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Cirrhosis
Most chronic hepatitis C sufferers will develop cirrhosis in later lifeStudy suggests cirrhosis and liver disease nearly inevitable for people with hep CBethesda, Maryland (Sept. 1, 2005) – Nearly 80 percent of chronic hepatitis C sufferers who have the disease for several decades will develop cirrhosis or end-stage liver disease later in life, according to a study published today in the American Gastroenterological Association (AGA) journal Clinical Gastroenterology and Hepatology. Researchers found that it is highly likely that people who are infected with hepatitis C (HCV) for more than 60 years will develop cirrhosis--the highest rate of hepatitis C-associated cirrhosis reported to date. Hepatitis C is a virus that affects the liver and is spread primarily by contact with blood and blood products in transfusions and among drug users who share needles. Other common routes of transmission are infants born to HCV-infected mothers, tattoos and body piercings and risky sexual behavior. Of those who are infected, more than 80 percent will be chronic carriers of the disease. HCV can cause long-term scarring of the liver and usually presents with mild and non-specific symptoms, if any. They include fatigue, nausea, poor appetite and muscle and joint pain. It is estimated that more than 4 million Americans are now infected with HCV (more than 170 million people worldwide) and nearly 10,000 Americans die from the disease each year. "Hepatitis C begins generally as a silent acute infection, with a fraction of the patients developing cirrhosis, end-stage liver disease or liver cancer," according to an editorial appearing in this month's journal. "Although this is a generally accepted scenario in persons infected with HCV, there remains uncertainty about the true frequency of evolution of liver disease and its rate of progression." According to results of the study from researchers at the Queen Mary's School of Medicine and Dentistry in London, the prevalence of cirrhosis in patients with chronic HCV increases with the duration of the disease. Nearly 80 percent of Asian patients who were infected at birth and lived with the disease for 60 years or more developed cirrhosis--a finding that researchers say can be applied to the general population because of the similarity in the way the disease progresses in all ethnic groups. "This study suggests that prolonged infection with hepatitis C leads to cirrhosis in the majority of those who are infected," said Graham R. Foster, PhD, FRCP, study author and professor of hepatology at Queen Mary's School of Medicine and Dentistry in London. "While previous studies have found differences in disease progression in various ethnic groups, our findings confirm that fibrosis progression is the same across these groups and leads to development of cirrhosis and liver disease at the same rate in everyone." Researchers conducted retrospective analyses of 382 patients diagnosed with hepatitis C at three hospitals in northeast London between 1992 and 2003. Study participants were divided into two groups: Asian patients presumably infected in childhood and Caucasian patients. While the prevalence of cirrhosis in Caucasian patients was similar to the findings of previous studies, the statistics in Asians were markedly higher than previously found. The higher prevalence was partially attributed to the longer duration of HCV in the Asian patient population, those patients having suffered with the disease nearly 30 years more than the Caucasian subjects.
