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We will be provided with an authorization token (please note: passwords are not shared with us) and will sync your accounts for you. Plants are natural producers of chemical substances, providing potential treatment of human ailments since ancient times. In this review article, we critically analyze actual key issues of herbal hepatotoxicity by herbal products of traditional and modern medicine and discuss future developments. The focus of our search was on publications in English language, but relevant reports of other languages also were considered. Prior to our analysis, the publications were assessed regarding their scientific and clinical quality.
Herbal products in traditional and modern medicine are commonly perceived by the general population as well tolerated and devoid of major adverse reactions. Basic knowledge of hepatotoxicity by drugs and numerous other chemicals was summarized by Hyman Zimmerman in his pioneering book 25 years ago, briefly mentioning already some herbs as culprits and referencing a few case reports of herbal hepatotoxicity (Zimmerman, 1999). Epidemiology data of hepatotoxicity cases in connection with herbal use are crucial to assess, both in traditional and modern medicine. Incidence commonly provides information about the risk of acquiring HILI, whereas prevalence signifies how widespread HILI is. For herbal TCM with potential liver injury, we identified 44 different TCM herbs and 21 herbal TCM mixtures, published in case reports and case series as provided by appropriate references (Table 1).
Other herbs and herbal products unrelated to TCM showed reported potential hepatotoxicity for 111 items (Table 2), presented as an update of an earlier compilation (Teschke et al., 2012h). Clinical symptoms of herbal hepatotoxicity in traditional and modern medicine are variable and described in published case reports, case series, and regulatory presented spontaneous reports as referenced (Tables 1, 2).
In a typical HILI case unrelated to PAs, the chronology of symptoms may follow a particular stepwise pattern, as described for HILI caused by Indian Ayurvedic herbs through an excellent observation by a patient under treatment for her vitiligo (Teschke and Bahre, 2009). Patients with HILI may be asymptomatic with increased values observed by chance, monosymptomatic, or polysymptomatic. The clinical course of HILI is variable with details provided in most publications as referenced (Tables 1, 2). HILI case assessment mandates clear hepatotoxicity criteria for disease characterization including causality assignment (Teschke et al., 2013f, 2014b). Concern emerges whenever hepatotoxicity is assumed even if liver values were only marginally increased, not reported, or not assessed. In spontaneous reports of regulatory agencies, a clear hepatotoxicity definition was provided by EMA (2007) but not by the U.S. This means that you will not need to remember your user name and password in the future and you will be able to login with the account you choose to sync, with the click of a button. This page doesn't support Internet Explorer 6, 7 and 8.Please upgrade your browser or activate Google Chrome Frame to improve your experience. Some herbal chemicals in medicinal plants of traditional and modern medicine carry the risk of herb induced liver injury (HILI) with a severe or potentially lethal clinical course, and the requirement of a liver transplant.
The world market for herbal medicines based on traditional knowledge is estimated at US$60,000 million annually (WHO, 2002), according to a UN report dating back to 2000 (UN, 2000). The expressions of herbal hepatotoxicity and herb induced liver injury (HILI) are used synonymously. Our search was then further qualified and extended using additional keywords denoting herbal modern medicine and herbal TCM, providing additional hits.
The retrieved publications included case reports, case series and review articles and were analyzed whether they were appropriate and relevant for the topic of this article. One of the most important goals in clinical practice is to offer patients an efficient therapy for their ailment(s), without harming their health. Actually, the true prevalence of herbal hepatotoxicity is the total number of HILI cases in the population at a given time (Teschke et al., 2013f). These referenced reports present clinical case details, summarized in part also earlier (Teschke, 2014).
Compilation of reported cases with suspected hepatotoxicity by herbal traditional Chinese medicine (TCM). Most of the actual 111 items identified single herbs, rarely mixtures with HDS as examples with various ingredients (Table 2). Compilation of narrative case details and clinical data of patients with HILI by Greater Celandine (GC) and established causality.
