- Email: [email protected]
Chaos in hepatology: Do we know what our patients are taking?
January 2005
SELECTED SUMMARIES
include studies of patient groups that did not precisely seem to fit into the category of critical illness, but that the issue was moot because, if a treatment does not provide benefit, we should not use it whether or not it causes harm. We now have a clearer insight into the potential benefits and harms of the respective therapies. This single trial contained more than twice as many patients as the larger meta-analysis. Perhaps even more importantly, great effort was expended to control for a variety of potential biases that can crop up even in randomized studies. What was particularly appealing to me was the fact that this effort included an attempt to blind the interventions. Furthermore, a wide variety of patients were included, so the results can be more readily extrapolated. Using the delayed consent strategy, the patients were entered into the trial as they were seen, again reinforcing the generalizability of the results. The various subgroup analyses should be interpreted with care. As is obvious, the investigators did conduct a large number of them. It is entirely possible that some of these apparent differences were just chance observations. If you flip a coin often enough, you will eventually toss 10 heads in a row. So, what have we learned? The data do reassure us that, overall, albumin is not causing premature mortalities in the ICU (although it may be a problem in certain subgroups, such as patients with head trauma). It also would appear that, volume for volume, albumin does provide more resuscitative power. On the other hand, albumin is much more expensive than saline and, if the only issue is some transient peripheral edema at the end of the day, the price of albumin may be too high. In this regard, no cost analyses were undertaken by the investigators. In the accompanying editorial (N Engl J Med 2004;350:2294 – 2296), Dr. Deborah Cook noted that yet another large multi-institutional randomized trial is going on in Europe. That trial has multiple treatment arms (hypo- or isotonic saline compared to gelatin, starch, or albumin). No further information was provided, and it is not clear if the results of this study on the opposite side of the world will cause the European one to stop prematurely. However, in the absence of a very dramatic finding to the contrary in that trial, it would seem that saline and albumin result in equivalent clinical outcomes, in which case the payer may ultimately make the decision. There is another aspect of this trial that deserves comment. Dr. Cook also informed the readers that this study was put together by a dedicated team of intensive care specialists who essentially funded the trial themselves. The previous randomized controlled trials in critically ill patients (about 1300 published prior to 1995) were usually from a single center and, half of the time, included less than 100 patients. It is to the credit of intensivists that they have developed large cooperative groups of investigators. These individuals seek answers to questions that interest them because they encounter them in their daily practices (as opposed to questions that interest industry for purposes of improving a bottom line). These groups are even funding these studies from sources that have less potential conflicts of interest. Finally, these groups are using sound experimental methodology. The resultant data may be SAFEr to accept. RONALD L. KORETZ, MD
CHAOS IN HEPATOLOGY: DO WE KNOW WHAT OUR PATIENTS ARE TAKING? Neff GW, O’Brien C, Montalbano M, De Manno A, Kahn S, Safda K, Nishida S, Tzakis A (Departments of Medicine, Surgery and
239
Nutrition, University of Miami, Miami, Florida). Consumption of dietary supplements in a liver transplant population. Liver Transplantation 2004;10:881– 885. The investigators deployed a questionnaire in their liver transplant population to determine the extent of the patients’ use of herbal remedies and vitamins. A total of 290 patients (30.5%) completed the questionnaire, and 156 (54%) admitted taking non-prescribed products. One hundred one patients admitted taking only vitamins continuously, and 55 patients were using vitamins and herbal remedies. Three patients with primary biliary cirrhosis (PBC) had persistently elevated liver enzymes, despite adequate immunosuppression, and in 1 case, steroid pulses. On direct questioning, these patients eventually admitted to taking high doses, of more than 1 gram per day, of vitamin E (tocopherol). When the tocopherol was discontinued, the liver enzymes gradually returned to normal after 4 – 8 weeks. As far as the herbal remedies were concerned, the patient admitted to taking over 30 different types of remedy. Of these, at least colostrum, echinacea, and noni juice were associated with abnormal liver enzymes that returned to normal with withdrawal of the remedy. In light of their findings, the authors conclude that all transplant teams need to question their patients directly and in