James H. Lewis

Efficacy and safety of high‐dose pravastatin in hypercholesterolemic patients with well‐compensated chronic liver disease: Results of a prospective, randomized, double‐blind, placebo‐controlled, multicenter trial

The hepatotoxic potential of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors in patients with underlying chronic liver disease remains controversial. We performed a multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group trial that compared pravastatin (80 mg) to a placebo administered once daily to hypercholesterolemic subjects greater than 18 years of age with at least a 6‐month history of compensated chronic liver disease and with a low‐density lipoprotein cholesterol (LDL‐C) level greater than or equal to 100 mg/dL and a triglyceride (TG) level lower than 400 mg/dL. The efficacy was determined by the percentage change in LDL‐C [along with the total cholesterol (TC), high‐density lipoprotein cholesterol, and TG] from the baseline to week 12. The safety was analyzed by the proportion of subjects who developed at least 1 alanine aminotransferase (ALT) value greater than or equal to 2 times the upper limit of normal for those with normal ALT at the baseline or a doubling of the baseline ALT for those with elevated ALT at the baseline during 36 weeks of treatment. A total of 630 subjects were screened, and 326 subjects were randomized; nonalcoholic fatty liver disease was present in 64%, and chronic hepatitis C was present in 23%. In the intent‐to‐treat population, pravastatin (80 mg/day) significantly lowered the mean LDL‐C, TC, and TG values at week 12 and at other times (weeks 4, 8, 24, and 36) in comparison with the placebo. The incidence of subjects who met the primary prespecified ALT event definition was lower in the pravastatin group at all times over the 36 weeks of therapy in comparison with the placebo group, although the difference was not statistically significant. No differences were seen on the basis of the baseline ALT values or among the different liver disease groups. Conclusion: High‐dose pravastatin (80 mg/day) administered to hypercholesterolemic subjects with chronic liver disease significantly lowered LDL‐C, TC, and TGs in comparison with the placebo and was safe and well tolerated. The concern over an increased potential for statin‐induced hepatotoxicity in patients with chronic liver disease appears to be lessened on the basis of these results. (HEPATOLOGY 2007.)

Hepatic Findings in Long-Term Clinical Trials of Ximelagatran

AbstractObjective: In clinical trials, the efficacy and safety of the oral direct thrombin inhibitor ximelagatran have been evaluated in the prevention or treatment of thromboembolic conditions known to have high morbidity and mortality. In these studies, raised aminotransferase levels were observed during long-term use (>35 days). The aim of this analysis is to review the data regarding these hepatic findings in the long-term trials of ximelagatran.n Patients and methods: The prospective analysis included 6948 patients randomised to ximelagatran and 6230 patients randomised to comparator (warfarin, low-molecular weight heparin followed by warfarin or placebo). Of these, 6931 patients received ximelagatran for a mean of 357 days and 6216 patients received comparator for a mean of 389 days. An algorithm was developed for frequent testing of hepatic enzyme levels. A panel of four hepatologists analysed all cases of potential concern with regard to causal relation to ximelagatran treatment using an established evaluation tool (Roussel Uclaf Causality Assessment Method [RUCAM]).n Results: An elevated alanine aminotransferase (ALT) level of >3 × the upper limit of normal (ULN) was found in 7.9% of patients in the ximelagatran group versus 1.2% in the comparator group. The increase in ALT level occurred 1–6 months after initiation of therapy and data were available to confirm recovery of the ALT level to <2 × ULN in 96% of patients, whether they continued to receive ximelagatran or not. There was some variability in the incidence of ALT level elevation between indications, those with simultaneous acute illnesses (acute myocardial infarction or venous thromboembolism) having higher incidences. Combined elevations of ALT level of >3 × ULN and total bilirubin level of >2 × ULN (within 1 month of the ALT elevation), regardless of aetiology, were infrequent, occurring in 37 patients (0.5%) treated with ximelagatran, of whom one sustained a severe hepatic illness that appeared to be resolving when the patient died from a gastrointestinal haemorrhage. No death was observed directly related to hepatic failure caused by ximelagatran.n Conclusion: Treatment with ximelagatran has been associated with mainly asymptomatic elevation of ALT levels in a mean of 7.9% of patients in the long-term clinical trial programme and nearly all of the cases occurred within the first 6 months of therapy. Rare symptomatic cases have been observed. An algorithm has been developed for testing ALT to ensure appropriate management of patients with elevated ALT levels. Regular ALT testing should allow the clinical benefits of ximelagatran to reach the widest population of patients while minimising the risk of hepatic adverse effects.

