Francesca Menniti-Ippolito

Hepatotoxicity from green tea: a review of the literature and two unpublished cases

PurposeTo review the current literature on suspected green tea-related hepatic reactions and to describe two new cases reported within the framework of the Italian surveillance system of natural health products.ResultsA literature search of publication between 1999 and October 2008 retrieved 34 cases of hepatitis. Histological examination of the liver revealed inflammatory reactions, cholestasis, occasional steatosis, and necrosis. A positive dechallenge was reported in 29 cases. There was one reported death. A positive rechallenge occurred in seven cases (20%). In the two new cases, the causality assessment was judged as “possible” according to the RUCAM score.ConclusionsOur analysis of the published case reports suggests a causal association between green tea and liver damage. The hepatotoxicity is probably due to (-)-epigallocatechin gallate or its metabolites which, under particular conditions related to the patient’s metabolism, can induce oxidative stress in the liver. In a few cases, toxicity related to concomitant medications could also be involved.

Suspected adverse drug events requiring emergency department visits or hospital admissions.

AbstractObjective: To analyse the contribution of adverse drug events (ADEs) to the overall number of referrals or visits at an emergency department, to determine the proportion of more severe episodes requiring hospital admission and to characterize the different causes of drug-related visits or admissions. Methods: A 1-year prospective collection of data on visits performed at an emergency department. All visits, observed during 1 week every month, were analyzed in order to identify suspected ADEs. The effects of age and sex on the frequency of ADE-related visits and admissions were evaluated. All patients hospitalized because of an ADE were followed up in order to collect information about progress and outcome of the events, which were also assessed in terms of avoidability. Results: Among the 5497 patients who visited the Emergency Department over 1 year, 235 (4.3%) experienced an ADE, 45 of these (19.1%) were subsequently hospitalized, among whom there were five deaths. Dose-related therapeutic failures were the main causes of drug-related admissions (55.6%), whereas adverse drug reactions caused the most frequent drug-related visits to the Emergency Department (63.8%). Although the frequency of drug-drug interactions leading to a visit to the Emergency Department was small (3.8%), this type of event was more severe, because most of these patients were hospitalized. No age/sex effect was observed in the proportion of ADE-related hospital admissions. Twenty-five (1.4% of the total admissions) of the 45 ADE-related admissions were evaluated as preventable, contributing by more than 61% of the overall length of hospital stay. Conclusion: The high proportion of drug therapeutic failures leading to an admission highlights the need for public education, particularly to prevent non-compliance.

Cohort study of hepatotoxicity associated with nimesulide and other non-steroidal anti-inflammatory drugs

Abstract Objective To estimate the risk of acute hepatotoxicity associated with nimesulide compared with other non-steroidal anti-inflammatory drugs. Design Retrospective cohort and nested case-control study. Setting Umbria region, Italy. Participants 400 000 current, recent, and past users (almost 2 million prescriptions) of non-steroidal anti-inflammatory drugs between 1 January 1997 and 31 December 2001. Main outcome measures Admissions to hospital for acute non-viral hepatitis and incidence of all hepatopathies and liver injury among users of nimesulide and other non-steroidal anti-inflammatory drugs. Results Current use of non-steroidal anti-inflammatory drugs was associated with a 1.4 (95% confidence interval 1.0 to 2.1) increased risk of hepatopathy compared with past use. In current users of nimesulide the rate ratio for all hepatopathies and more severe liver injury was 1.3 (0.7 to 2.3) and 1.9 (1.1 to 3.8), respectively. Conclusion The risk of liver injury in patients taking nimesulide and other non-steroidal anti-inflammatory drugs is small.

Hepatitis C virus infection in spouses: sexual transmission or common exposure to the same risk factors?

