Is There Any Use for Nontraditional or Alternative Therapies in Patients with Chronic Liver Disease?
Is There Any Use for Nontraditional or Alternative Therapies in Patients with Chronic Liver Disease?
by Nathan M. Bass, MD, PhD
Is There Any Use for Nontraditional or Alternative Therapies in Patients with Chronic Liver Disease?
by Nathan M. Bass, MD, PhD
There has been a substantial increase in the use of so-called complementary and alternative therapies by patients with liver disease. Although many such modalities are available, herbal therapies are the most popular, and of these remedies, silymarin extracted from the milk thistle is most widely subscribed to as a remedy for liver diseases. Available evidence points to a potential, but unproven, benefit for this as well as other therapies based on free radical scavenger or antioxidant principles in treating patients with liver disease. These therapies deserve further investigation through experimental studies and well-controlled clinical trials. Benefits to patients from these therapies, especially to patients with established cirrhosis, are most likely to be modest and insignificant. Conversely, the hepatotoxic potential of some alternative treatments is well recognized. As practitioners educating and treating patients with liver disease, we are obliged to be informed about popular alternative therapies, understanding of our patients’ need to be partners in their care, and open-minded to the possibility that some benefit may come from some therapies currently regarded as alternative. We need to be effective and tolerant in learning about which alternative treatments our patients are taking, so that we can monitor their effects if any and counsel appropriately against those that may cause harm.
Alternative therapies, now commonly referred to as complementary and alternative medicine (CAM) , have been variously defined as therapies not widely taught in medical schools, not generally used in hospitals, and not typically reimbursed by medical insurance companies . This situation is rapidly changing. It is now estimated that more than 50 medical schools in the offer courses in CAM, with some acknowledging the huge popularity of these therapies through establishing centers for integrative medicine. In a landmark paper, Eisenberg et al.  estimated the use of CAM to be 34% in the general population, close to the estimates for the use of these approaches among patients with cancer , and the self-medication with alternative therapies to be from 30% to 80% among people with HIV or AIDS . Based on questionnaires administered to patients attending the University of California, San Francisco Liver Transplant Clinic, my own estimate of the prevalence of CAM use among patients with chronic liver disease across the board is closer to 80%. The growing demand for CAM and its impact in the marketplace led the US Congress to instruct the National Institutes of Health (NIH/OAM) to establish an Office of Alternative Medicine in 1992 to support studies of alternative therapies (their informative website is at http://www.nih.gov). Consumer demand is now motivating more insurers and hospitals to incorporate CAM into the services they cover and provide [5, 6**]. From an economic perspective, this is a major market force with an estimated $13 billion per year in 1990 . Recent data certainly suggest at least a threefold growth in this amount .
A more recent definition for CAM proposed by NIH/OAM takes into consideration the changes in acceptance of these therapies by the public and, in many cases, providers, but the definition is still not entirely satisfactory. CAM is thus defined as “a broad domain of healing resources that encompass all health systems, modalities and practices and their accompanying theories and beliefs, other than those intrinsic to the politically dominant health system of a particular society or culture in a given historical period…boundaries within CAM and between the CAM domain and the domain of the dominant system are not always sharp or fixed” . Although it emphasizes the sociopolitical aspects of CAM, this definition, in the eyes of the physician and scientist, must be seen as deemphasizing the scientific basis for what we advocate and practice as conventional medicine. This system is not perfect, certainly, but is has been advanced and tested by a process that has evolved through the application of the most disinterested, logical, and honest principles available to us. Although the dangers inherent in the uncritical acceptance and widespread use of CAM have led to strong opinion focused against this growing practice [9**], CAM represents a means of empowerment to patients, and it is decidedly here to stay. Perhaps its growth is part of the millennial phenomenon; perhaps it is a means of empowerment for patients frustrated with the diminished time their physicians spend explaining the mysteries of their ailments to them as we rush to meet the demands of the new medical marketplace. In hepatology, where we often must confront diseases that are physically and emotionally devastating, with demoralizing symptoms such as pruritus, fatigue, and pain, perhaps it should come as no surprise that patients often seek alternatives.
