A Hidden Cause of Hypertransaminasemia: Liver Toxicity Caused by Chelidonium Majus L. : Report of Two Cases of Herb-Induced Liver Injury and Literature Review.

BACKGROUND: In instances where individuals manifest elevated transaminase levels without a clearly discernible cause, a comprehensive patient history proves invaluable in unveiling latent triggers. In this report, we present 2 cases of herb-induced liver injury (HILI) characterized by severe hypertransaminasemia attributed to the consumption of Chelidonium majus L . (also known as greater celandine [GC]), an agent considered an alternative therapeutic remedy. AREAS OF UNCERTAINTY: Exploring the occurrence and range of clinical manifestations in HILI linked to Chelidonium majus L ., while also investigating the potential triggers and predisposing factors for hepatotoxic reactions post Chelidonium majus L. usage, remains challenging due to the absence of definitive laboratory tests to identify the causative agent. DATA SOURCES: Two case reports were detailed, and a systematic literature review using PubMed was conducted including published literature till March 2023. Moreover, a manual search of reference lists of pertinent articles was performed to identify any additional relevant missed publications. RESULTS: In the first case, a 64-year-old woman presented with jaundice, revealing a 1-month history of using GC capsules to manage gallstones. Diagnostic assessment identified HILI, gallstones, and choledocolithiasis, with transaminase levels exceeding 1000 IU/L. After discontinuing GC and receiving intravenous therapy with amino acids and phospholipids, the patient's condition significantly improved. Subsequently, she underwent endoscopic common bile duct stone removal and cholecystectomy. In the second case, a 66-year-old woman presented with elevated liver function test results discovered incidentally during musculoskeletal pain evaluation. Upon further questioning, the patient disclosed regular consumption of GC tea for "health promotion." Following intravenous therapy using amino acids and phospholipids, her transaminase levels returned to normal. The literature review identified 38 cases of HILI associated with GC preparations, primarily in adult women aged 27-77 years, with a predominant reporting location in Germany. Various forms of GC were used, with treatment durations ranging from 1 week to a year. Discontinuation of GC generally led to recovery in these cases. CONCLUSION: Chelidonium majus L ., a potent herb often used in alternative medicine, has significant hepatotoxic potential, requiring physicians to be vigilant in cases of unexplained liver injury.

Herbal hepatotoxicity: analysis of cases with initially reported positive re-exposure tests.

BACKGROUND: Positive re-exposure tests are diagnostic hallmarks for hepatotoxicity. OBJECTIVE: To test validity of positive re-exposures in herb induced liver injury. METHODS: We searched Medline database for cases of herb induced liver injury with positive re-exposures and analysed 34 cases for positive re-exposure test criteria of baseline alanine aminotransferase< 5N before re-exposure, and re-exposure alanine aminotransferase ≥ 2× baseline alanine aminotransferase. Re-exposure test was negative, if baseline alanine aminotransferase< 5N combined with re-exposure alanine aminotransferase< 2× baseline alanine aminotransferase, or if baseline alanine aminotransferase≥ 5N regardless of the re-exposure alanine aminotransferase including no available re-exposure alanine aminotransferase result. RESULTS: In 21/34 cases (61.8%), criteria for a positive re-exposure were fulfilled, with negative tests in 6/34 cases (17.6%) or uninterpretable ones in 7/34 cases (20.6%). Confirmed positive re-exposure tests established potential of herb induced liver injury for Aloe, Chaparral, Chinese herbal mixtures, Chinese Jin Bu Huan, Chinese Syo Saiko To, Germander, Greater Celandine, Green tea, Kava, Mistletoe, Polygonum multiflorum, and Senna, with up to 4 case reports per herb. CONCLUSIONS: Among 34 cases of herb-induced liver injury with initially reported positive re-exposure tests, 61.8% of the cases actually fulfilled established test criteria and provided firm diagnoses of herb induced liver injury by various herbs.

Greater Celandine hepatotoxicity: a clinical review.

Herbal hepatotoxicity is a rare and poorly described disease because reported cases are mostly scattered and lack an appropriate causality assessment. We now describe in detail the clinical picture of herbal hepatotoxicity by extracts of Greater Celandine (GC), syn. Chelidonium majus L. from the Papaveraceae family, which contain more than 20 ingredients including various biologically active isoquinoline alkaloids. For this purpose, we analyzed and reviewed published cases of 16 patients from various European countries. In all patients, herbal hepatotoxicity was of probable and highly probable causality for GC, using the original and updated scale of CIOMS (Council for International Organizations of Medical Sciences). GC associated hepatotoxicity usually has an acute clinical course exhibiting a hepatocellular pattern of injury and is correlated to an idiosyncratic reaction with its metabolic subtype. Jaundice combined with high values of serum aminotransferases was present in virtually all cases with favourable outcome despite severe clinical course. In conclusion, GC hepatotoxicity is a typical herbal hepatotoxicity with a sound causality track for GC, but there is uncertainty regarding the respective causative compound(s). The present detailed review of GC hepatotoxicity may serve as an example for clinical causality assessments of future cases of liver injury due to other herbs.

Suspected Greater Celandine hepatotoxicity: liver-specific causality evaluation of published case reports from Europe.

