Liver Transplantation for Acute Liver Injury in Asians Is More Likely Due to Herbal and Dietary Supplements.

Drug-induced liver injury (DILI) due to medications and herbal and dietary supplements (HDSs) is a major cause of acute liver injury leading to liver transplantation (LT). This study used United Network for Organ Sharing LT data to analyze severe HDS-induced acute liver injury in the United States. By convention, patients with acute DILI are listed as "Acute Hepatic Necrosis" (AHN) under the subheading "AHN: Drug Other Specify." All patients waitlisted from 1994 to 2020 were divided into 3 subgroups: "HDS DILI," "Non-HDS DILI," and "AHN: unknown drug." Analyses were performed to identify epidemiologic differences between patients with HDS DILI and non-HDS DILI. A subanalysis was performed for transplanted patients, including longitudinal changes. Of 1875 patients waitlisted for LT, 736 (39.2%) underwent LT. The proportion of Asian patients in the HDS DILI group was significantly higher compared with that in the non-HDS DILI group (17.4% versus 3.8%; P < 0.001). Excluding acetaminophen cases, the proportion of Black patients in the HDS DILI versus non-HDS group was significantly lower (8.7% versus 25.3%; P < 0.001). Waitlisted patients with HDS DILI were significantly older (median age, 38 years for HDS DILI versus 31 years for non-HDS DILI; P = 0.03). Lastly, the number of patients requiring LT due to HDS DILI increased significantly over time with more than 70% of cases occurring in the last 10 years (2010-2020) compared with the prior 15 years (1994-2009; Ptrend  = 0.001). Ethnicity may help in identifying the cause of severe acute DILI, a growing problem as more patients experiment with HDS.

Drug induced liver injury: from pathogenesis to liver transplantation.

Drug induced liver injury (DILI) is a necro-inflammatory liver disease caused by several drugs commonly used in clinical practice, herbs and dietary supplements prescribed for medical purposes. Despite its rarity, it represents the major cause of acute liver failure (ALF) requiring liver transplantation in USA and its frequency is increasing in Europe too. Two types of drug induced liver injury have been recognized: intrinsic and idiosyncratic. Predisposing factors may be classified in environmental, drugs- and individual- related risk factors, with the latter further distinguished in genetics and non-genetics. The liver injury can present with a hepatocellular, cholestatic or mixed pattern of disease. A definitive diagnosis of DILI is, nowadays, one of the main challenging issue in the management of these patients. Diagnosis often is based on suspicion derived from clinical history, biochemical exams and eventually on histological examination from liver biopsy. Score system may be helpful in these setting and new markers are gaining more prominence. Evaluation for liver transplantation is indicated when spontaneous resolution does not occur or in cases of ALF. Overall, the 1-year survival rate following liver transplantation is lower than that seen in patients who have been transplanted for chronic liver failure; however long-term survival is higher compared to other indications.

Acute Liver Failure Caused by Use of Fat Burner: A Case Report.

Acute liver failure is a rare condition consisting of abrupt and extensive hepatocyte injury, leading to significant liver dysfunction associated with a high mortality. Liver transplantation is the most effective treatment in severe cases. The most common cause of acute liver failure in Western countries is drug-induced liver injury caused by prescription drugs and herbal and dietary supplements. Thermogenics, or fat burners, are a category of dietary supplements that claim to increase the resting metabolic rate, leading to weight loss. There are previous reports of acute liver failure associated with specific thermogenic formulations. We report the case of a 36-year-old male patient who developed jaundice 7 days after he started taking a thermogenic dietary supplement (Thermo Gun), with progressive deterioration of hepatic function and development of hepatic encephalopathy 19 days after the beginning of the symptoms. He had a Model for End-Stage Liver Disease score of 38 and fulfilled 4 of the King's College Criteria for poor prognosis in patients with acute liver failure. He underwent liver transplantation, receiving a graft from a cadaveric donor, and is alive with good liver graft function 2 years after the transplant. No possible causes for acute liver injury were identified other than the use of the supplement, which contained N-acetyl-L-tyrosine; 1,3,7-trimenthylxanthine; white willow; and 1-hydroxypholedrine. We found no previous reports in the literature of acute liver failure associated with those particular substances. This manuscript is compliant with the Helsinki Congress and the Istanbul Declaration.

