ABSTRACT
The association between air pollutants and hepatobiliary pancreatic diseases remains inconclusive. This study analyzed up to 247,091 participants of White European ancestry (aged 37 to 73 years at recruitment) from the UK Biobank, a large-scale prospective cohort with open access. An air pollution score was utilized to assess the combined effect of PM2.5, PM2.5-10, PM10, NO2, and NOX on total hepatobiliary pancreatic diseases, liver diseases, cholecyst diseases, and pancreatic diseases. Cox proportional hazard models were employed to evaluate the relationships between air pollutants and the incidence of these diseases. Restricted cubic spline regressions were used to examine the dose-response association between air pollutants and the risk of hepatobiliary pancreatic diseases. We identified 4865 cases of total hepatobiliary pancreatic diseases, over a median follow-up of 10.86 years. The air pollution scores were moderately associated with increased liver disease risk (HR = 1.009, 95 % CI: 1.004, 1.014), but not with cholecyst and pancreatic diseases. Among the individual air pollutants, PM2.5 (HR = 1.069, 95 % CI: 1.025, 1.115) and PM10 (HR = 1.036, 95 % CI: 1.011, 1.061) significantly increased liver disease risk. Males showed a higher risk of liver diseases with PM2.5 (HR = 1.075, 95 % CI: 1.015, 1.139). Additionally, individuals with overweight (HR = 1.125, 95 % CI: 1.052, 1.203), age ≥ 60 and ≤73 (HR = 1.098, 95 % CI: 1.028, 1.172), and alcohol intake ≥ 14 unit/week (HR = 1.078, 95 % CI: 1.006, 1.155) had a higher risk of developing liver diseases at high expose to PM2.5. This study suggests that prolonged exposure to ambient air pollutants may elevate the risk of liver diseases.
Subject(s)
Air Pollutants , Air Pollution , Environmental Exposure , Liver Diseases , Humans , Middle Aged , Male , Prospective Studies , Liver Diseases/epidemiology , Female , United Kingdom/epidemiology , Aged , Air Pollutants/analysis , Adult , Air Pollution/statistics & numerical data , Environmental Exposure/statistics & numerical data , Particulate Matter/analysis , Biological Specimen Banks , Risk Factors , Incidence , Biliary Tract Diseases/epidemiology , Biliary Tract Diseases/chemically induced , Pancreatic Diseases/epidemiology , Pancreatic Diseases/chemically induced , UK BiobankABSTRACT
BACKGROUND AND AIMS: Anesthesiologists prefer ketamine for certain surgeries due to its effectiveness as a non-competitive inhibitor of the N-methyl-D-aspartate receptor in the brain. Recently, this agent has also shown promise as an antidepressant. However, ketamine can cause hallucinogenic effects and is sometimes abused as an illicit drug. Ketamine abuse has been associated with liver and bile duct complications. This systematic study aims to better understand cholangiopathy in ketamine abusers by reviewing case reports. METHODS AND MATERIAL: In this systematic review, a comprehensive literature search was conducted with the terms "biliary tract diseases" and "ketamine". Case reports and case series of adult patients with documented ketamine abuse and reported cholangiopathy or biliary tract disease were included. We extracted the data of relevant information and the results were reported through narrative synthesis and descriptive statistics. RESULTS: A total of 48 studies were initially identified, and 11 studies were finally included in the review. The mean age of the patients was 25.88 years. Of the 17 patients, 64.7% were men. Symptoms often included abdominal pain, nausea, and vomiting. Most patients were discharged with improved symptoms and liver function. Common bile duct dilation and other findings were observed in imaging results and other diagnostic studies. CONCLUSION: This review highlights the diverse presentations and diagnostic modalities used in ketamine-induced cholangiography. These patients tend to be young men with deranged liver function tests and abdominal pain, which should be taken into consideration. These patients often require a multidisciplinary approach in their management.
