Acute liver failure secondary to the use of unmonitored drugs and herbal supplements: an underreported and serious issue.

Acute liver failure (ALF) is a potentially fatal illness marked by the abrupt development of jaundice, coagulopathy, and hepatic encephalopathy (HE) in persons having no previous history of hepatic disease. It is a relatively uncommon illness, having an incidence of 1 to 8 per million people. Hepatitis A, B, and E viruses have been documented as the most prevalent etiologies of acute liver failure in Pakistan and other developing nations. However, ALF may also occur secondary to toxicity caused by the unmonitored overdosing and toxicity of traditional medicines, herbal supplements, and alcohol. Similarly, in some instances, the etiology remains unknown. Herbal products, alternative, and complementary therapies are frequently practiced across the globe for treating various illnesses. In recent times, their use has gained much popularity. Indications and the use of these supplementary drugs vary significantly. The majority of these products have not gained approval from Food and Drug Administration (FDA). Unfortunately, the incidence of documented adverse effects linked to the usage of herbal products has increased recently, but still, these events are underreported, and the condition is known as drug-induced liver injury (DILI) and herb-induced liver injury (HILI). The estimated total herbal retail sales increased from $4230 million in 2000 to $6032 million in 2013, representing a total of 42 and 3.3% per annum increase. To reduce the occurrence of HILI and DILI, physicians in general practice settings should inquire about patients' understanding of potential toxicity with the consumption of hepatotoxic and herbal medicines.

Secular Trends in Severe Idiosyncratic Drug-Induced Liver Injury in North America: An Update From the Acute Liver Failure Study Group Registry.

INTRODUCTION: Idiosyncratic drug-induced liver injury (DILI) is the second leading cause of acute liver failure (ALF) in the United States. Our study aims were to characterize secular trends in the implicated agents, clinical features, and outcomes of adults with DILI ALF over a 20-year period. METHODS: Among 2,332 patients with ALF enrolled in the ALF Study Group registry, 277 (11.9%) were adjudicated as idiosyncratic DILI ALF (INR ≥ 1.5 and hepatic encephalopathy) through expert opinion. The 155 cases in era 1 (January 20, 1998-January 20, 2008) were compared with the 122 cases in era 2 (January 21, 2008-January 20, 2018). RESULTS: Among 277 cases of DILI ALF, 97 different agents, alone or in combination, were implicated: antimicrobials, n = 118 (43%); herbal/dietary supplements (HDS), n = 42 (15%); central nervous system agents/illicit substances, n = 37 (13%); oncologic/biologic agents, n = 29 (10%); and other, n = 51 (18%). Significant trends over time included (i) an increase in HDS DILI ALF (9.7% vs 22%, P < 0.01) and decrease in antimicrobial-induced DILI ALF (45.8% vs. 38.5%, P = 0.03) and (ii) improved overall transplant-free survival (23.5%-38.7%, P < 0.01) while the number of patients transplanted declined (46.4% vs 33.6%, P < 0.03). DISCUSSION: DILI ALF in North America is evolving, with HDS cases rising and other categories of suspect drugs declining. The reasons for a significant increase in transplant-free survival and reduced need for liver transplantation over time remain unclear but may be due to improvements in critical care, increased NAC utilization, and improved patient prognostication.

Acute Hepatic Failure and Nutrition.

Malnutrition is prevalent in patients with hepatic failure and remains an independent risk factor for morbidity and mortality in these patients. Factors that contribute to malnutrition in this patient population include altered metabolic rate, fat malabsorption, and impaired gastric emptying, all in the setting of an acute and potentially prolonged hospitalization. Acute liver failure (ALF), different from cirrhosis or chronic liver disease, is an uncommon but dramatic clinical syndrome that demonstrates severe and rapid decline in hepatic metabolic function. ALF has a significant risk of mortality. There are >10 cases per million persons per year in developed countries, but ALF presents with unique challenges in clinical management related to heterogeneity in severity and etiology. Patients with ALF by definition should not have a prior history of liver disease, and liver disease is subsequently defined by the onset of liver injury, the presence of hepatic encephalopathy (HE), and coagulopathy as defined by an international normalized ratio > 1.5. HE usually develops within 1-4 weeks of the onset of liver injury but may occur within 26 weeks of the initial presentation. Rates of survival from ALF have improved over recent years, but the rarity and severity of presentation have resulted in traditionally limited evidence to guide basic supportive care. Over time, advances in critical care management and the use of emergency liver transplantation have improved. In this article, we will review current nutrition considerations for patients with ALF.

