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Fulminant Liver Failure Due to Usnic Acid for Weight Loss
Abstract
The use of complementary and alternative medicine (CAM) in developed countries has increased significantly over the years. Among the most popular are the weight loss supplements or "fat burners." Liver failure due to these popular remedies has been widely recognized. Usnic acid has been an ingredient of dietary supplements that cause liver failure. Its hepatotoxicity has not been recognized because it is usually mixed with other ingredients that are presumably hepatotoxic. We describe a case of a 28-yr-old woman who presented with fulminant liver failure requiring orthotopic liver transplantation, after taking pure usnic acid for weight loss. This is the first report on fulminant liver failure associated with the ingestion of pure usnic acid. A discussion about hepatotoxicity of the different compounds of dietary supplements is presented. This is a reminder for the clinicians about the potential side effects of CAM.
... Several cases of acute liver failure (ALF) related to a combination of DS with usnic acid alone or in combination with other products have been reported, including cases requiring liver transplantation [70][71][72][73][74]. Hepatotoxicity has been described related to the intake of a multiingredient preparation LipoKinetix, a product that contains norephedrine, caffeine, yohimbine, diiodothyronine, and sodium usniate (usnic acid) [70,73,74]. ...
... Durazo et al. reported a case of a 28-year-old woman who developed ALF and required orthotopic liver transplantation after two weeks of intake of pure usnic acid for weight loss [71]. Another two cases of severe liver toxicity related to a multi-ingredient health supplement UCP-1 (BDC Nutrition, Richmond, KY, USA), a combination containing usnic acid, L-carnitine, and calcium pyruvate, were published by Sanchez et al. in 2006. ...
... The different forms of DSILI considered in this review can be differentiated into two groups based on their characteristic phenotypes: AAS and the remaining DSILI cases. While AAS hepatotoxicity typically produce high values of TB with low levels of transaminases, and no cases of ALF described to date [10,11,[23][24][25][26], liver injury due to the remaining DS has typically a hepatocellular pattern of liver damage with very high transaminase levels [8,47,49,[64][65][66]97,103] and a high number of cases with ALF [53,60,62,65,[70][71][72][73][74]78,80,92,101,102]. Hence, DSILI constitutes an important cause of ALF in transplantation centers [73,74]. ...
Dietary supplements (DS) are extensively consumed worldwide despite unproven efficacy. The true incidence of DS-induced liver injury (DSILI) is unknown but is probably under-diagnosed due to the general belief of safety of these products. Reported cases of herbals and DS-induced liver injury are increasing worldwide. The aim of this manuscript is to report a tabular listing with a description of DS associated with hepatotoxicity as well as review the phenotype and severity of DSILI. Natural remedies related to hepatotoxicity can be divided into herbal product-induced liver injury and DS-induced liver injury. In this article, we describe different DS associated with liver injury, some of them manufactured DS containing several ingredients (Herbalife™ products, Hydroxycut™, LipoKinetix™, UCP-1 and OxyELITE™) while others have a single ingredient (green tea extract, linoleic acid, usnic acid, 1,3-Dimethylamylamine, vitamin A, Garcinia cambogia and ma huang). Additional DS containing some of the aforementioned ingredients implicated in liver injury are also covered. We have also included illicit androgenic anabolic steroids for bodybuilding in this work, as they are frequently sold under the denomination of DS despite being conventional drugs.
... However, severe hepatic reactions have been reported, including liver necrosis, fulminant hepatitis, and liver failure, in people consuming dietary supplements containing usnic acid [12][13][14][40][41][42][43]. The U.S. FDA received at least 21 case reports of hepatotoxicity after LipoKinetix consumption (includes phenylpropanolamine, usnic acid, 3,5-diiodo-Lthyronine, yohimbine hydrochloride, and caffeine). ...
... Reactive metabolites are speculated to be involved in the hepatotoxic effects of high doses of usnic acid. However, several reports have shown that individuals suffer from severe hepatonecrosis, fulminant hepatic failure, and other toxicity effects after taking usnic acid or dietary supplements containing usnic acid [12][13][14][40][41][42][43]. Several reports have suggested that usnic acid in Lipokineti causes hepatotoxicity and usnic acid can cause moderate hepatic injury in normal rats in a dose-dependent manner [2,112,113]. ...
Lichens are among the most widely distributed plants on earth and have the longest growth cycle. Usnic acid is an abundant characteristic secondary metabolite of lichens and the earliest lichen compound used commercially. It has diverse pharmacological activities, such as anti-inflammatory, antibacterial, antiviral, anticancer, antioxidant, and photoprotective effects, and promotes wound healing. It is widely used in dietary supplements, daily chemical products (fodder, dyes, food, perfumery, and cosmetics), and medicine. However, some studies have found that usnic acid can cause allergic dermatitis and drug-induced liver injury. In this paper, the bioactivity, toxicity, in vivo and in vitro metabolism, and pharmacokinetics of usnic acid were summarized. The aims were to develop and utilize usnic acid and provide reference for its future research.
... Besides applications in traditional medicine, usnic acid extracts and pure usnic acid have been taken as dietary supplements to stimulate weight loss. However, over 30 cases of acute liver failure (some severe cases even required liver transplantation) have been reported due to the use of relatively high doses of usnic acid that are required to produce significant weight reduction in some individuals (Durazo et al. 2004; Favreau et al. 2002; Neff et al. 2004; Yellapu et al. 2011). Despite the fact that the U.S. FDA has posted warnings on dietary Abstract Many usnic acid-containing dietary supplements have been marketed as weight loss agents, although severe hepatotoxicity and acute liver failure have been associated with their overuse. ...
... It is worth noting that the human plasma concentration after intake of usnic acid remains unclear because it was marketed as dietary supplement and did not require clinical studies for regulatory approval. The calculated plasma concentration of usnic acid is 7.4–37 μM (Chen et al. 2014a) based on the recommended daily dose of 100–500 mg (Durazo et al. 2004; Favreau et al. 2002 ). The concentration of 3.13–50 μM used in this study falls in the range of plasma concentration and thus is clinically relevant. ...
Many usnic acid-containing dietary supplements have been marketed as weight loss agents, although severe hepatotoxicity and acute liver failure have been associated with their overuse. Our previous mechanistic studies revealed that autophagy, disturbance of calcium homeostasis, and ER stress are involved in usnic acid-induced toxicity. In this study, we investigated the role of oxidative stress and the Nrf2 signaling pathway in usnic acid-induced toxicity in HepG2 cells. We found that a 24-h treatment with usnic acid caused DNA damage and S-phase cell cycle arrest in a concentration-dependent manner. Usnic acid also triggered oxidative stress as demonstrated by increased reactive oxygen species generation and glutathione depletion. Short-term treatment (6 h) with usnic acid significantly increased the protein level for Nrf2 (nuclear factor erythroid 2-related factor 2), promoted Nrf2 translocation to the nucleus, up-regulated antioxidant response element (ARE)-luciferase reporter activity, and induced the expression of Nrf2-regulated targets, including glutathione reductase, glutathione S-transferase, and NAD(P)H quinone oxidoreductase-1 (NQO1). Furthermore, knockdown of Nrf2 with shRNA potentiated usnic acid-induced DNA damage and cytotoxicity. Taken together, our results show that usnic acid causes cell cycle dysregulation, DNA damage, and oxidative stress and that the Nrf2 signaling pathway is activated in usnic acid-induced cytotoxicity.
... Lichens also contain many unique, biologically active compounds. Some of these compounds are potent toxins that can sicken or kill animals that lack adequate detoxification mechanisms (Dailey et al. 2008;Durazo et al. 2004;Guo et al. 2008). R. bieti is clearly able to handle these otherwise negative nutritional aspects of lichen. ...
... However, oral administration of usnic acid to sheep resulted in a different constellation of symptoms (lethargy, anorexia, muscle weakness, and abdominal discomfort), indicating that other compounds may have been involved, or that the elk microbial community metabolized the usnic acid into a different toxic compound, or that elk and sheep respond differently to usnic acid (Dailey et al. 2008). In monogastric animals including humans, usnic acid has been associated with liver damage and failure (Durazo et al. 2004;Pramyothin et al. 2004). It is thought to have antifeedant properties, perhaps as an antiherbivore defense (Dubay et al. 2008;Lawrey 1986). ...
The endangered black-and-white snub-nosed monkey, Rhinopithecus bieti, consumes a diet that often consists primarily of lichen, which serves as both a dietary staple and an important fallback food, particularly in winter. The colobine lineage of R. bieti may explain how this primate is able to subsist for long periods on this low-protein food and detoxify its toxins. Climate change will have profound impacts on the flora of this region, particularly on lichen, and it is increasingly important to establish baseline surveys of lichen in this region to understand how the R. bieti population will be affected.
... Due to the development of signs and symptoms of hepatotoxicity, she was transferred to the Medical Center of the University of California, Los Angeles (UCLA), where she underwent liver transplant. She recovered completely, and the examination of the injured liver demonstrated a shrunken organ (470 g, while the weight of a normal liver is usually around 1,200 g) with scattered irregularly shaped nodules of residual parenchyma [55]. Sanchez et al. described two subjects who developed severe hepatotoxicity while using UCP-1 at the recommended daily dose. ...