OBJECTIVES:The aim of this study was to evaluate whether the transmission of hepatitis C virus (HCV) between spouses occurs through sexual contact or through other types of exposure.METHODS:We consecutively enrolled 311 chronic HCV carriers and their spouses. The spouses underwent HCV blood testing. Exposure to parenteral risk factors was compared between couples of which both partners were HCV positive and couples with one positive partner. In couples with both partners positive, qualitative detection of serum HCV RNA and genotyping were performed.RESULTS:The prevalence among spouses was 10.3% (32/311). The mean age was higher for HCV-positive spouses (57.7 vs 49.6 yr for HCV-negative spouses; p < 0.01). The prevalence among spouses increased with the duration of marriage, whereas no difference was found in relation to the clinical status of the index case. The 32 HCV-positive spouses reported parenteral exposure (blood transfusion, drug use, and use of multiple-use glass syringes inside or outside the family) more often than the 279 HCV-negative spouses (84.4% vs 26.2%; odds ratio [OR], adjusted for age by multiple logistic regression analysis, 12.4; 95% CI = 4.5–34.0). The percentage of couples sharing glass syringes was significantly higher among those with both partners infected (65.6% vs 12.9%; OR = 12.9; 95% CI = 5.4–31.4). Qualitative serum HCV RNA was determined in 22 couples with both partners infected; in 13 of them, both partners were HCV RNA positive, whereas in the remaining nine, only one partner was positive. In eight of the 13 couples with both partners HCV RNA positive, the same genotype was found for both partners.CONCLUSIONS:The findings that the same genotype was detected for both partners in relatively few couples, and that a history of parenteral exposure was an independent predictor of HCV positivity, suggest that the risk of sexual transmission is low. The sharing of glass syringes may have played an important role in transmission between spouses.

Surveillance of suspected adverse reactions to natural health products in Italy

Natural health products are promoted to the public as equally or more effective and less toxic than conventional drugs. However, some ‘natural’ medicines, and in particular some herbal medicines, are known to have adverse effects. The Italian Pharmacovigilance System, in charge of the Italian Medicines Agency, collects spontaneous reports only for registered drugs. The awareness of the need of surveillance of the safety of natural health products has stimulated the implementation of a suspected adverse reaction reporting system in Italy. The system has been set up by the Italian National Institute of Health.

Myopathies associated with red yeast rice and liquorice: spontaneous reports from the Italian Surveillance System of Natural Health Products

Many drugs can be responsible for muscle injuries. Besides statins, recognised as the drugs most commonly associated with severe myopathies, other medications such as neuroleptics, proton pump inhibitors and recently gabapentin [1] have been associated with this type of adverse drug reaction (ADR). Recent case reports have highlighted that active compounds from medicinal plants can also be responsible for myopathies [2, 3], including rhabdomyolysis but a systematic evaluation of reporting databases is still lacking. In the present study, the Italian ADR database [4, 5] of natural health products was analyzed with the aim of evaluating the possible ‘signal alarms’ due to herbal medicines and muscle injuries. A panel of experts, including a medical toxicologist, a pharmacist and a physician expert in herbal medicine reviewed all reports of myopathy to define the causality assessment using the Naranjo probability scale [6]. From April 2002 to December 2007, nine reports of muscle disorders were identified, of which seven were reported by phytotherapy specialists, one by a hospital physician, and one by a general practitioner. As shown in Table 1 most disorders (7/9) were due to red yeast rice (Monascus purpureus) (n = 4) and liquorice (n = 3) (Glycyrrhiza glabra). In all reports Monascus purpureus was used to treat hypercholesterolaemia, and all events were assessed as ‘probable’, according to the Naranjo probability scale; all cases showed increased concentrations of serum creatinine phosphokinase (CPK) and their onset varied from 2 to 6 months. One of the patients reported previous statin intolerance, while the one who showed the highest increase in CPK (401 IU l−1; normal range 24–195 IU l−1) reported concurrent muscle pain. In the latter case the ADR did not resolve after discontinuation of red yeast rice. Table 1 Reports of myopathies associated with use of herbal drugs A case of rhabdomyolysis was diagnosed after 3 months of liquorice consumption (30–40 g day−1) but signs and symptoms disappeared after dechallenge. Laboratory data were unavailable. Another patient presented with a remarkable increase in CPK (8000 IU l−1) and blood nitrogen (6.0 mg dl−1, normal range: 0.2–6.0 mg l−1) after 20 days of self-administration of a laxative product containing liquorice. At a 6-month follow up, CPK concentrations were still elevated. Causality was assessed as ‘possible’ since the patient had undergone a previous 8-year consumption of simvastatin and lansoprazole, two drugs possibly associated with muscle injury. Although both drugs were stopped several weeks before the onset of rhabdomyolysis, their previous consumption was taken into account when assessing the causality relationship. A case of hypertension, hypokalaemia, hypernatraemia and increased CPK was also reported after 3 months of liquorice juice consumption as self-medication for chronic hypotension. After dechallenge and anti-aldosterone treatment, the patient completely recovered. According to a WHO critical term list, all reports referring to liquorice consumption were classified as ‘serious’ due to hospital admission and two out of three reactions were assessed as ‘probable’. In two cases, symptoms completely resolved after product discontinuation. Major alternative causes of muscle disorders, including alcohol abuse, illicit drug use, infections, metabolic, endocrine or inflammatory diseases were excluded in all seven patients. We can confirm the recent ‘signal’ seen in the medical literature of case reports of muscle disorders associated with red yeast rice and liquorice through our analysis of the Italian national database of adverse reactions to natural health products. All reported cases of ADRs are biologically plausible and supported by preclinical and physiopathological rationale. For instance, chronic or acute liquorice use, through glycyrrhizic acid, is able to inhibit 11β-hydroxysteroid deydrogenase-2 impairing lipid metabolism in muscle cells [3], while Monascus purpureus contains mevalonic acid and Monacolin K, an agent that has the same structure and activity as lovastatin [2, 7]. Although some case reports [4, 8, 9] have already raised this concern, favourable attitudes towards herbal preparations are still strong in industrialized countries [10]. In the majority of the cases reported here, red yeast rice was used to treat dyslipidaemia, often as a self-medication, without a physicians and/or pharmacists supervision. Many patients could therefore be exposing themselves dangerously to the additive effect of herbal and synthetic drugs, such as statins, whose potential adverse effect on muscle is well documented. Moreover, a previous statin intolerance constitutes a critical point for red yeast rice use; this should be taken into account by physicians when suggesting this kind of natural remedy to their patients, as well as by statin-intolerant patients seeking natural alternatives to synthetic drugs, who might be unaware of the real benefit–harm profile of these products.