Incidence and Etiology of Drug-Induced Liver Injury in Mainland China.

BACKGROUND & AIMS: We performed a nationwide, retrospective study to determine the incidence and causes of drug-induced liver injury (DILI) in mainland China. METHODS: We collected data on a total of 25,927 confirmed DILI cases, hospitalized from 2012 through 2014 at 308 medical centers in mainland China. We collected demographic, medical history, treatment, laboratory, disease severity, and mortality data from all patients. Investigators at each site were asked to complete causality assessments for each case whose diagnosis at discharge was DILI (n = 29,478) according to the Roussel Uclaf Causality Assessment Method. RESULTS: Most cases of DILI presented with hepatocellular injury (51.39%; 95% confidence interval [CI] 50.76-52.03), followed by mixed injury (28.30%; 95% CI 27.73-28.87) and cholestatic injury (20.31%; 95% CI 19.80-20.82). The leading single classes of implicated drugs were traditional Chinese medicines or herbal and dietary supplements (26.81%) and antituberculosis medications (21.99%). Chronic DILI occurred in 13.00% of the cases and, although 44.40% of the hepatocellular DILI cases fulfilled Hy's Law criteria, only 280 cases (1.08%) progressed to hepatic failure, 2 cases underwent liver transplantation (0.01%), and 102 patients died (0.39%). Among deaths, DILI was judged to have a primary role in 72 (70.59%), a contributory role in 21 (20.59%), and no role in 9 (8.82%). Assuming the proportion of DILI in the entire hospitalized population of China was represented by that observed in the 66 centers where DILI capture was complete, we estimated the annual incidence in the general population to be 23.80 per 100,000 persons (95% CI 20.86-26.74). Only hospitalized patients were included in this analysis, so the true incidence is likely to be higher. CONCLUSIONS: In a retrospective study to determine the incidence and causes of DILI in mainland China, the annual incidence in the general population was estimated to be 23.80 per 100,000 persons; higher than that reported from Western countries. Traditional Chinese medicines, herbal and dietary supplements, and antituberculosis drugs were the leading causes of DILI in mainland China.

Acute liver injury following Garcinia cambogia weight-loss supplementation: case series and literature review.

Herbal weight-loss supplements are sold as self-medication products, and are often used under the misconception that their natural origin guarantees their safety. Food supplements are not required to provide any benefit/risk profile evaluation before marketing; however, possible risks associated with use of herbal extracts in food supplements are becoming more and more documented in the literature. Some herbs are listed as the leading cause of herb-induced liver injury, with a severe or potentially lethal clinical course, and unpredictable herb-drug interactions. Garcinia cambogia (GC) extract and GC-containing products are some of the most popular dietary supplements currently marketed for weight loss. Here, we present four cases of acute liver failure in women taking GC extract for weight loss, and a literature review of clinical evidences about hepatic toxicity in patients taking dietary supplements containing GC extract.

Population-representative incidence of drug-induced acute liver failure based on an analysis of an integrated health care system.

BACKGROUND & AIMS: Medications are a major cause of acute liver failure (ALF) in the United States, but no population-based studies have evaluated the incidence of ALF from drug-induced liver injury. We aimed to determine the incidence and outcomes of drug-induced ALF in an integrated health care system that approximates a population-based cohort. METHODS: We performed a retrospective cohort study using data from the Kaiser Permanente Northern California (KPNC) health care system between January 1, 2004, and December 31, 2010. We included all KPNC members age 18 years and older with 6 months or more of membership and hospitalization for potential ALF. The primary outcome was drug-induced ALF (defined as coagulopathy and hepatic encephalopathy without underlying chronic liver disease), determined by hepatologists who reviewed medical records of all KPNC members with inpatient diagnostic and laboratory criteria suggesting potential ALF. RESULTS: Among 5,484,224 KPNC members between 2004 and 2010, 669 had inpatient diagnostic and laboratory criteria indicating potential ALF. After medical record review, 62 (9.3%) were categorized as having definite or possible ALF, and 32 (51.6%) had a drug-induced etiology (27 definite, 5 possible). Acetaminophen was implicated in 18 events (56.3%), dietary/herbal supplements in 6 events (18.8%), antimicrobials in 2 events (6.3%), and miscellaneous medications in 6 events (18.8%). One patient with acetaminophen-induced ALF died (5.6%; 0.06 events/1,000,000 person-years) compared with 3 patients with non-acetaminophen-induced ALF (21.4%; 0.18/1,000,000 person-years). Overall, 6 patients (18.8%) underwent liver transplantation, and 22 patients (68.8%) were discharged without transplantation. The incidence rates of any definite drug-induced ALF and acetaminophen-induced ALF were 1.61 events/1,000,000 person-years (95% confidence interval, 1.06-2.35) and 1.02 events/1,000,000 person-years (95% confidence interval, 0.59-1.63), respectively. CONCLUSIONS: Drug-induced ALF is uncommon, but over-the-counter products and dietary/herbal supplements are its most common causes.

