Wilson Disease: Copper-Mediated Cuproptosis, Iron-Related Ferroptosis, and Clinical Highlights, with Comprehensive and Critical Analysis Update.

Wilson disease is a genetic disorder of the liver characterized by excess accumulation of copper, which is found ubiquitously on earth and normally enters the human body in small amounts via the food chain. Many interesting disease details were published on the mechanistic steps, such as the generation of reactive oxygen species (ROS) and cuproptosis causing a copper dependent cell death. In the liver of patients with Wilson disease, also, increased iron deposits were found that may lead to iron-related ferroptosis responsible for phospholipid peroxidation within membranes of subcellular organelles. All topics are covered in this review article, in addition to the diagnostic and therapeutic issues of Wilson disease. Excess Cu2+ primarily leads to the generation of reactive oxygen species (ROS), as evidenced by early experimental studies exemplified with the detection of hydroxyl radical formation using the electron spin resonance (ESR) spin-trapping method. The generation of ROS products follows the principles of the Haber-Weiss reaction and the subsequent Fenton reaction leading to copper-related cuproptosis, and is thereby closely connected with ROS. Copper accumulation in the liver is due to impaired biliary excretion of copper caused by the inheritable malfunctioning or missing ATP7B protein. As a result, disturbed cellular homeostasis of copper prevails within the liver. Released from the liver cells due to limited storage capacity, the toxic copper enters the circulation and arrives at other organs, causing local accumulation and cell injury. This explains why copper injures not only the liver, but also the brain, kidneys, eyes, heart, muscles, and bones, explaining the multifaceted clinical features of Wilson disease. Among these are depression, psychosis, dysarthria, ataxia, writing problems, dysphagia, renal tubular dysfunction, Kayser-Fleischer corneal rings, cardiomyopathy, cardiac arrhythmias, rhabdomyolysis, osteoporosis, osteomalacia, arthritis, and arthralgia. In addition, Coombs-negative hemolytic anemia is a key feature of Wilson disease with undetectable serum haptoglobin. The modified Leipzig Scoring System helps diagnose Wilson disease. Patients with Wilson disease are well-treated first-line with copper chelators like D-penicillamine that facilitate the removal of circulating copper bound to albumin and increase in urinary copper excretion. Early chelation therapy improves prognosis. Liver transplantation is an option viewed as ultima ratio in end-stage liver disease with untreatable complications or acute liver failure. Liver transplantation finally may thus be a life-saving approach and curative treatment of the disease by replacing the hepatic gene mutation. In conclusion, Wilson disease is a multifaceted genetic disease representing a molecular and clinical challenge.

Hemochromatosis: Ferroptosis, ROS, Gut Microbiome, and Clinical Challenges with Alcohol as Confounding Variable.

