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Silymarin and Hepatitis C
Silymarin, a collection of flavonolignans in milk thistle (Silybum marianum), shows antiviral and liver-protective effects in patients with hepatitis C, according to a 2011 Iranian pilot study led by Hamid Kalantari. Milk thistle has a long history as an herbal treatment for liver disorders. Kalantari and colleagues report that many people with chronic hepatitis C infection use milk thistle preparations in addition to or instead of ribavirin-interferon combination therapy, which is expensive and has adverse effects. Kalantari and colleagues decided to test a locally available commercial silymarin product (Goldaru Pharmaceutical Co.; Isfahan, Iran) for efficacy and safety.
Fifty-five people infected with hepatitis C virus, ages 10 to 67 years, took part in the prospective, self-controlled pilot study. Each patient took 630 mg of silymarin per day for 24 weeks. The researchers measured serum hepatitis C virus RNA, liver enzymes (ALT, AST), liver fibrosis markers, and patient well-being at baseline and after treatment. ALT and AST (which indicate liver injury) declined. Mean ALT before treatment was 108.7 and 70.3 at posttreatment (p < 0.001). Mean AST was 99.4 before treatment and 59.7 after treatment (p = 0.004). Nine patients showed no signs of the hepatitis C virus at treatment's end (p = 0.004). Liver fibrosis markers significantly improved in patients with fibrosis at baseline (p = 0.015). Quality of life, as measured by the Iranian version of a validated short-form healthy survey (SF-36), also significantly improved (p < 0.001).
In the study's discussion section, Kalantari and colleagues point out that their positive results contradict two earlier studies. A 2006 randomized, double-blind, placebo-controlled, crossover study involving patients with chronic hepatitis C, conducted by A. Gordon et al., found no significant effect on serum hepatitis C viral RNA, liver enzyme levels, quality of life, or psychological well-being. The Iranian researchers suggest that this lack of effect may be due to the small number of subjects and/or the study's design. A 2004 Egyptian double-blind study, led by M. D. Tanamly, also showed no significant improvement in liver enzyme levels, liver fibrosis markers, or viral RNA even though patients' symptoms and quality of life improved. In this case, Kalantari and colleagues cite patient genotype, study design, and/or the dose of silymarin as possible reasons for the negative results.
Conflicting trial results are common when looking at botanicals because herb quality varies. Unlike the active ingredient in pharmaceutical medications, botanicals contain a variety of compounds that may act synergistically. Moreover, compound levels vary in different strains of the same herb. In the case of milk thistle, silymarin content in raw plant material can vary from season to season, depending upon growing conditions. Extraction and processing, which differ from company to company, also affect a botanical product's potency.
Given the interest in silymarin for treating hepatitis C, Kevin Anthony and colleagues assessed 45 commercially sold silymarin products for a recent study. They measured each product's silymarin content, antioxidant activity, and antiviral response to the hepatitis C virus. Total silymarin content varied greatly among the products and often did not match the content listed on the product label.
In general, total silymarin content directly corresponded to HCV antiviral activity and free radical scavenging and antioxidant activity, but there were several exceptions. One product, for example, with a total silymarin content of 248.5 ± 0.1 mg/gram tablet showed more viral inhibition (88 ± 8%) than a product with 274.3 ± 0.5 mg/gram tablet (46 ± 19% inhibition) and more than another product with 848.7 ± 1.1 mg of silymarin per tablet (76 ± 11% inhibition). '"Many of these products consist of a mixture of multiple extracts and/vitamins that also may contribute some biological activity in our assays," say the authors. Such mixtures complicate the process of assessing silymarin's affect. The analysis conducted by Anthony et al. gives practitioners and patients a starting point for choosing a silymarin product, but the real proof lies in clinical application.
Anthony K, Subramanya G, Uprichard S, Hammouda F, Saleh M. Antioxidant and anti-hepatitis C viral activities of commercial milk thistle food supplements. Antioxidants. 2013;2:23–26. Available at www.mdpi.com/journal/antioxidants. Accessed December 27, 2013.