Severe liver injury due to herbal and dietary supplements and the role of liver transplantation.

Herbal and dietary supplements (HDS) are increasingly used worldwide for numerous, mainly unproven health benefits. The HDS industry is poorly regulated compared to prescription medicines and most products are easily obtainable. Drug induced liver injury (DILI) is a well-recognized entity associated with prescription and over the counter medications and many reports have emerged of potential HDS-related DILI. There is considerable geographic variability in the risk and severity of DILI associated with HDS but the presentation of severe liver injury is similar with a hepatocellular pattern accompanied by jaundice. This type of injury can lead to acute liver failure and the need for liver transplantation. Patients will often fail to mention their use of HDS, considering it natural and therefore harmless. Hence physicians should understand that these products can be associated with DILI and explicitly ask about HDS use in any patient with otherwise unexplained acute liver injury.

Marked Decrease in Urgent Listing for Liver Transplantation Over Time: Evolution of Characteristics and Outcomes of Status-1 Liver Transplantation.

BACKGROUND: Approximately 5% of liver transplants annually are performed urgently with "status-1" designation. This study aims to determine if the demand, characteristics, and outcome for status-1 liver transplantation has changed over time. METHODS: We used the Scientific Registry of Transplant Patients (2003-2015) to characterize 2352 adult patients who underwent 2408 status-1 liver transplants and compared them between Era1 (2003-6/2009) and Era2 (7/2009-2015). RESULTS: Overall, there were fewer liver transplants performed with the status-1 designation in Era2 than Era1 (1099 vs 1309). Although the number of urgent liver transplants was relatively constant with successive years, the proportion transplanted with status-1 designation decreased markedly over time. Era2 patients were older (43.2 years vs 41.7 years, P = 0.01) and less likely be ABO-incompatible (1.1% vs 2.4%, P = 0.01) or retransplant (77 vs 124, P = 0.03). In terms of disease etiology, the largest group was "acute liver failure (ALF), nonspecified" (43.4%). There was no difference in proportion with drug-induced liver injury (DILI), but the subset of herbal/dietary supplements increased in Era2 (1.3% vs 0.46%, P = 0.04). Survival was increased in Era2 in the overall cohort and for patients with autoimmune disease (P < 0.05), despite longer waiting times for this etiology (186 days vs 149 days). DILI or nonspecified ALF had shorter waiting times, and 90% were transplanted within 7 days. CONCLUSIONS: Liver transplantation for the most urgent indications (status-1) is decreasing while survival remains excellent. Fewer incidences of ALF are classified as indeterminate, mostly as a result of increasing awareness of autoimmune hepatitis and DILI as causes of the syndrome.

Successful Treatment of Combined Aspergillus and Cytomegalovirus Abscess in Brain and Lung After Liver Transplant for Toxic Fulminant Hepatitis.

Invasive aspergillosis is one of the most important and fatal complications after liver transplant, especially in patients with involvement of the central nervous system. We present a case of a patient who developed cerebral and pulmonary aspergillosis, coinfected with cytomegalovirus, after liver transplant for toxic fulminant hepatitis. The patient was treated successfully with neurosurgical intervention and voriconazole. Voriconazole is considered more effective in cerebral aspergillosis than other anti-fungal agents due to the greater penetration into central nervous system and higher cerebrospinal fluid and brain tissue levels.

Dangerous dietary supplements: Garcinia cambogia-associated hepatic failure requiring transplantation.

Commercial dietary supplements are marketed as a panacea for the morbidly obese seeking sustainable weight-loss. Unfortunately, many claims cited by supplements are unsupported and inadequately regulated. Most concerning, however, are the associated harmful side effects, often unrecognized by consumers. Garcinia cambogia extract and Garcinia cambogia containing products are some of the most popular dietary supplements currently marketed for weight loss. Here, we report the first known case of fulminant hepatic failure associated with this dietary supplement. One active ingredient in this supplement is hydroxycitric acid, an active ingredient also found in weight-loss supplements banned by the Food and Drug Administration in 2009 for hepatotoxicity. Heightened awareness of the dangers of dietary supplements such as Garcinia cambogia is imperative to prevent hepatoxicity and potential fulminant hepatic failure in additional patients.