Her symptoms started with pruritus, followed by loss of appetite, fatigue, nausea, vomiting, dark urine, light stool, until finally jaundice was recognized by her family physician; this sequence of symptoms stretched over almost 4 months under continued herbal medication. Latency period describes the interval between initiation of herb use and time of onset, evidenced by emerging symptoms or increased liver values. For HILI cases, some details of treatment modalities by herbal products of traditional and modern medicine are provided, with focus on daily and cumulative dose, treatment duration, latency period, and reexposure duration (Table 5). Some chracteristics of daily and cumulative doses, treatment duration, latency period, and reexposure period of cases with hepatotoxicity by herbs of traditional and modern medicine. Strategy for assessing HILI cases according to details presented previously (Teschke et al., 2013f). Discontinuation of herbal use is mandatory in time when HILI is first suspected as diagnosis.
Indigenous cultures such as African, North American, Middle and South American, Australian, and South Pacific islandic also used herbs in their healing rituals (IARC Monographs, 2002). Some similarities of HILI exist with DILI (drug induced liver injury) (Teschke et al., 2013f). However, efficacy and safety by the use of herbs in traditional and modern medicine are features that may apply to some herbs and patients but certainly not to others.

It represents an estimate of how common herbal hepatotoxicity is within a population and at a fixed time. Global epidemiology considerations of prevalence and incidence refer to all herbs contained in herbal drugs and herbal supplements, whereas specific epidemiology is restricted to one single herb.
The 12 most common Chinese herbal medicines with hepatotoxicity detailed in a recent review (Ma et al., 2014) are also included in the present compilation (Table 1). Clinical signs may emerge alone or in combination with other features, while jaundice is the symptom initially best recognized by the patient, facilitating the search for advice by the primary care physician.
For instance, EMA mentions cases with assumed HILI by BC but clarifies that a causal attribution cannot be made with the required certainty in face of missing liver values (EMA, 2007). Although, herbal hepatotoxicity is of utmost clinical and regulatory importance, lack of a stringent causality assessment remains a major issue for patients with suspected HILI, while this problem is best overcome by the use of the hepatotoxicity specific CIOMS (Council for International Organizations of Medical Sciences) scale and the evaluation of unintentional reexposure test results. Similar shortcomings are known from conventional chemical drugs, which also are not effective in all patients. Conversely, the incidence of herbal hepatotoxicity is expressed as the total number of new HILI cases during a certain period of time, divided by the number of individuals in the population initially at risk. Global epidemiology data therefore may be used for health economy assessment whereas specific epidemiology data pertain to herbal product safety. A well described dechallenge of liver values in suspected HILI is one of the key items to suspect causality for a particular herb.
In other HILI case series, however, criteria were not or incompletely documented; neglecting these aspects in effect invalidates the causality assessment. The disease is contagious, particularly during an outbreak, and is incurable with present technology.
Sixty five different commonly used herbs, herbal drugs, and herbal supplements and 111 different herbs or herbal mixtures of the traditional Chinese medicine (TCM) are reported causative for liver disease, with levels of causality proof that appear rarely conclusive. With TCM originating in China and Ayurveda in India, two most ancient yet living traditions of herbal medicine presently remain and experience some extension over the globe (Patwardhan et al., 2005). The risk of rare adverse reactions occurring in various organs including the liver relates to both, herbs (NIH, 2014a) and synthetic drugs (NIH, 2014b). Therefore, incidence differs from prevalence measuring new HILI cases; for chronic liver injury, these values may change.
For this purpose, true global prevalence and incidence of HILI still has to be determined through cohort studies or case control-studies, a difficult approach. In another study of 16 cases of Greater Celandine (GC) with established HILI, symptoms were present in 15 cases (Teschke et al., 2012a). Patients with HILI caused by herbal TCM or modern herbal medicine commonly experience an acute type of liver injury, which is self-limited upon withdrawal of the offending herb with an overall good prognosis. Considering patients with ALT values of >2N will initially also include numerous cases with nonspecific increases, which then require thorough assessment and stringent exclusion of causes unrelated to the used herb(s).