detail as to whether they are taking vitamins and /or herbal remedies, and to educate them on the potential hazards. I would extend this to all physicians. Comment. From 1997 to 2001 it was estimated that between $4 and $5.4 billion was being spent annually in the USA on herbal remedies (JAMA 1998;280:1569 –1575, N Engl J Med 2002;347: 2073–2075). Herbal remedies for treating disease have been used in South East Asia for over 4000 years. However, it was with the diagnosis of acute hepatic necrosis due to mushroom poisoning (Am J Med 1965;38:787–792, Hepatogastroenterol 1985;32:229 –231), the identification of the toxin alpha-amatin (Science 1968;159:946 –947), and the diagnosis of veno-occlusive disease in Jamaican tea drinkers due to the pyrrolizidine alkaloids in crotalaria (Gastroenterology 1997;113:1408 –1412) that physicians began to realize that natural does not always mean safe. Indeed, in recent reviews, more than 15 different herbal remedies have been listed as having potential hepatotoxicity (Gastroenterology 1997;113:1408 –1412, N Engl J Med 2002;347:2046 –2056). In a survey of the UNOS database from 1990 to 2002, it was found that 5% of drug-induced fulminant hepatic failure leading to liver transplantation was due to herbal remedies, and 11.7% of nonacetomenophen-induced FHF were due to herbal remedies and mushrooms (Liver Transplant 2004;10:1018 –1023). The remedies included Kava-kava, chaparral tea, and vitamin A. The area is beset with problems. In the USA, herbal remedies have been regulated as dietary supplements, without the stringent requirements applied to proprietary drugs. The remedies have lacked standardization, and 32% of them were reported to contain undeclared pharmaceuticals and heavy metals (N Engl J Med 1998;339:847). It is estimated that only about 10% of adverse events associated with herbal remedies are reported, and there is no penalty for withholding reports of adverse reactions (N Engl J Med 2002;347:2073–2076). Finally and perhaps most importantly for practicing physicians is the question of interactions between prescribed drugs and herbal remedies. In one survey, about 16% of patients taking prescription drugs also admitted to taking a herbal remedy (JAMA 2002;287:337–344).
240
SELECTED SUMMARIES
More specifically, in a survey of 6 liver clinics, 21% of patients on medication admitted using a herbal remedy as well, and 12% admitted using extract of milk thistle for the treatment of their liver disease (Am J Gastroenterol 2002;97:2391–2396). In one liver clinic in California, 50% of patients used some form of herbal remedy. Hypericum perforatum, or St John’s wort, which was used by 1 patient in the present study, has been shown to interact with several drugs resulting in decreased blood levels (Clin Pharmacol Ther 1999;66: 338 –345, Lancet 1999;354:2014 –2015, Am J Clin Pathol 2003; 120:127–137). One of the drugs reported was cyclosporine A, and a patient developed acute graft rejection following liver transplantation as a result of St John’s wort, enhancing cyclosporine metabolism (J Hepatol 2000;33:853– 855). The detrimental effects of mega doses of vitamins, such as vitamin A on the liver is clear (J Clin Gastroenterol 2002;34:275–279, Eur J Gastroenterol Hepatol 2000;12:361–364). In the present study, the authors report 3 transplant patients with PBC, in whom the abnormal liver enzymes were associated with the intake of large doses of vitamin E. In 1 patient, the enzymes responded to increased immunosuppression with prednisolone, but recurred with tapering of the prednisolone. Liver biopsy showed no evidence of rejection or recurrence of PBC. During the 6-month period, the doctors discovered that the patient was taking more than 1 gram of vitamin E daily. This was stopped and the liver enzymes returned to normal within 4 weeks. Vitamin E is an essential fat-soluble vitamin, which includes 2 classes of naturally occurring compounds, tocopherols and tocotrienols (Lancet 1995;345:170 –176). D-␣-tocopherol has the highest biological activity and is the most widely available vitamin in food, such as vegetables and seed oils. The recommended dietary allowance of vitamin E is between 8 and 10 mg. Vitamin E is a most effective chain-breaking lipid-soluble antioxidant in the biological membrane, where it contributes to membrane stability (Lancet 1995;345:170 – 176). It has been investigated therapeutically for this function in cardiovascular diseases (Eur J Clin Pharmacol 1989;37:541–544), neurological, hemolytic, and cholestatic conditions. However, vitamin E has also been shown to have immunostimulatory effects. It has been shown to decrease prostaglandin production in immune cells and to enhance cell-mediated immunity. In fact, it has been shown to enhance age-associated indices of T cell–mediated function, in patients over 60 years with doses of 800 mg per day, without side effects. Therefore, why did 1000 mg of vitamin E daily cause elevated liver enzymes in the posttransplant PBC patients. One possibility is that its immunostimulatory effect interfered with