Glucagon augments the secretion of FGF21 and GDF15 in MASLD by indirect mechanisms.

INTRODUCTION: Glucagon receptor agonism is currently explored for the treatment of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). The metabolic effects of glucagon receptor agonism may in part be mediated by increases in circulating levels of Fibroblast Growth Factor 21 (FGF21) and Growth Differentiation Factor 15 (GDF15). The effect of glucagon agonism on FGF21 and GDF15 levels remains uncertain, especially in the context of elevated insulin levels commonly observed in metabolic diseases. METHODS: We investigated the effect of a single bolus of glucagon and a continuous infusion of glucagon on plasma concentrations of FGF21 and GDF15 in conditions of endogenous low or high insulin levels. The studies included individuals with overweight with and without MASLD, healthy controls (CON) and individuals with type 1 diabetes (T1D). The direct effect of glucagon on FGF21 and GDF15 was evaluated using our in-house developed isolated perfused mouse liver model. RESULTS: FGF21 and GDF15 correlated with plasma levels of insulin, but not glucagon, and their secretion was highly increased in MASLD compared with CON and T1D. Furthermore, FGF21 levels in individuals with overweight with or without MASLD did not increase after glucagon stimulation when insulin levels were kept constant. FGF21 and GDF15 levels were unaffected by direct stimulation with glucagon in the isolated perfused mouse liver. CONCLUSION: The glucagon-induced secretion of FGF21 and GDF15 is augmented in MASLD and may depend on insulin. Thus, glucagon receptor agonism may augment its metabolic benefits in patients with MASLD through enhanced secretion of FGF21 and GDF15.

Correction to: Diagnosis and Treatment of Genetic HFE-Hemochromatosis: The Danish Aspect.

[This corrects the article DOI: 10.14740/gr1206.].

A novel hepcidin mutation.

BACKGROUND: The bioactive peptide hormone hepcidin-25 regulates iron levels by inhibiting iron transport to plasma via ferroportin. Hepcidin-25 is synthesized in the liver where the 84 amino acids pro-hepcidin is cleaved into the bioactive hepcidin-25. A patient admitted to the hospital presented with infertility and fatigue. METHODS: Genomic DNA was purified from whole blood using the Maxwell 16 system (Promega). MLPA analysis was performed to detect large genomic rearrangements using the SALSA MLPA kit # P347, Hemochromatosis (MRC Holland, Holland). Plasma hepcidin measurements were performed using liquid chromatography/tandem mass spectrometry (LC-MS/MS). RESULTS: A novel HAMP mutation (homozygous one base deletion in c.215delG, p.Cys72Serfs*?) was detected. The deletion in nucleotide 215 causes a frameshift altering the predicted protein sequence from cysteine13 in mature peptide. Whether this leads to nonsense mediated decay of the mRNA or synthesis of an aberrant peptide in unknown, but bioactive hepcidin-25 was undetectable in plasma. The patient had massive iron overload with ferritin up to 8360 µg/L. He was anaemic with a Hb at 7.0 mmol/L (11.3 g/dL) and suffered from hypogonadotropic hypogonadism with a total testosterone of 1.2 nmol/l. Continued treatment with venesection and gonadotropins led to reduced fatigue, reduction in iron overload, a normalized Hb and improvement of semen quality. CONCLUSION: A novel hepcidin mutation was detected in a patient with massive iron overload, fatigue and hypogonadotropic hypogonadism.

Development of a glucagon sensitivity test in humans: Pilot data and the GLUSENTIC study protocol.