Subject(s)
Biliary Tract Diseases , Biliary Tract , Illicit Drugs , Ketamine , Substance-Related Disorders , Humans , Abdominal Pain/etiology , Bile Ducts , Biliary Tract Diseases/chemically induced , Biliary Tract Diseases/complications , Ketamine/adverse effects , Substance-Related Disorders/complications , Case Reports as TopicABSTRACT
ABSTRACT: In this single-center retrospective study, we intended to evaluate the frequencies and characteristics of computed tomography findings of pancreatobiliary inflammation (PBI) in patients treated with lenvatinib and the relationship of these findings with treatment-planning changes.We included 78 patients (meanâ±âstandard deviation, 69.8â±â9.4âyears, range: 39-84âyears, 62 men) with hepatocellular carcinoma (nâ=â62) or thyroid carcinoma (nâ=â16) who received lenvatinib (June 2016-September 2020). Two radiologists interpreted the posttreatment computed tomography images and assessed the radiological findings of PBI (symptomatic pancreatitis, cholecystitis, or cholangitis). The PBI effect on treatment was statistically evaluated.PBI (pancreatitis, nâ=â1; cholecystitis, nâ=â7; and cholangitis, nâ=â2) was diagnosed in 11.5% (9/78) of the patients at a median of 35âdays after treatment initiation; 6 of 9 patients discontinued treatment because of PBI. Three cases of cholecystitis and 1 of cholangitis were accompanied by gallstones, while the other 5 were acalculous. The treatment duration was significantly shorter in patients with PBI than in those without (median: 44âdays vs. 201âdays, Pâ=â.02). Overall, 9 of 69 patients without PBI showed asymptomatic gallbladder subserosal edema.Lenvatinib-induced PBI developed in 11.5% of patients, leading to a significantly shorter treatment duration. Approximately 55.6% of the PBI cases were acalculous. The recognition of this phenomenon would aid physicians during treatment planning in the future.
Subject(s)
Antineoplastic Agents/adverse effects , Biliary Tract Diseases/chemically induced , Pancreatitis/chemically induced , Phenylurea Compounds/adverse effects , Quinolines/adverse effects , Adult , Aged , Aged, 80 and over , Biliary Tract Diseases/diagnostic imaging , Biliary Tract Diseases/epidemiology , Female , Humans , Incidence , Japan/epidemiology , Male , Middle Aged , Pancreatitis/diagnostic imaging , Pancreatitis/epidemiology , Retrospective Studies , Tomography, X-Ray ComputedABSTRACT
Individuals with cystic fibrosis (CF) have an increased risk for gallbladder abnormalities and biliary tract disease, but the reported incidence of these manifestations of CF varies widely in the literature. With the approval of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA), increasing numbers of CF patients have been initiated on highly effective cystic fibrosis transmembrane regulator (CFTR) modulator therapy. While elevations in hepatic panel are known potential side effects of CFTR modulators, there have been no published cases of biliary disease or acute cholecystitis attributed to these medications. In this case series, we describe seven patients at two adult CF centers with biliary colic shortly after initiation with ELX/TEZ/IVA, six of whom required cholecystectomy.