Association between drug and vaccine use and acute immune thrombocytopenia in childhood: a case-control study in Italy.

AbstractBackground: Immune thrombocytopenic purpura (ITP) is an immuno-mediated disease characterized by a decrease in platelet count and, in its more severe forms, by bleeding symptoms. Many drugs have been implicated in the pathogenesis of drug-induced thrombocytopenia in adults; only limited data on drug-related ITP in children have been published. Objective: Our study was set up to evaluate the consistency of the association between drug and vaccine use and ITP in children. Study Design: This study is part of an Italian multicentre study on adverse drug reactions in children, coordinated by the Italian National Institute of Health, which was started in November 1999 and is ongoing. Patients or Other Participants: The study was conducted by enrolling all children aged more than 1 month who were hospitalized through the paediatric emergency department for the following conditions: thrombocytopenia (platelet count <100×103/L); acute neurological disorders; non-infectious mucocutaneous diseases and vasculitis; and endoscopically confirmed gastroduodenal lesions and/or clinically defined haematemesis and melaena. Children with chronic pathologies or concomitant diagnoses of cancer or immunodeficiency were not included in our study. Main Outcome Measure: During hospital admission, a physician interviewed parents using a structured questionnaire. The main aim of the interview was to collect information on drug exposure in a time period of 3 weeks and vaccine exposure in a period of 6 weeks preceding hospitalization. Using a case-control study design, exposure of children with thrombocytopenia (cases) to drugs and vaccines was compared with similar exposure of children with gastroduodenal lesions and neurological disorders (controls); this allowed us to estimate the odds ratios (ORs) of the occurrence of thrombo-cytopenia associated with the use of drugs or vaccines. Results: Up to December 2007, the study population included 387 cases of thrombocytopenia and 1924 controls. Despite the low platelet count, ITP was generally a mild disease, without serious bleeding in the majority of cases and associated with a short length of hospital stay. After adjusting for concurrent use of other drugs, use of the antibacterials was associated with a more than 2-fold increase in the risk of developing ITP (OR 2.4; 95% CI 1.8, 3.1). Mucolytics and NSAIDs were associated with an OR of 1.9; 95% CI 1.2, 2.9 and 1.5; 95% CI 1.0, 2.1 respectively, while paracetamol (acetaminophen) was associated with an OR of 1.5; 95% CI 1.2, 2.0. MMR vaccination was associated with an increased risk of developing ITP (OR 2.4; 95% CI 1.2, 4.7). Conclusions: The results of this study provide evidence for an association between ITP and exposure to selected antibacterials, NSAIDs, paracetamol, mucolytics and MMR vaccination.