A physiological feedback system exists between hepatocytes and the alpha cells, termed the liver-alpha cell axis and refers to the relationship between amino acid-stimulated glucagon secretion and glucagon-stimulated amino acid catabolism. Several reports indicate that non-alcoholic fatty liver disease (NAFLD) disrupts the liver-alpha cell axis, because of impaired glucagon receptor signaling (glucagon resistance). However, no experimental test exists to assess glucagon resistance in humans. The objective was to develop an experimental test to determine glucagon sensitivity with respect to amino acid and glucose metabolism in humans. The proposed glucagon sensitivity test (comprising two elements: 1) i.v. injection of 0.2 mg glucagon and 2) infusion of mixed amino acids 331 mg/hour/kg) is based on nine pilot studies which are presented. Calculation of a proposed glucagon sensitivity index with respect to amino acid catabolism is also described. Secondly, we describe a complete study protocol (GLUSENTIC) according to which the glucagon sensitivity test will be applied in a cross-sectional study currently taking place. 65 participants including 20 individuals with a BMI 18.6-25 kg/m2, 30 individuals with a BMI ≥ 25-40 kg/m2, and 15 individuals with type 1 diabetes with a BMI between 18.6 and 40 kg/m2 will be included. Participants will be grouped according to their degree of hepatic steatosis measured by whole-liver magnetic resonance imaging (MRI). The primary outcome measure will be differences in the glucagon sensitivity index between individuals with and without hepatic steatosis. Developing a glucagon sensitivity test and index may provide insight into the physiological and pathophysiological mechanism of glucagon action and glucagon-based therapies.

Hereditary hemochromatosis: data from a single center Copenhagen cohort.

OBJECTIVES: We aimed to describe a cohort of hereditary hemochromatosis (HH) patients from a single urban center in Copenhagen. METHODS: Retrospectively, data from patients with HH from the years 2009-2020 were collected. RESULTS: A total of 203 patients was recorded. Males constituted 65.0% of the patients. Homozygous HH (HHH)/compound heterozygous HH (CHH) accounted for 69.4%/30.6%. HHH patients had significantly higher ferritin and transferrin saturation (TS) levels at debut than CHH patients. Fifty-five HHH patients (39.0%) had ferritin >1000 ug/L versus 9 (14.5%) in the CHH group (p < .001). Age at debut did not differ between female and male patients. Ferritin (but not TS) levels were significantly higher in male patients. The proportion of patients with ferritin >1000 did not differ between males and females. One-hundred patients (49.3%) had one or more symptoms at the time of diagnosis; arthralgias of the metacarpophalangeal joints and/or ankles (n = 46 (22.7%)), fatigue (n = 67 (33.0%)) and decreased libido (n = 20 (9.9%)). The proportion of patients with symptoms did not differ between HHH and CHH or between male and female patients. Severe organ complications (cardiomyopathy, late onset type 1 diabetes or cirrhosis) were present in 14 patients (6.9%). CONCLUSIONS: We report a high proportion of compound HH, constituting almost one-third of patients. We found that the proportion of patients with symptoms did not differ between HHH and CHH and recommend that CHH should be treated and examined in the same way as HHH.

Dehydration as referral diagnosis to a medical admittance department.

INTRODUCTION: Patients are frequently admitted to hospital on suspicion of dehydration. The diagnosis is widely used for referral to admittance departments. We aimed to prospectively evaluate patients admitted with a diagnosis of dehydration in terms of the accuracy of this diagnosis, to evaluate clinical and biochemical data and to evaluate the outcome and provide a review of the concept of dehydration. METHODS: Patients who had dehydration as their primary referral diagnosis were prospectively included over a 70-day period. We defined dehydration based on osmolality > 295 mmol/kg. Biochemistry, imaging and outcome were examined. RESULTS: A total of 128 patients were admitted on suspicion of dehydration, accounting for 7.5% of all patients admitted. In all, 82 of the 128 (64%) were dehydrated. The diagnoses at discharge included infections mainly, but also diagnoses such as cancers and stroke were registered. Mortality during hospitalisation was 9%. Mortality at six months was 27% for the entire group; 37% in the dehydration group versus 11% in the non-dehydration group (p = 0.002). Older age was the strongest predictor of death. CONCLUSIONS: Suspicion of dehydration is a frequent admittance diagnosis. We suspect that a referral diagnosis of dehydration often reflects an unspecified concern rather than a real suspicion of dehydration. Patients with dehydration had a high in-hospital and six-month mortality, reflecting the severity of this diagnosis. FUNDING: not relevant. TRIAL REGISTRATION: The Danish Data Protection Agency, R. no. 05380, BFH-2017-029.

Echocardiographic abnormalities and predictors of mortality in hospitalized COVID-19 patients: the ECHOVID-19 study.