Causes and outcomes of acute liver failure in China.

OBJECTIVES: No extensive investigation has been performed and thus no representative data are available regarding acute liver failure (ALF) in China. This study aims to investigate the causes and outcomes of ALF in China and establish a prognostic model. METHODS: Patients diagnosed as ALF in seven hospitals in different areas of China from January 2007 to December 2012 were retrospectively selected. RESULTS: Of the 177 patients included in this study, 112 (63.28%) eventually died. The common causes of ALF were drug toxicity (43.50%), indeterminate etiology (29.38%) and acute viral hepatitis (11.30%). Additionally, traditional Chinese herbs predominated in the causes of drug-induced ALF (30/77). No patients in this study received liver transplantation. In the established model for predicting death in ALF, four variables were finally selected out, including age (P=0.01), the entry hepatic encephalopathy grade (P=0.04), international normalized ratio (P<0.01) and arterial blood ammonia (P=0.02). Using a threshold value of 0.5683, this model had a sensitivity of 95.24% and a specificity of 91.30%. CONCLUSIONS: Traditional Chinese medicine was a major cause of ALF in China. The spontaneous mortality of ALF was high, whereas the rate of liver transplantation was significantly low. The established prognostic model of ALF had superior sensitivity and specificity.

Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States.

BACKGROUND & AIMS: Idiosyncratic drug-induced liver injury (DILI) is among the most common causes of acute liver failure in the United States, accounting for approximately 13% of cases. A prospective study was begun in 2003 to recruit patients with suspected DILI and create a repository of biological samples for analysis. This report summarizes the causes, clinical features, and outcomes from the first 300 patients enrolled. METHODS: Patients with suspected DILI were enrolled based on predefined criteria and followed up for at least 6 months. Patients with acetaminophen liver injury were excluded. RESULTS: DILI was caused by a single prescription medication in 73% of the cases, by dietary supplements in 9%, and by multiple agents in 18%. More than 100 different agents were associated with DILI; antimicrobials (45.5%) and central nervous system agents (15%) were the most common. Causality was considered to be definite in 32%, highly likely in 41%, probable in 14%, possible in 10%, and unlikely in 3%. Acute hepatitis C virus (HCV) infection was the final diagnosis in 4 of 9 unlikely cases. Six months after enrollment, 14% of patients had persistent laboratory abnormalities and 8% had died; the cause of death was liver related in 44%. CONCLUSIONS: DILI is caused by a wide array of medications, herbal supplements, and dietary supplements. Antibiotics are the single largest class of agents that cause DILI. Acute HCV infection should be excluded in patients with suspected DILI by HCV RNA testing. The overall 6-month mortality was 8%, but the majority of deaths were not liver related.

[Incidence and risk factors of acute hepatic failure after transcatheter arterial chemoembolization for hepatocellular carcinoma].