The Role of Adverse Event Reporting in the FDA Response to a Multistate Outbreak of Liver Disease Associated with a Dietary Supplement.

OBJECTIVE: Liver disease is a potential complication from using dietary supplements. This study investigated an outbreak of non-viral liver disease associated with the use of OxyELITE Pro(TM), a dietary supplement used for weight loss and/or muscle building. METHODS: Illness details were ascertained from MedWatch reports submitted to the U.S. Food and Drug Administration (FDA) describing consumers who ingested OxyELITE Pro alone or in combination with other dietary supplements. FDA's Forensic Chemistry Center analyzed samples of OxyELITE Pro. RESULTS: From February 2012 to February 2014, FDA received 114 reports of adverse events of all kinds involving consumers who ingested OxyELITE Pro. The onset of illness for the first report was December 2010 and for the last report was January 2014. Thirty-three states, two foreign nations, and Puerto Rico submitted reports. Fifty-five of the reports (48%) described liver disease in the absence of viral infection, gallbladder disease, autoimmune disease, or other known causes of liver damage. A total of 33 (60%) of these patients were hospitalized, and three underwent liver transplantation. In early 2013, OxyELITE Pro products entered the market with a formulation distinct from products sold previously. The new formulation replaced 1,3-dimethylamylamine with aegeline. However, the manufacturer failed to submit to FDA a required "new dietary ingredient" notice for the use of aegeline in OxyELITE Pro products. Laboratory analysis identified no drugs, poisons, pharmaceuticals, toxic metals, usnic acid, N-Nitroso-fenfluramine, pyrrolizidine alkaloids, aristocholic acid, or phenethylamines in the products. CONCLUSIONS: Vigilant surveillance is required for adverse events linked to the use of dietary supplements.

Model for end-stage liver disease score as a predictor of short-term outcome in patients with drug-induced liver injury.

OBJECTIVES: The purposes of this study were to investigate the clinical presentation, cause and outcome of drug-induced liver injury (DILI) and to evaluate the predictive value of the model for end-stage liver disease (MELD) score in DILI. METHODS: Patients diagnosed with DILI between January 1, 2010 and December 31, 2012 in the Emergency Department at Asan Medical Center in Seoul, Korea were analyzed retrospectively. The primary end point was poor outcome, defined as liver transplantation or death within 30 days of the initial hospital visit. RESULTS: Of 213 patients, 13.1% had a 30-day poor outcome. Folk remedies were the most common cause of DILI in 147 patients (69%). Univariate logistic regression analysis showed that multiple drugs (odds ratio [OR] 2.30, 95% confidence interval [CI]: 1.03-5.15), concurrent alcohol consumption (OR 3.69, 95% CI: 1.03-13.18), white blood cell (WBC) count (OR 1.17, 95% CI: 1.07-1.28), hemoglobin (Hb) (OR 0.60, 95% CI: 0.49-0.74), platelet count (OR 0.993, 95% CI: 0.987-0.998), total bilirubin (OR 1.09, 95% CI: 1.06-1.13) and MELD (OR 1.23, 95% CI: 1.15-1.32) were significantly associated with 30-day poor outcomes. Multivariate analysis showed that the MELD (OR 1.21, 95% CI: 1.12-1.30) and Hb (OR 0.77, 95% CI: 0.61-0.98) were independent predictors of poor outcome. For 30-day mortality, the c-statistics for MELD alone and for combination of MELD and Hb were 0.93 (95% CI: 0.89-0.97) and 0.94 (95% CI: 0.90-0.97), respectively. CONCLUSION: The outcome of patients with DILI was poor. MELD score and Hb were reliable predictors of short-term outcome in patients with DILI.

Liver injury from herbals and dietary supplements in the U.S. Drug-Induced Liver Injury Network.