Hemochromatosis represents clinically one of the most important genetic storage diseases of the liver caused by iron overload, which is to be differentiated from hepatic iron overload due to excessive iron release from erythrocytes in patients with genetic hemolytic disorders. This disorder is under recent mechanistic discussion regarding ferroptosis, reactive oxygen species (ROS), the gut microbiome, and alcohol abuse as a risk factor, which are all topics of this review article. Triggered by released intracellular free iron from ferritin via the autophagic process of ferritinophagy, ferroptosis is involved in hemochromatosis as a specific form of iron-dependent regulated cell death. This develops in the course of mitochondrial injury associated with additional iron accumulation, followed by excessive production of ROS and lipid peroxidation. A low fecal iron content during therapeutic iron depletion reduces colonic inflammation and oxidative stress. In clinical terms, iron is an essential trace element required for human health. Humans cannot synthesize iron and must take it up from iron-containing foods and beverages. Under physiological conditions, healthy individuals allow for iron homeostasis by restricting the extent of intestinal iron depending on realistic demand, avoiding uptake of iron in excess. For this condition, the human body has no chance to adequately compensate through removal. In patients with hemochromatosis, the molecular finetuning of intestinal iron uptake is set off due to mutations in the high-FE2+ (HFE) genes that lead to a lack of hepcidin or resistance on the part of ferroportin to hepcidin binding. This is the major mechanism for the increased iron stores in the body. Hepcidin is a liver-derived peptide, which impairs the release of iron from enterocytes and macrophages by interacting with ferroportin. As a result, iron accumulates in various organs including the liver, which is severely injured and causes the clinically important hemochromatosis. This diagnosis is difficult to establish due to uncharacteristic features. Among these are asthenia, joint pain, arthritis, chondrocalcinosis, diabetes mellitus, hypopituitarism, hypogonadotropic hypogonadism, and cardiopathy. Diagnosis is initially suspected by increased serum levels of ferritin, a non-specific parameter also elevated in inflammatory diseases that must be excluded to be on the safer diagnostic side. Diagnosis is facilitated if ferritin is combined with elevated fasting transferrin saturation, genetic testing, and family screening. Various diagnostic attempts were published as algorithms. However, none of these were based on evidence or quantitative results derived from scored key features as opposed to other known complex diseases. Among these are autoimmune hepatitis (AIH) or drug-induced liver injury (DILI). For both diseases, the scored diagnostic algorithms are used in line with artificial intelligence (AI) principles to ascertain the diagnosis. The first-line therapy of hemochromatosis involves regular and life-long phlebotomy to remove iron from the blood, which improves the prognosis and may prevent the development of end-stage liver disease such as cirrhosis and hepatocellular carcinoma. Liver transplantation is rarely performed, confined to acute liver failure. In conclusion, ferroptosis, ROS, the gut microbiome, and concomitant alcohol abuse play a major contributing role in the development and clinical course of genetic hemochromatosis, which requires early diagnosis and therapy initiation through phlebotomy as a first-line treatment.

Aluminum, Arsenic, Beryllium, Cadmium, Chromium, Cobalt, Copper, Iron, Lead, Mercury, Molybdenum, Nickel, Platinum, Thallium, Titanium, Vanadium, and Zinc: Molecular Aspects in Experimental Liver Injury.

Experimental liver injury with hepatocelluar necrosis and abnormal liver tests is caused by exposure to heavy metals (HMs) like aluminum, arsenic, beryllium, cadmium, chromium, cobalt, copper, iron, lead, mercury, molybdenum, nickel, platinum, thallium, titanium, vanadium, and zinc. As pollutants, HMs disturb the ecosystem, and as these substances are toxic, they may affect the health of humans and animals. HMs are not biodegradable and may be deposited preferentially in the liver. The use of animal models can help identify molecular and mechanistic steps leading to the injury. HMs commonly initiate hepatocellular overproduction of ROS (reactive oxygen species) due to oxidative stress, resulting in covalent binding of radicals to macromolecular proteins or lipids existing in membranes of subcellular organelles. Liver injury is facilitated by iron via the Fenton reaction, providing ROS, and is triggered if protective antioxidant systems are exhausted. Ferroptosis syn pyroptosis was recently introduced as mechanistic concept in explanations of nickel (Ni) liver injury. NiCl2 causes increased iron deposition in the liver, upregulation of cyclooxygenase 2 (COX-2) protein and mRNA expression levels, downregulation of glutathione eroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), nuclear receptor coactivator 4 (NCOA4) protein, and mRNA expression levels. Nickel may cause hepatic injury through mitochondrial damage and ferroptosis, defined as mechanism of iron-dependent cell death, similar to glutamate-induced excitotoxicity but likely distinct from apoptosis, necrosis, and autophagy. Under discussion were additional mechanistic concepts of hepatocellular uptake and biliary excretion of mercury in exposed animals. For instance, the organic anion transporter 3 (Oat3) and the multidrug resistance-associated protein 2 (Mrp2) were involved in the hepatic handling of mercury. Mercury treatment modified the expression of Mrp2 and Oat3 as assessed by immunoblotting, partially explaining its impaired biliary excretion. Concomitantly, a decrease in Oat3 abundance in the hepatocyte plasma membranes was observed that limits the hepatic uptake of mercury ions. Most importantly and shown for the first time in liver injury caused by HMs, titanium changed the diversity of gut microbiota and modified their metabolic functions, leading to increased generation of lipopolysaccharides (LPS). As endotoxins, LPS may trigger and perpetuate the liver injury at the level of gut-liver. In sum, mechanistic and molecular steps of experimental liver injury due to HM administration are complex, with ROS as the key promotional compound. However, additional concepts such as iron used in the Fenton reaction, ferroptosis, modification of transporter systems, and endotoxins derived from diversity of intestinal bacteria at the gut-liver level merit further consideration.