AIMS: The present study had two aims: (i) compare echocardiographic parameters in COVID-19 patients with matched controls and (2) assess the prognostic value of measures of left (LV) and right ventricular (RV) function in relation to COVID-19 related death. METHODS AND RESULTS: In this prospective multicentre cohort study, 214 consecutive hospitalized COVID-19 patients underwent an echocardiographic examination (by pre-determined research protocol). All participants were successfully matched 1:1 with controls from the general population on age, sex, and hypertension. Mean age of the study sample was 69 years, and 55% were male participants. LV and RV systolic function was significantly reduced in COVID-19 cases as assessed by global longitudinal strain (GLS) (16.4% ± 4.3 vs. 18.5% ± 3.0, P < 0.001), tricuspid annular plane systolic excursion (TAPSE) (2.0 ± 0.4 vs. 2.6 ± 0.5, P < 0.001), and RV strain (19.8 ± 5.9 vs. 24.2 ± 6.5, P = 0.004). All parameters remained significantly reduced after adjusting for important cardiac risk factors. During follow-up (median: 40 days), 25 COVID-19 cases died. In multivariable Cox regression reduced TAPSE [hazard ratio (HR) = 1.18, 95% confidence interval (CI) [1.07-1.31], P = 0.002, per 1 mm decrease], RV strain (HR = 1.64, 95%CI[1.02;2.66], P = 0.043, per 1% decrease) and GLS (HR = 1.20, 95%CI[1.07-1.35], P = 0.002, per 1% decrease) were significantly associated with COVID-19-related death. TAPSE and GLS remained significantly associated with the outcome after restricting the analysis to patients without prevalent heart disease. CONCLUSIONS: RV and LV function are significantly impaired in hospitalized COVID-19 patients compared with matched controls. Furthermore, reduced TAPSE and GLS are independently associated with COVID-19-related death.

Sepsis-related Organ Failure Assessment Score is a strong predictor of survival in acute-on-chronic liver failure.

INTRODUCTION: The mortality of patients with an exacer-bation of decompensated liver cirrhosis is high even if treated in the intensive care unit (ICU), and the criteria for referral to ICU are not well defined. The objective of this study was to identify variables associated with mortality. METHODS: A single-centre retrospective cohort analysis was conducted in a university-affiliated ICU. A total of 53 adult patients with decompensated alcoholic liver cirrhosis were admitted from January 2012 to June 2015. Variables associated with survival were identified using Cox regression analysis. RESULTS: The ten-day, 30-day, 90-day, and one-year mortality were 36%, 57%, 66%, and 80%, respectively. Univariate Cox regression analysis showed that mortality was significantly associated with a low oxygen saturation, low diastolic blood pressure, terlipressin treatment, high Acute Physiology And Chronic Health Evaluation II score, high Simplified Acute Physiology Score II score, high Sepsis-related Organ Failure Assessment (SOFA) score and high Model For End-Stage Liver Disease score, but only a high SOFA score and old age were independently associated with increased mortality. These two variables were combined to the Age-SOFA index to predict the probability of surviving a given period. CONCLUSIONS: The mortality was high in these severely ill patients, even when they received optimum supportive therapy in the ICU. The finding that the SOFA score and age best predicted mortality shows that the increased mortality was caused mainly by insufficiency of organs other than the liver. FUNDING: none. TRIAL REGISTRATION: not relevant.

Hepatocellular carcinoma in Danish patients: a single Copenhagen center experience.

OBJECTIVE: Hepatocellular carcinoma (HCC) is a common cause of cancer, and most HCC patients have underlying cirrhosis. Retrospectively, we aimed to characterize patients with newly diagnosed HCC at a Danish hospital and to investigate survival and identify predictive factors for survival. METHODS: All patients diagnosed with HCC from January 2008 to December 2014 were retrospectively enrolled in this study. Overall survival was estimated by using the Kaplan-Meier method. A multivariate Cox regression analysis was performed to identify predictive factors for survival. RESULTS: Sixty-seven patients were diagnosed with HCC (incidence rate 3.55/100,000 people/year). Ninety-three percent had underlying cirrhosis. Alcohol-related liver disease and chronic viral hepatitis B or C were responsible for 55 and 31% of cases, respectively. Median survival was 81 days and 1-month, 3-months and 1-year cumulative survival rates were 74, 40 and 17%, respectively. We identified the presence of portal vein thrombosis, high Child-Pugh score, high MELD score and high AST as independent negative prognostic factors for survival. Survival was poorer in patients seen for the first time when the diagnosis of HCC was made than in patients followed in the outpatient clinic (p = .06) indicating a substantial delay in diagnosis. CONCLUSIONS: Survival was poor in this cohort of patients, almost exclusively caused by delay in diagnosis and admittance to hospital. An increased general information about HCC and the possibilities of therapy seems warranted.

