Bethesda, 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
The American Gastroenterological Association (AGA) is dedicated to the mission of advancing the science and practice of gastroenterology. Founded in 1897, the AGA is the oldest medical-specialty society in the United States. The AGA's 14,500 members include physicians and scientists who research, diagnose and treat disorders of the gastrointestinal tract and liver. On a monthly basis, the AGA publishes two highly respected journals, Gastroenterology and Clinical Gastroenterology and Hepatology. The AGA's annual meeting is Digestive Disease Week®, which is held each May and is the largest international gathering of physicians, researchers and academics in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery.

About Clinical Gastroenterology and Hepatology
The mission of Clinical Gastroenterology and Hepatology is to provide readers with a broad spectrum of themes in clinical gastroenterology and hepatology. This monthly peer-reviewed journal includes original articles as well as scholarly reviews, with the goal that all articles published will be immediately relevant to the practice of gastroenterology and hepatology. For more information, visit www.cghjournal.org.

http://www.eurekalert.org/pub_releases/2005-09/aga-mch083105.php

Can treating HCV prevent progression to cirrhosis?
Henry Bodenheimer, NYSGE, 29 August 2005

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:

Alcohol consumption is a modifiable cofactor which has been associated with more rapid progression of liver fibrosis. Although regular consumption of alcohol at levels more than 50gms of alcohol per day has been linked with rapid progression of disease, no safe level of alcohol consumption has been identified. It is wise therefore that patients with chronic hepatitis C infection avoid alcohol consumption.
A second factor associated with disease progression is fatty liver. Non-alcoholic fatty liver disease is increasingly recognized as a co-factor in disease progression in patients with various underlying liver conditions. This disorder is difficult to treat and pathogenesis may, in part, be related to insulin resistance associated with hyperlipidemia, diabetes and obesity. Hepatitis C infection itself, however, may contribute to lipid deposition within the infected liver. It is advisable that modifiable factors such as body weight, hyperlipidemia and insulin resistance be addressed and treated in patients with chronic hepatitis C infection.
A third factor which is not able to be modified but is associated with disease progression is the acquisition of HCV at an age greater than 40 years. Older patients appear to have more rapid progression of fibrosis than younger patients. Such information may be important in assessing prognosis and need for antiviral treatment.

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.

Join the debate! Click here to post your comments about this Soapbox Speech.

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

Castilla A, Prieto J, Fausto N. Transforming growth factors beta 1 and alpha in chronic liver disease. Effects of interferon alfa therapy. N Engl J Med1991; 324: 933-40.
Yano M, Kumada H, Kage M, et al. The long-term pathological evolution of chronic hepatitis C. Hepatology 1996: 23: 1334-40.
Poynard T, Dedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 1997; 349: 825-32.
Shiffman ML, Hofmann CM, Contos MJ, et al. A randomized, controlled trial of maintenance interferon therapy for patients with chronic hepatitis C virus and persistent viremia. Gastroenterology 1999; 117: 1164-72.