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This study was funded by local investigators and an unrestricted research grant from Roche Pharmaceuticals. For more information on hepatitis C, visit www.gastro.org. About the AGA About Clinical Gastroenterology and Hepatology http://www.eurekalert.org/pub_releases/2005-09/aga-mch083105.php
Can treating HCV prevent progression to cirrhosis? Hepatic fibrosis is a progressive insult responsible for morbidity and mortality in chronic hepatitis C infection. Thierry Poynard in his 1999 paper in Hepatology analyzed a large data set of liver biopsies in patients with hepatitis C and suggested that liver fibrosis progression was not uniform in individuals infected with hepatitis C. Some individuals appear to progress slowly while others rapidly progressed to cirrhosis. This dichotomy is perhaps most widely recognized in patients who have under gone liver transplantation. Patients with recurrent hepatitis C following transplant may develop cirrhosis in as short an interval as 4 to 5 years while progression to cirrhosis in a non-transplant setting typically takes 2, 3 or more decades. Multiple factors have been identified as contributing to progression of fibrosis in hepatitis C. Three of the factors identified deserve highlighting:
A major question is whether liver fibrosis is reversible. Patients with established fibrous septa have shown gradual resolution of fibrosis with years of effective control of viral replication. The question remains, whether decrease in hepatic fibrosis in patients undergoing treatment for hepatitis C is a direct result of anti-fibrotic effect of alpha interferon, or is the beneficial effect a consequence of viral control. A recent report by Poynard in Gastroenterology 2002, addressed this question. Greater than 80% of liver biopsies evaluated in patients with sustained virologic response showed improved fibrosis while less than 10% showed a worsening. In contrast, less than 34% of individuals who showed non-response to interferon showed improvement in fibrosis while more than 20% showed a worsening. Such data suggest that the primary mechanism by which fibrosis is diminished in patients treated with alpha interferon is through control of viral replication . In summation, chronic hepatitis C infection is an epidemic infection leading to chronic liver injury with hepatocyte necrosis subsequent inflammation and stimulation of hepatic fibrosis. This chronic process gradually leads to cirrhosis. Fortunately, with control of viral replication modulation of the intercellular matrix is possible and alpha interferon treatment regimens generating sustained virologic response are associated with improvement in hepatic fibrosis and even resolution of cirrhosis. In the future, assessment of hepatic fibrosis may be possible with non invasive assays and direct anti-fibrotic therapy maybe available to be coupled with inhibitors of viral replication to maximize the resolution of hepatic injury.
This "Soapbox" was published as part of the syllabus for the New York Society for Gastrointestinal Endoscopy 27th Annual Postgraduate Course - Endoscopic Decision Making 2003, held in New York, NY. 15 and 16 December 2003. See the NYSGE website.
References
http://clinicaloptions.com/hep/conf/easl2005/cs/546.asp
August 1, 2005 — In a pilot study, a low accelerating dose regimen (LADR) of interferon plus ribavirin produced a sustained virologic response (SVR) in one quarter of patients with advanced liver disease due to HCV infection, and those patients who achieved SVR before liver transplantation tended to remain HCV-negative posttransplant. Patients with advanced liver disease from HCV infection are candidates for liver transplantation, but HCV often recurs afterwards and can lead to cirrhosis and graft loss. Achieving SVR before transplantation is desirable; however, traditional regimens of interferon or peginterferon plus ribavirin are difficult to maintain in cirrhotic patients. In this study, Everson and colleagues tested the efficacy of a LADR of interferon plus ribavirin. Eligible patients had either biopsy-proven cirrhosis or obvious clinical complications of cirrhosis such as ascites, spontaneous bacterial peritonitis, varices, or encephalopathy. Fourteen patients with bridging fibrosis on biopsy who had either abnormal bloodwork (platelet count of less than 100,000/ěL, bilirubin greater than 3.0 mg/dL, a prothrombin international normalized ratio (INR) greater than 1.2, albumin less than 3.0 g/dL) or intraabdominal collaterals or splenomegaly on radiologic imaging were also included. Patients were required to abstain from alcohol and controlled substances. Those with refractory ascites, renal failure, ongoing gastrointestinal bleeding, refractory encephalopathy, extensive hepatoma, or severe intolerance to or neuropsychiatric complications with prior courses of interferon or ribavirin were excluded. Patients who had failed a full course of previous interferon plus ribavirin were also excluded. A total of 124 patients