Subject(s)
Biliary Tract Diseases/chemically induced , Biliary Tract Diseases/surgery , Chloride Channel Agonists/adverse effects , Cholecystectomy , Cystic Fibrosis/drug therapy , Adult , Aminophenols/adverse effects , Benzodioxoles/adverse effects , Drug Combinations , Female , Humans , Indoles/adverse effects , Male , Pyrazoles/adverse effects , Pyridines/adverse effects , Pyrrolidines/adverse effects , Quinolones/adverse effectsABSTRACT
PURPOSE: To investigate the frequency and imaging features of radiographically evident abdominal immune-related adverse events (irAEs) in patients with metastatic non-small-cell lung cancer (NSCLC) treated with PD-1 inhibitors. METHODS: This retrospective study included 137 patients with metastatic NSCLC treated with PD-1 inhibitor nivolumab monotherapy (75 women; median age: 65 years), who had a baseline CT and at least one follow-up abdomen CT during therapy. Baseline and all follow-up abdominal CTs performed for monitoring of nivolumab therapy were reviewed to identify the organ-specific abdominal irAEs including colitis/enteritis, hepatitis, biliary toxicity, pancreatitis, nephritis, sarcoid-like reaction, and pancreatic and adrenal atrophy. Their frequency and imaging features were described. RESULTS: Eighteen (13%) patients had radiologically identified abdominal irAEs (median 2.1 months after starting nivolumab; interquartile range 1.17-5.83 months); 16 patients developed enteritis/colitis (12 pancolitis, two segmental colitis, one enterocolitis, one enteritis), two hepatitis, one adrenalitis. One patient with hepatitis also developed colitis/enteritis. Radiographic abdominal irAE occurred after nivolumab therapy was discontinued in six patients before any subsequent therapy was started. IrAEs prompted nivolumab interruption and treatment with steroids in four patients (three colitis/enteritis, one hepatitis). Most common CT features of colitis/enteritis included mesenteric hyperemia (n = 15), bowel wall thickening (n = 13), mucosal hyperenhancement (n = 10), and fluid-filled colon (n = 9). CONCLUSION: Abdominal irAEs were detected on CT in 13% of NSCLC patients treated with nivolumab, and colitis, in the pancolitis form, was the most common irAE. Given the expanding role of immunotherapy, radiologists should be aware of the frequency and imaging manifestations of abdominal irAEs and the impact on patient management.
Subject(s)
Antineoplastic Agents, Immunological/adverse effects , Biliary Tract Diseases/chemically induced , Carcinoma, Non-Small-Cell Lung/drug therapy , Gastrointestinal Diseases/chemically induced , Immunotherapy/adverse effects , Lung Neoplasms/drug therapy , Nivolumab/adverse effects , Positron Emission Tomography Computed Tomography , Tomography, X-Ray Computed , Aged , Biliary Tract Diseases/diagnostic imaging , Female , Fluorodeoxyglucose F18 , Gastrointestinal Diseases/diagnostic imaging , Humans , Male , Radiography, Abdominal , Radiopharmaceuticals , Retrospective StudiesABSTRACT
BACKGROUND: Ceritinib demonstrated a statistically significant effect on the progression-free survival versus chemotherapy in patients with advanced anaplastic lymphoma kinase (ALK) rearrangement in non-small cell lung cancer (NSCLC) as the first therapy or after previous treatment with crizotinib and one or two prior chemotherapy regimens in global phase 3 studies. However, some serious adverse effects related to ceritinib therapy were reported across these clinical studies. Among them, a grade 3 and 4 increase in hepatobiliary enzymes was one of the common adverse events related to treatment with ceritinib. However, the pathology remains unclear. Previously, increased Interleukin (IL)-18 was observed in both biliary duct disease and liver disease. Therefore, we hypothesized that IL-18 is involved in the pathology of hepatobiliary adverse effects related to treatment with ceritinib and evaluated the serum IL-18. CASE PRESENTATION: The patient was a 53-year-old Japanese woman that we previously reported as having severe hepatobiliary adverse effects related to ceritinib therapy. Laboratory data, CT and MRI were obtained at each time point. IL-18 was evaluated by ELISA method at each time point. Immunochemical staining of liver tissue was performed as a standard protocol using antibodies against IL-18. Our records showed that the levels of serum IL-18 increased from the early stage of hepatobiliary adverse effects related to the treatment with ceritinib and were became worse with an increase in hepatobiliary enzymes and the progression of imaging abnormalities in the bile duct. Furthermore, IL-18 positive cells were detected in the inflammatory sites around the interlobular bile duct of the liver tissue. CONCLUSION: Our case report shows that the increase of serum IL-18 had a positive correlation with the progression of severe hepatobiliary adverse effects related to treatment with ceritinib and the involvement of IL-18 in the hepatobiliary inflammation by pathological evaluation. These results suggest that IL-18 could be a useful surrogate marker for the hepatobiliary toxicity of ceritinib. However, this is only one case report and further prospective observations will complement our data in the future.