Gastric Lipase: Localization in the Human Stomach

The aim of this study was to determine the range of activity and the location of lipase in the human stomach. The range of lipase activity in gastric mucosa of surgical specimens from the fundic area of 22 subjects was 594 to 3350 mU [mean, 1598 +/- 144 mU tri[3H]olein, (1 mU-1 nmol [3H]oleic acid released from tri[3H]olein per minute per milligram protein)]. For localization of activity, pinch biopsy specimens of gastric mucosa from 6 subjects were taken from the greater and lesser curvatures within 2 cm of the gastroesophageal junction (upper greater curvature and upper lesser curvature) and within 2 cm of the pylorus (lower greater curvature and lower lesser curvature). Lipase activity was higher in the upper greater curvature (405 +/- 92 mU) than in the upper lesser curvature (32 +/- 13 mU) and lowest in the antral area (16 +/- 9 mU in the lower lesser curvature and 10 +/- 2 mU in the lower greater curvature). The data show that in the human, lipase activity is localized primarily in the fundic area of the stomach. Comparison of the lipase activity levels in the gastric mucosa with lingual lipase activity levels in specimens of lingual serous glands indicates that in humans, gastric lipase is the main lipase active in the stomach.

The frequency of peptic ulcer as a cause of upper-GI bleeding is exaggerated

BACKGROUNDnPeptic ulcer disease is considered the cause of upper-GI bleeding in 50% of cases. A recent decline in the proportion of cases of upper-GI bleeding because of a peptic ulcer was noted by us. The objectives of this study were to evaluate the frequency of peptic ulcer in patients with upper-GI bleeding and the proportion of bleeding peptic ulcers with a non-bleeding visible vessel.nnnMETHODSnPatients with upper-GI bleeding seen from December 1999 until April 2001 at a tertiary, university-affiliated medical center were studied prospectively. The Clinical Outcome Research Initiative (CORI) database was used to correlate the single institution data with nationwide data. Endoscopic data in the CORI database for patients who had endoscopy for upper-GI bleeding between December 1999 and July 2001 were retrieved and analyzed.nnnRESULTSnA total of 126 patients were included in the prospective study. The endoscopic findings were: peptic ulcer in 31.8%: 95% confidence interval (CI) [23.7%, 40.6%] of patients; a non-bleeding visible vessel was present in 10%: 95% CI[2.8%, 23.7%] of these peptic ulcers. From the nationwide CORI database, data for 7822 patients with upper-GI bleeding were obtained. The endoscopic findings were: peptic ulcer in 20.6%:95% CI[19.7%, 21.5%] of patients with upper-GI bleeding; a non-bleeding visible vessel was present in 7.3%: 95% CI[6.1%, 8.6%] of the ulcers.nnnCONCLUSIONSnThe frequency of peptic ulcer in patients with upper-GI bleeding and the proportion of bleeding ulcers with a non-bleeding visible vessel are less than previously reported.

Reasons Why Patients Infected with Chronic Hepatitis C Virus Choose to Defer Treatment: Do They Alter Their Decision with Time?