Anti-Diabetes, Anti-Gout, and Anti-Leukemia Properties of Essential Oils from Natural Spices Clausena indica, Zanthoxylum rhetsa, and Michelia tonkinensis.

Essential oils (EOs) of Clausena indica fruits, Zanthoxylum rhetsa fruits, and Michelia tonkinensis seeds were analyzed for their phytochemical profiles and biological activities, including anti-diabetes, anti-gout, and anti-leukemia properties. Sixty-six volatile compounds were identified by gas chromatography-mass spectrometry (GC-MS), in which, myristicin (68.3%), limonene (44.2%), and linalool (49.3%) were the most prominent components of EOs extracted from C. indica, Z. rhetsa, and M. tonkinensis, respectively. In addition, only EOs from C. indica inhibited the activities of all tested enzymes comprising α-amylase (IC50 = 7.73 mg/mL), α-glucosidase (IC50 = 0.84 mg/mL), and xanthine oxidase (IC50 = 0.88 mg/mL), which are related to type 2 diabetes and gout. Remarkably, all EOs from C. indica, Z. rhetsa (IC50 = 0.73 mg/mL), and M. tonkinensis (IC50 = 1.46 mg/mL) showed a stronger anti-α-glucosidase ability than acarbose (IC50 = 2.69 mg/mL), a known anti-diabetic agent. Moreover, the growth of leukemia cell Meg-01 was significantly suppressed by all EOs, of which, the IC50 values were recorded as 0.32, 0.64, and 0.31 mg/mL for EOs from C. indica, Z. rhetsa, and M. tonkinensis, respectively. As it stands, this is the first report about the inhibitory effects of EOs from C. indica and Z. rhetsa fruits, and M. tonkinensis seeds on the human leukemia cell line Meg-01 and key enzymes linked to diabetes and gout. In conclusion, the present study suggests that EOs from these natural spices may be promising candidates for pharmaceutical industries to develop nature-based drugs to treat diabetes mellitus or gout, as well as malignant hematological diseases such as leukemia.

Treatment of Drug-Induced Liver Injury.

Current pharmacotherapy options of drug-induced liver injury (DILI) remain under discussion and are now evaluated in this analysis. Needless to say, the use of the offending drug must be stopped as soon as DILI is suspected. Normal dosed drugs may cause idiosyncratic DILI, and drugs taken in overdose commonly lead to intrinsic DILI. Empirically used but not substantiated regarding efficiency by randomized controlled trials (RCTs) is the intravenous antidote treatment with N-acetylcysteine (NAC) in patients with intrinsic DILI by N-acetyl-p-aminophenol (APAP) overdose. Good data recommending pharmacotherapy in idiosyncratic DILI caused by hundreds of different drugs are lacking. Indeed, a recent analysis revealed that just eight RCTs have been published, and in only two out of eight trials were DILI cases evaluated for causality by the worldwide used Roussel Uclaf Causality Assessment Method (RUCAM), representing overall a significant methodology flaw, as results of DILI RCTs lacking RUCAM are misleading since many DILI cases are known to be attributable erroneously to nondrug alternative causes. In line with these major shortcomings and mostly based on anecdotal reports, glucocorticoids (GCs) and other immuno-suppressants may be given empirically in carefully selected patients with idiosyncratic DILI exhibiting autoimmune features or caused by immune checkpoint inhibitors (ICIs), while some patients with cholestatic DILI may benefit from ursodeoxycholic acid use; in other patients with drug-induced hepatic sinusoidal obstruction syndrome (HSOS) and coagulopathy risks, the indication for anticoagulants should be considered. In view of many other mechanistic factors such as the hepatic microsomal cytochrome P450 with a generation of reactive oxygen species (ROS), ferroptosis with toxicity of intracellular iron, and modification of the gut microbiome, additional therapy options may be available in the future. In summation, stopping the offending drug is still the first line of therapy for most instances of acute DILI, while various therapies are applied empirically and not based on good data from RCTs awaiting further trials using the updated RUCAM that asks for strict exclusion and inclusion details like liver injury criteria and provides valid causality rankings of probable and highly probable grades.