(Link to article: http://www.mdpi.com/2076-3921/2/1/23)
Kalantari H, Shahshahan Z, Hejazi SM, Ghafghazi T, Sebghatolahi V. Effects of Silybum marianum on patients with chronic hepatitis C. J Res Med Sci. March 2011;16(3):287–290. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3214335. Accessed December 31, 2013.
When sucralose, a synthetic organochlorine sweetener, became available in Canada in 1991, it was heralded as a new calorie-free sweetener with no negative biological effects. A detailed 52-page overview by Susan S. Schiffman and Kristina I. Rother indicates otherwise. The overview was partially funded by the National Institutes of Health and published in the Journal of Toxicology & Environmental Health (2013). Unlike other artificial sweeteners, sucralose is soluble in ethanol, methanol, and water, making it the sweetener of choice for thousands of low-calorie foods and drinks worldwide as well as pharmaceutical medications. Its biological effects have largely been ignored because manufacturers claim that virtually all of the chemical is excreted from the body intact.
In their overview, Schiffman and Rother discuss research pertaining to sucralose's effect on body weight, its alteration of gastrointestinal microflora, its effect on detoxification and possible interaction with therapeutic drugs, and questions about sucralose metabolite safety and toxicity. Metabolites have been detected in feces and urine from rats and from humans using thin-layer chromatography, but the identity and the safety of these metabolites is unknown. None of the research that Schiffman and Rother present is conclusive, but they do raise troubling questions.
The rationale for using a noncaloric artificial sweetener is weight reduction and blood sugar control for people with diabetes. Animal studies show that sucralose interacts with sweet taste receptors in the GI tract, the pancreas, and the hypothalamus. As a result, glucose transport and insulin secretion increase. How does this affect human weight? Schiffman and Rother found two studies in which sugar-sweetened drinks were replaced with sucralose-sweetened diet drinks: a 2-year study with adolescents and an 18-month study with children. The adolescent study found "no consistent reduction of weight gain," according to Schiffman and Rother. In the other study, the difference in total weight gain between children who drank artificially sweetened soda and children drinking sugar-sweetened soda was minimal – just 1 kilogram after 18 months. Schiffman and Rother found no long-term prospective weight studies involving sucralose use in adults. "Because [organochloride] compounds and artificial sweeteners have both been associated with weight gain, and because sucralose is a member of both categories, it is important to determine its effect on mechanisms that regulate body weight," state Schiffman and Rother.
Sucralose in the form of Splenda alters the bacterial composition of the gastrointestinal tract in rats, according to a 2008 study by Mohamed B. Abou-Donia and colleagues at Duke University Medical Center (Durham, NC). Splenda consists of sucralose, maltodextrin, and glucose. For 12 weeks, male Sprague-Dawley rats were given a daily dose of sucralose: 0 (vehicle control), 1.1, 3.3, 5.5, or 11 mg/kg of body weight. All dose levels were below the EU's Acceptable Daily Intake (ADI) of 15 mg/kg/day. (The US ADI is 5 mg/kg of body weight.) Researchers collected fecal samples during each week of treatment and for an additional 12-week follow-up. "Data showed that bacterial counts in the [gastrointestinal tract] from daily sucralose ingestion decreased progressively and monotonically in a methodical pattern during each successive week of sucralose treatment," write Schiffman and Rother. The numbers of lactobacilli, bifidobacteria, and other beneficial anaerobes declined significantly more than harmful bacteria such as enterobacteria. Three months after sucralose treatment ceased, the total number of beneficial anaerobes was still less than pretreatment levels. Does sucralose/Splenda have the same effect on human gut bacteria?
As part of the same study, Abou-Donia and colleagues measured intestinal P-gp, CYP3A, and CYP2D activity. P-gp transports harmful chemicals out of intestinal cells and back into the lumen so that they can be excreted. Enzymes CYP3A and CYP2D metabolize drugs and other foreign chemicals. Activity levels of P-gp and the CYP enzymes did not change much when the rats were given 1.1 mg/kg of sucralose per day. All three increased with a dosage of 3.3 mg/kg/d sucralose, the equivalent of about two 12 oz servings (340 grams of sucralose) of diet soda for a 130-pound (58.9 kg) adult or one 12 oz serving for a 70-pound (31.8 kg) child. "CYP3A and CYP2D expression increased in a linear, dose-dependent manner as the dosage of sucralose increased from 3.3 to 5.5 to 11 mg/kg/d," report Schiffman and Rother. P-gp expression, however, "decreased significantly" at 11 mg/kg. Changes in P-gp and CYP expression were still evident at the end of the 12-week recovery period.