We have an even larger challenge to contend with following the recent wave of publicity regarding hepatitis C infection. The ominous overtones of articles such as Groopman’s  dramatic report on the “shadow epidemic” have produced awareness and also much anxiety in the affected population. As noted in one alternative self-help newsletter [11*], it is not surprising that patients faced with the recommendation of a conventional treatment that entails months of injecting a substance that produces flu-like symptoms, or worse, and a response rate of at best about 50%, would seek alternative treatment. The increased awareness of hepatitis C, coupled with blood bank look-back programs, is predicted to uncover a population estimated at 4 million individuals infected with a virus the natural history of which we are learning a great deal about–but not fast enough for the needs of most patients.
Parallels have been drawn between the AIDS epidemic and the explosion of public awareness regarding hepatitis C infection. The huge difference is that, as opposed to the devastating diseases that affected the majority of patients with AIDS in the early days, in most cases of newly discovered hepatitis C infection, individuals will be faced with a lifetime of anxiety over the potential outcome of their infection, and decades in which to seek the broad array of services offered by the CAM industry.
Types of Alternative Therapies
Many therapies fall under the general heading of CAM, more than could be listed in specific detail in this review. NIH/OAM classifies these into six broad fields of alternative medicine: diet-nutrition-lifestyle changes, mind-body interventions, bioelectromagnetic applications, alternative systems of medical practice, manual healing, pharmacologic and biologic treatments, and herbal medicine. Table 1 lists some of the more commonly practiced and sought-after specific therapies. Information about these therapies is disseminated via a variety of books, newsletters, and, more recently, through the Internet. The power of this colorful, enticing, and unregulated medium in providing information and boldly advertising both conventional and alternative therapies is tremendous. Of all the therapies aimed at the patient with liver disease, nutritional counseling and herbal remedies are by far the most popular.
Table 1: Examples of Complementary and Alternative Medical Therapies
Chiropractic Ethnomedicine (includes Chinese herbal medicine)
Psychosocial therapies (guided imagery, biofeedback, massage)
Alternative therapy and self-help newsletters can provide an excellent source of education to patients, including advice on testing for hepatitis and recommendations that current conventional understanding would endorse strongly: avoidance of alcohol, overuse of acetaminophen, and illegal drug use [11*]. These same publications, however, are also the purveyors of advice that often seems to be based on a little learning borrowed from the mainstream of medicine and then rehashed in misinterpreted form. For example, newsletters [11*] and websites (such as http://www.liverdoctor.com/) often advise patients to eat a very low-protein (and often a very low-fat) diet, presumably on the basis of knowledge that protein is a source of ammonia or that fat digestion and absorption are impaired in cholestasis. When this advice is applied to patients with early disease or well-compensated cirrhosis, however, it goes against current recommendations regarding appropriate nutritional management of all but the most severe end-stage liver disease [12, 13*]. Other dietary avoidances that I have seen advocated include chocolate and caffeine. Often emphasized as the basis for dietary therapies is the need for liver “cleansing,” a quaint and appealing concept that at least recognizes the central role played by the liver in nutrient processing and drug and toxin elimination.
Our task as physicians is to pay attention to the fact that the two most common questions that our patients with liver disease wish us to address today (apart from how long they are going to live) are diet and sex. The latter lies beyond the scope of this paper, but we should take a proactive approach to the issue of nutrition in our patients. Pointing out that our best knowledge supports simple principles of nutrition for liver disease provides relief and satisfaction to most patients.
Table 2: Various Herbal and Alternative Remedies Recommended for Liver Diseases
|Comfrey*||Olive leaf extract|
Herbalism: the predominant practice
Herbalism is the most widely used type of CAM. This is not surprising given the extensive historical basis for the extraction of medicinal principals from botanicals. One need only consider foxglove, chincona bark, the poppy, and Fleming’s bacterial culture gone moldy with Penicillium to appreciate this truism. In many instances the therapeutic efficacy of herbal or botanical remedies has been dramatic; other remedies have been accepted into the mainstream eventually by withstanding the stringency of scientific testing and by demonstrating efficacy in well-designed, peer-reviewed clinical trials.