Usnic acid (UA) is a dibenzofuran derivative naturally present in lichens, organisms resulting from the symbiosis between a fungus and a cyanobacterium, or an alga. UA shows antimicrobial, antitumor, antioxidant, analgesic, anti-inflammatory as well as UV-protective activities. Its use as pharmacological agent is widely described in traditional medicine, and in the past few years, the product has been marketed as a food supplement for the induction of weight loss. However, the development of severe hepatotoxicity in a limited number of subjects prompted the FDA to issue a warning letter, which led to the withdrawal of the product from the market in November 2001. Data published in literature on UA toxicology, genotoxicity, mutagenesis, and teratogenicity have been reviewed, as well as the case reports of subjects who developed hepatotoxicity following oral administration of UA as a slimming agent. Finally, we reviewed the most recent studies on the topical use of UA, as well as studies aimed at improving UA pharmacologic activity and reducing toxicity. Indeed, advancements in this field of research could open the possibility to reintroduce the use of UA as therapeutical agent.
... Usnic acid has been widely used as an ingredient for daily necessities including toothpastes and mouthwashes 55 . It has also been used as a dietary supplement for weight loss 61 . Unfortunately, usnic acid exhibits hepatotoxicity because of the uncoupling of oxidative phosphorylation, resulting in the destruction of mitochondrial respiration at very high concentrations 62 . ...
The pandemic caused by severe acute respiratory Coronavirus-2 (SARS-CoV-2) has been ongoing for over two years, and treatment for COVID-19, other than monoclonal antibodies, is urgently required. Accordingly, we have investigated the inhibitors of SARS-CoV-2 protein targets by high-throughput virtual screening using a marine natural products database. Considering the calculated molecular properties and availability of the compounds, (+)-usnic acid was selected as a suitable hit. In the in vitro antiviral assay of (+)-usnic acid by the immunofluorescence method, IC50 was 7.99 μM, which is similar to that of remdesivir used as a positive control. The generalized Born and surface area continuum solvation (MM/GBSA) method was performed to find the potent target of (+)-usnic acid, and the Mpro protein showed the most prominent value, −52.05 kcal/mol, among other SARS-CoV-2 protein targets. Thereafter, RMSD and protein–ligand interactions were profiled using molecular dynamics (MD) simulations. Sodium usnate (NaU) improved in vitro assay results with an IC50 of 5.33 μM and a selectivity index (SI) of 9.38. Additionally, when (+)-usnic acid was assayed against SARS-CoV-2 variants, it showed enhanced efficacy toward beta variants with an IC50 of 2.92 μM and SI of 11.1. We report the in vitro anti-SARS-CoV-2 efficacy of (+)-usnic acid in this study and propose that it has the potential to be developed as a COVID-19 treatment if its in vivo efficacy has been confirmed.
... Вместе с тем, следует отметить, что употребление различных БАД могут в том числе и негативно сказываться на состоянии пациента с хронической патологией печени. К таким продуктам относится и усниновая кисота, продукт лишайника Usnea [13], используемая в БАД для похудения, применение которой ассоциировано с развитием токсического поражения печени, острой печеночной недостаточности и осуществления транспланта печени [10]. В настоящее время не существует научно доказанной безопасности и эффективности применения этого препарата для понижения веса, что требует от клинициста внимания и настороженности в проведении опроса в каждом отдельном случае, особенно у больных с ХДЗП у которых риск ухудшения состояния печени особенно велик. ...
Recently, there has been a gradually but steadily growing interest of medical scientific community in the nutritional state of the population. Scientists of various specialties develop models for assessing the metabolic state of the patient's body based on the main links that make up the nutritive balance. Nutrition is one of the important factors that make up the picture of metabolic nutritive status. Currently, there are many tools for assessing the nutritional stare of a patient, including those with chronic liver disease. Knowledge of this subject will allow the correct use of a certain tool in each individual case, including in clinical practice.
... These studies suggested the anti-metastatic potential of usnic acid in cancer cells [33]. Additionally, a few studies have suggested that usnic acid can induce hepatotoxicity if consumed frequently [34,35]. This should be taken into consideration for its pharmacokinetic analysis. ...
... These studies suggested the anti-metastatic potential of usnic acid in cancer cells [33]. Additionally, a few studies have suggested that usnic acid can induce hepatotoxicity if consumed frequently [34,35]. This should be taken into consideration for its pharmacokinetic analysis. ...
... These studies suggested the anti-metastatic potential of usnic acid in cancer cells [33]. Additionally, a few studies have suggested that usnic acid can induce hepatotoxicity if consumed frequently [34,35]. This should be taken into consideration for its pharmacokinetic analysis. ...
... Another relevant study associated with human hepatotoxicity was carried out by Durazo et al. (2004). The authors described an acute liver failure after 2 weeks of UA administration in a dosage of 500 mg/day. ...
Among the various compounds of natural origin, usnic acid (UA) is one of the best studied. It has several pharmacological activities, standing out as an antimicrobial, antitumor, antiviral, and antiparasitic agent, and despite these relevant properties, it is a toxic molecule. In this context, research has driven the development of innovative alternatives, such as their encapsulation in controlled release systems, an attractive tool for pharmaceutical nanotechnology. These systems allow the active ingredient to be released at the optimal yield speed and reduce the dosing regimen. Consequently, they are able to increase therapeutic efficacy by minimizing side effects. Given the above, this paper presents a review of the literature on chemical and biological properties, analytical methods, mechanism of action and toxicology of UA, and discusses the use of nanotechnology as a tool to overcome the obstacles of its pharmacological application.
... Dietary supplements containing usnic acid is used for weight reduction in the United States. The chronic consumption of higher doses of usnic acid may induce hepatotoxicity and genotoxicity [9,10]. However, this was claimed by the study which was focused on a single human patient. ...
Usnic acid, a dibenzofuran derivative found in many lichen species, is reported to have anticancer activity against human gastric cancer. We investigated the molecular alterations associated with anticancer effects of usnic acid against human gastric adenocarcinoma AGS and gastric carcinoma SNU-1 cells. Usnic acid (10-25 μM) treatment to these cells caused a significant increase in mitochondrial membrane depolarization and apoptotic cells. Apoptosis induction was accompanied by an increase in the ratio of Bax:Bcl-2 expression and cleaved-PARP. Usnic acid increased the comet tail length and tail DNA in alkaline comet assay indicating DNA double-strand breaks which was also evidenced by an increase in γH2A.X (Ser139) phosphorylation. The expression of DNA damage response proteins including DNA-PKcs, pATM (Ser1981), Chk-2 and p53 were increased. Further, N-acetyl cysteine, a known reactive oxygen species (ROS) scavenger, reversed the effects of usnic acid on expression of DNA damage response proteins and γH2A.X (Ser139) phosphorylation. This reversal was also observed in comet assay in a time and dose-dependent manner suggesting that usnic acid-induced DNA damage was caused by ROS. In addition, the non-toxic concentrations (1-10 μM) of usnic acid inhibited colony forming potential of AGS cells indicating its anti-proliferation activity. More importantly, the concentration of usnic acid that caused significant death in gastric cancer cells, did not show any considerable toxicity to normal human embryonic kidney HEK293 cells, human keratinocyte HaCaT cells and mouse primary gastric cells. Collectively, these results for the first time demonstrated the selective apoptotic effect of usnic acid (10-25 μM) through ROS generation and DNA damage on human gastric cancer cells accompanied with upregulation of γH2A.X (Ser139) phosphorylation, DNA-PKcs and p53.
... 12 The excellent inhibitory effect of usnea sodium on T. gondii in vitro has been proven by Chinese researchers. 20 However, the toxicity of usnic acid, especially liver failure 21 and cultured mouse hepatocyte necrosis, 22 has also been reported. Nevertheless, poor solubility in water 23 and hepatotoxicity 24 limit the application of usnic acid to some extent. ...
Six series of (+)-usnic acid derivatives were synthesized. The IC50 values of these compounds were determined in T. gondii-infected HeLa cells (μM) and in HeLa cells (μM), and their selectivity indexes (SI) were calculated. In vitro, most of the derivatives tested in this study exhibited more anti-T. gondii activity than that of the parent compound (+)-usnic acid and the positive control drugs. Among these derivatives, methyl(E)- (1-(6-acetyl-7,9-dihydroxy-8,9b-dimethyl-1,3-dioxo-3,9b-dihydrodibenzo[b,d]furan-2(1H)-ylidene)ethyl)phenylalaninate (D3) showed the most effective anti-T. gondii activity (Selectivity: > 2.77). And compared with the clinically used positive control drugs sulfadiazine (Selectivity: 1.15), pyrimethamine (Selectivity: 0.89), spiramycin (Selectivity: 0.72) and the lead compound (+)-usnic acid (Selectivity: 0.96), D3 showed better results in vitro. Furthermore, D3 and (E)-6-acetyl-7,9-dihydroxy-8,9b-dimethyl-2-(1-(quinolin-6-ylamino)ethylidene)dibenzo[b,d]furan-1,3(2H,9bH)-dione (F3) had more inhibitory effects on T. gondii (inhibition rate: 76.0% and 64.6%) in vivo than spiramycin (inhibition rate: 55.2%) and in the peritoneal cavity of mice, the number of tachyzoites was significantly reduced (p < 0.001) in vivo. Additionally, some biochemical parameters were measured, spleen indexes were comprehensively evaluated, and the results indicated that mice treated with both compound D3 and compound F3 showed reduced hepatotoxicity and significantly enhanced antioxidative effects compared to the normal group. And granuloma and cyst-formation were effected by the inhibition of compound D3 and compound F3 in liver sections. Overall, these results indicated that D3 and F3 for use as anti-T. gondii agents are promising lead compounds.