Metabolic Toxification of 1,2-Unsaturated Pyrrolizidine Alkaloids Causes Human Hepatic Sinusoidal Obstruction Syndrome: The Update.

Saturated and unsaturated pyrrolizidine alkaloids (PAs) are present in more than 6000 plant species growing in countries all over the world. They have a typical heterocyclic structure in common, but differ in their potential toxicity, depending on the presence or absence of a double bond between C1 and C2. Fortunately, most plants contain saturated PAs without this double bond and are therefore not toxic for consumption by humans or animals. In a minority of plants, however, PAs with this double bond between C1 and C2 exhibit strong hepatotoxic, genotoxic, cytotoxic, neurotoxic, and tumorigenic potentials. If consumed in error and in large emouns, plants with 1,2-unsaturated PAs induce metabolic breaking-off of the double bonds of the unsaturated PAs, generating PA radicals that may trigger severe liver injury through a process involving microsomal P450 (CYP), with preference of its isoforms CYP 2A6, CYP 3A4, and CYP 3A5. This toxifying CYP-dependent conversion occurs primarily in the endoplasmic reticulum of the hepatocytes equivalent to the microsomal fraction. Toxified PAs injure the protein membranes of hepatocytes, and after passing their plasma membranes, more so the liver sinusoidal endothelial cells (LSECs), leading to life-threatening hepatic sinusoidal obstruction syndrome (HSOS). This injury is easily diagnosed by blood pyrrolizidine protein adducts, which are perfect diagnostic biomarkers, supporting causality evaluation using the updated RUCAM (Roussel Uclaf Causality Assessment Method). HSOS is clinically characterized by weight gain due to fluid accumulation (ascites, pleural effusion, and edema), and may lead to acute liver failure, liver transplantation, or death. In conclusion, plant-derived PAs with a double bond between C1 and C2 are potentially hepatotoxic after metabolic removal of the double bond, and may cause PA-HSOS with a potential lethal outcome, even if PA consumption is stopped.

Efficacy of Xuebijing Injection for Acute Pancreatitis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