BACKGROUND AND OBJECTIVES: In 21 published case reports, the use of the herb Greater Celandine (GC) (Chelidonium majus L.) has been causally related to liver injury, but a variety of confounding variables were evident that might have offset causality. This study reanalyses causality levels in these cases with a liver-specific causality evaluation method. METHODS: All 21 cases were submitted to the liver-specific, standardized, structured, quantitative and updated scale of the Council for International Organizations of Medical Sciences. This scale considers, among other items, latency period, course of alanine aminotransferase after treatment discontinuation, risk factors, comedication and alternative causes. RESULTS: Using this method for assessment, causality for GC was highly probable in two and probable in six cases, with lower causality grading in the remaining 13 cases. In these patients, causality for GC was possible in 10 cases and excluded in three cases. On the basis of the eight cases with highly probable and probable causality gradings, GC hepatotoxicity represents an idiosyncratic reaction of the metabolic type, whereas immunologic or obligatory hepatotoxic features are lacking. In some cases, alternative diagnoses and poor data quality were confounding variables that reduced causality levels. CONCLUSION: Confounding variables reduced causality levels for GC in reported cases of liver injury, but there is still striking evidence for herb-induced liver injury by GC with high causality gradings. GC hepatotoxicity is caused by an idiosyncratic reaction of the metabolic form, but there is uncertainty with respect to its culprit(s).

Drug-induced liver injury due to "natural products" used for weight loss: a case report.

Taking herbal-extracts to lose weight is an underestimated health hazard. Often, these products contain active agents that can cause acute liver damage. In this case report, a 22-year-old female patient, who presented with a feature of cholestatic syndrome, was so sure that the "natural products" were not dangerous that she did not inform her physicians that she had taken them, making their task that much more challenging. Clinical presentation mimicked acute cholecystitis and the patient underwent a cholecystectomy. Surgery was without any consequences and complications, although it did not completely cure the illness. She later admitted to having taken herbal remedies and this led to the correct diagnosis of phytotherapy-related hepatotoxicity and a successful therapeutic approach. The true incidence of phytotherapy-related hepatotoxicity and its pathogenic mechanisms are largely unknown. It is important to increase the awareness of both clinicians and patients about the potential dangers of herbal remedies.

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.

[Severe drug hepatitis caused by Chelidonium]. / 58-jähriger Patient mit schwerer cholestatischer Hepatitis.

We report the case of a 58-year-old male patient who was admitted with severe acute cholestatic hepatitis. Liver biopsy showed signs of drug-induced hepatitis. Other causes of acute hepatitis were excluded. Therefore, the ingestion of a Chelidonium-containing preparation (celandine) was thought to be responsible for the hepatitis. Shortly after stopping the administration of Chelidonium, the highly pathological levels of several liver parameters began to normalise. As no autoantibodies were detectable, an idiosyncratic reaction as the cause of drug-induced hepatitis is probable. In cases of unknown hepatitis, herbal medications should be taken into account as a possible cause.

Acute hepatitis induced by Greater Celandine (Chelidonium majus).

We report on two cases of acute liver injury along with the intake of Greater Celandine (Chelidonium majus), a well-known herbal remedy frequently used for irritable bowel syndrome. All other possible causes of acute liver damage were excluded in both patients. In one patient, cholestatic hepatitis recurred rapidly after involuntary re-exposition. Both patients fully recovered after the withdrawal of Greater Celandine. The two cases add to the existing database about the potential hepatotoxicity of drugs containing Greater Celandine and raise the question whether the approval of this drug should be re-evaluated in the light of lacking evidence for a therapeutic benefit.

["Dosis solum facit venenum" also for herbal products]. / Dosis solum facit venenum, ook bij plantaardige producten.

A report of severe hepatitis due to the use of material from the plant Chelidonium majus, reminds us that herbal products can be much more life-threatening than many people realise. The widespread use of plants for food has reinforced the idea that eating plants promotes health. With the development of organic chemistry in the 19th century it became possible for the first time to purify and identify pharmacologically active plant constituents and later on to synthesize related compounds with an even stronger activity. The development of the antimalarial artemotil from Artemisia plants is a recent example. The activity, safety and composition of such compounds can be controlled in just the same manner as purely synthetic compounds. However, some people still believe that traditional plants are much safer and better than modern synthetic pharmaceuticals. The qualitative and quantitative composition of such herbal medicines from alternative medical sources, are not covered by public health legislation. Whereas phytotherapists consider plants to be a source of useful drugs, regular physicians maintain that the composition of a preparation and not the provenance, determines its effects.

[Acute hepatitis after use of a herbal preparation with greater celandine (Chelidonium majus)]. / Acute hepatitis na gebruik van een plantaardig preparaat met stinkende gouwe (Chelidonium majus).

A 42-year-old woman developed jaundice due to acute hepatitis several weeks after ingestion of a herbal preparation containing greater celandine (Chelidonium majus) and curcuma root, which had been prescribed by an alternative therapist due to a skin complaint. After the medication had been withdrawn, clinical recovery was rapid and the hepatic functions returned to normal within 2 months. The hepatitis was ascribed to the known hepatotoxic effects of C. majus. In view of the increasing popularity of herbal remedies, greater awareness of side effects, such as hepatotoxicity, is needed. Quite a number of herbal preparations carry the risk of liver damage. The supposed clinical effectiveness of herbal remedies does not seem to always outweigh the potential risks. In the event of non-clarified liver function disturbances the ingestion of supposedly harmless, but potentially hepatotoxic, herbal products should be considered.