... Atranorin is antibacterial, but its toxicity has not been shown in animal models so far (De Melo et al. 2011), while usnic acid can be toxic to both animals and humans (Dailey et al. 2008) and even lethal in high doses, as shown for sheep (Durazo et al. 2004). Still lichens may contribute more than 50% of the winter diet of reindeer in Subarctic and Arctic areas where lichens are an abundant part of the vegetation (Borch-Iohnsen et al. 1996;Svihus & Holand 2000;Storeheier et al. 2002;Denryter et al. 2017). ...
Previous studies of Eurasian tundra reindeer (Rangifer tarandus tarandus) in
Norway indicate that their rumen microbiota play a key role in degrading lichen
secondary metabolites. We investigated the presence of usnic acid and atranorin
in faecal samples from Svalbard reindeer (R. tarandus platyrhynchus). Samples
were collected in Bolterdalen valley together with vegetation samples from the
study site. The mesic tundra in this area was dominated by vascular plants (59%
of vegetation cover). Bryophytes (16%) and lichens (25%) were also present.
Qualitative and quantitative analyses of usnic acid and atranorin in lichen and
faeces samples were performed using high-performance liquid chromatography. Contents of atranorin averaged 12.49 ± 0.41 mg g–1 in the thalli of Stereocaulon alpinum, while the average level of usnic acid was lowest in Cladonia mitis
(12.75 ± 2.86 mg g–1) and highest in Flavocetraria cucullata (34.87 ± 0.47 mg g–1).
Atranorin and usnic acid were detected in the faecal samples, averaging 0.41 ±
0.53 and 0.74 ± 1.11 (mean ± SD) mg g–1 dry matter, respectively. The presence
of lichen secondary compounds in faeces from Svalbard reindeer shows that
lichens are indeed included in their diet, although probably in small amounts
because of depleted pastures. Contrary to previous fndings in reindeer on
mainland Norway, atranorin and usnic acid are not completely degraded or
absorbed in Svalbard reindeer. To elucidate the mechanisms behind detoxifcation of lichen secondary compounds in reindeer, more research is needed on
their respective rumen microbiomes and digestive enzymes.
... Accumulating evidence indicates that caffeine and yohimbine are the two most frequent components of HDS linked to adverse health effects . For instance, both were present in Lipokinetix™, a multi-ingredient HDS marketed for weight loss, suspected of causing acute hepatitis and liver failure and ultimately banned by the U.S. FDA (Favreau et al., 2002;Durazo et al., 2004). Although usnic acid present in Lipokinetix™ was believed to be the causative agent, the contributions of caffeine, yohimbine, and other phytochemicals in exacerbating liver injury cannot be ruled out. ...
... Hepatitis has been reported in WLS containing usnic acid. In the early 2000s, a supplement marketed under the name LipoKinetix was linked to several cases of serious liver injury with some severe enough to require transplantation [74,75]. LipoKinetix was withdrawn from the market in 2001 per the recommendation of the FDA [74]. ...
Purpose of Review
To highlight the current trends of weight loss supplement (WLS) use in the United States, detail their potential for drug-induced liver injury (DILI), identify specific compounds associated with hepatoxicity that are commonly found in WLS, and address ongoing diagnostic as well as treatment challenges.
Recent Findings
The regulatory nature of WLS exposes patients to a variety of potential healthcare pitfalls associated with WLS use. These include marketing claims with little supportive evidence, compound adulteration, and herb-drug interactions. While well-known historical cases have resulted in specific compound banning, supplements associated with DILI remain on the market. Trends in the clinical presentation of DILI due to WLS are present but are by no means dogmatic. Furthermore, DILI predictability is clinically challenging due to a variety of complexities. Cessation of the offending agent continues to be the treatment mainstay outside of liver transplantation in the most severe of cases.
Summary
Increased accessibility and consumer demand will continue to drive WLS usage. With this, clinicians must actively screen all patients for their use and be aware of specific herbals implicated in DILI. Educating patients on the risks of WLS use is imperative given limited treatment options.
... Usnic acid (Durazo et al. 2004;Erba et al. 1998), a natural compound found in some species of lichen of the genus Usnea, has a variety of biological effects (Pramyothin et al. 2004), including against protozoa (Ingolfsdottir 2002). Due to its toxicity and low solubility in water, the utilization of liposomes can improve transport to target cells. ...
Toxoplasmosis is an infectious disease caused by the intracellular parasite Toxoplasma gondii that affects about one third of the world’s population. The diagnosis of this disease is carried out by parasite isolation and host antibodies detection. However, the diagnosis presents problems in regard to test sensitivity and specificity. Currently, the most effective T. gondii treatment is a combination of pyrimethamine and sulfadiazine, although both drugs are toxic to the host. In addition to the problems that compromise the effective diagnosis and treatment of toxoplasmosis, there are no reports or indications of any vaccine capable of fully protecting against this infection. Nanomaterials, smaller than 1000 nm, are currently being investigated as an alternative tool in the management of T. gondii infection. This article reviews how recent nanotechnology advances indicate the utility of nanomaterials in toxoplasmosis diagnosis, treatment, and vaccine development.
... A pesar de sus presuntos beneficios para la pérdida de peso, el ácido úsnico es considerado como una hepatotoxina directa. Los casos publicados han documentado que causa insuficiencia hepática fulminante 24,25 . ...
... In 1990s, UA was extensively used as a component of fat burners. There were several reports of intoxica tion caused by the burners, mainly associated with hepatotoxicity [37][38][39][40]. The intoxication manifested itself as high levels of alanine aminotransferase (ALT, EC 2.6.1.2), ...
Usnic acid (UA) is a commercially available lichen metabolite. Its biological activity is diverse, and it is of interest for pharmacopoeia. The second part of the review is dedicated to the biological action of UA and its derivatives on higher organisms. Effects exhibited by UA at the cellular level and the molecular and physicochemical aspects of its biological activity are considered. Special attention is placed on the possibility of modifying the biological activity of UA by change of its bioavailability or modification of its molecular structure.
... Despite its purported weight-loss effects, usnic acid has been labeled as a direct hepatotoxin, leading to fulminant liver failure as documented in previously published case reports. 24,25 Noni Juice Extracted from the Noni fruit, Morinda citrifolia, the juice has been used for a variety of purposes from the seasonal flu to diabetes. Cases of acute liver failure, with one patient requiring liver transplantation, have been reported. ...
... To cause this effect, the product contained norephedrine, caffeine, yohimbine, diodothyronine, and sodium usniate. Usnic acid was believed to be the ingredient that caused liver injury [139,140]. ...
In the United States (US), the risk of hepatotoxicity linked to the widespread use of certain herbal products has gained increased attention among regulatory scientists. Based on current US law, all dietary supplements sold domestically, including botanical supplements, are regulated by the Food and Drug Administration (FDA) as a special category of foods. Under this designation, regulatory scientists do not routinely evaluate the efficacy of these products prior to their marketing, despite the content variability and phytochemical complexity that often characterizes them. Nonetheless, there has been notable progress in the development of advanced scientific methods to qualitatively and quantitatively measure ingredients and screen for contaminants and adulterants in botanical products when hepatotoxicity is recognized.
... In Hepatotoxicity of usnic acid may restrict their potential medicinal use in cancer therapeutics [28]. However, most of hepatotoxicity in human was observed when high dose of usnic acid was orally administrated as a dietary supplement for the purpose of weight loss [29][30][31]. In cancer therapeutics, hepatotoxicity can be avoided by adjusting dosage, formulation and/or route of medication. ...