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	http://www.medscape.com/viewarticle/506626 August 31, 2005 Issues in Cirrhosis and Liver Transplantation CME Disclosures Tram T. Tran, MD Introduction Liver transplantation remains the only viable therapeutic option for acute and chronic liver failure. Excellent long-term outcomes have been achieved over the past 2 decades, with posttransplant survival rates approaching 90% at 1 year and 60% at 5 years.[1] Unfortunately, the continued limited availability of deceased donor organs as compared with the number of patients currently awaiting transplantation necessitates that gastroenterologists and hepatologists must try to effectively prevent and manage the common complications of cirrhosis in order to prolong survival until transplantation. The Model for End Stage Liver Disease (MELD) allocation system, now in place for 3 years, has proven to be an effective predictor of mortality in those patients with decompensated cirrhosis.[2] Research presented on end-stage liver disease and transplantation during this year's Digestive Disease Week (DDW) meeting explored new developments in the management of complications of chronic liver disease, such as gastrointestinal bleeding, spontaneous bacterial peritonitis, hepatocellular carcinoma, MELD score utility, and posttransplant management. Issues in Cirrhosis and Liver Transplantation Decompensation of Cirrhosis Because waiting times may approach months to years for some patients awaiting liver transplant, the management of common known complications of cirrhosis and portal hypertension is paramount to the survival of patients. D'Amico and colleagues[3] reported the outcome of 494 consecutive patients with newly diagnosed cirrhosis at their center who were followed for evidence of decompensation in the form of ascites, bleeding, encephalopathy, jaundice, or hepatocellular carcinoma. The majority of these patients had hepatitis C infection, and 117/494 (24%) had decompensation at the time of inclusion into the study. During the study period of 25 years, 63% of those patients who were compensated eventually developed decompensation. Ten-year actuarial survival for decompensated vs compensated cirrhosis was 7% vs 63%, respectively, and cumulative survival rates at 2, 5, and 10 years for decompensated cirrhotics were 50%, 31%, and 14%. Of patients who died, 43% died at the time of the first decompensation. This study highlights that although a cirrhotic patient may remain stable for a long period of time, once an event occurs signaling decompensation of liver function, referral to a transplant center should be done in a timely fashion, because mortality dramatically increases thereafter. Ascites First-line management of ascites in the cirrhotic patient entails dietary sodium restriction and judicious use of diuretics as tolerated by renal function. Although still somewhat controversial, the use of transjugular intrahepatic portosystemic shunting (TIPS) has been used in refractory ascites that is not responsive to maximal diuretic dosages. Peritovenous shunting is rarely performed as risks of infection and malfunction are high. Large-volume paracentesis is a viable option for patients intolerant or refractory to diuretics, but should not be first line. The pathophysiology of TIPS seems to be a reduction in sinusoidal portal pressure resulting in a fall in the plasma renin activity and serum aldosterone levels, a rise in renal blood flow and glomerular filtration rate, and associated naturesis and diuresis.[4] Probability for 1-year survival without transplant in 1 cohort after TIPS was 69% compared with 52% in a non-TIPS large-volume paracentesis group.[5] However, risks include worsened hepatic encephalopathy, hepatic decompensation, and stent occlusion or malfunction. Measurement of hepatic venous pressure gradient (HVPG) has been suggested as a means of monitoring degree of portal hypertension for risk of recurrent variceal bleeding secondary to esophageal varices. Campbell and colleagues[6] examined the measurement of HVPG after TIPS to determine the correlation with recurrent ascites. Fifty-two patients who had TIPS for refractory ascites were followed for recurrent ascites. Twenty-two of 52 patients (42%) developed recurrent ascites requiring large-volume paracentesis, and hepatic venous pressure measurements were obtained showing mean HVPG of 12 mmHg for patients with recurrent ascites compared with 10 mmHg in the non-recurrent group (P = .45). Sodium, MELD score, volume of paracentesis, and percent change in HVPG after TIPS did not predict recurrent ascites. Further detailed analysis of this patient population may yield other influencing factors in recurrent ascites, such as rapidity of diuretic withdrawal, patient dietary compliance after TIPS, and TIPS stenosis, but etiology may be multifactorial. Additional data are emerging on the use of TIPS for this indication, but at this time, only the carefully selected patient should be considered for TIPS. Spontaneous Bacterial Peritonitis Spontaneous bacterial peritonitis (SBP) occurs in cirrhotic patients with ascites and is usually due to infection with