and causality assessment of liver injury revealed many differentially expressed priority 1 proteins among groups. Expression of fumarylacetoacetase was correlated with alanine aminotransferase (ALT; r = 0.237; P = 0.047), aspartate aminotransferase (AST; r = 0.389; P = 0.001) and alkaline phosphatase (r = -0.240; P = 0.043), and this was the only protein with significant differential expression when comparing patients with hepatocellular vs. cholestatic or mixed injury. In the longitudinal analysis, expression of 53 priority 1 proteins changed significantly from onset of DILI to 6-month follow-up, and nearly all proteins returned to expression levels comparable to control subjects. Ninety-two serum priority 1 proteins with significant differential expression were identified when comparing the DILI and control groups. Pattern analysis revealed proteins that are components of inflammation, immune system activation and several hepatotoxicity-specific pathways. Apolipoprotein E expression had the greatest power to differentiate DILI patients from controls (89% correct classification; AUROC = 0.97). CONCLUSION: This proteomic analysis identified differentially expressed proteins that are components of pathways previously implicated in the pathogenesis of idiosyncratic drug-induced liver injury.

The effects of midodrine on the natriuretic response to furosemide in cirrhotics with ascites.

BACKGROUND: Resistance to loop diuretics is common in patients with ascites. Diminished glomerular filtration rate (GFR) is thought to mediate resistance to loop diuretics. Midodrine, a commonly used alpha-1 agonist, has been shown to improve GFR in non-azotemic patients with cirrhosis. AIM: To conduct a randomized, double-blind, placebo-controlled, cross-over study to test the hypothesis that midodrine significantly increases natriuretic response of IV furosemide in non-azotemic cirrhotics with ascites. METHODS: All subjects participated in both phases, which were (i) furosemide IV infusion + oral midodrine 15 mg administered 30 min before furosemide (ii) furosemide IV infusion + oral placebo administered 30 min before furosemide. Primary outcomes were 6-h urine sodium excretion and 6-h total urine volume. RESULTS: A total of 15 patients (men: 8; age: 52.7 ± 7.6 years; serum creatinine: 1.06 ± 0.2 mg/dL) were studied. Total 6-h urine sodium excretion was 109 ± 42 mmol in the furosemide + midodrine treatment phase and was not significantly different from that in the furosemide + placebo treatment phase (126 ± 69 mmol, P = 0.6). Similarly, mean 6-h total urine volume was not significantly different between two groups (1770 ± 262 mL vs. 1962 ± 170 mL, P = 0.25). CONCLUSIONS: Oral midodrine does not increase the natriuretic response to furosemide in non-azotemic cirrhotic patients with ascites. Orally administered midodrine does not increase natriuretic response to furosemide in non-azotemic cirrhotic patients with ascites.

Duloxetine hepatotoxicity: a case-series from the drug-induced liver injury network.

BACKGROUND: Case reports suggest that duloxetine hepatotoxicity may arise, but risk factors, presenting features and clinical course are not well-described. AIM: To describe the presenting features and outcomes of seven well-characterized patients with suspected duloxetine hepatotoxicity. METHODS: Patients enrolled in the Drug-Induced Liver Injury Network Prospective Study underwent an extensive laboratory and clinical evaluation to exclude competing aetiologies of liver injury as well as a standardized assessment for causality and disease severity. RESULTS: Between 1/2006 and 9/2009, six of the seven cases of DILI attributed to duloxetine were assessed as definite or very likely. Median patient age was 49 years, six (86%) were women and the median latency from drug initiation to DILI onset was 50 days. Six patients developed jaundice and the median peak alanine aminotransferase in the five patients with acute hepatocellular injury was 1633 IU/L. Ascites developed in one patient and acute renal dysfunction in two others (29%). All patients recovered without liver transplantation even though three had pre-existing chronic liver disease. Liver histology in four cases demonstrated varying patterns of liver injury. CONCLUSIONS: Duloxetine hepatotoxicity developed within 2 months of drug intake and led to clinically significant liver injury. A spectrum of laboratory, histological and extra-hepatic features were noted at presentation.