Lichens are symbiotic organisms that produce various unique chemicals that can be used for pharmaceutical purposes. With the aim of screening new anti-cancer agents that inhibit cancer cell motility, we tested the inhibitory activity of seven lichen species collected from the Romanian Carpathian Mountains against migration and invasion of human lung cancer cells and further investigated the molecular mechanisms underlying their anti-metastatic activity. Among them, Alectoria samentosa, Flavocetraria nivalis, Alectoria ochroleuca, and Usnea florida showed significant inhibitory activity against motility of human lung cancer cells. HPLC results showed that usnic acid is the main compound in these lichens, and (+)-usnic acid showed similar inhibitory activity that crude extract have. Mechanistically, β-catenin-mediated TOPFLASH activity and KITENIN-mediated AP-1 activity were decreased by (+)-usnic acid treatment in a dose-dependent manner. The quantitative real-time PCR data showed that (+)-usnic acid decreased the mRNA level of CD44, Cyclin D1 and c-myc, which are the downstream target genes of both β-catenin/LEF and c-jun/AP-1. Also, Rac1 and RhoA activities were decreased by treatment with (+)-usnic acid. Interestingly, higher inhibitory activity for cell invasion was observed when cells were treated with (+)-usnic acid and cetuximab. These results implied that (+)-usnic acid might have potential activity in inhibition of cancer cell metastasis, and (+)-usnic acid could be used for anti-cancer therapy with a distinct mechanisms of action.
... In addition to acetic acid, Kombucha tea contains several organic acids [6,33]. Some of these metabolites have the potential to damage liver and kidney at high concentrations, as evident by few case reports [56,59,60]. Kombucha tea is contraindicated in pregnant and lactating women [53]. ...
Functional foods have been identified as whole foods and fortified, enriched, or enhanced products which have a potentially beneficial effect on health when consumed as part of a varied diet on a regular basis, at effective levels. As consumer awareness on functional food escalates, the interest towards conducting scientific studies in this field has also proportionately increased. Many of the traditional food products are known to possess bioactive components, thus qualifying as functional food. Kombucha tea is produced by fermenting sugared black tea with a mixed culture of yeast and bacteria. Kombucha tea has gained immense popularity in recent times due to many associated health benefits. The therapeutic effects of this beverage are thought to be derived from the chemical composition of this beverage, mainly the polyphenols and secondary metabolites which are produced during fermentation. However, the safety aspects of the beverage also need to be taken into account when qualifying the beverage as a functional food. Nevertheless, Kombucha tea could be easily recognized as a beverage which is able to replace the consumption of carbonated beverages due to its possession of health benefits and therapeutic properties.
... The interaction of herbal products with hepatic enzymes can also result in pharmacodynamic effects (van den Bout-van den Beukel et al., 2008;Nivitabishekam et al., 2009;Asdaq and Inamdar, 2010;Dasgupta et al., 2010;Kim et al., 2010a.) Specific liver injury inducible by phytochemical agents includes elevation in transaminases (Zhu et al., 2004;Saleem et al., 2010), acute and chronic hepatitis (Stedman, 2002;Pierard et al., 2009), liver failure (Durazo et al., 2004), veno-occlusive disorders (DeLeve et al., 2002), liver cirrhosis (Lewis et al., 2006), fibrosis (Chitturi and Farrell, 2000), cholestasis (Chitturi and Farrell, 2008), zonal or diffusive hepatic necrosis (Savvidou et al., 2007), and steatosis . Mechanism of liver injury may include bioactivation of CYP, oxidative stress, mitochondrial injury, and apoptosis (Cullen, 2005). ...
... Data recorded on each patient include the duration of therapy, time to the presentation from the last ingestion, and the determination of the contribution of other possible underlying diseases or medical conditions (Neff et al. 2004). Durazo et al. (2004) reported on a healthy 28-year-old woman who developed acute liver failure within one month after commencing UA (Pure Usnic acid, Industrial strength; AAA Services, USA) 500 mg/day for 2 weeks . Han et al. (2004) evaluated in primary cultured murine hepatocytes that the UA treatment (5 mM) resulted in 98% necrosis within 16 h (no apoptosis was detected). ...
Since its first isolation in 1844, usnic acid [2,6-diacetyl-7,9-dihydroxy-8,9b-dimethyl-1,3(2H,9bH)-dibenzo-furandione] has become the most extensively studied lichen metabolite and one of the few that are commercially available. Lichens belonging to usnic acid-containing genera have been used as crude drugs throughout the world. There are indications of usnic acid being a potentially interesting candidate for such activities as anti-inflammatory, analgesic, healing, antioxidant, antimicrobial, antiprotozoal, antiviral, larvicidal and UV protection. However, some studies reported the liver toxicity and contact allergy. Thus, further studies are needed to establish the efficacy and safety of usnic acid.
Background: Herbal and dietary supplements are commonly used around the world, either supplanting conventional medical therapy or as a supplement to treatment. However, worldwide cases of liver damage have been observed from the consumption of these supplements. Objectives: Carry out a bibliographic review on the damages caused by nutritional and herbal supplements, generating an emerging problem for public health. Material and methods: A selective literature search was conducted in PubMed, MedScape, Google Scholar using terms such as: supplements and liver injury, herbal-induced liver injury, hepatotoxicity related to Herbalife use. The search was mainly focused on case reports, case series and clinical reviews, published from 1984 to 2019. Results: Most of the reports are written in English, only one in Spanish. Conclusions: There is a severe underreporting worldwide, despite the fact that there are reported cases of hepatoxicity caused by dietary supplements , thus pointing to an important public health problem.
Ethnopharmacological relevance
Usnea sp. is a fruticose thalli lichen with interesting medicinal properties. Since ancient times, Usnea sp. has been used in traditional medicine worldwide to treat various diseases. The broad scientific studies on this lichen have proved its multidirectional biological effect, such as antimicrobial activity, which is attributed to its usnic acid content.
Purpose
The main aim of this review is to provide an up-to-date overview of the antimicrobial activities of Usnea sp., including the traditional and medicinal uses, and a critical evaluation of the presented data. Also, the mechanism of this type of action will be explained.
Methods
To prepare this manuscript, the information was extracted from scientific databases (Pubmed, ScienceDirect, Wiley, Springer, and Google Scholar), books, and theses. The available scientific information was critically analysed.
Results
Analysis of the scientific literature regarding traditional uses and bioactivity research showed that Usnea sp. extracts exhibit high antibacterial activity. The Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis, Bacillus cereus, and Mycobacterium tuberculosis) and aquatic oomycetous fungi were the most sensitive Usnea sp. extracts. Moderate activity against Malassezia furfur and dermatophytes was observed, as well. Gram-negative bacteria, yeast, and fungi were more frequently resistant to Usnea sp. extracts (included Escherichia coli, Candida sp., Saccharomyces cerevisiae, and Aspergillus sp.). The antiviral activity of Usnea sp. was limited.
Conclusion
The results show that the use of Usnea sp. in traditional medicine can be scientifically documented. Studies show that usnic acid is the active compound present in Usnea sp. extracts. This compound, which has a high antibacterial and cytotoxic activity, exists in large quantities in low-polarity extracts, and low concentration in these of high-polarity. Usnea sp. extracts contain compounds other than usnic acid as well with biological effects. Usnea barbata is a species that has been employed in modern-day cosmetic and pharmaceutical preparations. The information presented in the review can be considered as a source of knowledge about the Usnea sp. It presents research on biological properties reported for different species of Usnea genus and thus can facilitate their use in medicine.
Lichens are traditionally used as medicine since the medieval period. More than 1000 secondary metabolites have been identified in lichens. It is still unknown why the lichens produce such a plethora of secondary metabolites. However, scientists have successfully utilized them for taxonomy and bioprospecting. The extracts of lichens have exhibited wide range of biological activities, such as antimicrobial (antibacterial, antifungal, antiviral, anti-HIV), antioxidant, anti-inflammatory, antipyretic, analgesic, anti-ulcer, and anticancer activities. The lichen metabolites are also being assayed and found useful as hepatoprotective, cardiovascular protective, gastrointestinal protective, antidiabetic, and probiotic, which are considered as the lifestyle diseases of modern days. Polyketides are one of the major groups of secondary metabolites produced by lichens involving polyketide synthase genes. Interestingly among the 1000 secondary metabolites known from lichens only a few are isolated and tested for their biological activities, while in all remaining cases, activity is indirectly attributed to the presence of various metabolites. In the present chapter, a total of 35 secondary metabolites that are isolated from lichens were tested for biological activities and are listed along with their structure, substance class, and occurrence. Further scope for bioprospecting studies is also discussed.
Dietary supplements “fat burners” freely available on the market, are intended to promote weight loss and reduce fat accumulation, either via stimulation of lipolysis or by inhibition of lipogenesis. Proponents claim that fat burners can increase fat metabolism, although their usefulness remains controversial. Fat burners are usually claimed to be of natural origin and viewed as being inherently safe. This review focuses on the most common ingredients of natural origin usually found in the fat burners, their molecular mechanisms of action and the toxicological profiles of these compounds in order to gain an insight into their safety.
The liver may sustain injury from a variety of environmental, dietary and therapeutic agents. Injury from drugs and toxin may mimic patterns of injury found in other liver diseases, but different agents affect the liver in different ways. Liver biopsy of cases of suspected toxic injury may be used to exclude alternate causes of injury and assess the severity of the injury as well as to compare the injury to literature reports of toxic injury. This chapter reviews the patterns of injury observed in toxic injury as well as what is known about injury due to particular substances.
