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Liver cirrhosis

Cirrhosis is a chronic disease of the liver in which liver tissue is replaced by connective tissue, resulting in the loss of liver function. Cirrhosis is caused by damage from toxins (including alcohol), metabolic problems, chronic viral hepatitis or other causes. Cirrhosis is sometimes referred to by its obsolete eponym Laennec's cirrhosis after René Laënnec. Cirrhosis is irreversible but treatment of the causative disease will slow or even halt the damage. more...

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Cirrhosis may refer to chronic interstitial inflammation of any tissue, but is rarely used for other diseases than cirrhosis of the liver.


Initial symptoms

Early symptoms include red palms, spider angioma (red spots on the upper body), hypertrophy of the parotid glands, and fibrosis of tendons in the hands. Clubbing may develop.

Many people with cirrhosis have no symptoms in the early stages of the disease. However, as scar tissue replaces healthy cells, liver function starts to fail and a person may experience the following symptoms:

  • exhaustion
  • fatigue
  • loss of appetite
  • nausea
  • weakness
  • weight loss
  • abdominal pain


As the disease progresses, complications may develop. In some people, these may be the first signs of the disease.

  • Bruising and bleeding due to decreased production of coagulation factors.
  • Jaundice due to decreased processing of bilirubin.
  • Itching due to bile products deposited in the skin.
  • Hepatic encephalopathy - the liver does not clear ammonia and related nitrogenous substances from the blood, which affect cerebral functioning: neglect of personal appearance, unresponsiveness, forgetfulness, trouble concentrating, or changes in sleep habits.
  • Sensitivity to medication due to decreased metabolism of the active compounds.
  • Hepatocellular carcinoma is primary liver cancer, commonly caused by cirrhosis. It has a high mortality rate.
  • Portal hypertension - blood normally carried from the intestines and spleen through the portal vein flows more slowly and the pressure increases; this leads to the following complications:
    • Ascites - fluid leaks through the vasculature into the abdominal cavity.
    • Esophageal varices - collateral portal blood flow through vessels in the stomach and esophagus. These blood vessels may become enlarged and are more likely to burst.
  • Problems in other organs. Cirrhosis can cause immune system dysfunction, leading to infection. Fluid in the abdomen (ascites) may become infected with bacteria normally present in the intestines (spontaneous bacterial peritonitis). Cirrhosis can also lead to impotence, kidney dysfunction and renal failure (hepatorenal syndrome) and osteoporosis.


Cirrhosis has many possible causes; sometimes more than one cause are present in the same patient. In the Western World, chronic alcoholism and hepatitis C are the most common causes.

  • Alcoholic liver disease (ALD). Alcoholic cirrhosis develops after more than a decade of heavy drinking in 15% of all alcoholics. There is great variability in the amount of alcohol needed to cause cirrhosis (3-4 drinks a day in some men and 2-3 in some women). Alcohol seems to injure the liver by blocking the normal metabolism of protein, fats, and carbohydrates.
  • Chronic hepatitis B (with or without D agent). The hepatitis B virus is probably the most common cause of cirrhosis worldwide, especially South-East Asia, but it is less common in the United States and the Western world. Hepatitis B causes liver inflammation and injury that over several decades can lead to cirrhosis. Hepatitis D is dependant on the presence of hepatitis B, but accelerates cirrhosis in co-infection.
  • Chronic hepatitis C. The hepatitis C virus ranks with alcohol as a major cause of chronic liver disease and cirrhosis. Infection with this virus causes inflammation of and low grade damage to the liver that over several decades can lead to cirrhosis.
  • Autoimmune hepatitis. This disease is caused by the immune system attacking the liver and causing inflammation, damage, and eventually scarring and cirrhosis.
  • Inherited diseases. These interfere with the way the liver produces, processes, and stores enzymes, proteins, metals, and other substances the body needs to function properly.
    • Alpha 1-antitrypsin deficiency
    • Hemochromatosis (iron accumulation)
    • Wilson's disease (copper accumulation)
    • Galactosemia
    • Glycogen storage diseases
    • Cystic fibrosis
  • Non-alcoholic steatohepatitis (NASH). In NASH, fat builds up in the liver and eventually causes scar tissue. This type of hepatitis appears to be associated with diabetes, protein malnutrition, obesity, coronary artery disease, and treatment with corticosteroid medications.
  • Diseases that lead to chronic obstruction of the bile ducts. Accumulated bile damages liver tissue:
    • In babies, blocked bile ducts are most commonly caused by biliary atresia, a disease in which the bile ducts are absent or injured.
    • In adults, the most common cause is primary biliary cirrhosis, a disease in which the ducts become inflamed, blocked, and scarred.
    • Secondary biliary cirrhosis can happen after gallbladder surgery if the ducts are inadvertently tied off or injured.
  • Drugs or toxins, including chronic use of acetaminophen.
  • Repeated bouts of heart failure with liver congestion.
  • Certain parasitic infections (like schistosomiasis).
  • "Cardiac cirrosis" (ICD-10 K76.1) is not a true cirrosis. It is more accurately referenced as "congestive hepatopathy", but the old name is still commonly used.


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Milk Thistle: Effects on Liver Disease and Cirrhosis and Clinical Adverse Effects - Pamphlet
From Pamphlet by: Agency for Healthcare Research and Quality (Alt Med Mod), 9/1/00


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.

Overview / Reporting the Evidence / Methodology / Findings / Future Research / Availability of Full Report


This evidence report details a systematic review summarizing clinical studies of milk thistle in humans. 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:

1. Effects of milk thistle on liver disease of alcohol, viral, toxin, cholestatic, and primary malignancy etiologies.

2. 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.

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.


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 nonplacebo 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.


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 nonplacebo 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[R], 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.


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 compliance and dropouts.

* 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 the 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. It is expected to be available in winter 2000. At that time, 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).

When available online, the Evidence Report will be at

AHRQ Publication Number 01-E024 Current as of September 2000

Internet Citation:

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.

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