The herbs and botanical preparations in use through CAM number in excess of 1400 species , and most have not yet shown any true efficacy by trusted standards. Herbal treatments have enjoyed a protected status since 1962, when manufacturers were able to bypass US Food and Drug Administrations regulation by selling herbs as “food” products off the shelves of health food stores . The confusion between opinion and fact in the field of herbalistic practice is apparent both from the breadth of claimed hepatic remedies and from the inconsistencies and disagreements among the manufacturers’ and herbal practitioners’ views of what constitutes a liver remedy (see Table 2). There is certainly no lack of debate among medical specialists regarding even some state-of-the-art conventional therapies, but it is odd to find a book on the shelves of a major drugstore chain that claims to be “the ultimate guide to the curative power of natures medicines” listing a variety of herbal remedies posited to aid and heal the liver, with no mention, even in the index, of milk thistle.
Milk thistle (Silybum marianum) is by far the most widely used herbal remedy among patients with liver disease. It enjoys a considerable and ancient reputation, based on a combination of historical legacy and interesting, often positive, but essentially flawed data. For a detailed and excellent review of this interesting herbal remedy, the reader is referred to the recent paper by Flora et al. [16**]. Milk thistle derives its name from its spiked leaves and white veins, the latter, according to legend, believed to carry the milk of the Virgin Mary. The plant has bright purple flowers and stout spines (Fig. 1). It is native to Europe but is grown commercially throughout the . The use of milk thistle as an herbal remedy dates back 2000 years, and Pliny the Elder is credited with observing that its seeds were “excellent for carrying off bile” [16**]. After holding a consistent place in the herbal armamentarium over the centuries, the active principal, silymarin (a mixture of flavonoids of which silibin appears to be the most active) was extracted in 1968. This marked the beginning of the marketing of this agent as a liver protectant under the trade name of Legalon in and continental Europe. Milk thistle is currently marketed in the under various labels of differing purity and silymarin content. Popular brands include Thisilyn (Nature’s Way, Hamilton, OH) and Milk Thistle Plus, Liv-a-gen (BenSalem Naturals, Bensalem, PA). Most formulations are sold as capsules, and some are sold as liquid preparations. Prices range from $26 to $32 per 100 capsules.
An abundance of experimental in vitro and animal data supports a hepatoprotective effect of silymarin, with acute toxicology studies suggesting a similar protective effect to N-acetylcysteine and a variety of other compounds that have “made the grade” in this type of study [17, 18, 19, 20]. Available evidence from seemingly reliable experimental studies suggests a broader spectrum of biologic actions including functioning as an antioxidant; affecting cellular membrane permeability; providing stability against xenobiotic injury; increasing the synthesis of ribosomal RNA by stimulating DNA polymerase I; exerting a steroidlike regulatory action on DNA transcription ; and exerting antifibrotic [21, 22] and anti-inflammatory effects through inhibition of Kupffer cell production of cytokines . Much of the early research into the hepatoprotective properties of silymarin, including animal studies and small, uncontrolled patient studies, was completed in the late 1970s, and most was sponsored by the manufacturer . There have been several subsequent clinical trials of the efficacy of this agent in a variety of settings including acute viral hepatitis, toxic hepatitis, alcoholic liver disease, and cirrhosis [16**]. The results for the most part have been published in the more obscure literature, and although they are interesting from the point of view of the potential for a true hepatoprotective effect from silymarin in some situations, these studies are difficult to interpret because of small numbers; poor study design; heterogeneity of etiologies, dosing, and control groups; and poorly defined endpoints.
In Europe, many physicians accept silymarin as part of standard therapy for Amanita phalloides mushroom poisoning. This practice is based on one controlled animal study in which silymarin administered to beagles poisoned with powdered Amanita reduced biochemical evidence of liver damage as well as mortality . A subsequent uncontrolled study in humans suggested a relationship between the brevity of the interval from presentation to silymarin administration and the favorability of outcome . A retrospective study of 250 patients suggested that the combination of penicillin with silybin was associated with increased survival . Several human studies, mostly uncontrolled or poorly designed controlled studies, have reported a protective or ameliorative effect of silymarin in acute or chronic viral hepatitis or toxin-, alcohol-, or drug-induced liver damage [16**, 28, 29, 30]. When statistically significant improvements have been reported, they have usually been in biochemical parameters and occasionally histology. It is abundantly clear from all studies to date that the preparations used have been safe and without side effects. The overall positive body of largely uncontrolled or poorly controlled data encourages the further exploration of silymarin as a therapy for liver disease. At the very least, silymarin may assume a place similar to that of ursodeoxycholic acid as a harmless treatment that has some true, albeit modest, benefit in cholestatic as well as other liver diseases.