BACKGROUND/AIMS: Although transcatheter arterial chemoembolization (TACE) is a major treatment modality for unresectable hepatocellular carcinoma (HCC), acute hepatic failure after TACE is not rare. However, reports dealing with this important complication are not good enough and results are often variable. The purpose of this study was to evaluate the incidence and associated risk factors of acute hepatic failure after TACE. METHODS: From January 2001 to November 2004, six hundred and thirty-two TACE sessions were performed in 377 patients (294 men and 83 women). Adriamycin mixed lipiodol solution and gelfoam were used for TACE. Various clinical and radiological factors before and after the procedure were reviewed retrospectively. Univariate and multivariate analyses were performed to evaluate the risk factors associated with the development of acute hepatic failure after TACE. RESULTS: Acute hepatic failure occurred in 76 (12.0%) of the 632 TACE sessions within 14 days. Univariate analysis revealed that Child-Pugh class, 1st TACE, total bilirubin level, number of involved segments, total size of tumor, presence of right portal vein thrombosis (PVT) or main PVT, involvement of segment 1, 5, 6, 7, modified UICC stage, and doses of chemotherapeutic agent were significantly different between the patients with or without hepatic failure after TACE. Among them, elevated total bilirubin (p=0.001, E (beta)=1.449), presence of right (p=0.035, E (beta)=2.109) or main (p=0.011, E (beta)=4.067) PVT were independently associated factors in multivariate analysis. CONCLUSIONS: The incidence of acute hepatic failure after TACE was 12.0%. Elevated bilirubin level and portal vein thrombosis could be considered as the predictive factors for acute hepatic failure after TACE in HCC patients.

Epidemiology of acute liver failure.

Acute liver failure (ALF) is an uncommon disorder that leads to jaundice, coagulopathy, and multisystem organ failure. Its definition is based on the timing from onset of jaundice to encephalopathy. In 2005, ALF accounted for 6% of liver-related deaths and 7% of orthotopic liver transplants (OLT) in the United States. Several classification systems have been developed for ALF, with the King's College criteria most widely used for prediction of OLT. Specific diagnostic tests should be implemented to identify the cause of ALF, which will help to determine its treatment and prognosis. Viral hepatitis was previously reported to be the most common cause of ALF in the United States, but acetaminophen overdose and idiosyncratic drug reactions have emerged as the most frequent causes in recent studies. Malignancy is an uncommon cause of ALF, and thus imaging studies may not be useful in this setting, but liver biopsy may be beneficial in selected cases. An overall strategy for ALF should start with identifying the cause, assessing the prognosis, and early transfer to a transplantation center for suitable candidates. OLT has emerged as a life-saving procedure leading to marked improvement in survival rates. Improved surgical techniques, immunosuppression, and comprehensive care have led to an overall survival rate of approximately 65% with OLT. N-acetylcysteine is effective in ALF caused by acetaminophen overdose, with results strongly related to how soon it is given rather than the route of administration. Liver support systems show potential for the treatment of ALF, but their role needs validation in large multicenter randomized trials.

Incidence and Risk Factors of Acute Hepatic Failure after Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma / 대한소화기학회지

BACKGROUND/AIMS: Although transcatheter arterial chemoembolization (TACE) is a major treatment modality for unresectable hepatocellular carcinoma (HCC), acute hepatic failure after TACE is not rare. However, reports dealing with this important complication are not good enough and results are often variable. The purpose of this study was to evaluate the incidence and associated risk factors of acute hepatic failure after TACE. METHODS: From January 2001 to November 2004, six hundred and thirtytwo TACE sessions were performed in 377 patients (294 men and 83 women). Adriamycin mixed lipiodol solution and gelfoam were used for TACE. Various clinical and radiological factors before and after the procedure were reviewed retrospectively. Univariate and multivariate analyses were performed to evaluate the risk factors associated with the development of acute hepatic failure after TACE. RESULTS: Acute hepatic failure occurred in 76 (12.0%) of the 632 TACE sessions within 14 days. Univariate analysis revealed that Child-Pugh class, 1st TACE, total bilirubin level, number of involved segments, total size of tumor, presence of right portal vein thrombosis (PVT) or main PVT, involvement of segment 1, 5, 6, 7, modified UICC stage, and doses of chemotherapeutic agent were significantly different between the patients with or without hepatic failure after TACE. Among them, elevated total bilirubin (p=0.001, E (beta)=1.449), presence of right (p=0.035, E (beta)=2.109) or main (p=0.011, E (beta)=4.067) PVT were independently associated factors in multivariate analysis. CONCLUSIONS: The incidence of acute hepatic failure after TACE was 12.0%. Elevated bilirubin level and portal vein thrombosis could be considered as the predictive factors for acute hepatic failure after TACE in HCC patients.