the immunosuppression, although there were no signs of rejection on liver biopsy. Among the other herbal remedies, 2 transplant patients were taking kava kava, which is prepared from piper mesthysticum, a South Pacific plant. Kava kava has been recommended for symptoms of anxiety. Yet kava kava has been shown to cause inhibition of cytochrome P450 and a decrease of glutathione in the liver (Toxicol Lett 2004;150:85–96). Heavy intake of kava kava is commonly associated with elevated gamma glutamyl peptidase levels, and occasionally with severe hepatitis, resulting in at least 11 reported cases of fulminant hepatic failure leading to liver transplantation and, in 4 cases, death (Med J Aust 2003;178:442– 443). Although not all the cases were convincing, because of these reports, the FDA and Health Canada issued an advisory warning to the public against the use of kava kava. However, in a recent follow-up survey in Toronto, Canada, 22 of 34 health stores still recommended kava kava for anxiety (J Gen Intern Med 2004;19:269 –272). Finally, 1 patient was recommended bovine colostrum for its immunostimulatory properties. After 2 weeks, the serum ALT levels rose to 2300 U/L. Liver biopsy showed
GASTROENTEROLOGY Vol. 128, No. 1
severe endothelialitis, indicating acute severe rejection. After pulse steroids and stopping the herbal remedy, the rejection resolved. Clearly, there is a major problem in any clinic, including liver clinics, with patients taking herbal remedies unknown to their physicians. In the present series, 30 patients (11%) admitted taking milk thistle. This was almost identical to a recently reported survey of veterans with hepatitis C, of whom 12% were taking milk thistle, known as silymarin (J Clin Gastroenterol 2004;38:605– 610). A standard extract of milk thistle (silybum marianum) contains flavinoids, the most active of which is silibinin, which constitutes 60%– 70% of silymarin. Extract of milk thistle has been used for the treatment of liver disease for hundreds of years. Recently, interest increased in Europe and the USA, and its hepatoprotective properties have been confirmed experimentally (Hepatology 1999;30:1099 – 1104). However, in clinical studies the beneficial effect of silymarin is unclear. Studies in patients with acute viral hepatitis either showed accelerated normalization of liver enzymes (Med Klin 1978;73:1060 – 1065) or no effect (Med Klin 1977;72:513–518). In alcoholic hepatitis, silymarin showed a significant effect on liver enzymes compared to placebo (Scand J Gastroenetrol 1982;17:517–522). In long-term studies in alcoholic cirrhotic patients, silymarin either resulted in an increased survival (J Hepatol 1989;9:105–113) or had no significant effect (J Hepatol 1998;28:615– 621). In summary, experimentally silymarin has many effects on the liver including antioxidant and antifibrotic effects (Hepatology 1987;26:643– 649), but whether these laboratory effects will ever turn into beneficial clinical effects remains unclear (J Clin Gastroenterol 2003;37:278 –279). However, this has not prevented milk thistle extract from being continuously propagated as a panacea for the liver, resulting in around 10%–12% of liver clinic patients taking milk thistle. In summary, physicians seeing patients with liver disease are faced with the probability, unknown to them, that a third of the patients, at least, will be using alternative forms of therapy including herbal remedies, in addition to the prescribed medications. Fortunately, most of them do not seem to be harmful. However, in most cases, we simply do not know whether the herbal substances used by our patients have an additional therapeutic effect, positive or negative on the prescribed therapy (Liver Int 2003;23:213–220). It, therefore, behooves all of us to include routine questions on the use of alternative therapy in our history taking. However, I have the feeling that unless we show our patients a comprehensive list of all the common herbal substances used, we will still not arrive at the truth. Without that we will likely continue to have an incomplete understanding of the effects of our therapy, and continue to be faced from time to time with puzzling clinical conundrums. This situation needs to be clarified urgently since it is important for our regulatory bodies to know the true facts about the effect of herbal remedies in patients being treated for liver disease. LAURIE BLENDIS, MD
Reply. The summary by Dr. Blendis portrays the problems associated with herbs and vitamins and underscores the importance of increased awareness regarding their use and effects. However, to better control the problems with herbal and vitamin remedies in today’s society, we must first understand the basics. Most physicians in the United States have little knowledge about the plethora of vitamins and herbs available to patients, partly because of the paucity of education on the subject in American medical school curriculum. Additionally, many physicians unfortunately feel that herbs and vitamins have nothing more than a placebo effect.