Encouraging steps in the field of herbal hepatotoxicity focus on introducing analytical methods that identify cases of intrinsic hepatotoxicity caused by pyrrolizidine alkaloids, and on omics technologies, including genomics, proteomics, metabolomics, and assessing circulating micro-RNA in the serum of some patients with intrinsic hepatotoxicity. Although, most other ancient herbal medicine cultures vanished or are restricted to local use without potential globalization, many countries use herbal medicines (WHO, 2002, 2013). Considering this enormous economic impact and the resulting expenditures, the question is whether these high costs as burden for the consumers and the society are warranted. For an appropriate assessment of the risks from a specific herbal product, there is lack of quantitative data for consumption of herbal products, number of HILI patients, and the population at risk. Single or multiple symptoms were anorexia (n = 3), fatigue (n = 5), nausea (n = 6), vomiting (n = 2), dyspepsia (n = 1), bloating (n = 1), abdominal discomfort (n = 1), right upper quadrant pains (n = 1), epigastric pains (n = 1), unspecified abdominal pains (n = 1), fever (n = 1), dark urine (n = 3), pale stool (n = 1), pruritus (n = 3), and jaundice (n = 15) (Teschke et al., 2012a). It remains to be established whether these new technologies can identify idiosyncratic HILI cases. In addition, herbal product authentication is missing in most cases of suspected HILI and impedes causality assessment for the incriminated herb (Teschke et al., 2013f). However, persistence of increased liver values raises the question whether these are due to a preexisting liver disease present prior to herbal use rather than to HILI (Picciotti et al., 1998).
Other values such as aspartate aminotransferase (AST) are not required, unless to be used as substitute for ALT if not available. These are sometimes confused with canker sores or Apthous ulcers which have a similar appearance; these appear inside the mouth and are not caused by the herpes simplex virus.
Case underreporting and overdiagnosing also prevent determination of the true incidence; future studies will have to address these issues in order to provide firm data of prevalence and incidence in HILI. Detailed information also allows characterization of HILI by a single herb such as GC (Table 4). It is known that the virus lies dormant in the ganglion of the trigeminal or fifth cranial nerve. Even with the best modern treatment, it is fatal in around 20% of cases, and causes serious long-term neurological damage in over half the survivors. Although herpes simplex is by no means the most common cause of viral encephalitis (accounting for about 10% of cases in the US), because of the high risk associated with it if it is not treated, patients presenting with encephalitis symptoms are likely to be treated against this disorder without waiting for a positive diagnosis.
The virus usually infects through the mouth and enters the nucleus during the first 7 days, and will remain latent for 10 days to 100 years, and will then reactivate from common stress, fever, or a sunburn. The virus will soon be contagious through more cold sores, and the disease will start to attack the brain. The mortality rate from neonatal HSV disease is high (up to 25%) despite current interventions with antiviral therapies.
The virus travels through tiny breaks in the skin or through moist areas, but symptoms may not appear for up to a month or more after infection. Transmission was thought to be most common during an active outbreak - however, in the early 1980s, it was found that the virus can be shed from the skin in the absence of symptoms.

It is estimated that between 50% and 80% of new HSV-2 cases are from asymptomatic viral shedding. Shedding is known to be more frequent within the first 12 months of acquiring HSV-2, and concurrent infection with HIV also increases the frequency and duration of asymptomatic shedding.[4] There are some indications that some individuals may have much lower patterns of shedding, but evidence supporting this is not fully verified.
Oral sex performed by someone with oral lesions, or other symptoms, should be avoided, to avoid transmission of HSV1 to the partner's genitals.
On an annual basis, without the use of antivirals or condoms, the transmission risk from infected male to female is approximately 8-10%.