Alcoholic liver disease patients' perspective of a coping and physical activity-oriented rehabilitation intervention after hepatic encephalopathy.

AIM AND OBJECTIVE: To identify and describe the impact of a coping and physical activity-oriented rehabilitation intervention on alcoholic liver disease patients after hepatic encephalopathy in terms of their interaction with professionals and relatives. BACKGROUND: Patients who have experienced alcohol-induced hepatic encephalopathy have reduced quality of life, multiple complications, and social problems, and rehabilitation opportunities for these patients are limited. DESIGN: A grounded theory study and an evaluation study of a controlled intervention study. METHODS: Semi-structured interviews were conducted with 10 alcoholic liver disease patients who were diagnosed with hepatic encephalopathy and participated in a coping and physical activity-oriented rehabilitation intervention. Richard S. Lazarus's theory of stress and coping inspired the interview guide. RESULTS: The significance of a coping and physical activity-oriented rehabilitation intervention on alcoholic liver disease patients' ability to cope with problems after surviving alcohol-induced hepatic encephalopathy in terms of their interaction with professionals and relatives was characterised by the core category 'regain control over the diseased body'. This is subdivided into three separate categories: 'the experience of being physically strong', 'togetherness' and 'self-control', and they impact each other and are mutually interdependent. CONCLUSION: Alcoholic liver disease patients described the strength of the rehabilitation as regaining control over the diseased body. Professionals and relatives of patients with alcoholic liver disease may need to focus on strengthening and preserving patients' control of their diseased body by facilitating the experience of togetherness, self-control and physical strength when interacting with and supporting patients with alcoholic liver disease. RELEVANCE TO CLINICAL PRACTICE: A coping and physical activity-oriented rehabilitation intervention may help alcoholic liver disease patients to regain control over their diseased body and give patients the experience of togetherness, self-control and physical strength. Professionals should be aware of giving the patients the experience of togetherness in their interactions, help them perceive self-control and gain physical strength during their rehabilitation.

Coping and rehabilitation in alcoholic liver disease patients after hepatic encephalopathy--in interaction with professionals and relatives.

AIMS AND OBJECTIVES: To identify and describe conditions that limit or support patients, with alcoholic liver disease after surviving alcohol-induced hepatic encephalopathy, ability to cope with current and potential physical and psychosocial problems--in interaction with professionals and relatives--and to recommend appropriate interventions. BACKGROUND: Alcoholic liver disease patients surviving alcohol-induced hepatic encephalopathy have significantly impaired quality of life. Internationally, there is a lack of knowledge about the conditions that affect alcoholic liver disease patients' coping and rehabilitation. DESIGN: A grounded theory study. METHODS: Semi-structured interviews, conducted with 11 alcoholic liver disease patients who were diagnosed with hepatic encephalopathy. The interview guide was inspired by Richard S. Lazarus's theory of stress and coping. RESULTS: The elements that support or limit alcoholic liver disease patients' ability to cope with physical and psychosocial problems in interaction with professionals and relatives were represented by the core category 'Struggle for preservation of identity as a significant individual'. It was characterised by three categories, which are interrelated and impact upon each other: 'Acknowledgement', 'Struggle to maintain control' and 'Achieving a sense of security'. CONCLUSION: Alcoholic liver disease patients experience a struggle to preserve their identity as a significant individual. It can be assumed that professionals and relatives in their interaction with, and support of, patients should focus on strengthening and preserving patients' identity in the form of acknowledgement, helping alcoholic liver disease patients maintain self-control and providing a safety net so patients feel a sense of security. RELEVANCE TO CLINICAL PRACTICE: It can be assumed that professionals should support alcoholic liver disease patients' appraisal of, and coping with, physical and psychosocial problems based on acknowledgment, understanding and a sympathetic attitude. Professionals should proactively approach patients when they withdraw. It may be useful for professionals to be aware of alcoholic liver disease patients' individual coping strategies and thereby their individual requirements for professional supportive intervention.

[Hypoxic hepatitis]. / Hypoksisk hepatitis.