In the few available studies of treatment of patients with established cirrhosis, in which endpoints have been more stringent and more realistic with respect to survival, outcomes with silymarin have been less clearly positive. Ferenci et al.  recently published a double-blind, prospective, randomized study enrolling 170 patients with cirrhosis. Eighty-seven patients received 140 mg of silymarin three times daily, and 83 patients received a placebo. The mean observation period was 41 months. The 4-year survival rate was 58% 9% in the silymarin-treated patients and 39% 9% in the placebo group (P = 0.036). Subgroup analysis indicated that treatment was effective in patients with alcoholic cirrhosis (P = 0.01) and in patients initially rated “Child A” (P = 0.03). Thus, select subgroups appeared to benefit in this study, but in the end the numbers were small, and the reasons for this selective benefit are unclear. Countering this report are findings from a well-designed randomized, double-blind, multicenter trial from [32*] in which the effect of silymarin was studied in alcoholics with cirrhosis with respect to survival and clinical and laboratory changes. Two hundred alcoholics with proven cirrhosis were randomly assigned to receive either 450 mg of silymarin per day or placebo. The primary outcome was time to death, and the secondary outcome was the progression of liver disease. One hundred and three patients were assigned to receive silymarin and 97 to receive placebo. A 2-year study period was completed in 125 patients (57 receiving silymarin and 68 receiving placebo). Survival was similar in patients receiving silymarin and those receiving placebo. The effect of silymarin on survival was not influenced by sex, persistent alcohol abuse, histologic alcoholic hepatitis, or severity of liver dysfunction. Silymarin clearly did not have any significant effect on the course of the disease in these patients.
In this setting of scientific curiosity but ongoing uncertainty regarding any real benefit from silymarin in patients with liver disease, especially chronic liver disease, the next wave of alternative treatments is already on the horizon. As has often been the case with silymarin, data supporting its use come from the uncritical interpretation of the experimental literature and the assumption that if it is good for one ailment it must be good for others. Some examples illustrate how the boundaries between conventional and alternative therapies may become blurred and include rigorously studied agents such as S-adenosyl methionine  and N-acetylcysteine . For the purpose of preventing necrosis and liver failure from acetaminophen, the latter is hardly regarded by hepatologists as an alternative therapy, but the broader purposes for which it may come to be used by patients could soon cast it in that light.
Chinese herbal medicine
Chinese herbal medicines are probably next in popularity among patients with liver disease. Claims for their efficacy, mainly in chronic viral hepatitis, range from the purely anecdotal  to rare controlled studies that suggest that certain Chinese herbal medicines may have a role in the management of chronic liver diseases. Batey et al.  recently reported a placebo-controlled study in which a Chinese herbal preparation, CH-100, was associated with a significant reduction in alanine aminotransferase levels over the 6-month study period in patients with chronic hepatitis C infection. Experimental studies of the preparation sho-saiko-to, popular in for treatment of liver disease, have provided evidence for an antifibrotic effect in the liver (Bissell, personal communication). Paradoxically, the same preparation has been associated with liver damage in humans (see the section on “The Dark Side: Hazards of Alternative Therapies”). The major difference between Chinese herbal medicines and single herbal therapies such as milk thistle lies in the often complex and unknown contents of the Chinese herbal preparations, which may vary from batch to batch and can contain adulterants of considerable potential harm to the patient. This is also discussed in “The Dark Side: Hazards of Alternative Therapies.”