Altered first-pass effects in a liver transplant recipient explained intraindividual variation in calcineurin inhibitor concentrations: a case report.

BACKGROUND: The significant interindividual and intraindividual variability in the blood concentrations of the most commonly used calcineurin inhibitors such as tacrolimus and cyclosporine makes the exact dosing of these agents in transplant recipients very challenging. As both of these drugs have narrow therapeutic index and are metabolized by hepatic and intestinal cytochrome P450 3A, we tested the hypothesis that these variations are secondary to varying first-pass effects in the gut and the liver over a period of time. CASE REPORT: A liver transplant recipient, who had previously presented with tacrolimus toxicity on his usual dosing regimen and intolerant to standard doses of cyclosporine, was selected to undergo the study. Oral and intravenous midazolam was used as the probe to measure hepatic and intestinal CYP3A4 activities at two different time points (phases one and two). Small intestinal biopsies were also obtained for measuring CYP3A4 activity for in vitro studies. On serially determining the patient's hepatic and intestinal CYP3A activities, we concluded that the variability in the dosing requirements is due to altered first-pass effects in the intestine. DISCUSSION: Transplant recipients receive multiple medications that may inhibit or induce these metabolizing enzymes, which eventually determine the concentrations of these narrow therapeutic agents. If no obvious etiology of intolerance to calcineurin inhibitors in a transplant recipient is identified, one should consider altered first-pass effects in the gut and the liver contributing to intraindividual variations in the blood concentrations.

Predictors of outcome in patients with unresectable hepatocellular carcinoma receiving transcatheter arterial chemoembolization.

BACKGROUND: Transcatheter arterial chemoembolization (TACE) has been shown to improve survival in patients with unresectable hepatocellular carcinoma (HCC). AIM: To identify pretreatment factors that predicts increased mortality in HCC patients receiving TACE. METHODS: Retrospective review of all patients who underwent TACE for HCC from January 1999 to November 2004. Patient demographics, aetiology of liver disease, laboratory and imaging data regarding tumour characteristics were obtained. RESULTS: Eighty-eight patients (57 +/- 1 years age) received 1-4 sessions of TACE (1.4 +/- 0.1). Tumour size was 3.3 +/- 0.2 cm (range 1-13 cm, median 3 cm) with mean number of lesions 1.9 +/- 0.1 (range 1-7). Mean model for the end stage liver disease score: 11 +/- 0.4; cancer of the liver Italian program score: 1.3 +/- 0.1. Survival post-TACE (excluding those underwent orthotopic liver transplantation) was 12 +/- 0.3 months. By multivariate analysis, tumour size (HR = 1.37, 95% CI: 1.11-1.68, P = 0.003), hypovascularity (HR = 12.62, 95% CI: 1.79-88.92, P = 0.01) and elevated international normalized ratio (HR = 1.46, 95% CI: 1.10-1.92 P = 0.008) are shown to be significant risk factors for increased mortality. CONCLUSION: TACE therapy leads to a mean survival of 12 months in patients not receiving orthotopic liver transplantation. Tumour size, hypovascularity on imaging, and elevated international normalized ratio are predictors of increased mortality after TACE therapy for HCC.

Diltiazem inhibits human intestinal cytochrome P450 3A (CYP3A) activity in vivo without altering the expression of intestinal mRNA or protein.

AIMS: To determine the effect of diltiazem on intestinal CYP3A activity and protein and mRNA expression in vivo in healthy subjects. METHODS: Intestinal biopsies were obtained from ten healthy controls and from ten healthy subjects after receiving diltiazem 120 mg bid for 7 days. Intestinal CYP3A activity, CYP3A4 protein and mRNA concentrations were quantified in both groups. Intestinal CYP3A activity was determined by incubation of small bowel homogenate with midazolam (25 microM) and NADPH for 5 min and the rate of formation of 1'-hydroxymidazolam was quantified. RESULTS: All subjects in the treatment group had detectable diltiazem concentration in the serum. While there was no significant difference in CYP3A4 protein and mRNA expression between the control and treatment groups, the formation of 1'-hydroxymidazolam (446 pmol min(-1) mg(-1) 6 (control) vs. 170 (CI 112, 228) pmol min(-1) mg(-1) 95% confidence interval (CI 269, 623) (diltiazem group)) was significantly reduced (P < 0.05). CONCLUSION: Diltiazem decreased small bowel CYP3A activity by 62% as a result of irreversible inhibition with no corresponding change in intestinal CYP3A4 mRNA or protein concentrations.