enteric gram-negative organisms. A high morbidity and mortality is associated with SBP, with one third of patients admitted for SBP dying from gastrointestinal bleeding, liver failure, or hepatorenal syndrome[7]; renal failure develops in 30% to 40% of these patients even with control of the infection. SBP can also occur more often after gastrointestinal bleeding. During this year's DDW meeting, Planas and colleagues[8] reported the results of a randomized multicenter controlled trial comparing oral norfloxacin with intravenous ceftriaxone in decompensated cirrhotics for prophylaxis after gastrointestinal bleeding. They randomized patients to receive either norfloxacin 400 mg orally twice daily for 7 days (n = 55) or ceftriaxone 1 g intravenously for 7 days (n = 53). They found that the group receiving ceftriaxone had a lower probability of developing all bacterial infections than the oral norfloxacin group (11% vs 27%; P = .02). The types of bacterial infections included pneumonia, urinary tract infections, and SBP. It appeared that patients with more severe gastrointestinal bleeding, and those who already had been on norfloxacin prophylaxis, were at increased risk for acute bacterial infection. Patients admitted for gastrointestinal bleeding are clearly at increased risk for a host of complications, including infections. The role of antibiotic prophylaxis in these high-risk patients has been recommended, but the routine use of intravenous antibiotics needs further study as the development of more resistant bacterial strains needs to be considered. Hepatic Encephalopathy Portosystemic encephalopathy (PSE) is a common complication of cirrhosis, and can present mildly with only minimal symptoms such as memory loss, irritability, and an altered sleep-wake cycle, or more severely with deep somnolence or coma. It is important that when a patient presents with PSE underlying risk factors be ruled out, including infections, gastrointestinal bleeding, and medications that may precipitate encephalopathy, such as benzodiazepines. The mechanism underlying PSE is not clearly understood, but is believed to be partly due to hyperammonemia. PSE can often be controlled with the administration of lactulose, a nonabsorbable disaccharide that acts by several different mechanisms, including acidification of the gut lumen, leading to ammonia being converted into ammonium (NH4+), which is less membrane-permeable. Lactulose also acts as an osmotic agent, decreasing intestinal transit time. Other agents used in the management of PSE include nonabsorbable antibiotics such as neomycin, although its long-term use may be limited by nephrotoxicity because it has some systemic absorption and ototoxicity. Administration of ornithine, which is a substrate for urea, has been explored as a treatment for PSE because it may increase the conversion of ammonia to urea. Mumtaz and colleagues[9] reported the results of a randomized study assessing the benefit of intravenous L-ornithine L-aspartate in patients with PSE. Patients admitted with PSE were randomized to receive either L-ornithine L-aspartate 20 g per day (n = 50) intravenously or placebo for 4 consecutive days. Measurement of PSE stage, the number connection test, serum ammonia level, length of hospital stay, and mortality were recorded. In this study, all of the reported measures of PSE were improved with L-ornithine L-aspartate compared with placebo, with no reported change in mortality or side effects related to the drug. Unfortunately, difficulty in defining and diagnosing PSE hampers the ability to really assess therapeutic benefits in this setting. Attempts to use quantifiable measures, such as serum ammonia levels, are not readily applicable, because serum ammonia is not well correlated to severity of encephalopathy. Additionally, this study compared L-ornithine L-aspartate with placebo, not lactulose, which would be considered the current standard of care; thus, further studies are needed at this time. Gastrointestinal Bleeding Upper gastrointestinal bleeding (UGIB) is often the first and most dramatic presentation in a patient with cirrhosis. Mortality can approach 50% with an upper gastrointestinal bleed from esophageal or gastric varices. Secondary prevention of UGIB with nonselective beta-blockers (such as propranolol) should be considered in patients with a history of upper gastrointestinal hemorrhage. The use of TIPS is reserved for patients with UGIB that is not controlled with endoscopic management, but it carries risk of worsened encephalopathy or hepatic decompensation. The especially difficult bleeding patient is one with gastric varices, which are difficult to manage with traditional variceal band ligation or injection sclerotherapy. Seewald and colleagues[10] reported the use of tissue glue N-butyl-2-cyanoacrylate (CA)* in 131 patients with gastric fundal UGIB. They used a mixture of CA and lipiodol, and restricted the amount injected to 1.0 mL into a varix at one time to reduce risk of embolism; endoscopy was repeated at 4 days with repeat CA injection until obliteration of the varices. Rebleeding-free rates at 1 and 3 years were 94% and 89%, respectively. No