Usnea longissima Ach. (Usnea) has been used in pharmaceuticals, food, cosmetics. Evernic acid (EA), barbatic acid (BA), diffractaic acid (DA), and usnic acid (UA) are the most typical ingredients in U. longissima and exert a wide variety of biological functions. The study aim to develop a sensitive method for simultaneous analysis of EA, BA, DA, and UA in rat plasma and applied to pharmacokinetic studies after consumption of UA and ethanol extract from U. longissima (UE). The samples were separated on BEH C18 column by gradient elution with 0.5% formic acid in water and in methanol. The relative molecular masses of analytes were obtained in full scan range from 50.0 to 750.0 m/z under negative ionization mode by UPLC-Q-Exactive Orbitrap MS. All validation parameters, such as lower limit of quantitation, linearity, specificity, precision, accuracy, extraction recovery, matrix effect and stability, within acceptable ranges and the method was appropriate for biological specimen analysis. The pharmacokinetics results indicated that the absolute bioavailability of UA after oral administration of UA and UE reaches 69.2% and 146.9%, respectively. Comparing to UA in UE, the relative bioavailability of DA, BA and EA reaches 103.7%, 10.4%, and 0.7% after oral administration of UE.
Xenobiotics: Xenobiotics are defined as exogenously administered or endogenously produced foreign substances that impair and ultimately damage the ecology and homoeostasis of cellular systems. This definition also includes medicinal preparations. (s. p. 56)
Les lichens, organismes symbiotiques associant un champignon et un partenaire photosynthétique (algue verte et/ou cyanobactérie), sont caractérisés par la biosynthèse de métabolites secondaires uniques dotés de bioactivités variées. Pour valoriser au mieux cette ressource privilégiée, des méthodes innovantes de spectrométrie de masse ont été développées dans le but de minimiser la préparation de l’échantillon et la durée des analyses. Deux techniques de spectrométrie de masse ont été évaluées en ce sens : le DART-MS et le LDI-MS. L’apport de chacune de ces deux méthodes a pu être établi sur un large panel de lichens, représentant une part importante de l’espace chimique couvert par ces organismes. Il a été démontré que des profils chimiques complets pouvaient être obtenus respectivement à partir de thalles lichéniques et d’extraits acétoniques totaux. Compte tenu de la très large utilisation de la CCM pour l’analyse chimique de lichens, les possibilités offertes par le couplage de la CCM à l’ionisation electrospray ont également été explorées. Une seconde partie de ces travaux avait pour but de cartographier la distribution des métabolites secondaires au sein du thalle lichénique. À ces fins, des analyses d’imagerie LDI ont été réalisées sur une coupe transversale d’un lichen crustacé modèle : Ophioparma ventosa. Ce lichen a été étudié en phytochimie pour identifier six napthopyranones à partir des apothécies dont quatre nouvelles structures. Les principaux métabolites de ce lichen ont pu être imagés par LDI-MSI avec une résolution spatiale de 50 μm environ. Une corrélation entre la distribution des molécules et leur rôle écologique présumé permet d’avancer des hypothèses d’écologie chimique. Des approches conjointes reliant histolocalisation et étude génétique des partenaires de la symbiose ont été entreprises. La recherche des gènes de la biosynthèse de la mycosporine sérinol chez les symbiontes isolés de Lichina pygmaea par microdissection capture laser a été initiée en ce sens. D’autres approches innovantes comme l’analyse cristallographique par diffraction de poudre par les rayons X sont également abordées dans ce document articulé autour de six publications issues de ce travail et de deux articles en cours de soumission.
Since ages, medicine is the most consistent companion of man. While in primeval time, disease was cured through natural preparations, onset of technology has made today’s formulations synthetic or nature derived. Across the ages, the plausibility of the “savior-turned-slayer” functionality of these drugs remained constant. With the increment in documentation, it becomes evident that many of the commonly used drugs are associated with toxicities. Thus, any drug, irrespective of its origin, needs to be thoroughly assessed. Rampant use of herbal drugs has often been a threat to human health owing to the scarcity in quality assessment. What needs to be understood is that everything natural is not safe. They may pose a threat and thus need to be verified before being touted as a healer. Herein, we discuss the toxicity quotient of herbal medicine in reference to the liver – the metabolic controller of our body. Liver holds a prime position owing to its multitudinal functionality. We attempt to present a brief overview of the mechanisms of hepatotoxicity and highlight the nexus between herbal medicines and liver injury. We discuss the potential ways that can assure quality check of herbal medicines through imposition of regulatory laws, databases, and resorting to toxicogenomics. While constant endeavors need to be made in the quest for novel and more effective drugs, at the same time, assuring its safety is of paramount significance. Thus, plants, which are a huge reservoir of drug leads, necessitate the need to examine products derived from them and subsequently propose their efficacies in human health.
Toxoplasma gondii pathogen is a threat to human health that results in economic burden. Unfortunately, there are very few high-efficiency and low-toxicity drugs for toxoplasmosis in the clinic. (+)-Usnic acid derived from lichen species has been reported to have anti-inflammatory, antibacterial, anti-parasitology, and even anti-cancer activities. Herein, the systematic effect of (+)-usnic acid and (+)-usnic acid-liposome on toxoplasma were studied in vitro and in vivo. The viability of toxoplasma tachyzoite was assayed with trypan blue and Giemsa staining; while the invasive capability of tachyzoite to cardiofibroblasts was detected using Giemsa staining. The survival time of mice and the changes in tachyzoite ultrastructure were studied in vivo. The results showed that (+)-usnic acid inhibited the viability of tachyzoite; pretreatment with (+)-usnic acid significantly decreased the invasion of tachyzoite to cardiofibroblasts in vitro; (+)-usnic acid and (+)-usnic acid-liposome extensively prolonged the survival time of mice about 90.9% and 117%, respectively; and improved the ultrastructural changes of tachyzoite, especially in dense granules, rhoptries, endoplasmic reticulum, mitochondria and other membrane organelles. In summary, these results demonstrate that (+)-usnic acid and (+)-usnic acid-liposome with low toxicity have an inhibitory effect on the viability of toxoplasma tachyzoite, and mainly destructed membrane organelles which are connected with the virulence of toxoplasma. These findings provide the basis for further study and development of usnic acid as a potential agent for treating toxoplasmosis.
Acetaminophen (APAP) is the leading cause of drug-induced acute liver failure in the United States. At normal therapeutic doses, APAP is a safe drug when used by itself. Problems arise when multiple products containing APAP are used and the therapeutic dose is exceeded. A recent US FDA Advisory Committee concluded that other factors such as ethnicity, genetics, and nutrition may also play a role in a person's susceptibility to APAP-induced liver injury. One nutrition factor that is likely to play a role is dietary supplements. Dietary supplement use continues to rise and many consumers consider these products as inherently safe by themselves or in combination with other products, including drugs, since they are ?natural?. However, the safety of most dietary supplements by themselves has not been adequately tested and even less data are available on potential drug - dietary supplement interactions. APAP is metabolized by the liver to a reactive metabolite, NAPQI, that causes a wide array of cellular effects such as depletion of cytoprotective molecules, covalent binding to cellular macromolecules, oxidative stress, and impaired mitochondrial function. Dietary supplements that increase the metabolism of APAP are likely to increase the hepatotoxicity of APAP; whereas, those that decrease APAP metabolism are likely to provide protection. Dietary supplements that affect endpoints downstream of APAP metabolism could also either reduce or increase APAP hepatotoxicity depending on the magnitude and direction of the effect. This chapter reviews the key areas of potential interaction between APAP and dietary supplements and reviews the available data on specific dietary supplements.
Liver injury from dietary supplement mimicking other liver diseases is increasingly recognized. Usnic acid has been marketed as weight-loss aid many years ago in spite its chronic or subchronic effects on animal were not studied. To assess the effect of Usnic acid on the structure of the hepatocytes of male rats and correlate this effect to those changes detected if any in the biochemical study. Forty adult male rats were divided into four groups ten animals each (n = 10); control received standard diet, Gl received 1% carboxymethyl cellulose water solution, G2 received 100 mg usnic acid kg -1 and G3 received 300 mg usnic acid/ kg, 5 days for 7 weeks using gastric gavages. Serum glucose, liver functions, lipid profile, lipase, leptin and Insulin were estimated. Liver was processed for electron microscope studies and results were analyzed using SPSS. The liver index was increased significantly in high-dose Usnic acid compared to the control. Hepatocytes showed an increase in lipid droplets, swollen mitochondria, fragmented rough endoplasmic reticulum cisterns, abundant smooth endoplasmic reticulum and focal damage of hepatocyte membranes near bile canahcuh, all these changes were dose dependent. There was significant increase in total protein, albumin and total bilirubin in group received low-dose of Usnic acid. Glucose, magnesium, total protein, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and total bilirubin were significantly increased in group received Usnic acid at high-dose. Serum cholesterol and high density lipoprotein were significantly increased in all treated groups while triglycendes were slightly increased.