CYP3A and CYP2D take part in the breakdown of about 70% of all therapeutic medications. When the expression of these enzymes increases in response to sucralose, the bioavailability of some medications may decrease; the ramped-up CYP activity would break down the medications more quickly. "The finding by Abou-Donia et al. that the sucralose (delivered as Splenda) interacts with efflux and metabolizing proteins is consistent with an extensive scientific literature that indicates [organochlorine] compounds characteristically interact with CYP (and in some cases P-GP)," say Schiffman and Rother.
Sucralose manufacturer Tate & Lyle deems the Abou-Donia study "not credible" and the Schiffman and Rother overview as being based on "old, discredited" research, according to E. Watson. The article offers no specifics. I did find a rebuttal to the Abou-Donia study in Regulatory Toxicology & Pharmacology (October 2009): "Expert panel report on a study of Splenda in male rats." Its abstract claims the Abou-Donia study "was deficient in several critical areas." It, too, offers no specifics, and I could not access the full article. I wonder who declared the authors an "expert panel."
Abou-Donia MB, El-Masry EM, Abdel-Rahman AA, McLendon RE, Schiffman SS. Splenda alters gut microflora and increases intestinal P-glycoprotein and cytochrome P-450 in male rats. J Toxicol Environ Health. Part A: Current Issues. 2008;71(21). Available at www.ncbi.nlm.nih.gov/pubmed/18800291. Accessed January 25, 2014.
Brusick D, Borzelleca JF, Gallo M et al. Expert panel report on a study of Splenda in male rats [abstract]. Regul Toxicol Pharmocol. October 2009;55(1):6–12. Available at www.ncbi.nlm.nih.gov/pubmed/19567260. Accessed February 5, 2014.
Schiffman SS, Rother KI. Sucralose, a synthetic organochlorine sweetener: overview of biological issues. J Toxicol Environ Health. Part B. 2013;16:399–451. Available at www.tandfonline.com/loi/uteb20. Accessed December 27, 2013.
(Link to article: http://www.tandfonline.com/doi/full/10.1080/10937404.2013.842523)
Watson E. Tate & Lyle defends sucralose safety after researchers claim the sweetener is 'not biologically inert.' November 18, 2013. Available at www.foodnavigator-usa.com. Accessed January 29, 2014.
(Link to article: http://www.foodnavigator-usa.com/R-D/Tate-Lyle-defends-sucralose-safety-after-researchers-claim-the-sweetener-is-not-biologically-inert)
Supplements and Liver Injury
"Dietary supplements account for nearly 20 percent of drug-related liver injuries that turn up in hospitals, up from 7 percent a decade ago, according to an analysis by a national network of liver specialists," declared a December 21, 2013, New York Times article. Dietary supplements – vitamins, minerals, herbs, functional foods – cause 20% of liver injuries? The article, written by Anahad O'Connor, was based on new data from the Drug-Induced Liver Injury Network (DILIN) that tracks patients with liver damage from "certain drugs and alternative medicines." These data were presented at the November 2012 Liver Conference in Washington, DC. I was unable to find a published study with these data to see what drugs and supplements were included. However, a 2008 study from DILIN specifically states that liver injury due to acetaminophen, a primary cause of drug-induced liver injury, is not included.
The 2008 prospective study, led by Naga Chalasani, followed the first 300 patients with acute liver failure to enroll in DILIN for at least 6 months. The authors reported that a single prescription medication was linked to 73% of the patient injuries: "antimicrobials (45.5%) and central nervous system agents (15%) were the most common." Dietary supplements were associated with 9% of drug-induced liver injuries, and the remaining 18% of cases occurred in patients taking more than one drug/supplement. At the November conference, researchers said that supplements accounted for one-fifth of the 313 drug-related liver injuries reported to DILIN in 2010 to 2012. Weight-loss and muscle-building products are the biggest threats, according to O'Connor.