SELECTED SUMMARIES
include studies of patient groups that did not precisely seem to fit into the category of critical illness, but that the issue was moot because, if a treatment does not provide benefit, we should not use it whether or not it causes harm. We now have a clearer insight into the potential benefits and harms of the respective therapies. This single trial contained more than twice as many patients as the larger meta-analysis. Perhaps even more importantly, great effort was expended to control for a variety of potential biases that can crop up even in randomized studies. What was particularly appealing to me was the fact that this effort included an attempt to blind the interventions. Furthermore, a wide variety of patients were included, so the results can be more readily extrapolated. Using the delayed consent strategy, the patients were entered into the trial as they were seen, again reinforcing the generalizability of the results. The various subgroup analyses should be interpreted with care. As is obvious, the investigators did conduct a large number of them. It is entirely possible that some of these apparent differences were just chance observations. If you flip a coin often enough, you will eventually toss 10 heads in a row. So, what have we learned? The data do reassure us that, overall, albumin is not causing premature mortalities in the ICU (although it may be a problem in certain subgroups, such as patients with head trauma). It also would appear that, volume for volume, albumin does provide more resuscitative power. On the other hand, albumin is much more expensive than saline and, if the only issue is some transient peripheral edema at the end of the day, the price of albumin may be too high. In this regard, no cost analyses were undertaken by the investigators. In the accompanying editorial (N Engl J Med 2004;350:2294 – 2296), Dr. Deborah Cook noted that yet another large multi-institutional randomized trial is going on in Europe. That trial has multiple treatment arms (hypo- or isotonic saline compared to gelatin, starch, or albumin). No further information was provided, and it is not clear if the results of this study on the opposite side of the world will cause the European one to stop prematurely. However, in the absence of a very dramatic finding to the contrary in that trial, it would seem that saline and albumin result in equivalent clinical outcomes, in which case the payer may ultimately make the decision. There is another aspect of this trial that deserves comment. Dr. Cook also informed the readers that this study was put together by a dedicated team of intensive care specialists who essentially funded the trial themselves. The previous randomized controlled trials in critically ill patients (about 1300 published prior to 1995) were usually from a single center and, half of the time, included less than 100 patients. It is to the credit of intensivists that they have developed large cooperative groups of investigators. These individuals seek answers to questions that interest them because they encounter them in their daily practices (as opposed to questions that interest industry for purposes of improving a bottom line). These groups are even funding these studies from sources that have less potential conflicts of interest. Finally, these groups are using sound experimental methodology. The resultant data may be SAFEr to accept. RONALD L. KORETZ, MD
CHAOS IN HEPATOLOGY: DO WE KNOW WHAT OUR PATIENTS ARE TAKING? Neff GW, O’Brien C, Montalbano M, De Manno A, Kahn S, Safda K, Nishida S, Tzakis A (Departments of Medicine, Surgery and
239
Nutrition, University of Miami, Miami, Florida). Consumption of dietary supplements in a liver transplant population. Liver Transplantation 2004;10:881– 885. The investigators deployed a questionnaire in their liver transplant population to determine the extent of the patients’ use of herbal remedies and vitamins. A total of 290 patients (30.5%) completed the questionnaire, and 156 (54%) admitted taking non-prescribed products. One hundred one patients admitted taking only vitamins continuously, and 55 patients were using vitamins and herbal remedies. Three patients with primary biliary cirrhosis (PBC) had persistently elevated liver enzymes, despite adequate immunosuppression, and in 1 case, steroid pulses. On direct questioning, these patients eventually admitted to taking high doses, of more than 1 gram per day, of vitamin E (tocopherol). When the tocopherol was discontinued, the liver enzymes gradually returned to normal after 4 – 8 weeks. As far as the herbal remedies were concerned, the patient admitted to taking over 30 different types of remedy. Of these, at least colostrum, echinacea, and noni juice were associated with abnormal liver enzymes that returned to normal with withdrawal of the remedy. In light of their findings, the authors conclude that all transplant teams need to question their patients directly and in detail as to whether they are taking vitamins and /or herbal remedies, and