Table 3: Nutritional, Folk, and Herbal Therapies Reported to Cause Liver Disease
|Asafetida||Abnormal liver test results|
|Chaparral leaf||Zonal necrosis|
|Jin Bu Huan Anodyne tablets||Hepatitis, fibrosis, steatosis|
|Xiao-chai-hu-tang (sho-saiko-to)||Zonal, bridging necrosis, fibrosis, microvesicular fat|
|Gentian||Abnormal liver test results|
|Germander||Zonal necrosis, fibrosis|
|Lady’s mantle||Abnormal liver test results|
|Life root (Senecio aureus)||Veno-occlusive disease|
|Megavitamin A therapy||Hepatic fibrosis|
|Mistletoe||Abnormal liver test results|
|Senna fruit extracts||Abnormal liver test results|
|Skullcap||Abnormal liver test results|
Antioxidants and vitamins
Oxidative stress has emerged as a key pathophysiologic mechanism in liver disease [37, 38]. Not surprisingly, antioxidants are becoming increasingly attractive and popular as alternative therapies for a variety of liver diseases, with vitamins A, C, and E as well as selenium receiving most attention . Most are generally safe with the exception of megadose vitamin A therapy, the potential hepatotoxicity of which is generally known, even among practitioners of alternative therapy. There may be other, less established long-term adverse impacts from the indiscriminant use of popular mixed antioxidant formulations. Thus, there is a reasonable practice among some hepatologists to counsel patients with potential or proven hepatic iron overload (including hereditary hemochromatosis, hepatitis C infection, and alcoholic liver disease) to avoid dietary vitamin C supplementation given the proabsorptive effect of vitamin C on nonheme iron  and also the evidence for a prooxidant effect of ascorbate in the liver in the presence of iron overload .
The experimental literature is replete with evidence for a hepatoprotective role for vitamin E in toxin-induced liver damage and in preventing hepatic oxidant stress . The argument supporting supplementation with vitamin E has perhaps been best substantiated in patients with cholestatic liver disease, who may absorb it poorly [41, 42]. However, evidence for vitamin E deficiency as a much broader phenomenon in patients with liver diseases has been presented . A small experimental study in human subjects showed that vitamin E administration altered parameters of oxidative stress and fibrogenesis determined in liver biopsies . A prospective, randomized, double-blind crossover study of vitamin E treatment in 23 patients with hepatitis C infection showed a significant improvement in aminotransferase levels [45*]. A small nonplacebo controlled study of vitamin E treatment in patients with hepatitis B infection has reported a greater frequency of alanine aminotransferase normalization and loss of detectable hepatitis B DNA in treated patients . The authors of this study have suggested that these results point to an effect of vitamin E on the immune system beyond its effects as an antioxidant. As promising as these results may seem, not all therapeutic studies have been equally positive. A long-term double-blind trial of vitamin E supplementation in patients with alcoholic cirrhosis found no influence on hepatic laboratory parameters, mortality, or hospitalization rates for decompensated patients with alcoholic cirrhosis, although serum levels of the vitamin increased significantly . Vitamin E, taken even in large doses, appears to be innocuous and is therefore in the same class of safety as milk thistle as an alternative therapy. The experimental literature and small body of clinical studies to date are encouraging, however, and show that larger, well-designed studies with this agent are now indicated.
The Dark Side: Hazards of Alternative Therapies
Certain alternative therapies, even some purported to be of particular value in treating liver disease, may be potentially harmful and produce liver disease [14, 48**, 49, 52]. This may result from excessive use of plant products or extracts thereof with relatively mild hepatotoxic potential, from adulterants or contaminants present in complex formulations, or even from potent hepatotoxicity of preparations taken for other purposes (Table 3). Among those most commonly implicated have been Chinese herbal or traditional medicines, which commonly comprise multiple products, some of which have caused serious illness . Paradoxically, an herbal remedy or traditional medicine such as xiao-chai-hu-tang (sho-saiko-to) that has been used in the treatment of liver disease has been implicated in causing liver injury [48**]. Finally, the potential for acupuncture to transmit hepatitis C and B infection is well recognized , but other more obscure therapies such as autohemotherapy may do so as well .