Herbal and dietary supplements are forms of complementary and alternative medicines commonly used throughout the world and are responsible for billions of dollars in commerce in the United States alone. The use of herbal and dietary supplements is deep-rooted in many cultures. However, the global regulatory environment is not standardized and is particularly lax in the United States. As a result, herbal and dietary supplements are vulnerable to batch-to-batch variability in composition and concentration, contamination, and deliberate adulteration. Some herbal and dietary supplements have purported benefits, such as glycyrrhizin and silymarin. However, many more examples exist of preparations that have been linked to liver injury. These include single ingredients, such as kava, germander, and the pyrrolizidine alkaloids, as well as products consisting of multiple ingredients and marketed under a single label, such as Hydroxycut and Herbalife. The attribution of liver injury to herbal and dietary supplements depends upon a careful approach to exclude other causes, leaving the practitioner to further implicate an herbal or dietary supplement based on the chronology of use and recognition of previously described patterns of injury seen with the product or ingredient in question.
The use of usnic acid as a weight loss agent is a safety concern due to reports of acute liver failure in humans. Previously we demonstrated that usnic acid induces apoptosis and cytotoxicity in hepatic HepG2 cells. We also demonstrated that usnic acid induces autophagy as a survival mechanism against its cytotoxicity. In this study, we investigated and characterized further molecular mechanisms underlying the toxicity of usnic acid in HepG2 cells. We found that usnic acid causes endoplasmic reticulum (ER) stress demonstrated by the increased expression of typical ER stress markers, including CHOP, ATF-4, p-eIF2α, and spliced XBP1. Usnic acid inhibited the secretion of Gaussia luciferase measured by an ER stress reporter assay. An ER stress inhibitor 4-phenylbutyrate attenuated usnic acid-induced apoptosis. Moreover, usnic acid significantly increased the cytosolic free Ca(2+) concentration. Usnic acid increased the expression of calcium release-activated calcium channel protein 1 (CRAM1 or ORAI1) and stromal interaction molecule 1 (STIM1), two key components of store-operated calcium entry (SOCE), which is the major Ca(2+) influx pathway in non-excitable cells, this finding was also confirmed in primary rat hepatocytes. Furthermore, knockdown of ORAI1 prevented ER stress and ATP depletion in response to usnic acid. In contrast, overexpression of ORAI1 increased ER stress and ATP depletion caused by usnic acid. Taken together, our results suggest that usnic acid disturbs calcium homeostasis, induces ER stress, and that usnic acid-induced cellular damage occurs at least partially via activation of the Ca(2+) channel of SOCE.
Published by Oxford University Press on behalf of the Society of Toxicology 2015. This work is written by US Government employees and is in the public domain in the US.
AIM: To study the protective effect of eukaryotic expression plasmid encoding augmenter of liver regeneration (ALR) on acute hepatic injury and hepatic failure in rats.
METHODS: The PCR-amplified ALR gene was recombined with pcDNA3 plasmid, and used to treat rats with acute hepatic injury. The rats with acute hepatic injury induced by intraperitoneal injection of 2 mL/kg 50% carbon tetrachloride (CCl4) were randomly divided into saline control group and recombinant pcDNA3-ALR plasmid treatment groups. Recombinant pcDNA3-ALR plasmid DNA (50 or 200 μg/kg) was injected into the rats with acute hepatic injury intraven-ously, intraperitoneally, or intravenously and intraperitoneally in combination 4 h after CCl4 administration, respectively. The recombinant plasmid was injected once per 12 h into all treatment groups four times, and the rats were decapitated 12 h after the last injection. Hepatic histopathological alterations were observed after HE staining, the expression of proliferating cell nuclear antigen (PCNA) in liver tissue was detected by immunohistochemical staining, and the level of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) was determined by biochemical method. The recombinant plasmid DNA (200 μg/kg) and saline were intraperitoneally injected into the rats with acute hepatic failure induced by intraperitoneal injection of 4 mL/kg 50% CCl4 after 4 h of CCl4 administration, respectively. Rats living over 96 h were considered as survivals.
RESULTS: The sequence of ALR cDNA of recombinant pcDNA3-ALR plasmid was accordant with the reported sequence of rat ALR cDNA. After the rats with acute hepatic injury were treated with recombinant pcDNA3-ALR plasmid, the degree of liver histopathological injury markedly decreased. The pathologic liver tissues, in which hepatic degeneration and necrosis of a small amount of hepatocytes and a large amount of infiltrating inflammatory cells were observed, and they became basically normal in the most effective group after four times of injection of recombinant pcDNA3-ALR plasmid. The indexes of PCNA significantly increased in the recombinant pcDNA3-ALR plasmid treatment groups compared to model group. The level of serum AST and ALT remarkably reduced in recombinant pcDNA3-ALR plasmid treatment groups compared to model group. The results showed that the effect of 200 μg/kg recombinant pcDNA3-ALR plasmid in the rats with acute liver injury was stronger than that of 50 μg/kg pcDNA3-ALR DNA. The effect of intravenous injection of recombinant pcDNA3-ALR plasmid was better. After the rats with acute hepatic failure were treated with recombinant pcDNA3-ALR plasmid, the survival rate (40%) significantly increased in treatment groups compared to control group (15%, P<0.01).
CONCLUSION: The ALR gene may play an important role in relieving acute hepatic injury and hepatic failure by promoting hepatic cell proliferation and reducing level of AST and ALT in CCl4-intoxicated rats.
Herbal and dietary supplements (HDS) have been used for health-related purposes since more than 5000 years, and their application is firmly anchored in all societies worldwide. Over last decades, a remarkable renaissance in the use of HDS can be noticed in affluent societies for manifold reasons. HDS are forms of complementary and alternative medicines commonly used to prevent or treat diseases, or simply as a health tonic. Another growing indication for HDS is their alleged benefit for weight loss or to increase physical fitness. Access is easy via internet and mail-order pharmacies, and their turnover reaches billions of dollars in the USA and Europe alone. However, HDS are generally not categorized as drugs and thus less strictly regulated in most countries. As a result, scientific evidence proving their beneficial effects is mostly lacking, although some HDS may have purported benefits. However, the majority lacks such proof of value, and their use is predominantly based on belief and hope. In addition to missing scientific evidence supporting their use, HDS are typically prone to batch-to-batch variability in composition and concentration, contamination, and purposeful adulteration. Moreover, numerous examples of preparations emerged which have been linked to significant liver injury. These include single ingredients, such as kava, germander, and several Chinese herbals. Other HDS products associated with liver toxicity consist of multiple, often ill-defined ingredients, such as Hydroxycut and Herbalife. Affirmative diagnostic tests are not available, and the assessment of liver injury ascribed to HDS depends on a thorough and proactive medical history, careful exclusion of other causes, and a search for available reports on similar events linked to the intake of the suspected preparation or ingredients contained therein.
Usnic acid (UA), an active dibenzofuran derivative mainly found in lichens, is considered an antineoplastic agent based on its activity against tumor cells. However, the exact molecular mechanism through which UA mediates this activity has yet to be elucidated. Here, we have shown that UA selectively inhibited the viability of human breast cancer MCF-7 cells in a concentration- and time-dependent manner. UA provoked the generation of reactive oxygen species (ROS), which triggered the mitochondrial/caspase apoptotic pathway in MCF-7 cells. N-acetylcysteine (NAC) blocked the generation of ROS, which reduced the stimulation of apoptotic mechanisms including activation of c-Jun-N-terminal kinase (JNK), loss of mitochondrial membrane potential (MMP), release of cytochrome-c, and activation of the caspase-cascade. Moreover, UA markedly inhibited tumor growth in a dose-dependent manner in MCF-7 tumor-bearing mice without inducing significant toxicity. Taken together, these findings suggested that UA stimulated apoptosis through an ROS-dependent mitochondrial pathway in MCF-7 cells.
Kombucha tea is a health beverage made by incubating the Kombucha "mushroom" in tea and sugar. Although therapeutic benefits have been attributed to the drink, neither its beneficial effects nor adverse side effects have been reported widely in the scientific literature. Side effects probably related to consumption of Kombucha tea are reported in four patients. Two presented with symptoms of allergic reaction, the third with jaundice, and the fourth with nausea, vomiting, and head and neck pain. In all four, use of Kombucha tea in proximity to onset of symptoms and symptom resolution on cessation of tea drinking suggest a probable etiologic association.
Although recent research has shown that many people in the United States use complementary and alternative medical (CAM) therapies, little is known about time trends in use.
To present data on time trends in CAM therapy use in the United States over the past half-century.
Nationally representative telephone survey of 2055 respondents that obtained information on current use, lifetime use, and age at first use for 20 CAM therapies.
The 48 contiguous U.S. states.
Household residents 18 years of age and older.
Retrospective self-reports of age at first use for each of 20 CAM therapies.
Previously reported analyses of these data showed that more than one third of the U.S. population was currently using CAM therapy in the year of the interview (1997). Subsequent analyses of lifetime use and age at onset showed that 67.6% of respondents had used at least one CAM therapy in their lifetime. Lifetime use steadily increased with age across three age cohorts: Approximately 3 of every 10 respondents in the pre-baby boom cohort, 5 of 10 in the baby boom cohort, and 7 of 10 in the post-baby boom cohort reported using some type of CAM therapy by age 33 years. Of respondents who ever used a CAM therapy, nearly half continued to use many years later. A wide range of individual CAM therapies increased in use over time, and the growth was similar across all major sociodemographic sectors of the study sample.