This is believed to be due to the increased exposure of mucosal tissue to potential infection sites. Antivirals also help prevent the development of symptomatic HSV in infection scenarios by about 50%, meaning the infected partner will be seropositive but symptom free. Condom use is much more effective at preventing male to female transmission than vice-versa. It is important to note that these figures reflect experiences with subjects having frequently recurring genital herpes (>6 recurrences per year), subjects with low recurrence rates and those with no clinical manifestations were excluded from these studies. Aciclovir was the original and prototypical member of this class and generic brands are now available at a greatly reduced cost. Valaciclovir and famciclovir are prodrugs of aciclovir and penciclovir respectively, with improved oral bioavailability (55% vs 20% and 75% vs 5% respectively). These antiviral medications work by interfering with viral replication, effectively slowing the replication rate of the virus and providing a greater opportunity for the immune response to intervene. All drugs in this class depend on the activity of the viral thymidine kinase to convert the drug to a monophosphate form and subsequently interfere with viral DNA replication. Docosanol works by preventing the virus from fusing to cell membranes, thus barring entry into the cell for the virus.
Aciclovir is the recommended antiviral for suppressive therapy to prevent transmission of herpes simplex to the neonate. The use of valaciclovir and famciclovir, while potentially improving treatment compliance and efficacy, are still undergoing safety evaluation in this context. Patent 5246937 protection expiring Sept 2010 Penciclovir (GlaxoSmithKline) protected under U.S. Patent 4874794 protection expiring April 2014 Research drugs BAY 57-1293, a helicase-primase inhibitor researched by Bayer AG scientist Gerald Kleymann's team in Wuppertal, Germany. Lysine supplementation is highly dose-dependent, with beneficial effects apparent only at doses exceeding 1000 mg per day. A small randomised controlled trial indicated a decrease in recurrence rates in nonimmunocompromised patients at a dose of 1248 mg of lysine monohydrochloride, but no effect at 624 mg daily.
The therapeutic consequence of this finding is unclear, but dietary arginine may affect the effectiveness of lysine supplementation.
A small study of 21 volunteers with recurrent HSV indicated a significant reduction in duration of active HSV infections, milder symptoms, and longer symptom-free periods as compared to a control group.
Long term daily doses of aspirin have a side effect of reduced blood coagulation, facilitating bruising. A single 81 mg "daily dose" aspirin is a safer regimen given that there are no studies of the correlation between dosage and anti-viral effects of aspirin. Cimetidine, a common component of heartburn medication, and probenecid have been shown to reduce the renal clearance of aciclovir. In addition, respective increases in the peak plasma concentration of acyclovir of 8% and 22% were observed. Due to the tendency of aciclovir to precipitate in renal tubules, combining these drugs should only occur under the supervision of a physician. Subsequently, another virus, human papillomavirus (HPV), has been shown to be a primary cause of cervical cancer in women.
Additionally, people with herpes are at a higher risk of HIV transmission because of open blisters. In newborns, however, herpes can cause serious damage: death, neurological damage, mental retardation, and blindness. The immune system is able to destroy active herpes virus particles but the herpes virus has the ability to hide from the immune system in an inactive (or latent) state. Current research suggests that this ability to hide may be achieved via modification to cellular enzyme histone deacetylases (HDACs), namely HDAC1 and HDAC2.
Findings showed proportions of people who experienced depression 82% fear of rejection 75% feeling of isolation 69% fear of being found out 55% self-destructive feelings 28% All of these proportions reduced over time. Results from one study show that people are less likely to inform what they consider to be 'casual' partners.
An event such as a couple moving in together was found to be the point when some people disclosed their status. The study showed people informed 62% of regular partners and 22% of casual partners, and was unrelated to the gender of the person.
Strategies used when telling partners included keeping the issue "low key," choosing a relaxed environment and suggestions of the couple being tested jointly for a range of sexually transmitted infections. Doctors at some hospitals and health clinics actually advise men not to tell their partners[citation needed] unless the woman is pregnant, reasoning that the psychological effects of herpes far outweigh the physical effects in adults.
This advice is still controversial, especially as genital herpes affects women significantly worse than it does men.

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