METHODS: PubMed Medline, Embase, Cochrane Library, China National Knowledge Infrastructure, China Biology Medicine disc, VIP, and Wanfang databases were searched. The primary outcome was treatment response. The secondary outcomes included changes in clinical and laboratory indicators and incidence of AP-related complications. Meta-analyses were performed by using a random-effect model. Risk ratios (RRs) with 95% confidence intervals (CIs) or weighted mean differences (WMDs) with 95% CIs were calculated. RESULTS: Overall, 23 RCTs were included. The rates of overall (RR = 1.16; 95% CI = 1.12 to 1.20; P < 0.00001) and complete (RR = 1.40; 95% CI = 1.30 to 1.50; P < 0.00001) responses were significantly higher in the Xuebijing injection group. After treatment, the levels of interleukin-6 (WMD = -18.22; 95% CI = -23.36 to -13.08; P < 0.00001), tumor necrosis factor-α (WMD = -16.44; 95% CI = -20.49 to -12.40; P < 0.00001), serum amylase (WMD = -105.61; 95% CI = -173.77 to -37.46; P=0.002), white blood cell (WMD = -1.51; 95% CI = -1.66 to -1.36; P < 0.00001), and C-reactive protein (WMD = -11.05; 95% CI = -14.32 to -7.78; P < 0.00001) were significantly lower in the Xuebijing injection group. Abdominal pain (WMD = -1.74; 95% CI = -1.96 to -1.52; P < 0.00001), abdominal distension (WMD = -1.56; 95% CI = -2.07 to -1.04; P < 0.00001), gastrointestinal function (WMD = -2.60; 95% CI = -3.07 to -2.13; P < 0.00001), body temperature (WMD = -2.16; 95% CI = -2.83 to -1.49; P < 0.00001), serum amylase level (WMD = -1.81; 95% CI = -2.66 to -0.96; P < 0.0001), and white blood cell (WMD = -2.16; 95% CI = -2.99 to -1.32; P < 0.00001) recovered more rapidly in the Xuebijing injection group. The incidence of multiple organ dysfunction syndrome (RR = 0.18; 95% CI = 0.05 to 0.62; P=0.006), pancreatic pseudocyst (RR = 0.17; 95% CI = 0.04 to 0.77; P=0.02), and renal failure (RR = 0.16; 95% CI = 0.05 to 0.60; P=0.006) was significantly lower in the Xuebijing injection group. CONCLUSIONS: Xuebijing injection added on the basis of conventional treatment has a potential benefit for improving the outcomes of AP.

Antioxidant, Anti-tyrosinase, Anti-α-amylase, and Cytotoxic Potentials of the Invasive Weed Andropogon virginicus.

Andropogon virginicus is an invasive weed that seriously threatens agricultural production and economics worldwide. In this research, dried aerial parts of A. virginicus were extracted, applying Soxhlet and liquid-liquid phase methods to acquire the total crude (T-Anvi), hexane (H-Anvi), ethyl acetate (E-Anvi), butanol (B-Anvi), and water (W-Anvi) extracts, respectively. In which, T-Anvi contains the highest total phenolic and flavonoid contents (24.80 mg gallic acid and 37.40 mg rutin equivalents per g dry weight, respectively). Via anti-radical (ABTS and DPPH), and reducing power assays, E-Anvi exhibits the most potent activities (IC50 = 13.96, 43.59 and 124.11 µg/mL, respectively), stronger than butylated hydroxytoluene (BHT), a standard antioxidant, while the lipid peroxidation inhibitory effect of E-Anvi (LPI = 90.85% at the concentration of 500 µg/mL) is close to BHT. E-Anvi shows the most substantial inhibition (IC50 = 2.58 mg/mL) on tyrosinase. Notably, α-amylase is significantly suppressed by H-Anvi (IC50 = 0.72 mg/mL), over twice stronger than the positive control, palmitic acid. In the cytotoxic assay, E-Anvi is the strongest extract inhibiting K562 cells (IC50 = 112.01 µg/mL). Meanwhile, T-Anvi shows the highest prevention on Meg-01 expansion (IC50 = 91.40 µg/mL). Dominant compounds detected in E-Anvi by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) are identified as flavonoids. However, among four major compounds identified in H-Anvi by gas chromatography-mass spectrometry (GC-MS), palmitic acid and phytol are the most abundant compounds with peak areas of 27.97% and 16.42%, respectively. In essence, this is the first report describing that A. virginicus is a potential natural source of antioxidants, tyrosinase and α-amylase inhibitors, and anti-chronic myeloid leukemia (CML) agents which may be useful in future therapeutics as promising alternative medicines.

Alcoholic Liver Disease: Current Mechanistic Aspects with Focus on Their Clinical Relevance.