were enrolled in the study. Initially, most patients (119) received interferon alfa-2b 1.5 MU 3 times a week plus ribavirin 600 mg daily. Five patients received peginterferon alfa-2b 0.5 ěg/kg once weekly plus ribavirin. The dose was then adjusted for each patient individually every 2 weeks until the patient reached the target standard dose or a maximally tolerated dose. Some patients required lowered dosages or shortened treatment times or both. LADR was modestly effective, and was able to be tolerated by the majority of the cohort. At the end of treatment, 46% of patients achieved HCV RNA negativity, 41% were nonresponders, and 13% discontinued treatment due to adverse events. Of those who were HCV RNA negative at the end of treatment, 47% maintained the response at 6 months post treatment, while the rest relapsed, giving an SVR rate of 22%. An additional 3 patients achieved SVR after either liver transplantation or retreatment with peginterferon plus ribavirin, bringing the overall SVR to 24%. SVR was associated with non-genotype 1, full course and duration of therapy, and HCV RNA negativity at week 24. Adverse events were common, and patients with genotype 1 infection and more advanced disease experienced the most. Twenty-two serious adverse events occurred in 15 patients, including infection, worsening ascites, encephalopathy, gastrointestinal bleeding, diabetes mellitus, severe thrombocytopenia, venous thrombosis with pulmonary embolus, and culture-negative pneumonitis. There were 4 deaths, of which the investigators considered 2 to be attributable to treatment complications (venous thromboembolism and staphylococcal sepsis). LADR was also beneficial in the long-term for some patients awaiting transplantation. A total of 90 patients in this study were listed for liver transplantation, and 47 underwent the procedure. Of these, 15 patients were HCV RNA negative before transplantation. Twelve of the 15 remained HCV RNA negative 6 months after transplantation. All of the patients who were HCV RNA positive before transplantation relapsed after transplantation. The investigators wrote, "Despite use primarily of nonpegylated interferon, and conservative application of growth factors. . . the [end of treatment response] was 30% and SVR 13% in patients with genotype 1 infection, but was 82% and 50% in patients with non-1 genotypes." They noted that the most important finding of their study was that those patients who achieved SVR before transplantation had a much higher chance of remaining HCV RNA negative posttransplantation. Although previous studies of antiviral therapy in patients with advanced disease have found prohibitively high levels of adverse events, the investigators in this study found the LADR protocol to be generally tolerable for the majority of patients, and they suggested that experienced clinicians might consider its use. References Everson GT, Trotter J, Forman L, et al. Treatment of advanced hepatitis C with a low accelerating dosage regimen of antiviral therapy. Hepatology. 2005;42:255-262.
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July 29, 2005 — A predictive model for cirrhosis in chronic hepatitis C that is based upon objective, widely-available laboratory tests appears to have a high degree of specificity, sensitivity, and predictive value, according to a large study. Approximately 25% of patients with chronic hepatitis C develop cirrhosis within 30 years of diagnosis. Once cirrhosis develops, screening for hepatocellular carcinoma (HCC), gastroesophageal varices, and hepatic decompensation becomes much more rigorous. Currently, liver biopsy is relied on to diagnose cirrhosis, but it is costly and painful. Although other predictive models of cirrhosis based on laboratory findings and imaging studies have been tested, none have been validated, nor have they been based on objective, routinely available laboratory test results. Here, Lok and colleagues analyzed data from the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) trial in order to develop such a model. HALT-C is a large, prospective, randomized, controlled study of the effects of long-term peginterferon therapy on progression to cirrhosis, decompensated liver disease, and HCC in patients with chronic hepatitis C. The eligibility criteria for HALT-C were serum positivity for antibodies to HCV and HCV RNA, failure to respond to standard interferon treatment with or without ribavirin, and bridging fibrosis or cirrhosis as diagnosed by a liver biopsy within 12 months of study entry. Patients with coexisting liver disorders or hepatic decompensation were excluded. At baseline, a complete history, physical examination, assessment of lifetime alcohol consumption, abdominal ultrasound, laboratory tests, and liver biopsy were conducted. The laboratory tests included complete blood count, liver panel, basic metabolic panel, prothrombin time/international normalized ratio (INR), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, alpha-fetoprotein, HCV genotype, quantitative HCV