Positron emission tomography for detecting occult hepatocellular carcinoma in hepatitis C cirrhotics awaiting for liver transplantation.

Patients with hepatitis C cirrhosis may sometimes have persistently elevated alpha feto protein (AFP) despite a lack of evidence for disease by ultrasound or computed tomography (CT). While this pattern may represent a benign manifestation of hepatitis C cirrhosis (HCC), it raises concern for the possibility of an occult hepatocellular carcinoma. It has previously been shown that positron emission tomography (PET scan) may detect occult cholangiocarcinoma in high-risk patients with primary sclerosing cholangitis. We hypothesized that PET scanning might similarly serve for occult HCC in hepatitis C cirrhotics. PET scanning was performed on eight hepatitis C cirrhotics who were on the liver transplantation list and displayed persistently elevated AFP (>100 ng/mL) but no detectable lesions on abdominal CT scan. The results of PET detection of occult HCC were compared to those obtained with lipiodol-enhanced CT scanning and with histologic examination of the live explant. Explant histology or prolonged clinical follow-up showed two subjects to have conclusive evidence of HCC; the remainder, no evidence of malignancy. Although PET imaging did not reveal abnormal lesions in any subject; lipiodol-enhanced CT scans revealed abnormal lipiodol retention in both subjects with HCC. These preliminary findings suggest that PET has no role in detecting occult HCC in high-risk patients. Additionally, these data suggest that some hepatitis C cirrhotics with persistently elevated AFP but no detectable lesions by conventional CT scan may show occult HCC using lipiodol-enhanced CT scans.

Hepatic and intestinal cytochrome P450 3A activity in cirrhosis: effects of transjugular intrahepatic portosystemic shunts.

Transjugular intrahepatic portosystemic shunt (TIPS) is performed to treat some complications of cirrhosis. This study investigated the effects of cirrhosis and TIPS on intestinal and hepatic cytochrome P450 3A (CYP3A) activity. Nine volunteers were cirrhotic patients with TIPS, 9 were cirrhotic controls (matched for sex, age, etiology, and Child-Pugh class), and 9 were sex- and age-matched healthy volunteers. Simultaneous doses of midazolam were given intravenously (0.05 mg/kg) and orally (3 mg of [15N3]midazolam). Peripheral and portal venous blood samples were assayed for midazolam and [15N3]midazolam. The systemic clearance of midazolam was significantly greater (P <.05) in healthy volunteers (0.42 +/- 0.10 L x h(-1) x kg(-1)) compared with cirrhotic controls (0.20 +/- 0.05) and with cirrhotic patients with TIPS (0.21 +/- 0.09). Hepatic availability followed the same trend. The bioavailability of midazolam was significantly higher (P <.05) in cirrhotic patients with TIPS (0.76 +/- 0.20) compared with cirrhotic controls (0.27 +/- 0.14) and with healthy volunteers (0.30 +/- 0.10). The intestinal availability was significantly greater (P <.05) in cirrhotic patients with TIPS (0.83 +/- 0.17) compared with cirrhotic controls (0.32 +/- 0.16) and with healthy volunteers (0.42+/-0.15). As expected, hepatic CYP3A activity was reduced in cirrhosis. However, in cirrhotic patients with TIPS, there was a marked loss in first-pass metabolism of midazolam as a result of diminished intestinal CYP3A activity.

Increase in hepatic arterial blood flow after transjugular intrahepatic portosystemic shunt creation and its potential predictive value of postprocedural encephalopathy and mortality.