The spectrum of alcoholic liver disease (ALD) is broad and includes alcoholic fatty liver, alcoholic steatohepatitis, alcoholic hepatitis, alcoholic fibrosis, alcoholic cirrhosis, and alcoholic hepatocellular carcinoma, best explained as a five-hit sequelae of injurious steps. ALD is not primarily the result of malnutrition as assumed for many decades but due to the ingested alcohol and its metabolic consequences although malnutrition may marginally contribute to disease aggravation. Ethanol is metabolized in the liver to the heavily reactive acetaldehyde via the alcohol dehydrogenase (ADH) and the cytochrome P450 isoform 2E1 of the microsomal ethanol-oxidizing system (MEOS). The resulting disturbances modify not only the liver parenchymal cells but also non-parenchymal cells such as Kupffer cells (KCs), hepatic stellate cells (HSCs), and liver sinusoidal endothelial cells (LSECs). These are activated by acetaldehyde, reactive oxygen species (ROS), and endotoxins, which are produced from bacteria in the gut and reach the liver due to gut leakage. A variety of intrahepatic signaling pathways and innate or acquired immune reactions are under discussion contributing to the pathogenesis of ALD via the five injurious hits responsible for disease aggravation. As some of the mechanistic steps are based on studies with in vitro cell systems or animal models, respective proposals for humans may be considered as tentative. However, sufficient evidence is provided for clinical risk factors that include the amount of alcohol used daily for more than a decade, gender differences with higher susceptibility of women, genetic predisposition, and preexisting liver disease. In essence, efforts within the last years were devoted to shed more light in the pathogenesis of ALD, much has been achieved but issues remain to what extent results obtained from experimental studies can be transferred to humans.

Is obesity rather than the dietary supplement used for weight reduction the cause of liver injury?

Acute liver injury has been attributed to dietary supplements (DS) used for weight loss, but their causal role was much questioned, and obesity as an alternative cause of the liver injury remained unclear. A comprehensive search of the Medline database was conducted with terms that included "DS," "liver injury," "obesity," "obesity-related liver diseases," and "nonalcoholic steatohepatitis." For each term, we focused on the first 50 publications. We undertook a manual search to identify additional reports. Underlying liver diseases and other health issues are common in patients taking DS for weight reduction. These include obesity or morbid obesity, as well as complex metabolic disorders complicated by excess morbidity and mortality due to associated liver diseases. Among these are nonalcoholic fatty liver disease with potential progression to nonalcoholic steatohepatitis and cirrhosis, often classified as cryptogenic with a rare risk of hepatocellular carcinoma. With the exception of hepatocellular carcinoma, these obesity-related liver diseases were observed to varying degrees in patients, and some even required a liver transplant. This raises the question whether the liver injury that occurred in these patients is due to DS consumed for weight loss or to the underlying obesity-related liver diseases. This analysis showed that, in many instances, the causal role of obesity has been neglected. Obesity-associated liver diseases should be considered as differential diagnosis of liver injury in obese patients using DS.

Alcoholic Liver Disease: Alcohol Metabolism, Cascade of Molecular Mechanisms, Cellular Targets, and Clinical Aspects.