Hypoxic hepatitis (HH), also known as ischaemic hepatitis or shock liver, is an acute liver injury caused by hepatic hypoxia. Cardiac failure, respiratory failure and septic shock are the main underlying conditions. In each of these conditions, several haemodynamic mechanisms lead to hepatic hypoxia. A shock state is observed in only 50% of cases. Thus, shock liver and ischaemic hepatitis are misnomers. HH can be a diagnostic pitfall but the diagnosis can be established when three criteria are met. Prognosis is poor and prompt identification and treatment of the underlying conditions are crucial.

Rehabilitation for cirrhotic patients discharged after hepatic encephalopathy improves survival.

INTRODUCTION: The 1-year mortality of cirrhotic patients with hepatic encephalopathy (HE) is approximately 60-80% in recent studies. We aimed to establish a rehabilitation out-patient clinic (RC) for alcoholic cirrhotic patients sur-viving HE. MATERIAL AND METHODS: Prospectively, patients surviving HE were offered participation in the RC and were seen by a nurse for a one-hour interview with 1-3 weeks' interval after discharge and by a physician, if needed. Clinical, psychological and social problems were identified and addressed. Alcohol consumption was recorded and alcohol cessation was encouraged at each visit. Minimal or overt HE prompted referral to the Liver Unit. The patients were compared with HE patients discharged in 2008 (the control group). RESULTS: A total of 19 patients were included in the RC group and compared with the 14 patients of the control group. The Child-Pugh score was higher in the RC group (median 13; range 8-14) than in the control group (median 11; range 7-13) (p = 0.033), whereas other clinical, demographic and biochemical parameters did not differ between the two groups. One-year survival was higher in the RC group (16/19; 84%) than in the control group versus (5/14; 36%) (p = 0.012). The log-rank test confirmed an improved survival for the RC group (p = 0.008). The economic costs of subsequent hospital admissions did not differ between the two groups. In the RC group, alcohol consumption was reduced in all but two patients. CONCLUSION: Survival was significantly improved for patients in the rehabilitation clinic. The improved survival did not subsequently cause higher hospital admission costs. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

Gc-globulin in liver disease.

This doctoral thesis is based on seven previously published papers and reports on the role of the actin-scavenger Gc-globulin in acute and chronic liver diseases. Gc-globulin is synthesized in the liver and is a multifunctional protein; however, its main physiologic function is presumably actin binding and actin scavenging. Actin is a major cellular protein released during cell necrosis that may cause fatal formation of actin-containing thrombi in the circulation if the actin scavenging capacity of Gc-globulin is exceeded. In my studies, I found serum Gc-globulin levels to be reduced in liver disease, most so in patients with acute liver failure (ALF). In patients admitted with acetaminophen (paracetamol) overdose, Gc-globulin concentrations were lower in patients with hepatic encephalopathy than in those without and the levels nadired at approximately 60-72 hours after acetaminophen ingestion, corresponding with the peak in aminotransferese levels (and thus, hepatic necrosis). In patients with ALF, admission Gc-globulin was significantly lower in 47 nonsurvivors than in 30 survivors, 26% and 46% of normal, respectively (P<0.001). The predictive value of outcome using a Gc-globulin cutoff level of 100 mg/L equaled that of the internationally accepted King's College Hospital criteria. The prognostic value of Gc-globulin was confirmed in a separate study including 106 patients from the United States with nonacetaminophen-induced ALF now using an automated nephelometric assay whereas the prognostic value seemed less obvious for acetaminophen-induced ALF. Multiple organ failure (MOF) is a frequent complication of ALF. In ALF patients with deep coma (hepatic encephalopathy grade III or IV) Gc-globulin levels correlated inversely with the number of failing organs. Levels were lower in patients who later developed MOF than in those who did not. Surprisingly, kinetic studies in patients with ALF and acute on chronic liver disease showed Gc-globulin production to be 7-fold increased in these conditions. Despite this increase Gc-globulin levels were severely reduced and the reduction must therefore be due to a highly increased consumption of Gc-globulin - probably because of hepatocyte necrosis and removal from the circulation of Gc-globulin:actin complexes or because of its role in immune-related functions. Patients with chronic liver disease had reduced Gc-globulin levels, but the reduction was less pronounced than in ALF. After liver transplantation, Gc-globulin concentrations normalized within two weeks, in contrast to the continuous decrease in albumin levels suggesting a very different regulation of these two phylogenetically related proteins. It remains to be studied if lack of Gc-globulin contributes to the pathogenesis of patients with ALF or chronic liver disease. Future studies should focus on the potential value of Gc-globulin substitution in these patients.