RNA level, thyroid-stimulating hormone and tests to exclude other causes of liver disease. Lok and colleagues examined the data from 1141 patients in the HALT-C trial, of whom 38% had cirrhosis. These patients were randomly divided into a training group (783 patients) and a validation group (358 patients). The investigators first conducted univariate chi-square and t-test analyses on the data from patients in the training group in order to identify variables that were significantly different between patients with and without cirrhosis. From there, all the significant variables were entered in a logistic regression model with backward selection. Predictive models for cirrhosis were then generated from the variables that remained in the final logistic regression model, and the performance of each predictive model was analyzed by constructing receiver-operating characteristic (ROC) curves. The 8 best predictive models were then tested for validity using the data from the validation group. The investigators found that the most predictive model relied on platelet count, AST/ALT ratio and INR. The regression formula and the formula to calculate predicted probability can be found on the HALT-C Trial website (http://www.haltctrial.org). Using a predicted cutoff value of less than 0.2 to exclude cirrhosis and greater than 0.5 to diagnose cirrhosis, the model misclassified only 7.8% of patients with cirrhosis as noncirrhotic and misclassified 14.8% of patients without cirrhosis as actually having cirrhosis. Half of the patients fell between the 2 cutoffs and could not be classified. The investigators next tested their model on a cohort of patients who were not in the HALT-C trial. Of the 40 treatment-naive patients, the model misclassified 2.5% as noncirrhotic and 5.3% as cirrhotic. In this cohort, cirrhosis could be confidently excluded or diagnosed without resorting to a liver biopsy in 58% of the patients; the rest fell between the cutoff values and could not be classified. Lok and colleagues wrote that this model "could have distinguished between the presence and absence of cirrhosis with sufficient reliability to avoid a liver biopsy in half of our patients. Theoretically, application of this model in practice could be cost-saving and helpful in identifying patients with chronic hepatitis C who require surveillance for hepatocellular carcinoma and varices as well as closer monitoring during antiviral therapy." They called on other investigators to validate the predictive model. References Lok AS, Ghany MG, Goodman ZD, et al. Predicting cirrhosis in patients with hepatitis C based on standard laboratory tests: Results of the HALT-C cohort. Hepatology. 2005;42:282-292.
Predicting Cirrhosis in Patients with Hepatitis C Based on Use of Standard
Laboratory Tests
The aim of this study was to develop a predictive model of cirrhosis in patients with CHC based on standard laboratory tests. Data from 1,141 CHC patients including 429 with cirrhosis were analyzed. All biopsies were read by a panel of pathologists (blinded to clinical features), and fibrosis stage was determined by consensus. The cohort was divided into a training set (n = 783) and a validation set (n = 358). The area under the receiver-operating characteristic curve of the final model comprising platelet count, AST/ALT ratio, and INR in the training and validation sets was 0.78 and 0.81, respectively. A cutoff of less than 0.2 to exclude cirrhosis would misclassify only 7.8% of patients with cirrhosis, while a cutoff of greater than 0.5 to confirm cirrhosis would misclassify 14.8% of patients without cirrhosis. The model performed equally well in fragmented and non-fragmented biopsies and in biopsies of varying lengths. Use of this model might obviate the requirement for a liver biopsy in 50% of patients with CHC, according to the authors. Based on these results, the authors conclude, “A model based on standard laboratory test results can be used to predict histological cirrhosis with a high degree of accuracy in 50% of patients with CHC.” Commentary “Our model should perform well in clinical practice,” state the authors. However, they also note that the formula is complex, requiring access to a calculator or computer, which might not be available in a busy clinic. For this reason they have also included the model prediction according to convenient levels of platelet count, AST/ALT ratio, and INR. The resulting table provided predicted probabilities of cirrhosis that were close to the observed prevalence. “Thus these simple algorithms could be applied with a fair degree of accuracy in practice to make informed decisions regarding the need for a liver biopsy,” according to the authors. “In conclusion,” write the authors, “we demonstrated that a model based on a few standard laboratory tests can be used to predict histological cirrhosis with a high degree of accuracy in patients with CHC and advanced fibrosis. Relying on cutoff values of less than 0.2 and more than 0.5, we could have distinguished between the presence and absence of cirrhosis with sufficient reliability to avoid a liver biopsy in half of our patients.” “Theoretically, application of this model in practice could be cost-saving and helpful in identifying patients with CHC who require surveillance for hepatocellular carcinoma and varices as well as closer monitoring during antiviral therapy.” Finally, the authors emphasize, “Clearly, our model needs to be validated by other investigators. Our results and those of similar studies underscore the need for development of noninvasive methods that reflect histological findings in patients with all forms of chronic liver disease.” 07/18/05