Subject(s)
Antineoplastic Agents/adverse effects , Biliary Tract Diseases/blood , Biliary Tract Diseases/chemically induced , Chemical and Drug Induced Liver Injury/blood , Interleukin-18/blood , Pyrimidines/adverse effects , Sulfones/adverse effects , Biliary Tract Diseases/diagnosis , Biomarkers/blood , Chemical and Drug Induced Liver Injury/diagnosis , Female , Humans , Middle Aged , Treatment OutcomeABSTRACT
OTC combination cold remedies are widely used in Japan. In the present study, we aimed to evaluate the adverse event profiles of OTC combination cold remedy based on the components using the Japanese Adverse Drug Event Report (JADER) database. The JADER database contained 430587 reports between April 2004 and November 2016. 1084 adverse events associated with the use of OTC combination cold remedy were reported. Reporting odds ratio (ROR) was used to detect safety signals. The ROR values for "skin and subcutaneous tissue disorders", "hepatobiliary disorders", and "immune system disorders" stratified by system organ class of the Medical Dictionary for Regulatory Activities (MedDRA) were 9.82 (8.71-11.06), 2.63 (2.25-3.07), and 3.13 (2.63-3.74), respectively. OTC combination cold remedy containing acetaminophen exhibited a significantly higher reporting ratio for "hepatobiliary disorders" than OTC combination cold remedy without acetaminophen. We demonstrated the potential risk of OTC combination cold remedy in a real-life setting. Our results suggested that the monitoring of individuals using OTC combination cold remedy is important.
Subject(s)
Acetaminophen/adverse effects , Adverse Drug Reaction Reporting Systems , Data Mining , Databases, Factual , Drug Utilization/statistics & numerical data , Drug-Related Side Effects and Adverse Reactions/epidemiology , Nonprescription Drugs/adverse effects , Acetaminophen/administration & dosage , Adverse Drug Reaction Reporting Systems/statistics & numerical data , Biliary Tract Diseases/chemically induced , Biliary Tract Diseases/epidemiology , Chemical and Drug Induced Liver Injury/epidemiology , Chemical and Drug Induced Liver Injury/etiology , Drug Combinations , Immune System Diseases/chemically induced , Immune System Diseases/epidemiology , Japan/epidemiology , Nonprescription Drugs/administration & dosage , Odds Ratio , Risk , Skin Diseases/chemically induced , Skin Diseases/epidemiology , Time FactorsABSTRACT
BACKGROUND: Ceftriaxone (CTRX) is a known cause of biliary pseudolithiasis (BPL) mainly in children. Biliary elimination of CTRX increases in patients with renal dysfunction. However, the influence of renal dysfunction on the incidence of CTRX-associated BPL has not been well investigated. The aim of this study was to investigate the cumulative incidence of CTRX-associated BPL in adults and to assess if renal dysfunction is a risk factor. METHODS: We retrospectively analyzed the medical records of 478 patients treated with CTRX to assess the incidence and risk factors of CTRX-associated BPL. We examined age, sex, body weight, dosage, and duration of CTRX therapy, and the concentrations of serum creatinine, estimated glomerular filtration rate (eGFR), albumin, and serum calcium in all the patients. The cumulative incidence of BPL was calculated using a competing risk model. The multivariate analysis of each variable for the development of BPL was assessed by a Cox proportional hazards model. RESULTS: A total of 362 patients (75.7%) had renal dysfunction (eGFR: < 60 mL/min). The cumulative incidence of BPL in patients with renal dysfunction was significantly higher than that in patients with normal kidney function (4.1 vs. 0.6%, p = 0.017). Renal dysfunction (Hazard ratio (HR) 8.14, 95% CI 1.05-63.0, p = 0.045) and female sex (HR 5.35, 95% CI 1.17-24.5, p = 0.031) were independent risk factors of CTRX-associated BPL, which was confirmed using multivariate analysis (renal dysfunction: HR 7.93, 95% CI 1.04-60.5, p = 0.046) (female sex HR 4.65, 95% CI 1.03-21.1, p = 0.046). CONCLUSIONS: Renal dysfunction is an independent risk factor of CTRX-associated BPL in adults.