to educate them on the potential hazards. I would extend this to all physicians. Comment. From 1997 to 2001 it was estimated that between $4 and $5.4 billion was being spent annually in the USA on herbal remedies (JAMA 1998;280:1569 –1575, N Engl J Med 2002;347: 2073–2075). Herbal remedies for treating disease have been used in South East Asia for over 4000 years. However, it was with the diagnosis of acute hepatic necrosis due to mushroom poisoning (Am J Med 1965;38:787–792, Hepatogastroenterol 1985;32:229 –231), the identification of the toxin alpha-amatin (Science 1968;159:946 –947), and the diagnosis of veno-occlusive disease in Jamaican tea drinkers due to the pyrrolizidine alkaloids in crotalaria (Gastroenterology 1997;113:1408 –1412) that physicians began to realize that natural does not always mean safe. Indeed, in recent reviews, more than 15 different herbal remedies have been listed as having potential hepatotoxicity (Gastroenterology 1997;113:1408 –1412, N Engl J Med 2002;347:2046 –2056). In a survey of the UNOS database from 1990 to 2002, it was found that 5% of drug-induced fulminant hepatic failure leading to liver transplantation was due to herbal remedies, and 11.7% of nonacetomenophen-induced FHF were due to herbal remedies and mushrooms (Liver Transplant 2004;10:1018 –1023). The remedies included Kava-kava, chaparral tea, and vitamin A. The area is beset with problems. In the USA, herbal remedies have been regulated as dietary supplements, without the stringent requirements applied to proprietary drugs. The remedies have lacked standardization, and 32% of them were reported to contain undeclared pharmaceuticals and heavy metals (N Engl J Med 1998;339:847). It is estimated that only about 10% of adverse events associated with herbal remedies are reported, and there is no penalty for withholding reports of adverse reactions (N Engl J Med 2002;347:2073–2076). Finally and perhaps most importantly for practicing physicians is the question of interactions between prescribed drugs and herbal remedies. In one survey, about 16% of patients taking prescription drugs also admitted to taking a herbal remedy (JAMA 2002;287:337–344).
240
SELECTED SUMMARIES
More specifically, in a survey of 6 liver clinics, 21% of patients on medication admitted using a herbal remedy as well, and 12% admitted using extract of milk thistle for the treatment of their liver disease (Am J Gastroenterol 2002;97:2391–2396). In one liver clinic in California, 50% of patients used some form of herbal remedy. Hypericum perforatum, or St John’s wort, which was used by 1 patient in the present study, has been shown to interact with several drugs resulting in decreased blood levels (Clin Pharmacol Ther 1999;66: 338 –345, Lancet 1999;354:2014 –2015, Am J Clin Pathol 2003; 120:127–137). One of the drugs reported was cyclosporine A, and a patient developed acute graft rejection following liver transplantation as a result of St John’s wort, enhancing cyclosporine metabolism (J Hepatol 2000;33:853– 855). The detrimental effects of mega doses of vitamins, such as vitamin A on the liver is clear (J Clin Gastroenterol 2002;34:275–279, Eur J Gastroenterol Hepatol 2000;12:361–364). In the present study, the authors report 3 transplant patients with PBC, in whom the abnormal liver enzymes were associated with the intake of large doses of vitamin E. In 1 patient, the enzymes responded to increased immunosuppression with prednisolone, but recurred with tapering of the prednisolone. Liver biopsy showed no evidence of rejection or recurrence of PBC. During the 6-month period, the doctors discovered that the patient was taking more than 1 gram of vitamin E daily. This was stopped and the liver enzymes returned to normal within 4 weeks. Vitamin E is an essential fat-soluble vitamin, which includes 2 classes of naturally occurring compounds, tocopherols and tocotrienols (Lancet 1995;345:170 –176). D-␣-tocopherol has the highest biological activity and is the most widely available vitamin in food, such as vegetables and seed oils. The recommended dietary allowance of vitamin E is between 8 and 10 mg. Vitamin E is a most effective chain-breaking lipid-soluble antioxidant in the biological membrane, where it contributes to membrane stability (Lancet 1995;345:170 – 176). It has been investigated therapeutically for this function in cardiovascular diseases (Eur J Clin Pharmacol 1989;37:541–544), neurological, hemolytic, and cholestatic conditions. However, vitamin E has also been shown to have immunostimulatory effects. It has been shown to decrease prostaglandin production in immune cells and to enhance cell-mediated immunity. In fact, it has been shown to enhance age-associated indices of T cell–mediated function, in patients over 60 years with doses of 800 mg per day, without side effects. Therefore, why did 1000 mg of vitamin E daily cause elevated liver enzymes in the posttransplant PBC patients. One possibility is that its immunostimulatory effect interfered with the immunosuppression, although