Reference
http://www.hivandhepatitis.com/hep_c/news/2005/ad/071805_b.htm Milk Thistle: Effects on Liver Disease and Cirrhosis and Clinical Adverse Effects
Under its Evidence-based Practice Program, the Agency for Healthcare Research and Quality (AHRQ) is developing scientific information for other agencies and organizations on which to base clinical guidelines, performance measures, and other quality improvement tools. Contractor institutions review all relevant scientific literature on assigned clinical care topics and produce evidence reports and technology assessments, conduct research on methodologies and the effectiveness of their implementation, and participate in technical assistance activities. This evidence report details a systematic review summarizing clinical studies of milk thistle in humans. OverviewThe scientific name for milk thistle is Silybum marianum. It is a member of the aster or daisy family and has been used by ancient physicians and herbalists to treat a range of liver and gallbladder diseases and to protect the liver against a variety of poisons. Two areas are addressed in the report: · Effects of milk thistle on liver disease of alcohol, viral, toxin, cholestatic, and primary malignancy etiologies. · Clinical adverse effects associated with milk thistle ingestion or contact. The report was requested by the National Center for Complementary and Alternative Medicine, a component of the National Institutes of Health, and sponsored by the Agency for Healthcare Research and Quality. Reporting the EvidenceSpecifically, the report addresses 10 questions regarding whether milk thistle supplements (when compared with no supplement, placebo, other oral supplements, or drugs): · Alter the physiologic markers of liver function. · Reduce mortality or morbidity, or improve the quality of life in adults with alcohol-related, toxin-induced, or drug-induced liver disease, viral hepatitis, cholestasis, or primary hepatic malignancy (hepatocellular carcinoma). One question addresses the constituents of commonly available milk thistle preparations, and three questions address the common and uncommon symptomatic adverse effects of milk thistle. MethodologySearch StrategyEleven electronic databases, including AMED, CISCOM, the Cochrane Library (including DARE and the Cochrane Controlled Trials Registry), EMBASE, MEDLINE, and NAPRALERT, were searched through July 1999 using the following terms: · Carduus marianus. · Legalon. · Mariendistel. · Milk thistle. · Silybin. · Silybum marianum. · Silybum. · Silychristin. · Silydianin. · Silymarin. An update search limited to PubMed was conducted in December 1999. English and non-English citations were identified from these electronic databases, references in pertinent articles and reviews, drug manufacturers, and technical experts. Selection CriteriaPreliminary selection criteria regarding efficacy were reports on liver disease and clinical and physiologic outcomes from randomized controlled trials (RCTs) in humans comparing milk thistle with placebo, no milk thistle, or another active agent. Several of these randomized trials had dissimilar numbers of subjects in study arms, raising the question that these were not actually RCTs but cohort studies. In addition, among studies using non placebo controls, the type of control varied widely. Therefore, qualitative and quantitative syntheses of data on effectiveness were limited to placebo-controlled studies. For adverse effects, all types of studies in humans were used to assess adverse clinical effects. Data Collection and AnalysisAbstractors (physicians, methodologists, pharmacists, and a nurse) independently abstracted data from trials; a nurse and physician abstracted data about adverse effects. Data were synthesized descriptively, emphasizing methodologic characteristics of the studies, such as populations enrolled, definitions of selection and outcome criteria, sample sizes, adequacy of randomization process, interventions and comparisons, cointerventions, biases in outcome assessment, and study designs. Evidence tables and graphic summaries, such as funnel plots, Galbraith plots, and forest plots, were used to examine relationships between clinical outcomes, participant characteristics, and methodologic characteristics. Trial outcomes were examined quantitatively in exploratory meta-analyses that used standardized mean differences between mean