Subject(s)
Anti-Bacterial Agents/adverse effects , Biliary Tract Diseases/chemically induced , Ceftriaxone/adverse effects , Renal Insufficiency/complications , Aged , Aged, 80 and over , Biliary Tract Diseases/epidemiology , Female , Humans , Incidence , Japan/epidemiology , Male , Middle Aged , Retrospective Studies , Risk FactorsABSTRACT
BACKGROUND AND OBJECTIVES: Short bowel syndrome (SBS) is a complicated and challenging disease where home parenteral nutrition (HPN) is widely used. The complications of long-term HPN-dependent in adult patients with SBS are poorly documented. This study was mainly aimed to assess the prevalence and risk factors of HPNassociated complications in adult patients with SBS, especially the catheter-related sepsis and HPN-associated liver/biliary disorders. METHODS AND STUDY DESIGN: 47 non-malignant adult patients with SBS who received HPN for more than 2 years in our clinical nutrition center were included. Patients were divided into two groups according to whether HPN-associated complications were present or not. Student's t-test and χ2 test were applied to compare the differences between the two groups. RESULTS: The mean frequency of catheter-related sepsis was 0.31±0.05 per catheter year of HPN. An higher incidence of catheter-related infections (p<0.001) and shorter delay between HPN onset and first infection (p<0.001) were identified as risk factors for catheter-related sepsis. A total of 25 patients (53.2%) developed HPN-associated liver/biliary diseases. The identified risk factors for HPNassociated liver/biliary disorders were higher rate of catheter-related infections (p=0.009), shorter delay between HPN onset and first infection (p=0.017), higher energy content of HPN (p=0.014), higher glucose rate of HPN (p=0.009), and lower lipid rate of HPN (p=0.022). CONCLUSION: Our study revealed that adult patients with SBS receiving long-term HPN treatment developed a low prevalence of catheter-related sepsis but a rather high prevalence of HPN-associated liver/biliary disorders. We also identified several risk factors for HPN-associated complications which should be taken notice of in clinical practice.
Subject(s)
Parenteral Nutrition, Home/adverse effects , Short Bowel Syndrome/diet therapy , Adult , Biliary Tract Diseases/chemically induced , Catheters/adverse effects , Chemical and Drug Induced Liver Injury , Female , Humans , Male , Middle Aged , Risk FactorsSubject(s)
Biliary Tract Diseases/chemically induced , Colic/chemically induced , Contrast Media/adverse effects , Diatrizoate Meglumine/adverse effects , Adult , Biliary Tract Diseases/surgery , Cholecystectomy/methods , Colic/surgery , Humans , Male , Time Factors , Tomography, X-Ray Computed/adverse effectsABSTRACT
New Direct-acting Antiviral Agents (DAA)-based anti-HCV therapies currently provide extraordinary opportunities to cure patients. Drug-drug interactions are however a real challenge during treatment. In particular, in HIV-infected patients in cART, DAA choice is limited by such interactions, which can result both in reduced efficacy and toxicity. We report the case of a HIV-infected patient on cART with atazanavir/ritonavir/abacavir/lamivudine, who presented kidney and biliary lithiasis, the latter treated with endoscopic retrograde cholangiopancreatography and endoscopic biliary sphincterotomy, after beginning anti-HCV treatment with daclatasvir/sofosbuvir/ribavirin. Hyperbilirubinemia with or without jaundice is a well known side effect of atazanavir, because of its inhibition of uridine diphosphate-glucuronosyl transferase. We speculate that in this case hyperbilirubinemia worsening was due to atazanavir/ribavirin co-administration. However, pharmacokinetic data are lacking about atazanavir/daclatasvir concomitant administration in real life setting.