embolism occurred in this study. This study is promising, and shows that in experienced hands, CA may be a "last ditch" lifesaving option; however, with the published risk of cerebral and pulmonary embolism, and lack of US FDA approval, cyanoacrylate will probably not be widely available to the clinician. Hepatocellular Carcinoma Hepatocellular carcinoma is an indication for liver transplantation, but only within set criteria that have yielded good survival and recurrence-free survival compared with nonhepatocellular carcinoma transplant indications. Mazzaferro and colleagues[11] published the current standard criteria for liver transplant in patients with hepatocellular carcinoma, the so-called "Milan criteria" also adopted by the United Network for Organ Sharing (UNOS), which are as follows: 1 lesion, not greater than 5 centimeters in diameter, or 3 lesions or fewer, none greater than 3 centimeters. With these criteria, overall 4-year survival was 75%. Yao and colleagues[12] have recently published University of California, San Francisco (UCSF) guidelines proposing expansion of these criteria (single lesion not greater than 6.5 cm, or 2 or 3 lesions, none greater than 4.5 cm with total tumor diameter less than 8 cm) with good outcomes. With the risk of tumor growth and metastasis and the current long waiting times for transplant, treatment of lesions with bridging modalities such as percutaneous ethanol injection, radiofrequency ablation, and chemoembolization, have become fairly common at transplant centers. In their analysis of more than 3700 patients with hepatocellular carcinoma, Johnson and colleagues[13] found that more patients are now undergoing local ablative therapies and transplant than previously, and fewer patients are having hepatic resection. During this year's DDW meeting, Yao and colleagues[14] reported on the impact of degree of tumor necrosis (as a marker of response to locoregional treatments) on tumor recurrence in 172 liver transplant recipients. Five-year recurrence-free probability was 93% for patients with > 60% necrosis of tumor on explant vs 83% for patients with < 60% necrosis (P = .027). Tumor necrosis > 60% was also associated with a significantly better 5-year recurrence-free probability in patients exceeding the Milan criteria (83% vs 63%; P = .46). The study authors concluded that pretransplant treatment of hepatocellular carcinoma that yields > 60% necrosis of the tumor may be associated with lower risk of recurrence. This study adds to the growing body of evidence that preoperative locoregional treatment of hepatocellular carcinoma, in carefully selected patients, is a viable option while awaiting transplantation, and may result in better short-term (getting the patient to transplant) and long-term (less recurrence) outcomes. Acute Liver Failure Acute liver failure is manifest by jaundice, coagulopathy, and encephalopathy within 26 weeks, and carries a high mortality (> 80%) without transplant. The US Acute Failure Study Group led by Lorenzo Rossaro published their study results investigating the prognostic value of the MELD score in 729 adult patients with acute liver failure.[15] Although they found that a MELD score of < 30 (negative predictive value 82%) may predict spontaneous survival, a high MELD score did not predict poor outcome well. Taylor and colleagues[16] analyzed 29 patients with acute liver failure secondary to acute hepatitis A, and reported a 45% death or transplant rate. Factors associated with poor outcome were sex (male), low alanine amino transferase (ALT) and alkaline phosphatase levels, and higher serum creatinine. The study authors then developed a 4-variable index for predicting poor prognosis using any 2 out of 4 criteria upon admission to yield a positive predictive value of 86% and negative predictive value of 93%: creatinine > 2.0 mg/dL, ALT < 2600 IU/mL, use of pressors, or intubation. This group also reported the outcome in patients who had acute liver failure secondary to hepatic ischemia and as would be expected, cardiopulmonary disease and hypotension were identified risk factors.[17] Mortality rate in this group was 34%, and renal function again played a role in prognosis. Early prediction of which patients will require transplantation is still a difficult and elusive clinical task, and will require further study. Viral Hepatitis in the Cirrhotic Patient Treatment of hepatitis C with interferon has been relatively contraindicated in patients with a history of decompensated cirrhosis due to the risk of hepatic decompensation, poor tolerability, and low success rates. Everson and colleagues[18] published their experience treating 102 patients with decompensated cirrhosis (mean Child-Pugh score 7) with combination interferon and ribavirin therapy using the low but accelerating dose regimen (LADR). Sustained virologic response was achieved in 22% of patients; however, most important, those patients with sustained virologic response prior to transplantation did not have recurrent hepatitis C virus infection, which is normally universal in the posttransplant hepatitis C patient. Kaiser and colleagues[19] investigated the role of