Use of CAM therapies by a large proportion of the study sample is the result of a secular trend that began at least a half century ago. This trend suggests a continuing demand for CAM therapies that will affect health care delivery for the foreseeable future.
Little is known about perceptions of complementary and alternative medical (CAM) therapy relative to conventional therapy among patients who use both.
To document perceptions about CAM therapies among persons who use CAM and conventional therapies.
Nationally representative, random-household telephone survey.
The 48 contiguous U.S. states.
831 adults who saw a medical doctor and used CAM therapies in 1997.
Perceptions about helpfulness and patterns of CAM therapy use relative to conventional therapy use and reasons for nondisclosure of CAM therapies.
Of 831 respondents who saw a medical doctor and used CAM therapies in the previous 12 months, 79% perceived the combination to be superior to either one alone. Of 411 respondents who reported seeing both a medical doctor and a CAM provider, 70% typically saw a medical doctor before or concurrent with their visits to a CAM provider; 15% typically saw a CAM provider before seeing a medical doctor. Perceived confidence in CAM providers was not substantially different from confidence in medical doctors. Among the 831 respondents who in the past year had used a CAM therapy and seen a medical doctor, 63% to 72% did not disclose at least one type of CAM therapy to the medical doctor. Among 507 respondents who reported their reasons for nondisclosure of use of 726 alternative therapies, common reasons for nondisclosure were "It wasn't important for the doctor to know" (61%), "The doctor never asked" (60%), "It was none of the doctor's business" (31%), and "The doctor would not understand" (20%). Fewer respondents (14%) thought their doctor would disapprove of or discourage CAM use, and 2% thought their doctor might not continue as their provider. Respondents judged CAM therapies to be more helpful than conventional care for the treatment of headache and neck and back conditions but considered conventional care to be more helpful than CAM therapy for treatment of hypertension.
National survey data do not support the view that use of CAM therapy in the United States primarily reflects dissatisfaction with conventional care. Adults who use both appear to value both and tend to be less concerned about their medical doctor's disapproval than about their doctor's inability to understand or incorporate CAM therapy use within the context of their medical management.
Because acute liver failure is rare, related data have been sparse. Studies have suggested that viral hepatitis is the most common underlying cause of this condition.
To describe the clinical features, presumed causes, and short-term outcomes of acute liver failure.
Prospective cohort study.
17 tertiary care centers participating in the U.S. Acute Liver Failure Study Group.
308 consecutive patients with acute liver failure, admitted over a 41-month period.
Detailed clinical and laboratory data collected during hospitalization, including outcome 3 weeks after study admission.
73% of patients were women; median age was 38 years. Acetaminophen overdose was the most common apparent cause of acute liver failure, accounting for 39% of cases. Idiosyncratic drug reactions were the presumptive cause in 13% of cases, viral hepatitis A and B combined were implicated in 12% of cases, and 17% of cases were of indeterminate cause. Overall patient survival at 3 weeks was 67%. Twenty-nine percent of patients had liver transplantation, and 43% survived without transplantation. Short-term transplant-free survival varied greatly, from 68% for patients with acetaminophen-related liver failure to 25% and 17% for those with other drug reactions and liver failure of indeterminate cause, respectively. Coma grade at admission appeared to be associated with outcome, but age and symptom duration did not.
Acetaminophen overdose and idiosyncratic drug reactions have replaced viral hepatitis as the most frequent apparent causes of acute liver failure. Apparent cause and coma grade at admission were associated with outcome. Although transplantation may improve patient survival, it was unavailable or unnecessary for most patients.
Background: Little is known about perceptions of complementary and alternative medical (CAM) therapy relative to conventional therapy among patients who use both. Objective: To document perceptions about CAM therapies among persons who use CAM and conventional therapies. Design: Nationally representative, random-household telephone survey. Setting: The 48 contiguous U.S. states. Participants: 831 adults who saw a medical doctor and used CAM therapies in 1997. Measurements: Perceptions about helpfulness and patterns of CAM therapy use relative to conventional therapy use and reasons for nondisclosure of CAM therapies. Results: Of 831 respondents who saw a medical doctor and used CAM therapies in the previous 12 months, 79% perceived the combination to be superior to either one alone. Of 411 respondents who reported seeing both a medical doctor and a CAM provider, 70% typically saw a medical doctor before or concurrent with their visits to a CAM provider; 15% typically saw a CAM provider before seeing a medical doctor. Perceived confidence in CAM providers was not substantially different from confidence in medical doctors. Among the 831 respondents who in the past year had used a CAM therapy and seen a medical doctor, 63% to 72% did not disclose at least one type of CAM therapy to the medical doctor. Among 507 respondents who reported their reasons for nondisclosure of use of 726 alternative therapies, common reasons for nondisclosure were "It wasn't important for the doctor to know" (61%), "The doctor never asked" (60%), "It was none of the doctor's business" (31%), and "The doctor would not understand" (20%). Fewer respondents (14%) thought their doctor would disapprove of or discourage CAM use, and 2% thought their doctor might not continue as their provider. Respondents judged CAM therapies to be more helpful than conventional care for the treatment of headache and neck and back conditions but considered conventional care to be more helpful than CAM therapy for treatment of hypertension. Conclusions: National survey data do not support the view that use of CAM therapy in the United States primarily reflects dissatisfaction with conventional care. Adults who use both appear to value both and tend to be less concerned about their medical doctor's disapproval than about their doctor's inability to understand or incorporate CAM therapy use within the context of their medical management.
Background: Little is known about perceptions of complementary and alternative medical (CAM) therapy relative to conventional therapy among patients who use both. Objective: To document perceptions about CAM therapies among persons who use CAM and conventional therapies. Design: Nationally representative, random-household telephone survey. Setting: The 48 contiguous U.S. states. Participants: 831 adults who saw a medical doctor and used CAM therapies in 1997. Measurements: Perceptions about helpfulness and patterns of CAM therapy use relative to conventional therapy use and reasons for nondisclosure of CAM therapies. Results: Of 831 respondents who saw a medical doctor and used CAM therapies in the previous 12 months, 79% perceived the combination to be superior to either one alone. Of 411 respondents who reported seeing both a medical doctor and a CAM provider, 70% typically saw a medical doctor before or concurrent with their visits to a CAM provider; 15% typically saw a CAM provider before seeing a medical doctor. Perceived confidence in CAM providers was not substantially different from confidence in medical doctors. Among the 831 respondents who in the past year had used a CAM therapy and seen a medical doctor, 63% to 72% did not disclose at least one type of CAM therapy to the medical doctor. Among 507 respondents who reported their reasons for nondisclosure of use of 726 alternative therapies, common reasons for nondisclosure were It wasn't important for the doctor to know (61%), The doctor never asked (60%), It was none of the doctor's business (31%), and The doctor would not understand (20%). Fewer respondents (14%) thought their doctor would disapprove of or discourage CAM use, and 2% thought their doctor might not continue as their provider. Respondents judged CAM therapies to be more helpful than conventional care for the treatment of headache and neck and back conditions but considered conventional care to be more helpful than CAM therapy for treatment of hypertension. Conclusions: National survey data do not support the view that use of CAM therapy in the United States primarily reflects dissatisfaction with conventional care. Adults who use both appear to value both and tend to be less concerned about their medical doctor's disapproval than about their doctor's inability to understand or incorporate CAM therapy use within the context of their medical management.
Background: LipoKinetix (Syntrax, Cape Girardeau, Missouri) is a dietary supplement marketed for weight loss. Objective: To describe a possible causal association between LipoKinetix and hepatotoxicity. Design: Case series. Setting: Outpatient clinic, tertiary care hospital, and U.S. Food and Drug Administration databases. Intervention: Routine medical and supportive care. Measurements: Clinical and laboratory evaluation. Results: All patients developed acute hepatotoxicity within 3 months of starting LipoKinetix. At presentation, symptoms and results of laboratory tests were characteristic of acute hepatitis. All patients recovered spontaneously after LipoKinetix use was discontinued. Three of the seven patients, including one who developed fulminant hepatic failure complicated by cerebral edema, were taking LipoKinetix alone at the time of presentation. Of the four patients who were taking multiple supplements, two resumed taking supplements other than LipoKinetix without incident. Conclusions: The use of LipoKinetix may be associated with hepatotoxicity. Despite extensive evaluations, no other cause for hepatotoxicity could be identified in the seven patients studied.