Subject(s)
Anti-HIV Agents/administration & dosage , Antiviral Agents/administration & dosage , Lithiasis/chemically induced , Adult , Anti-HIV Agents/adverse effects , Antiviral Agents/adverse effects , Atazanavir Sulfate/administration & dosage , Biliary Tract Diseases/chemically induced , Biliary Tract Diseases/pathology , Biliary Tract Diseases/therapy , Carbamates , Coinfection , Dideoxynucleosides/administration & dosage , Drug Combinations , Drug Interactions , Genotype , HIV Infections/complications , HIV Infections/drug therapy , Hepacivirus/genetics , Hepacivirus/isolation & purification , Hepatitis C/complications , Hepatitis C/drug therapy , Humans , Imidazoles/administration & dosage , Kidney Calculi/chemically induced , Kidney Calculi/pathology , Kidney Calculi/therapy , Lamivudine/administration & dosage , Lithiasis/pathology , Lithiasis/therapy , Male , Pyrrolidines , Ribavirin/administration & dosage , Ritonavir/administration & dosage , Sofosbuvir/administration & dosage , Valine/analogs & derivativesABSTRACT
BACKGROUND AND AIM: Chinese herbal medicine (CHM), as well as Western medicine (WM), is an important cause of drug-induced liver injury (DILI). However, the differences between CHM and WM as agents implicated in liver injury have rarely been reported. METHODS: Overall, 1985 (2.05%) DILI cases were retrospectively collected from the 96 857 patients hospitalized because of liver dysfunction in the 302 Military Hospital between January 2009 and January 2014. RESULTS: In all the enrolled patients with DILI, CHM was implicated in 563 cases (28.4%), while 870 cases (43.8%) were caused by WM and the remaining patients (27.8%) by the combination of WM and CHM. Polygonum multiflorum was the major implicated CHM. Compared with WM, the cases caused by CHM showed more female (51 vs 71%, P < 0.001) and positive rechallenge (6.1 vs 8.9%, P = 0.046), a much greater proportion of hepatocellular injury (62.2 vs 88.5%, P < 0.001), and a higher mortality (2.8 vs 4.8%, P = 0.042); however, no differences in the rates of chronic DILI and ALF were found (12.9 vs 12.4%, P = 0.807; 7.6 vs 7.6%, P = 0.971). Based on Roussel Uclaf Causality Assessment Method, 75.6% of cases caused by CHM were classified as probable and only 16.6% as highly probable, significantly different from WM (38.4 and 60.3%, all P < 0.001). CONCLUSIONS: The causal relationship between CHM and liver injury is much complex, and the clinical characteristics of DILI caused by CHM differ from those caused by WM.
Subject(s)
Biliary Tract Diseases/chemically induced , Chemical and Drug Induced Liver Injury/etiology , Drugs, Chinese Herbal/adverse effects , Medicine, Chinese Traditional/adverse effects , Pancreatic Diseases/chemically induced , Adult , Biliary Tract Diseases/diagnosis , Biliary Tract Diseases/mortality , Chemical and Drug Induced Liver Injury/diagnosis , Chemical and Drug Induced Liver Injury/mortality , Female , Hospitalization , Humans , Male , Middle Aged , Pancreatic Diseases/diagnosis , Pancreatic Diseases/mortality , Prognosis , Retrospective Studies , Risk Assessment , Risk Factors , Time FactorsABSTRACT
BACKGROUND: Gallstone disease is a leading cause of morbidity in Western countries and carries a high economic burden. Statin medications decrease hepatic cholesterol biosynthesis and may, therefore, lower the risk of cholesterol cholelithiasis by reducing the cholesterol concentration in the bile. Population-based evidence, however, is sparse. OBJECTIVE: To assess the risk of gallbladder diseases among statin users compared with nonusers in an American patient cohort. METHODS: We performed a retrospective cohort study of patients enrolled in the San Antonio Tricare health system using data between October 2003 and March 2012. We defined 2 groups: statin users (use for 90 days or greater) and nonusers (no prior statin). A propensity score based on 82 variables was generated to match statin users and nonusers 1:1. Outcomes included incidence of cholelithiasis, biliary tract diseases, and gallbladder procedures. RESULTS: A total of 43 438 patients were identified; 13 626 (31.4%) were statin users, and 29 812 (68.6%) were nonusers. We matched 6342 pairs of statin users and nonusers based on propensity score. The odds ratios (ORs) in statin users in comparison to nonusers were similar for cholelithiasis (OR = 0.86; 95% CI = 0.73, 1.02), biliary tract disease (OR = 0.85; 95% CI = 0.67-1.08), and gall bladder procedures (OR = 0.85; 95% CI = 0.69, 1.04). CONCLUSIONS: Statin use was not significantly associated with either an increased or decreased risk of cholelithiasis or gallbladder disease.