UNLABELLED: The Drug-Induced Liver Injury Network (DILIN) studies hepatotoxicity caused by conventional medications as well as herbals and dietary supplements (HDS). To characterize hepatotoxicity and its outcomes from HDS versus medications, patients with hepatotoxicity attributed to medications or HDS were enrolled prospectively between 2004 and 2013. The study took place among eight U.S. referral centers that are part of the DILIN. Consecutive patients with liver injury referred to a DILIN center were eligible. The final sample comprised 130 (15.5%) of all subjects enrolled (839) who were judged to have experienced liver injury caused by HDS. Hepatotoxicity caused by HDS was evaluated by expert opinion. Demographic and clinical characteristics and outcome assessments, including death and liver transplantation (LT), were ascertained. Cases were stratified and compared according to the type of agent implicated in liver injury; 45 had injury caused by bodybuilding HDS, 85 by nonbodybuilding HDS, and 709 by medications. Liver injury caused by HDS increased from 7% to 20% (P < 0.001) during the study period. Bodybuilding HDS caused prolonged jaundice (median, 91 days) in young men, but did not result in any fatalities or LT. The remaining HDS cases presented as hepatocellular injury, predominantly in middle-aged women, and, more frequently, led to death or transplantation, compared to injury from medications (13% vs. 3%; P < 0.05). CONCLUSIONS: The proportion of liver injury cases attributed to HDS in DILIN has increased significantly. Liver injury from nonbodybuilding HDS is more severe than from bodybuilding HDS or medications, as evidenced by differences in unfavorable outcomes (death and transplantation). (Hepatology 2014;60:1399-1408).

[Severe toxic acute liver failure: etiology and treatment]. / Insuffisances hépatiques aiguës sévères d'origine toxique : prise en charge étiologique et symptomatique.

Many substances, drugs or not, can be responsible for acute hepatitis. Nevertheless, toxic etiology, except when that is obvious like in acetaminophen overdose, is a diagnosis of elimination. Major causes, in particular viral etiologies, must be ruled out. Acetaminophen, antibiotics, antiepileptics and antituberculous drugs are the first causes of drug-induced liver injury. Severity assessment of the acute hepatitis is critical. Acute liver failure (ALF) is defined by the factor V, respectively more than 50% for the mild ALF and less than 50% for the severe ALF. Neurological examination must be extensive to the search for encephalopathy signs. According to the French classification, fulminant hepatitis is defined by the presence of an encephalopathy in the two first weeks and subfulminant between the second and 12th week after the advent of the jaundice. During acetaminophen overdose, with or without hepatitis or ALF, intravenous N-acetylcysteine must be administered as soon as possible. In the non-acetaminophen related ALF, N-acetylcysteine improves transplantation-free survival. Referral and assessment in a liver transplantation unit should be discussed as soon as possible.

[Liver damage detected after a hepatectomy for liver metastasis after 12 courses of mFOLFOX6 therapy as an adjuvant chemotherapy for colorectal cancer].

The FOLFOX regimen is approved as an adjuvant therapy for colon cancer in Japan. We report a case of pathological damage in the resected non-cancerous liver after 12 courses of mFOLFOX6 therapy as an adjuvant therapy for stage IIIb colon cancer. A 45-year-old man underwent laparoscopic right hemicolectomy for ascending colon cancer. After completing 12 courses of adjuvant mFOLFOX6 therapy, this patient exhibited liver metastasis. Lateral segment resection was performed, and pathological examination of the resected specimen revealed irregular sinusoidal dilatation and cell apoptosis in the non-tumorous part of the liver. This was probably due to the effects of mFOLFOX6. We stress that when resectable liver metastasis is found after 12 courses of FOLFOX as an adjuvant therapy for colon cancer, careful attention should be paid during surgery and during postsurgical management because there may be damage in the remnant liver.

Fulminant hepatitis during self-medication with conjugated linoleic acid.

The present report describes a 63-year-old female who presented with fulminant hepatic failure requiring liver transplantation caused by a weight loss dietary supplement containing conjugated linoleic acid (CLA). Thorough investigation, including liver biopsy, revealed no other cause of hepatotoxicity. In the last few years, a considerable number of reports have been published on toxic hepatitis, associated with non-conventional products, attributed with weight-reducing properties. We emphasize the importance of taking a cautious approach when consuming herbal supplements for the purpose of weight loss, as all that is "natural" may not always be healthy. Only one report of CLA-induced toxic hepatitis is related in the medical literature.