there were no signs of rejection on liver biopsy. Among the other herbal remedies, 2 transplant patients were taking kava kava, which is prepared from piper mesthysticum, a South Pacific plant. Kava kava has been recommended for symptoms of anxiety. Yet kava kava has been shown to cause inhibition of cytochrome P450 and a decrease of glutathione in the liver (Toxicol Lett 2004;150:85–96). Heavy intake of kava kava is commonly associated with elevated gamma glutamyl peptidase levels, and occasionally with severe hepatitis, resulting in at least 11 reported cases of fulminant hepatic failure leading to liver transplantation and, in 4 cases, death (Med J Aust 2003;178:442– 443). Although not all the cases were convincing, because of these reports, the FDA and Health Canada issued an advisory warning to the public against the use of kava kava. However, in a recent follow-up survey in Toronto, Canada, 22 of 34 health stores still recommended kava kava for anxiety (J Gen Intern Med 2004;19:269 –272). Finally, 1 patient was recommended bovine colostrum for its immunostimulatory properties. After 2 weeks, the serum ALT levels rose to 2300 U/L. Liver biopsy showed
GASTROENTEROLOGY Vol. 128, No. 1
severe endothelialitis, indicating acute severe rejection. After pulse steroids and stopping the herbal remedy, the rejection resolved. Clearly, there is a major problem in any clinic, including liver clinics, with patients taking herbal remedies unknown to their physicians. In the present series, 30 patients (11%) admitted taking milk thistle. This was almost identical to a recently reported survey of veterans with hepatitis C, of whom 12% were taking milk thistle, known as silymarin (J Clin Gastroenterol 2004;38:605– 610). A standard extract of milk thistle (silybum marianum) contains flavinoids, the most active of which is silibinin, which constitutes 60%– 70% of silymarin. Extract of milk thistle has been used for the treatment of liver disease for hundreds of years. Recently, interest increased in Europe and the USA, and its hepatoprotective properties have been confirmed experimentally (Hepatology 1999;30:1099 – 1104). However, in clinical studies the beneficial effect of silymarin is unclear. Studies in patients with acute viral hepatitis either showed accelerated normalization of liver enzymes (Med Klin 1978;73:1060 – 1065) or no effect (Med Klin 1977;72:513–518). In alcoholic hepatitis, silymarin showed a significant effect on liver enzymes compared to placebo (Scand J Gastroenetrol 1982;17:517–522). In long-term studies in alcoholic cirrhotic patients, silymarin either resulted in an increased survival (J Hepatol 1989;9:105–113) or had no significant effect (J Hepatol 1998;28:615– 621). In summary, experimentally silymarin has many effects on the liver including antioxidant and antifibrotic effects (Hepatology 1987;26:643– 649), but whether these laboratory effects will ever turn into beneficial clinical effects remains unclear (J Clin Gastroenterol 2003;37:278 –279). However, this has not prevented milk thistle extract from being continuously propagated as a panacea for the liver, resulting in around 10%–12% of liver clinic patients taking milk thistle. In summary, physicians seeing patients with liver disease are faced with the probability, unknown to them, that a third of the patients, at least, will be using alternative forms of therapy including herbal remedies, in addition to the prescribed medications. Fortunately, most of them do not seem to be harmful. However, in most cases, we simply do not know whether the herbal substances used by our patients have an additional therapeutic effect, positive or negative on the prescribed therapy (Liver Int 2003;23:213–220). It, therefore, behooves all of us to include routine questions on the use of alternative therapy in our history taking. However, I have the feeling that unless we show our patients a comprehensive list of all the common herbal substances used, we will still not arrive at the truth. Without that we will likely continue to have an incomplete understanding of the effects of our therapy, and continue to be faced from time to time with puzzling clinical conundrums. This situation needs to be clarified urgently since it is important for our regulatory bodies to know the true facts about the effect of herbal remedies in patients being treated for liver disease. LAURIE BLENDIS, MD
Reply. The summary by Dr. Blendis portrays the problems associated with herbs and vitamins and underscores the importance of increased awareness regarding their use and effects. However, to better control the problems with herbal and vitamin remedies in today’s society, we must first understand the basics. Most physicians in the United States have little knowledge about the plethora of vitamins and herbs available to patients, partly because of the paucity of education on the subject in American medical school curriculum. Additionally, many physicians unfortunately feel that herbs and vitamins have nothing more than a placebo effect.