Subject(s)
Biliary Tract Diseases/chemically induced , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Adult , Aged , Biliary Tract Diseases/epidemiology , Cholelithiasis/chemically induced , Cholelithiasis/epidemiology , Female , Humans , Incidence , Male , Middle Aged , Odds Ratio , Propensity Score , Retrospective Studies , RiskABSTRACT
BACKGROUND: Toluene is one of the most widely abused inhaled drugs due to its acute neurologic effects including euphoria and subsequent depression. However, dangerous metabolic abnormalities are associated to acute toluene intoxication. It has been previously reported that rhabdomyolysis and acute hepatorenal injury could be hallmarks of the condition, and could constitute risk factors for poor outcomes. The objective was to describe the clinical presentation, to characterize the renal and liver abnormalities, the management and prognosis associated to acute toluene intoxication. METHODS: We prospectively assessed 20 patients that were admitted to a single center's emergency department from September 2012 to June 2014 with clinical and metabolic alterations due to acute toluene intoxication. RESULTS: The main clinical presentation consisted of weakness associated to severe hypokalemia and acidosis. Renal glomerular injury (proteinuria) is ubiquitous. Biliary tract injury (alkaline phosphatase and gamma-glutamyl transpeptidase elevations) disproportional to hepatocellular injury is common. Rhabdomyolysis occurred in 80% of patients, probably due to hypokalemia and hypophosphatemia. There were three deaths, all female, and all associated with altered mental status, severe acidosis, hypokalemia and acute oliguric renal failure. The cause of death was in all cases due to cardiac rhythm abnormalities. CONCLUSION: The hallmarks of acute toluene intoxication are hypokalemic paralysis and metabolic acidosis. Liver injury and rhabdomyolysis are common. On admission, altered mental status, renal failure, severe acidemia and female gender (not significant in our study, but present in all three deaths) could be associated with a poor outcome, and patients with these characteristics should be considered to be treated in an intensive care unit.
Subject(s)
Illicit Drugs/poisoning , Substance-Related Disorders/diagnosis , Toluene/poisoning , Acidosis/chemically induced , Acute Disease , Adolescent , Adult , Biliary Tract Diseases/chemically induced , Chemical and Drug Induced Liver Injury/etiology , Critical Care , Female , Humans , Hypokalemia/chemically induced , Logistic Models , Male , Paralysis/chemically induced , Prognosis , Prospective Studies , Proteinuria/chemically induced , Rhabdomyolysis/chemically induced , Risk Factors , Substance-Related Disorders/complications , Substance-Related Disorders/mortality , Substance-Related Disorders/therapy , Young AdultABSTRACT
NSC-743380 (1-[(3-chlorophenyl)-methyl]-1H-indole-3-carbinol) is in early stages of development as an anticancer agent. Two metabolites reflect sequential conversion of the carbinol functionality to a carboxaldehyde and the major metabolite, 1-[(3-chlorophenyl)-methyl]-1H-indole-3-carboxylic acid. In an exploratory toxicity study in rats, NSC-743380 induced elevations in liver-associated serum enzymes and biliary hyperplasia. Biliary hyperplasia was observed 2 days after dosing orally for 2 consecutive days at 100mg/kg/day. Notably, hepatotoxicity and biliary hyperplasia were observed after oral administration of the parent compound, but not when major metabolites were administered. The toxicities of a structurally similar but pharmacologically inactive molecule and a structurally diverse molecule with a similar efficacy profile in killing cancer cells in vitro were compared to NSC-743380 to explore scaffold versus target-mediated toxicity. Following two oral doses of 100mg/kg/day given once daily on two consecutive days, the structurally unrelated active compound produced hepatic toxicity similar to NSC-743380. The structurally similar inactive compound did not, but, lower exposures were achieved. The weight of evidence implies that the hepatotoxicity associated with NSC-743380 is related to the anticancer activity of the parent molecule. Furthermore, because biliary hyperplasia represents an unmanageable and non-monitorable adverse effect in clinical settings, this model may provide an opportunity for investigators to use a short-duration study design to explore biomarkers of biliary hyperplasia.