Alcoholic liver disease is the result of cascade events, which clinically first lead to alcoholic fatty liver, and then mostly via alcoholic steatohepatitis or alcoholic hepatitis potentially to cirrhosis and hepatocellular carcinoma. Pathogenetic events are linked to the metabolism of ethanol and acetaldehyde as its first oxidation product generated via hepatic alcohol dehydrogenase (ADH) and the microsomal ethanol-oxidizing system (MEOS), which depends on cytochrome P450 2E1 (CYP 2E1), and is inducible by chronic alcohol use. MEOS induction accelerates the metabolism of ethanol to acetaldehyde that facilitates organ injury including the liver, and it produces via CYP 2E1 many reactive oxygen species (ROS) such as ethoxy radical, hydroxyethyl radical, acetyl radical, singlet radical, superoxide radical, hydrogen peroxide, hydroxyl radical, alkoxyl radical, and peroxyl radical. These attack hepatocytes, Kupffer cells, stellate cells, and liver sinusoidal endothelial cells, and their signaling mediators such as interleukins, interferons, and growth factors, help to initiate liver injury including fibrosis and cirrhosis in susceptible individuals with specific risk factors. Through CYP 2E1-dependent ROS, more evidence is emerging that alcohol generates lipid peroxides and modifies the intestinal microbiome, thereby stimulating actions of endotoxins produced by intestinal bacteria; lipid peroxides and endotoxins are potential causes that are involved in alcoholic liver injury. Alcohol modifies SIRT1 (Sirtuin-1; derived from Silent mating type Information Regulation) and SIRT2, and most importantly, the innate and adapted immune systems, which may explain the individual differences of injury susceptibility. Metabolic pathways are also influenced by circadian rhythms, specific conditions known from living organisms including plants. Open for discussion is a 5-hit working hypothesis, attempting to define key elements involved in injury progression. In essence, although abundant biochemical mechanisms are proposed for the initiation and perpetuation of liver injury, patients with an alcohol problem benefit from permanent alcohol abstinence alone.

Viewpoint: A Contributory Role of Shell Ginger (Alpinia zerumbet (Pers.) B.L. Burtt & R.M. Sm) for Human Longevity in Okinawa, Japan?

The longevity of the population in the Okinawa Islands of Japan has been ascribed to genetic factors and the traditional Okinawa cuisine, which is low in calories and high in plant content. This diet includes shell ginger (Alpinia zerumbet (Pers.) B.L. Burtt & R.M. Sm) of the ginger family (Zingiberaceae). Due to its local popularity, Alpinia zerumbet has become the subject of a good deal of study at the University of the Ryukyus in Okinawa. Personal local experience and review of the literature now suggest that culinary shell ginger may contribute to longevity among the population in Okinawa. This is supported by its abundant phytochemical content, with antioxidant and anti-obesity properties. The major bioactive phytochemicals are dihydro-5,6-dehydrokawain (DDK; 80-410 mg g-1 fresh weight), 5,6-dehydrokawain (DK; ≤100 mg g-1), and essential oils, phenols, phenolic acids, and fatty acids (≤150 mg g-1 each). Further, Alpinia zerumbet extends the lifespan in animals by 22.6%. In conclusion, culinary shell ginger may significantly contribute to human longevity in Okinawa.

Drug induced liver injury: accuracy of diagnosis in published reports.

The diagnosis of drug induced liver injury (DILI) is based primarily on the exclusion of alternative causes. To assess the frequency of alternative causes in initially suspected DILI cases, we searched the Medline database with the following terms: drug hepatotoxicity, drug induced liver injury, and hepatotoxic drugs. For each term, we used the first 100 publications. We reviewed references, selected those reports relevant to our study, and retrieved finally 15 publications related to DILI and alternative causes. A total of 2,906 cases of initially assumed DILI were analyzed in these 15 publications, with diagnoses missed in 14% of the cases due to overt alternative causes. In another 11%, the diagnosis of DILI could not be established because of confounding variables. Alternative diagnoses included hepatitis B, C, and E, CMV, EBV, ischemic hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, hemochromatosis, Wilson's disease, Gilbert's syndrome, fatty liver, non alcoholic steatohepatitis, alcoholic liver diseases, cardiac and thyroid causes, rhabdomyolysis, polymyositis, postictal state, tumors, lymphomas, chlamydial and HIV infections. Causality assessment methods applied in these 15 publications were the CIOMS (Council for International Organizations of Medical Sciences) scale alone (n = 5) or combined with the Maria and Victorino (MV) scale (n = 1), the DILIN (Drug-Induced Liver Injury Network) method (n = 4), or the Naranjo scale (n = 1); the qualitative CIOMS method alone (n = 3) or combined with the MV scale (n = 1). In conclusion, alternative diagnoses are common in primarily suspected DILI cases and should be excluded early in future cases, requiring a thorough clinical and causality assessment.

Drug induced liver injury: do we still need a routine liver biopsy for diagnosis today?