This study was designed to determine the percentage of treatment-naïve patients infected with chronic hepatitis C virus who make an informed choice to forego (defer) treatment with pegylated interferon regimens in the absence of any medical, psychosocial, or other contraindications, and to reassess their decision by using a questionnaire at least 1xa0year later. Patient charts dating from 2001 were retrieved and retrospectively analyzed for the following data: patient age, gender, race, hepatitis C viral load, genotype, liver biopsy results, hepatic imaging results, peak alanine aminotransferase (ALT) levels, comorbid conditions, source of infection, estimated duration of infection, and reasons given by the patient for declining pegylated interferon-based treatment at the time of their consultation. A questionnaire survey sought to determine their satisfaction with their initial decision. Of 446 patient charts reviewed, 280 patients were treatment-naïve and were judged to have no contraindications to receiving interferon-based therapy. Of these, 115 (41%) opted to defer treatment and are the subject of this analysis. Women declining therapy outnumbered men by approximately 3 to 2. Middle-aged patients (45–55 years) were most likely to choose expectant therapy compared with older or younger individuals. The proportion of African American patients who deferred therapy (48%) was higher than non-African American patients (36.6%). More than 90% of the patients choosing to be followed were genotype 1. Peak ALT values were normal in 37% and <2X upper limits of normal (ULN) in another 40%. The estimated duration of chronic hepatitis C infection was >16 years in approximately three-quarters of individuals. The most common source of their infection was intravenous drug use followed by transfusion-related. The most common reason for opting not to receive treatment, given by nearly two-thirds of patients, was the asymptomatic nature of their infection coupled with their concern about side effects of the medications. Approximately 10% had unfavorable social situations, including a lack of support or health insurance, that precluded receiving therapy (despite the availability of indigent care programs offered by the pharmaceutical manufacturers). Only five patients (4.3%) cited doubts about efficacy as the main reason that they did not want to be treated. The questionnaire survey at 1 year found that 79% of the patients confirmed their ongoing satisfaction with their initial decision to decline treatment, and another 10.6% indicated that they were still “moderately satisfied” with their decision and unlikely to change it in the near-future. Only six patients (7%) voiced their current dissatisfaction with expectant management and expressed the desire to have a follow-up discussion about treatment options. Of the remaining three patients (3.5%), two had already started treatment and one was deceased (of non-liver–related causes). A significant proportion of patients infected with hepatitis C virus who are otherwise eligible for therapy opt to defer treatment (41% overall in our series, with African American patients deferring in a higher proportion than non-African American patients). Nearly all of our patients were genotype 1 with clinically and histologically mild hepatitis of reasonably long duration. Our questionnaire survey found that most remained satisfied with their decision to defer treatment at the present time. Few patients cited a perceived low rate of efficacy of pegylated interferon and ribavirin therapy as the principal reason that they chose not to initiate treatment.

The rational use of potentially hepatotoxic medications in patients with underlying liver disease

Given the fact that as many as 9% of all adverse drug reactions involve toxic effects on the liver and with upwards of 50% of all cases of fulminant hepatic failure being ascribed to acetaminophen and other agents, the safe use of medications takes on an even greater importance whenever the prescription of potentially hepatotoxic drugs to patients with underlying liver disease is considered. In general, it is thought that most drugs can be safely administered in the setting of liver disease without an increased risk of hepatotoxicity, although the evidence on which this statement is based often relies more on clinical judgement than on clinical studies. Several drugs appear to have an increased risk of hepatotoxicity in patients with underlying liver disease based on either clinical reports or extrapolated pharmacological data. These agents, including methotrexate, niacin and the antiretroviral and antituberculosis drugs, carry warnings about their use in patients with a variety of liver conditions. The data supporting the hepatotoxic risk of scores of additional drugs, such as the 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (‘statins’), the newer thiazolidinediones (rosiglitazone, pioglitazone), and tamoxifen, among others, in patients with liver disease are generally lacking by evidence-based studies. However, clinical and biochemical monitoring is routinely recommended or required, often to make up for the lack of information on the true risk of clinically significant liver toxicity of these agents in individuals both with and without underlying liver disease. This article will review what is and what is not known about prescribing in the setting of acute and chronic liver disease and offers recommendations to help promote the safe and rational use of potentially hepatotoxic medications in these patients.