PURPOSE: To determine (i) whether there is a significant increase in hepatic artery blood flow (HABF) after transjugular intrahepatic portosystemic shunt (TIPS) creation and (ii) whether the extent of incremental increase in HABF is predictive of clinical outcome after TIPS creation. MATERIALS AND METHODS: Prospective, nonrandomized, nonblinded duplex Doppler ultrasound (US) examinations were performed on 24 consecutive patients (19 men; Child Class A/B/C: 4/12/8, respectively) with a mean age of 52.8 years who were referred for TIPS creation for variceal bleeding. Peak hepatic artery velocity and vessel dimensions were used to calculate the hepatic arterial blood flow (HABF) before and after TIPS creation. Patients were clinically followed in the gastrohepatology clinic and TIPS US surveillance was performed at 1 and 3 months to assess shunt function. The extent of incremental increase in HABF was analyzed as a predictor of post-TIPS encephalopathy and/or death. RESULTS: The technical success rate of TIPS creation was 100%. The shunt diameters were either 10 mm (n = 11) or 12 mm (n = 13). TIPS resulted in a significant reduction in the portosystemic gradient from 24.3 mm Hg +/- 5.7 to 9.3 mm Hg +/- 2.9 (P <.001). The hepatic artery peak systolic velocity and HABF increased significantly after TIPS creation, from 60.8 cm/sec +/- 26.7 to 121 cm/sec +/- 51.5 (P <.001) and from 254.2 mL/min +/- 142.2 to 507.8 mL/min +/- 261.3 (P <.001), respectively. The average incremental increase in HABF from pre-TIPS to post-TIPS was 253.6 mL/min +/- 174.2 and the average decremental decrease in portosystemic gradient was 15.0 mm Hg +/- 5.3, but there was no significant correlation (r = 0.04; P =.86) between the two. All shunts were patent at 30 and 90 days without sonographic evidence of shunt dysfunction. After TIPS creation, new or worsened encephalopathy developed in five patients at 30 days and in an additional three at 90 days. They were all successfully managed medically. Three patients (12.5%) died within 30 days of the TIPS procedure. The extent of incremental increase in HABF after TIPS was variable and did not correlate with the development of 30-day and 90-day encephalopathy (P =.41 and P =.83, respectively) or 30-day mortality (P =.2). CONCLUSIONS: HABF increases significantly after TIPS but is not predictive of clinical outcome. The significance of the incremental increase is yet to be determined.

Predictors of inadequate bowel preparation for colonoscopy.

OBJECTIVE: Inadequate preparation of the bowel for colonoscopy can result in both missed pathological lesions and cancelled procedures. We looked prospectively at the quality of colonic preparation and evaluated potential associations between specific patient characteristics and inadequate colonic preparation. METHODS: Data were gathered on consecutive patients presenting for colonoscopy who received either a polyethylene glycol lavage or oral sodium phosphate bowel preparation. Patient demographic and medical history information was gathered before scheduled colonoscopy. The endoscopist evaluated the preparation quality during the procedure. Complete data were gathered on 649 of 714 eligible patients (90.8%). Possible predictors of inadequate colonic preparation were analyzed using univariate statistics and multivariate logistic regression models. RESULTS: An inadequate colonic preparation was reported in 21.7% of observed colonoscopies. Only 18% of patients with an inadequate colonic preparation reported a failure to adequately follow preparation instructions. A later colonoscopy starting time, a reported failure to follow preparation instructions, inpatient status, a procedural indication of constipation, taking tricyclic antidepressants, male gender, and a history of cirrhosis, stroke or dementia were all independent predictors of an inadequate colon preparation (all p < 0.05). A procedural indication of previous polypectomy was a negative predictor of inadequate colonic preparation (p < 0.05). CONCLUSION: Several patient characteristics were significantly associated with colonic preparation quality independent of preparation type, compliance with preparation instructions, and procedure starting time. This information may help to identify patients at an increased risk for inadequate colonic preparation for whom alternative preparation protocols would be appropriate.