For the pathologist, the diagnosis of drug induced liver injury (DILI) is challenging, because histopathological features mimic all primary hepatic and biliary diseases, lacking changes that are specific for DILI. Therefore, in any patient of suspected DILI who underwent liver biopsy, the pathologist will assure the clinician that the observed hepatic changes are compatible with DILI, but this information is less helpful due to lack of specificity. Rather, the pathologist should assess liver biopsies blindly, without knowledge of prior treatment by drugs. This will result in a detailed description of the histological findings, associated with suggestions for potential causes of these hepatic changes. Then, it is up to the physician to reassess carefully the differential diagnoses, if not done before. At present, liver histology is of little impact establishing the diagnosis of DILI with the required degree of certainty, and this shortcoming also applies to herb induced liver injury (HILI). To reach at the correct diagnoses of DILI and HILI, clinical and structured causality assessments are therefore better approaches than liver histology results obtained through liver biopsy, an invasive procedure with a low complication rate.

Kava hepatotoxicity: pathogenetic aspects and prospective considerations.

Kava hepatotoxicity is a well-defined herb-induced liver injury, caused by the use of commercial anxyolytic ethanolic and acetonic kava extracts, and of traditional recreational aqueous kava extracts. The aim of this review is to elucidate possible pathogenetic factors for the development of kava-induced liver injury, considering also confounding variables. In patients with liver disease in a causal relation to kava ± comedication, confounding factors include non-adherence to therapy recommendations and comedication consisting of synthetic and herbal drugs and dietary supplements including herbal ones and herbs-kava mixtures. Various possible pathogenetic factors have to be discussed and comprise metabolic interactions with exogenous compounds at the hepatic microsomal cytochrome P450 level; genetic enzyme deficiencies; toxic constituents and metabolites derived from the kava extract including impurities and adulterations; cyclooxygenase inhibition; P-glycoprotein alterations; hepatic glutathione depletion; solvents and solubilizers of the extracts; and kava raw material of poor quality. In particular, inappropriate kava plant parts and unsuitable kava cultivars may have been used sometimes for manufacturing the kava extracts instead of the rhizome of a noble cultivar of the kava plant (Piper methysticum G. Forster). In conclusion, kava hepatotoxicity occurred independently of the extraction medium used for the kava extracts and may primarily be attributed to daily overdose, prolonged treatment and to a few kava extract batches of poor quality; by improving kava quality and adherence to therapy recommendation under avoidance of comedication, liver injury by kava should be a preventable disease, at least to a major extent.

Black cohosh hepatotoxicity: quantitative causality evaluation in nine suspected cases.

OBJECTIVE: Black cohosh (BC), synonym for Actaea racemosa and Cimicifuga racemosa, is a herbal remedy for the treatment of menopausal symptoms. Recently, worldwide discussions have emerged as to whether its use maybe associated with the risk of rare hepatotoxicity in a few susceptible women. METHODS: We have evaluated the causal relationship in nine cases with suspected hepatotoxicity by the use of BC. The updated Council for International Organizations of Medical Sciences scale was used to quantitatively assess the causality for BC. RESULTS: In eight of nine patients with liver disease, causality for BC +/- comedication was excluded (n = 4) or unlikely (n = 4). The failure to ascribe causality in these cases was mainly due to alternative diagnosis, missing temporal association and dechallenge, and presentation of low quality data. In only one case, causality was possible for a BC preparation of an unknown brand taken for 2 months with an unknown daily dose. Confounding factors in this case include symptomatic cholelithiasis and fatty liver. Comedication with synthetic drugs and herbal or other dietary supplements was reported in five of nine patients. CONCLUSIONS: In nine cases of patients with liver disease, causality for BC +/- comedication was possible (n = 1), unlikely (n = 4), or excluded (n = 4). Due to this lack of significant circumstantial evidence, the present study shows little, if any, hepatotoxic risks by the use of BC in the analyzed cases.