consensus interferon* in Child-Pugh class A and B patients using a protocol starting at 9 micrograms (mcg) 3-times weekly for 6 weeks, followed by 9 mcg daily, then adding ribavirin at escalating dosages, increased as tolerated to weight-based dosing. Low platelet counts required dose reduction in 31% of the 58 patients treated, and growth factors were used for anemia and neutropenia. Sustained virologic response rates were 45% overall, and were highest in the early (Child-Pugh class A) cirrhotic patient compared with the patients with Child-Pugh class B disease. Given the difficulties of posttransplant recurrent hepatitis C, more aggressive treatment is being attempted in the carefully selected cirrhotic patient -- but these patients should undergo therapy in clinical trials or at centers with extensive experience with treatment availability of liver transplantation. Concluding Remarks The continuing shortage of available donor organs for liver transplantation fuels the necessity for vigilance in the management of the patient with cirrhosis. Prevention of infection, control of ascites, effective endoscopic management of gastrointestinal bleeding, treatment of viral hepatitis, and surveillance and treatment of hepatocellular carcinoma are all important clinical goals. *The US Food and Drug Administration has not approved this medication for this use. References 2004 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1999-2001. Rockville, Md: HHS/HRSA/SPB/DOT; UNOS; URREA. Wiesner R, Edwards E, Freeman R, et al, and the United Network for Organ Sharing Liver Disease Severity Score Committee. The model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology. 2003;124:91-96. D'Amico G, Pasta L, D'Amico M, et al. Decompensation of cirrhosis: a 25-year inception cohort study. Gastroenterology. 2005;128(suppl 2):A-A686. [Abstract 187] Wong F, Sniderman K, Liu P, Allidina Y, Sherman M, Blendis L. Transjugular intrahepatic portosystemic stent shunt: effects on hemodynamics and sodium homeostasis in cirrhosis and refractory ascites. Ann Intern Med. 1995;122:816-822. Rossle M, Ochs A, Gulberg V, et al. A comparison of paracentesis and transjugular intrahepatic portosystemic shunting in patients with ascites. N Engl J Med. 2000;342:1701-1707. Campbell MS, Clark TW, Sanyal AJ, et al. Hepatic venous pressure gradient does not correlate with recurrent ascites after transjugular intrahepatic portosystemic shunting. Gastroenterology. 2005;128(suppl 2):A-687. [Abstract 190] Nasava M, Rodes J. Management of ascites in the patient with portal hypertension with emphasis on spontaneous bacterial peritonitis. Semin Gastrointest Dis, 1997;8:200-209. Planas R, Fernandez J, Ruiz L, et al. Randomized, multicenter, controlled trial comparing oral norfloxacin vs intravenous ceftriaxone in the prevention of bacterial infections in cirrhotics with severe liver failure and gastrointestinal bleeding. Gastroenterology. 2005;128(suppl 2):A-687. [Abstract 191] Mumtaz K, Abid S, Abbas Z, et al. Efficacy of infusion of L-ornithine L-aspartate in cirrhotic patients with portosystemic encephalopathy: a placebo controlled study. Gastroenterology. 2005;128(suppl 2):A-688. [Abstract 192] Seewald S, Naga M, Omar S, et al. Standardized Injection technique and regimen minimizes complication and ensures safety of N-butyl-2-cyanoacrylate injection for the treatment of gastric fundal varices. Gastrointest Endoscp. 2005;61. [Abstract 372] Mazzaferro JW, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996; 34:693-699. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size does not adversely impact survival. Hepatology. 2001;33:1394-1403. Johnson EW, Jensen CC, Yeung R, et al. Population trends in use and outcome of surgical treatments for primary liver cancer. Gastroenterology. 2005;128 suppl 2:A-690. [Abstract 232] Yao FY, Ferrell LD, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: the impact of the degree of tumor necrosis from pre-operative loco-regional therapy on recurrence. Gastroenterology. 2005;128(suppl 2):A-689. [Abstract 231] Rossaro L, Chambers CC, Polson J, et al. Performance of MELD in predicting outcome in acute liver failure. Gastroenterology. 2005;128(suppl 2):[Poster S1492] Taylor R, Fontana R, Bass NM, et al. A novel 4 variable index is superior to King's College Criteria in identifying non-survivors with acute liver failure due to hepatitis A. Gastroenterology. 2005;128(suppl 2):A-706. [Poster S1494] Taylor R, Fontana R, Shakil A, et al. Acute liver failure due to ischemic hepatitis: Natural history and predictors of outcome in a prospective, multi-center U.S. study. Gastroenterology. 2005;128(suppl 2):A-706. [Poster S1495] Everson GT, Trotter JF, Kugelmas M. Long-term outcome of patients with chronic hepatitis C and decompensated liver disease treated with the LADR protocol [low-accelerating-dose-regimen]. Hepatology. 2002;36:297A Kaiser S, Hass H, Gregor M. Treatment of chronic hepatitis C patients with Child A and B cirrhosis with a low ascending daily dosing regimen with consensus interferon and ribavirin results in significant viral eradication rates. Gastroenterology. 2005;128(suppl 2):A-714. [Poster S1534]