Fulminant liver disease.

Fulminant liver disease, acute liver failure (ALF), is one of the most intriguing and challenging conditions in the entire field of internal medicine. ALF is defined as the onset of hepatic encephalopathy and coagulopathy in patients with no known underlying liver disease within 8 to 26 weeks of onset of illness. Many cases develop within a few days, dramatically transforming an otherwise healthy individual to a patient with a high risk for developing multi-organ failure and death.

Viral hepatitis-related acute liver failure.

OBJECTIVES: Viral hepatitis has previously been the major cause of acute liver failure (ALF) in the United States. We aimed to determine the incidence of viral hepatitis-related ALF and to compare the outcome and clinical and biochemical variables in patients with hepatitis A and B. METHODS: A total of 354 patients with ALF from multiple centers were screened for possible acute viral etiology. RESULTS: Forty-three patients (12.1% of all ALF cases) had acute viral hepatitis: hepatitis A (n = 16), hepatitis B (n = 26), and herpes simplex virus infection (n = 1). There was no difference between groups with regard to age, gender, body mass index, admission or peak coma grade, symptom duration, admission mean arterial pressure, temperature, or biochemical liver tests, creatinine, arterial pH, or rate of infections. Platelet count was significantly higher in hepatitis A patients than in hepatitis B patients. The transplantation-free (spontaneous) survival rate was significantly higher for hepatitis A patients (69%) than for hepatitis B patients (19%, p = 0.007), whereas the liver transplantation rate was higher in hepatitis B patients (62%) than in hepatitis A patients (19%, p = 0.017). Spontaneous survivors had significantly higher mean arterial pressure, higher platelet count, and lower AST/ALT ratio than patients who did not survive spontaneously. CONCLUSIONS: Viral hepatitis now comprises only one-eighth of all ALF cases in the United States. The marked difference in spontaneous survival between hepatitis A and B cannot be explained by the severity of hepatic dysfunction on admission but may rather be an inherent feature of the infections or a bias toward transplanting patients with hepatitis B.

The value of plasma acetaminophen half-life in antidote-treated acetaminophen overdosage.

BACKGROUND: A plasma acetaminophen (INN, paracetamol) half-life of more than 4 hours has been correlated with hepatotoxicity in acetaminophen overdosing not treated with an antidote. Acetaminophen half-life has not been studied in patients receiving the antidote N -acetylcysteine. METHODS: Prospectively, 112 patients with acetaminophen overdosage all treated with intravenous N -acetylcysteine were studied. A minimum of 2 plasma acetaminophen values >20 micromol/L were available for calculation of acetaminophen half-life, assuming first-order kinetics. RESULTS: Overall, the median acetaminophen half-life was 5.4 hours (range, 0.8-119.7 hours). Forty-eight patients with no or little hepatotoxicity (ALT <1000 U/L), 43 patients with hepatotoxicity without encephalopathy, and 21 patients with hepatotoxicity and encephalopathy had acetaminophen half-lives of 3.0 hours (range, 0.8-10.0 hours), 6.4 hours (range, 1.3-19.0 hours), and 18.4 hours (range, 4.6-119.7 hours), respectively (P <.001). An acetaminophen half-life >4 hours was observed in 71 patients, and 56 of those (79%) had hepatotoxicity (ALT >1000 U/L or coma). Thirty-three of 41 patients (81%) with an acetaminophen half-life <4 hours had no hepatotoxicity. A receiver operating characteristic curve analysis showed that an acetaminophen half-life of 5.5 hours provided better discrimination; hepatotoxicity was therefore present in 49 of 54 patients with an acetaminophen half-life >5.5 hours (positive predictive value, 91%) and in 15 of 58 patients with a half-life below this limit (negative predictive value, 74%) despite treatment with N -acetylcysteine. CONCLUSIONS: Acetaminophen half-life correlates well with the degree of liver damage in patients treated with the antidote N-acetylcysteine. Longer half-lives reflect a greater toxic effect on the liver.