Living donor liver transplantation for acute liver failure in pediatric patients caused by the ingestion of fireworks containing yellow phosphorus.

Yellow phosphorus is a protoplasmic toxicant that targets the liver. The ingestion of fireworks containing yellow phosphorus, either by children who accidentally consume them or by adults who are attempting suicide, often results in death due to acute liver failure (ALF). We present the outcomes of 10 children who ingested fireworks containing yellow phosphorus. There were 6 boys and 4 girls, and their ages ranged from 21 to 60 months. One patient remained stable without liver complications and was discharged. Three patients died of hepatorenal failure and cardiovascular collapse, and living donor liver transplantation (LDLT) was performed for 6 patients. The patients had grade II or III encephalopathy, a mean alanine aminotransferase level of 1148.2 IU/L, a mean aspartate aminotransferase level of 1437.5 IU/L, a mean total bilirubin level of 6.9 mg/dL, a mean international normalized ratio of 6.6, a mean Pediatric End-Stage Liver Disease score of 33.7, and a mean Child-Pugh score of 11.3. Postoperatively, 2 patients had persistent encephalopathy and died on the second or third postoperative day, and 1 patient died of cardiac arrest on the first postoperative day despite a well-functioning graft. The other 3 patients were still alive at a mean of 204 days. In conclusion, the ingestion of fireworks containing yellow phosphorus causes ALF with a high mortality rate. When signs of irreversible ALF are detected, emergency LDLT should be considered as a lifesaving procedure; however, if yellow phosphorus toxicity affects both the brain and the heart in addition to the liver, the mortality rate remains very high despite liver transplantation.

Liver transplantation for acute liver failure due to toxic agent ingestion in children.

ALF is characterized by sudden onset, impaired liver function, jaundice and encephalopathy, without previous liver disease. We analyzed the patients who underwent LT due to toxic agent induced ALF to raise community awareness about preventing the toxic agent induced ALF. Five children (three boys, two girls) underwent LT due to toxic agent ingestion. Toxic agents were mushroom poisoning (n = 2), Datura stramonium (n = 1), yellow phosphorous (n = 1) and INH (n = 1). On admission, one patient had stage IV, two had stage III and two had stage II hepatic encephalopathy but worsened during the follow-up. One patient had renal failure, and three patients required mechanical ventilation. Three patients underwent LRLT and others from a DD. Post-operative complications were managed by supportive managements successfully, and overall all the patients are alive (100% survival) without any organ sequelae. Although outcome of these patients are excellent, ALF may be prevented in these cases by educating the public about consuming mushrooms and toxic effects of wild plants, prohibiting fireworks and serial liver enzyme measurements after initiating INH.

Acute hepatitis induced by kava kava.

BACKGROUND: Herbal preparations are available widely and regarded generally by the public as harmless remedies for a variety of medical ailments. We report a case of acute hepatitis associated with the use of kava kava, derived from the root of the pepper plant, Piper methysticum. It is used in the United States as an antianxiety and sedative agent. CASE REPORT: A previously healthy 14-year-old female was admitted to the hospital with hepatic failure. Initial therapy, including plasmapheresis, was unsuccessful and she deteriorated. She ultimately required a liver transplant and now remains well. The liver biopsy showed hepatocellular necrosis consistent with chemical hepatitis. A work-up for alternative causes of liver failure was negative. The patient gave a history of taking a kava kava-containing product for four months. The use of kava kava and liver failure, is supported by kava kava use, a negative work-up for alternative causes of liver failure, and histological changes in the liver. CONCLUSIONS: Health care professionals need to be aware of the possibility of kava kava-induced hepatotoxicity. The toxicity of these alternative remedies emphasizes the importance of surveillance programs and quality control in the manufacture of these products. Clinicians must remain aware of the toxic potential of herbal products and always inquire about their intake in cases of unexplained liver injury.