We1 have recently suggested that alpha-dinitrophenol (1-2-4) might have therapeutic value in conditions in which an increased metabolic rate would be beneficial. Study of its pharmacologic properties shows that it has the power to increase metabolism to very high levels without causing important damage to vital organs and functions. Serious harm is apparently only caused by the drug in large doses which produce too great metabolic stimulation, with resulting fever. In low, or therapeutic, doses, the metabolism may be increased 50 per cent or more over considerable periods of time without unpleasant symptoms or toxicity. Such an action is useful in treating obesity, since the increased metabolism results in loss of weight, just as it does with thyroid medication. This paper is in the nature of a progress report on results obtained to date of treating 113 consecutive cases of obesity observed in clinic and private practice.No attempt
Kombucha tea is a health beverage made by incubating the Kombucha “mushroom” in tea and sugar. Although therapeutic benefits have been attributed to the drink, neither its beneficial effects nor adverse side effects have been reported widely in the scientific literature. Side effects probably related to consumption of Kombucha tea are reported in four patients. Two presented with symptoms of allergic reaction, the third with jaundice, and the fourth with nausea, vomiting, and head and neck pain. In all four, use of Kombucha tea in proximity to onset of symptoms and symptom resolution on cessation of tea drinking suggest a probable etiologic association.
Herbal medicines are widely perceived by the public as being healthful and innocuous. A number of herbal medicines have now been linked with hepatotoxicity. We report a case of acute hepatitis associated with the use of ma-huang, a herbal product derived from plants of the Ephedra species, which is advertised as being useful for causing weight loss and enhancing energy levels. Given the lack of reports in the literature of hepatotoxicity with ma-huang and ephedrine, we speculate that the ma-huang product our patient took contained some other ingredient or contaminant or was misidentified. Our report and others in the literature, which we review, indicate that the clinician should consider herbal medicines as a possible cause of unexplained liver injury.
Three lichen acids-namely, (+)usnic acid, vulpinic acid, and atranorin-were isolated from three lichen species (Usnea articulata, Letharia vulpina, and Parmelia tinctorum, respectively). The effects of these lichen products on mice-liver mitochondrial oxidative functions in various respiratory states and on oxidative phosphorylation were studied polarographically in vitro. The lichen acids exhibited characteristics of the 2,4-dinitrophenol (DNP), a classical uncoupler of oxidative phosphorylation. Thus, they released respiratory control and oligomycin inhibited respiration, hindered ATP synthesis, and enhanced Mg(+2)-ATPase activity. (+)Usnic acid at a concentration of 0.75 microM inhibited ADP/O ratio by 50%, caused maximal stimulation of both state-4 respiration (100%) and ATPase activity (300%). Atranorin was the only lichen acid with no significant effect on ATPase. The uncoupling effect was dose-dependent in all cases. The minimal concentrations required to cause complete uncoupling of oxidative phosphorylation were as follows: (+)usnic acid (1 microM), vulpinic acid, atranorin (5 microM) and DNP (50 microM). It was postulated that the three lichen acids induce uncoupling by acting on the inner mitochondrial membrane through their lipophilic properties and protonophoric activities.
Usnic acid is a biosynthesis product characteristic of several epiphytic lichens such as Evernia, Cladonia and Parmelia. Usnic acid has several interesting biological properties. It is an antibiotic and it also seems to exert an antimitotic action. It has even been postulated that usnic acid can play a role as an environmental indicator, since its concentration varies according to the presence of toxic agents. A series of tests have been run on different biological systems such as fungi, yeasts, plant cells and neoplastic human cell cultures in order to make a general evaluation of the properties of usnic acid and to highlight any analogy between its effects on phylogenetically distant organisms. The results obtained confirm some of the already known properties of usnic acid and identify concentration ranges that are active against cells from different organisms. Furthermore, at low concentrations, the acid displays a capacity to stimulate cell metabolism in some of the biological systems tested.
The American Journal of Gastroenterology is published by Nature Publishing Group (NPG) on behalf of the American College of Gastroenterology (ACG). Ranked the #1 clinical journal covering gastroenterology and hepatology*, The American Journal of Gastroenterology (AJG) provides practical and professional support for clinicians dealing with the gastroenterological disorders seen most often in patients. Published with practicing clinicians in mind, the journal aims to be easily accessible, organizing its content by topic, both online and in print. www.amjgastro.com, *2007 Journal Citation Report (Thomson Reuters, 2008)
Controversy surrounding the efficacy of corticosteroids in severe alcoholic hepatitis (AH) persists. The aims of our study were: (a) to analyze individual data of patients with severe AH discriminant function (DF)> or =32 from the last three randomized controlled trials; and (b) to identify the independent prognostic factors associated with short-term survival.
Individual data were collected from the three principal investigators. Survival analysis was performed at 28 days using the Kaplan-Meier method and log-rank test. The independent prognostic values were assessed by the proportional hazards regression model.
About 102 placebo and 113 corticosteroid patients with DF > or =32 were analyzed. At 28 days, corticosteroid patients had significantly higher survival: 84.6+/-3.4% vs. 65.1+/-4.8%, P=0.001. In univariate analysis, corticosteroid treatment, age, DF, albumin, creatinine and encephalopathy were prognostic factors. In multivariate analysis, age (P=0.0001), serum creatinine (P<0.002) and corticosteroid treatment (P=0.002) were independent prognostic variables. A more dramatic decrease of median serum bilirubin values (micromol/l) was observed at 7 and 14 days in corticosteroid patients (P<0.05) : -76.5 vs. -35 and -105 vs. -45.
Corticosteroids improved short-term survival of patients with severe AH. Age and serum creatinine are independent prognostic factors. Corticosteroids are recommended for patients with severe AH.
LipoKinetix (Syntrax, Cape Girardeau, Missouri) is a dietary supplement marketed for weight loss.
To describe a possible causal association between LipoKinetix and hepatotoxicity.
Case series.
Outpatient clinic, tertiary care hospital, and U.S. Food and Drug Administration databases.
Routine medical and supportive care.
Clinical and laboratory evaluation.
All patients developed acute hepatotoxicity within 3 months of starting LipoKinetix. At presentation, symptoms and results of laboratory tests were characteristic of acute hepatitis. All patients recovered spontaneously after LipoKinetix use was discontinued. Three of the seven patients, including one who developed fulminant hepatic failure complicated by cerebral edema, were taking LipoKinetix alone at the time of presentation. Of the four patients who were taking multiple supplements, two resumed taking supplements other than LipoKinetix without incident.
The use of LipoKinetix may be associated with hepatotoxicity. Despite extensive evaluations, no other cause for hepatotoxicity could be identified in the seven patients studied.
Herbal hepatotoxicity is increasingly recognized as herbal medicines become more popular in industrialized societies. Some herbal products may potentially benefit people with liver disease; however, these benefits remain generally unproved in humans, and a greater awareness of potential adverse effects is required. Herbal use is often not disclosed, and this may result in a diagnostic delay and perpetuation or exacerbation of liver injury. Female gender may predispose to hepatotoxicity, and concomitant agents that induce cytochrome P450 enzymes may also increase individual susceptibility. The range of liver injury includes minor transaminase elevations, acute and chronic hepatitis, steatosis, cholestasis, zonal or diffuse hepatic necrosis, hepatic fibrosis and cirrhosis, veno-occlusive disease, and acute liver failure requiring transplantation. In addition to the potential for hepatotoxicity, drug-drug interactions between herbal medicines and conventional agents may affect the efficacy and safety of concurrent medical therapy. This review focuses on emerging hepatotoxins and patterns of liver injury, potential risk factors for herbal hepatotoxicity, and herb-drug interactions. Appropriate reporting and regulatory systems to monitor herbal toxicity are required, in conjunction with ongoing scientific evaluation of the potential benefits of phytotherapy.
The pathogenesis of drug- or toxin-induced liver injury usually involves the participation of toxic metabolites that either elicit an immune response or directly affect the biochemistry of the cell. The clinical appearance of hepatitis is then a consequence of cell death mediated by either the extrinsic immune system (e.g., cytotoxic T cells) or intracellular stress. Intracellular stress can lead to apoptotic or necrotic cell death, depending on the extent of mitochondrial involvement and the balance of factors that activate and inhibit the Bcl 2 family of proteins and the caspases. Drug metabolites can undergo or promote a variety of chemical reactions, including covalent binding, depletion of reduced glutathione, or oxidative stress with consequent effects on proteins, lipids, and DNA. These chemical consequences can directly affect organelles such as mitochondria, cytoskeleton, endoplasmic reticulum, microtubules, or nucleus or indirectly influence these organelles through activation or inhibition of signaling kinases, transcription factors, and gene expression profiles. The outcome may be either triggering of the necrotic or apoptotic process or sensitization to the lethal action of cytokines of the immune system intrinsic to the liver.
A component of herbal fat burners, usnic acid, induces necrosis of isolated murine hepatocytes
- K Matsumaru
- D Han
- N Kaplowitz
Matsumaru K, Han D, Kaplowitz N. A component of herbal
fat burners, usnic acid, induces necrosis of isolated murine
hepatocytes. Hepatology 2002;36:480A.
Acute hepatitis asso-ciated with the use of a Chinese herbal product
- A S Nadir
- King
- Pd
Nadir A, Agrawal S, King PD, et al. Acute hepatitis asso-ciated with the use of a Chinese herbal product, ma-huang.
The FDA Safety Information and Adverse Event Reporting Program
- Medwatch
Medwatch, The FDA Safety Information and Adverse Event
Reporting Program, 2003.