Peginterferon Alfa-2b Plus Ribavirin Elicits Sustained Response in Decompensated HCV Patients
- A report on data presented at the conference

Prospective, single-arm, open-label study

Summary of Key Conclusions

Combination therapy with peginterferon alfa-2b plus ribavirin elicited antiviral responses in a significant minority of decompensated HCV patients
- 32% achieved sustained virologic response (SVR)
Dose reduction required to manage toxicity in approximately 50% of patients
- Most required peginterferon dose reduction for neutropenia
Rate of treatment discontinuation low at 10%

Background

HCV therapy trials have largely excluded patients with advanced disease
- Antiviral therapy presumed poorly tolerated in decompensated patients
Limited evidence for use of peginterferon plus ribavirin in such patients
Current study evaluated use of combination therapy in HCV patients with decompensated cirrhosis

Summary of Study Design

31 decompensated cirrhotic patients treated with peginterferon and ribavirin
- Peginterferon alfa-2b 1.5 µg/kg weekly
- Ribavirin 10.6 mg/kg daily
Treatment for 24 or 48 weeks, dependent on genotype and early virologic response (EVR)
Outcomes
- Virologic response
  - Early
  - End of treatment
  - Sustained
- Treatment adherence and dosing changes

Baseline Characteristics

31 subjects
- Age, 37-73 years
- Male, 52%
- Genotype 1a/1b, 61%
All subjects clinically advanced with history of decompensation
- Mean model for end-stage liver disease (MELD) score, 9.9
- Mean Child-Pugh score, 7.6
- Mean platelet count, 111 x 10⁹ IU/L
- Mean neutrophil count, 2.4 x 10⁹ IU/L
- Mean hemoglobin, 13.8 g/dL
- Ascites, 35%
- Varices, 29%
- Coagulopathy, 23%
- Jaundice, 16%
- Spontaneous bacterial peritonitis, < 1%
- Hepatic encephalopathy, 0%

Main Findings

32% of decompensated HCV patients treated with peginterferon plus ribavirin obtained SVR
Dose reduction required to manage toxicity in approximately 50%
- Peginterferon dose reduction
  - Neutropenia, n = 11
  - Thrombocytopenia, n = 4
- Ribavirin dose reduction
  - Anemia, n = 2
Few treatment discontinuations
- Hepatic encephalopathy, n = 2
- Cytopenia, n = 1

Outcome	Response Rate, % (N = 31)
EVR	48
End-of-treatment response	39
SVR	32
No virologic response	42
Virologic breakthrough or relapse	16
Treatment discontinuation	10

Reference

Annicchiarico BE, Siciliano M, Franceschelli A, Milani A, Bombardieri G. Safety and efficacy of combination therapy with 12KD pegylated interferon and ribavirin for chronic hepatitis C virus infection in decompensated cirrhotics. Program and abstracts of the 40th Annual Meeting of the European Association for the Study of the Liver; April 13-17, 2005; Paris, France. Abstract 546.

http://clinicaloptions.com/hep/conf/easl2005/cs/546.asp

Accelerating regimen of interferon plus ribavirin reduces post-transplantation HCV relapse

By Jillian L. Lokere, MS

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/ìL, 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 ìg/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.

http://clinicaloptions.com/hep/news/news_imed_389.asp

Noninvasive predictive model for HCV cirrhosis has high specificity and sensitivity

By Jillian L. Lokere, MS

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.

http://clinicaloptions.com/hep/news/news_imed_388.asp

Predicting Cirrhosis in Patients with Hepatitis C Based on Use of Standard Laboratory Tests

Knowledge of the presence of cirrhosis is important for the management of patients with chronic hepatitis C (CHC). Most models for predicting cirrhosis were derived from small numbers of patients and included subjective variables or laboratory tests that are not readily available.

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
A S Lok and others. Predicting cirrhosis in patients with hepatitis C based on standard laboratory tests: Results of the HALT-C cohort. Hepatology 42(2): 282-292. August 2005.

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.

Overview

The 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 Evidence

Specifically, 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.

Methodology

Search Strategy

Eleven 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 Criteria

Preliminary 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 Analysis

Abstractors (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.

Findings

Mechanisms of Action

Evidence 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 Thistle

The 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 Effects

Adverse 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.

Conclusions

Clinical 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 Research

The 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 Report

The 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

Source
Milk Thistle: Effects on Liver Disease and Cirrhosis and Clinical Adverse Effects. Summary, Evidence Report/Technology Assessment: Number 21, September 2000. Agency for Healthcare Research and Quality, Rockville, MD. www.ahrq.gov/clinic/epcsums/milktsum.htm

Reviewed Sep 02 2005