Percutaneous Liver Biopsy

The technique of performing liver biopsy varies among physicians, even within the same practice. In an attempt to determine whether gastroenteroogists/hepatologists differ in their approach compared to radiologists, we surveyed a nearly equal number of physicians in the Washington, DC, USA, metropolitan area with respect to 26 variables. While the technique can vary considerably, relatively few differences were seen between the groups. Only about half of gastroenterologists and hepatologists use ultrasound guidance, a biopsy, gun, and conscious sedation; radiologists routinely used a biopsy gun and conscious sedation and rarely require an overnight stay.

Hepatotoxicity of agents used in the management of inflammatory bowel disease.

Patients with inflammatory bowel disease (IBD) are at risk for hepatobiliary disease and toxicity, and the diagnosis of drug-induced liver disease in patients being treated for IBD can represent a clinical challenge. There are a number of disease states associated with IBD, which are primary sclerosing cholangitis, cholangiocarcinoma and autoimmune hepatitis. There is a wide spectrum of hepatic injury that can occur from the agents used to treat IBD, such as acute or chronic hepatic injury directly attributable to the drugs used to treat IBD (e.g. sulfasalazine, mesalamine, thiopurines, methotrexate, TNF antagonists, quinolone antibiotics); liver toxicity from drugs used to treat complications of immunomodulators and TNF antagonists (e.g. isoniazid for treatment of reactivation tuberculosis), and exacerbation of underlying chronic viral hepatitis with infliximab and other TNF antagonists. Thiopurines are also associated with the development of hepatic vascular lesions, such as nodular regenerative hyperplasia and peliosis hepatic. In addition, biologics can be associated with the reactivation of underlying chronic viral hepatitis, mandating universal screening prior to initiation of TNF-alpha antagonist therapy.

Increased hepatic iron deposition resulting from treatment of chronic hepatitis C with ribavirin.

Increased levels of hepatic iron may impair the response of patients with chronic hepatitis C to treatment with interferon-alfa, but combination therapy with ribavirin has demonstrated efficacy in the treatment of hepatitis C. When used alone or with interferon-alfa, ribavirin may cause a dose-dependent reversible hemolytic anemia. We compared the extent and cellular localization of iron deposition in liver tissue from biopsy specimens obtained before and after 36 weeks of therapy with ribavirin or placebo for 59 patients with chronic hepatitis C. Paired slides were available for review from 26 ribavirin and 27 placebo recipients. Iron deposition was assessed using coded slides stained with Perls Prussian blue and was semi-quantitated in hepatocytes, Kupffer cells, and areas of fibrosis. The overall iron score fell by 0.96 in the placebo group and increased 1.69 in the ribavirin recipients. Iron was deposited mainly in hepatocytes; the hepatocyte iron score increased from 2.19 to 3.81 in the ribavirin group. The amount of iron staining in Kupffer cells declined in the placebo group and increased slightly in the ribavirin group. Iron changes in areas of fibrosis were minor and did not differ between groups. Increased total hepatic iron deposition occurred during a 9-month course of ribavirin. Ribavirin-associated hemolysis deposits iron preferentially in hepatocytes. This increased deposition of hepatic iron does not seem to affect the biochemical or histologic response to ribavirin therapy but may have implications for hepatocyte susceptibility to future injury.

Hepatotoxicity of antibiotics: a review and update for the clinician.

Collectively, the various classes of antibiotics are a leading cause of drug-induced liver injury (DILI). However, acute antibiotic-associated DILI can be difficult to diagnose, as the course of therapy is usually brief, and other confounding factors are often present. In addition to the broad clinicopathologic spectrum of hepatotoxicity associated with the antimicrobials, the underlying infectious disease being treated may itself be associated with hepatic dysfunction and jaundice. This review provides summarized information on several classes of antimicrobial agents, highlighting new agents causing DILI and updating information on older agents.