To illustrate the dangers of supplements, O'Connor presents a Texas high school student who "suffered severe liver damage after using a concentrated green tea extract he bought at a nutrition store as a 'fat burning' supplement. The damage was so extensive that he was put on the waiting list for a liver transplant." The actual case report, written by Dr. Shreena S. Patel and colleagues, appeared in World Journal of Gastroenterology (August 21, 2013). According to the case report, the young man was taking several products to lose weight: Nopal (cactus; 1 pill daily), Applied Nutrition Green Tea Fat Burner (2 pills/400 mg epigallocatechin-3-gallate [EGCG] daily), whey protein (3 times per week), and GNC Mega Men Sport (2 pills 3 times per week). He lost 56 pounds in 60 days – almost a pound a day. Rapid weight loss in itself (more than 4 pounds/week) can cause liver damage, according to Harvard Health Letter. Patel et al. did not mention this. "We are associating our patient's impending liver failure to his ingestion of green tea extract given the history taken, histological findings, and after literature review of all the products and ingredients ingested," said the authors. They relied solely on product labels to identify ingredients. The products themselves were not analyzed by a laboratory to identify contaminants or components not identified on the label. The authors assumed that green tea extract was the culprit because other reports have linked it to liver injury.
The catechins in green tea have shown therapeutic effects in animal and human trials for conditions such as cancer, metabolic syndrome and insulin resistance, and heart disease. The catechins have also prevented liver injury in research studies. An extract, however, is more concentrated than drinking a cup or two of tea. More is not always better. In addition, some green tea extract products contain other ingredients that may interact in unexpected ways. When reports of liver damage in users of green tea extract arose, a US Pharmacopeia (USP) Dietary Supplement Information Expert Committee reviewed over 40 years of clinical case reports, published reviews, animal pharmacological and toxicological testing, and reports from adverse event systems in the US, Australia, UK, and Canada. "A total of 216 case reports on green tea products were analysed, including 34 reports concerning liver damage," according to the panel's report. "Twenty-seven reports pertaining to liver damage were categorized as possible causality and seven as probably causality." The panel found that adverse effects occurred more often when green tea extract is taken on an empty stomach. Green tea products should be consumed with food to lessen the risk of adverse effects. As a result of the review, the USP panel classified green tea extract as "Class A," meaning that no cautionary/warning labeling statement is required, according to "USP Update on the USP Green Tea Extract Monograph" (April 10, 2009).
Contrary to O'Connor's article that paints the entire category of dietary supplements as liver damaging, the category is much smaller. When liver damage arises from taking dietary supplements, those supplements are nearly always aimed at weight-loss and/or muscle-building products – some of which have been adulterated with steroids or pharmaceuticals. Forcing quick weight loss may also be a factor.
Chalasani N, Fontana RJ, Bonkovsky HL, et al. Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States [abstract]. Gastroenterology. December 2008;135(6):1924–1934. Available at www.gastrojournal.org/article/S0016-5085(08)01674-0/abstract. Accessed January 17, 2014.
O'Connor A. Spike in harm to liver is tied to dietary aids. New York Times. December 21, 2013. Available at www.nytimes.com/2013/12/22/us/spike-in-harm-to-liver-is-tied-to-dietary-aids.html. Accessed December 27, 2013.
Patel SS, Beer S, Kearney DL, Phillips G, Carter BA. Green tea extract: A potential cause of acute liver failure. World J Gastroenterol. August 21, 2013;19(31):5174–5177. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3746392. Accessed December 31, 2013.
Sarma DN, Barrett ML, Chavez ML et al. Safety of green tea extracts: a systematic review by the US Pharmacopeia. Drug Saf. 2008;31(6):469–484. Available www.ncbi.nlm.nih.gov/pubmed/18484782. Accessed December 31, 2013.
Update on the USP Green Tea Extract Monograph. April 10, 2009. Available at www.usp.org. Accessed January 17, 2014.
(Link to article: http://www.usp.org/usp-nf/notices/retired-compendial-notices/update-usp-green-tea-extract-monograph)
When the liver gets fatty. Harvard Health Letter. January 2011. Available at www.health.harvard.edu/newsletters/Harvard_Health_Letter/2011/January/when-the-liver-gets-fatty. Accessed January 22, 2014.
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