There appears to be a growing and understandable backlash of irritation among some physicians with the growth and uncritical use of CAM. The recent editorial by Angell and Kassirer [9**] draws a line in the sand by stating that there can be only one type of medicine, that which has been adequately tested and which works by current scientific standards. Although few physicians would disagree with this point of view, it is likely that patients with liver disease will continue to avail themselves of the broad base of information and treatments offered by both their conventional physicians and the practitioners of CAM therapies. I believe it is important that we as physicians keep the lines of communication open. In this manner we can counsel our patients most appropriately. Renner, of the National Council Against Health Fraud (personal communication quoted by Carroll ), has proposed a useful five-point classification scheme within which to frame discussions of any therapeutic modality with patients. The five categories include quackery, folklore, unproven or untested treatments, investigational or research treatments, and proven remedies. This classification defines the spectrum of treatments ranging from those we would regard as completely dishonest and exploitative to those we would accept as effective and valuable therapy, proven by scientific evidence. If a treatment is harmless and may or may not be of benefit, we can afford to be more tolerant of what may be little more than a placebo, especially when we have little to offer that is more effective. The only harm that may come in such circumstances is to a patient’s bank balance. If a treatment may produce illness, interfere with the efficacy of conventional treatment, or lead patients to reject more effective conventional therapies, we must inform our patients unequivocally of these facts. It has been my experience that most are willing to follow advice and guidance, as long as it is given with an attitude of concern and respect, both for the patient’s freedom to choose and for the potential, although unproven, benefit of some unconventional therapies. In answer to the question of whether there is any use for nontraditional or alternative therapies in patients with chronic liver disease, the best answer at this time is “it depends.” We should not succumb, in the words of Angell and Kassirer [9**], to “giving alternative medicine a free ride.” Selected alternative therapies for which the available critical literature suggests some promise should be subjected to rigorous scientific testing in well-designed experimental studies and clinical trials before we accept or reject them. An alternative therapy that passes this scrutiny will soon cease to be regarded as alternative. Ursodeoxycholic acid, a constituent of bear bile, prized for centuries in as a remedy for liver ailments and now an accepted and extensively prescribed therapy in hepatology, can be cited as one such case.
References and Recommended Reading
1. Carroll RJ: When patients want “alternative” care. ACP-ASIM Oberserver 1998, 18: 1.
2. Eisenberg DM, Kessler RC, Foster C: Unconventional medicine in the United States: prevalence, costs, and patterns of use. N Engl J Med 1993, 328: 246-252.
3. Ernst E, Cassileth BR: The prevalence of complementary/alternative medicine in cancer: a systematic review. Cancer 1998, 83: 777-782.
4. Ryan JG: Who uses AIDS alternative therapies and what happens to them? Outcomes from the use of AIDS alternative therapies among people infected with HIV: a synthesis of the medical literature [abstract]. Ahsr Fhsr Annu Meet Abstr Book 1995, 12: 82-83.
5. Pelletier KR, Marie A, Krasner M, Haskell WL: Current trends in the integration and reimbursement of complementary and alternative medicine by managed care, insurance carriers, and hospital providers. Am J Health Promotion 1997, 12: 112-122.
6. ** Eisenberg DM: Advising patients who seek alternative medical therapies. Ann Intern Med 1997, 127: 61-69.
This thoughtful and timely discussion presents an update on patient use of alternative therapies and outlines a step-by-step strategy whereby conventionally trained medical providers and their patients can proactively discuss the use or avoidance of alternative therapies.
7. Breevoort P: The botanical market: an overview. Herbalgram 1996, 36: 49-57.
8. Panel on Definition and Description : Defining and describing complementary and alternative medicine. CAM Research Methodology Conference, 1995. Alternative Ther Health Med
9.** Angell M, Kassirer JP: Alternative medicine: the risks of untested and unregulated remedies [editorial]. N Engl J Med 1998, 339: 839-841.
An impassioned editorial taking a strongly skeptical and even disparaging look at the field of alternative medicine. The authors give appropriate cautionary advice to the medical community and make a rational plea for the consistent application of the scientific method to all therapies. An important, balanced viewpoint; essential reading.
10. Groopman J: Medical dispatches: the shadow epidemic. The New Yorker 1998: 48-60.
11.* Weil A: Natural help for hepatitis. Dr. Andrew Weil’s Self Healing 1998: 1, 6-7.
12. Nompleggi DJ, Bonkovsky HL: Nutritional supplementation in chronic liver disease: an analytical review. Hepatology 1994, 19: 518-533.
13. * Corish C: Nutrition and liver disease. Nutr Rev 1997, 55: 17-20.
14. Youngkin EQ, DS: A review and critique of common herbal alternative therapies. Nurse Pract 1996, 39: 43-52.
15. Castleman M: The Healing Herbs: The Ultimate Guide to the Curative Power of Nature’s Medicines New York: Bantam Books; 1995.
16.** Flora K, Hahn M, Rosen H, Benner K: Milk thistle (Silybum marianum) for the therapy of liver disease . Am J Gastroenterol 1998, 93: 139-143.
The best available review to date on the most popular herbal remedy used for liver disease. Good discussion of the history of its use and the available literature on its use in patients with liver disease.
View the PubMed notation for this reference.
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