change scores as the effect size measure. FindingsMechanisms of ActionEvidence exists that milk thistle may be hepatoprotective through a number of mechanisms: antioxidant activity, toxin blockade at the membrane level, enhanced protein synthesis, antifibriotic activity, and possible anti-inflammatory or immunomodulating effects. Preparations of Milk ThistleThe largest producer of milk thistle is Madaus (Germany), which makes an extract of concentrated silymarin. However, numerous other extracts exist, and more information is needed on comparability of formulations, standardization, and bioavailability for studies of mechanisms of action and clinical trials. Benefit of Milk Thistle for Liver Disease· Sixteen prospective trials were identified. Fourteen were randomized, blinded, placebo-controlled studies of milk thistle's effectiveness in a variety of liver diseases. In one additional placebo-controlled trial, blinding or randomization was not clear, and one placebo-controlled study was a cohort study with a placebo comparison group. · Seventeen additional trials used non placebo controls; two other trials studied milk thistle as prophylaxis in patients with no known liver disease who were starting potentially hepatotoxic drugs. The identified studies addressed alcohol-related liver disease, toxin-induced liver disease, and viral liver disease. No studies were found that evaluated milk thistle for cholestatic liver disease or primary hepatic malignancy (hepatocellular carcinoma, cholangiocarcinoma). · There were problems in assessing the evidence because of incomplete information about multiple methodologic issues, including etiology and severity of liver disease, study design, subject characteristics, and potential confounders. It is difficult to say if the lack of information reflects poor scientific quality of study methods or poor reporting quality or both. · Detailed data evaluation and syntheses were limited to the 16 placebo-controlled studies. Distribution of durations of therapy across trials was wide (7 days to 2 years), inconsistent, and sometimes not given. Eleven studies used Legalon®, and eight of those used the same dose. Outcome measures varied among studies, as did duration of therapy and the followup for which outcome measures were reported. · Among six studies of milk thistle and chronic alcoholic liver disease, four reported significant improvement in at least one measurement of liver function (i.e., aminotransferases, albumin, and/or malondialdehyde) or histologic findings with milk thistle compared with placebo, but also reported no difference between groups for other outcome measures. · Available data were insufficient to sort six studies into specific etiologic categories; these were grouped as chronic liver disease of mixed etiologies. In three of the six studies that reported multiple outcome measures, at least one outcome measure improved significantly with milk thistle compared with placebo, but there were no differences between milk thistle and placebo for one or more of the other outcome measures in each study. Two studies indicated a possible survival benefit. · Three placebo-controlled studies evaluated milk thistle for viral hepatitis. The one acute viral hepatitis study reported latest outcome measures at 28 days and showed significant improvement in aspartate aminotransferase and bilirubin. The two studies of chronic viral hepatitis differed markedly in duration of therapy (7 days and 1 year). The shorter study showed improvement in aminotransferases for milk thistle compared with placebo but not other laboratory measures. In the longer study, milk thistle was associated with a nonsignificant trend toward histologic improvement, the only outcome measure reported. · Two trials included patients with alcoholic or nonalcoholic cirrhosis. The milk thistle arms showed a trend toward improved survival in one trial and significantly improved survival for subgroups with alcoholic cirrhosis or Child's Group A severity. The second study reported no significant improvement in laboratory measures and survival for other clinical subgroups, but no data were given. · Two trials specifically studied patients with alcoholic cirrhosis. Duration of therapy was unclear in the first, which reported no improvement in laboratory measures of liver function, hepatomegaly, jaundice, ascites, or survival. However, there were nonsignificant trends favoring milk thistle in incidence of encephalopathy and gastrointestinal bleeding and in survival for subjects with concomitant hepatitis C. The second study, after treatment for 30 days, reported significant improvements in aminotransferases but not bilirubin for milk thistle compared with placebo. · Three trials evaluated milk thistle in the setting of hepatotoxic drugs: one for therapeutic use and two for prophylaxis with milk thistle. Results were mixed among the three trials. · Exploratory meta-analyses generally showed positive but small and nonsignificant effect sizes and a sprinkling of significant positive