Hepatitis from Greater celandine (Chelidonium majus L.): Review of literature and report of a new case

ETHNOPHARMACOLOGICAL RELEVANCE Folk medicine is a rich source of useful therapeutic tools. Nevertheless, use of medicinal plants can have unwanted, negative effects. By means of the description of an adverse reaction to a herbal remedy, we highlight the need for better efficacy-toxicity studies on these products. AIM OF THE STUDY To report a case of possible Chelidonium majus L. (Greater celandine)-induced hepatitis and evaluate the past published cases. MATERIALS AND METHODS We outlined the main features of hepatitis associated with use of Chelidonium majus by providing a review of cases reported and analysing in detail a new one. RESULTS Several cases of acute hepatitis related to Greater celandine consumption were found in the literature. The assessment for causality using Naranjo probability scale showed a probable relationship between the liver injury and the consumption of Chelidonium majus in the case we described. CONCLUSIONS Our case, along with the other ones reported in the literature, increases the concern about the safety of oral use of Chelidonium majus. Plants used in traditional medicine are not necessarily harmless. Customers and prescribers should be aware of this, especially when a herbal drug is used with therapeutic purposes in absence of reliable studies of clinical efficacy and benefit-risk assessment.

Gangliosides and Guillain-Barré syndrome

Cases of Guillain-Barré syndrome (GBS) associated with parenteral use of gangliosides have been reported in several European countries. To evaluate the hypothesis of association between ganglioside exposure and occurrence of GBS, a case-control study was conducted. GBS cases discharged during 1989 from public and private hospitals in three Italian provinces were identified: 42 GBS cases and 420 controls matched on age and gender were enrolled. Data of onset of symptoms of GBS was taken from clinical records. Exposure status of subjects was ascertained through the regional computerized drug prescription monitoring system. The odds ratio of association between ganglioside use, in the 30 days prior to onset of symptoms, and GBS was 9.1 (95% confidence interval 2.8-29.4). Although there are formidable difficulties in distinguishing prodromal therapy of GBS from drug causation, the association with ganglioside therapy is strong and supportive of the hypothesis of a role of ganglioside preparations in the occurrence of GBS.

Ketorolac use in outpatients and gastrointestinal hospitalization: a comparison with other non-steroidal anti-inflammatory drugs in Italy

AbstractObjective: To compare the risk of hospitalization for gastroduodenal ulcer associated with the use of ketorolac and other non-steroidal anti-inflammatory drugs (NSAIDs). Methods: A cohort and a nested case-control study were carried out. All residents in the region of Umbria (Italy), aged 35–84 years, who had been given at least one NSAID prescription in 1993 and 1994 were identified. Exposure to drugs was ascertained through a drug prescription database. We estimated rate ratios of hospitalization for gastroduodenal ulcer with or without complications in the current, recent or past period according to exposure to different NSAIDs. Results: Rate ratio estimates, adjusted for age and sex, were 2.8 for any current NSAID and 1.4 for any recent NSAID. The highest rate ratios of lesions of any severity for current NSAID use were observed for piroxicam (RR: 4.6) and ketorolac (RR: 3.4). For gastrointestinal haemorrhage or perforation the highest rate ratios were those for ketorolac (RR: 5.9) and piroxicam (RR: 4.8). Rate ratio estimates did not change after adjustment for concomitant use of gastrotoxic drugs, use of gastroprotective agents not associated with NSAIDs and prior use of NSAIDs. Conclusion: Our study demonstrates the need to adhere to the restrictions relating to the indications and duration of use of ketorolac. At present piroxicam represents a greater public health concern since it is confirmed to be among the most gastrotoxic NSAIDs and is one of the most commonly prescribed NSAIDs in Italy.