effects. · No studies were identified regarding milk thistle and cholestatic liver disease or primary hepatic malignancy. · Available evidence does not establish whether effectiveness of milk thistle varies across preparations. One Phase II trial suggested that effectiveness may vary with dose of milk thistle. Adverse EffectsAdverse effects associated with oral ingestion of milk thistle include: · Gastrointestinal problems (e.g., nausea, diarrhea, dyspepsia, flatulence, abdominal bloating, abdominal fullness or pain, anorexia, and changes in bowel habits). · Headache. · Skin reactions (pruritus, rash, urticaria, and eczema). · Neuropsychological events (e.g., asthenia, malaise, and insomnia). · Arthralgia. · Rhinoconjunctivitis. · Impotence. · Anaphylaxis. However, causality is rarely addressed in available reports. For randomized trials reporting adverse effects, incidence was approximately equal in milk thistle and control groups. ConclusionsClinical efficacy of milk thistle is not clearly established. Interpretation of the evidence is hampered by poor study methods and/or poor quality of reporting in publications. Problems in study design include heterogeneity in etiology and extent of liver disease, small sample sizes, and variation in formulation, dosing, and duration of milk thistle therapy. Possible benefit has been shown most frequently, but not consistently, for improvement in aminotransferases and liver function tests are overwhelmingly the most common outcome measure studied. Survival and other clinical outcome measures have been studied least often, with both positive and negative findings. Available evidence is not sufficient to suggest whether milk thistle may be more effective for some liver diseases than others or if effectiveness might be related to duration of therapy or chronicity and severity of liver disease. Regarding adverse effects, little evidence is available regarding causality, but available evidence does suggest that milk thistle is associated with few, and generally minor, adverse effects. Despite substantial in vitro and animal research, the mechanism of action of milk thistle is not fully defined and may be multifactorial. A systematic review of this evidence to clarify what is known and identify gaps in knowledge would be important to guide design of future studies of the mechanisms of milk thistle and clinical trials. Future ResearchThe type, frequency, and severity of adverse effects related to milk thistle preparations should be quantified. Whether adverse effects are specific to dose, particular preparations, or additional herbal ingredients needs elucidation, especially in light of equivalent frequencies of adverse effects in available randomized trials. When adverse effects are reported, concomitant use of other medications and product content analysis should also be reported so that other drugs, excipients, or contaminants may be scrutinized as potential causal factors. Characteristics of future studies in humans should include: · Longer and larger randomized trials. · Clinical as well as physiologic outcome measures. · Histologic outcomes. · Adequate blinding. · Detailed data about Systematic standardized surveillance for adverse effects. · Attention to specific study populations (e.g., patients with hepatitis B virus [HBV], or hepatitis C virus [HCV], or mixed infection or coinfection with human immunodeficiency virus [HIV]), comorbidities, alcohol consumption, and potential confounders. There also should be detailed attention to preparation, standardization, and bioavailability of different formulations of milk thistle (e.g., standardized silymarin extract and silybin-phosphatidylcholine complex). Precise mechanisms of action specific to different etiologies and stages of liver disease need explication. Further mechanistic investigations are needed and should be considered before, or in concert with, studies of clinical effectiveness. More information is needed about effectiveness of milk thistle for severe acute ingestion of hepatotoxins, such as occupational exposures, acetaminophen overdose, and amanita poisoning. Availability of Full ReportThe full evidence report from which this summary was derived was prepared by the San Antonio Evidence-based Practice Center based at The University of Texas Health Science Center at San Antonio and the Veterans Evidence-based Research, Dissemination, and Implementation Center (VERDICT), a Veterans Affairs Health Services Research and Development Center of Excellence under contract No. 290-97-0012. Printed copies may be obtained free of charge from the AHRQ Publications Clearinghouse by calling 800-358-9295. Requesters should ask for Evidence Report/Technology Assessment Number 21, Milk Thistle: Effects on Liver Disease and Cirrhosis and Clinical Adverse Effects (AHRQ Publication No. 01-E025). The Evidence Report is also online on the National Library of Medicine Bookshelf, or can be downloaded as a zipped file. 06/29/05
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Reviewed Sep 02 2005