Subject(s)
Acute Disease , Biliary Tract Diseases/chemically induced , Biliary Tract/drug effects , Indoles/adverse effects , Administration, Oral , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacokinetics , Biliary Tract/metabolism , Biliary Tract/pathology , Biliary Tract Diseases/blood , Biliary Tract Diseases/metabolism , Biliary Tract Diseases/pathology , Biomarkers/blood , Biotransformation , Chemical and Drug Induced Liver Injury/blood , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/pathology , Chemical and Drug Induced Liver Injury/physiopathology , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Drugs, Investigational/administration & dosage , Drugs, Investigational/adverse effects , Drugs, Investigational/metabolism , Drugs, Investigational/pharmacokinetics , Hyperplasia , Indoles/administration & dosage , Indoles/blood , Indoles/metabolism , Indoles/pharmacokinetics , Liver/drug effects , Liver/metabolism , Liver/pathology , Liver/physiopathology , Male , Random Allocation , Rats, Inbred F344 , Structure-Activity RelationshipABSTRACT
BACKGROUND: Development of cholecystitis in patients with malignancies can potentially disrupt their treatment and alter prognosis. This review aims to identify antineoplastic interventions associated with increased risk of cholecystitis in cancer patients. METHODS: A comprehensive search strategy was developed to identify articles pertaining to risk factors and complications of cholecystitis in cancer patients. FDA-issued labels of novel antineoplastic drugs released after 2010 were hand-searched to identify more therapies associated with cholecystitis in nonpublished studies. RESULTS: Of an initial 2,932 articles, 124 were reviewed in the study. Postgastrectomy patients have a high (5-30 %) incidence of gallstone disease, and 1-7 % develop symptomatic disease. One randomized trial addressing the role of cholecystectomy concurrent with gastrectomy is currently underway. Among other risk groups, patients with neuroendocrine tumors treated with somatostatin analogs have a 15 % risk of cholelithiasis, and most are symptomatic. Hepatic artery based therapies carry a risk of cholecystitis (0.02-24 %), although the risk is reduced with selective catheterization. Myelosuppression related to chemotherapeutic agents (0.4 %), bone marrow transplantation, and treatment with novel multikinase inhibitors are associated with high risk of cholecystitis. CONCLUSIONS: There are several risk factors for gallbladder-related surgical emergencies in patients with advanced malignancies. Incidental cholecystectomy at index operation should be considered in patients planned for gastrectomy, and candidates for regional therapies to the liver or somatostatin analogs. While prophylactic cholecystectomy is currently recommended for patients with cholelithiasis receiving myeloablative therapy, this strategy may have value in patients treated with multikinase inhibitors, immunotherapy, and oncolytic viral therapy based on evolving evidence.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biliary Tract Diseases/chemically induced , Cholecystitis/chemically induced , Cholelithiasis/chemically induced , Empyema/chemically induced , Stomach Neoplasms/drug therapy , Acute Disease , Humans , PrognosisSubject(s)
Biliary Tract Diseases/chemically induced , Biliary Tract Diseases/diagnosis , Cholangitis, Sclerosing/diagnosis , Ketamine/adverse effects , Substance-Related Disorders/complications , Administration, Inhalation , Anesthetics, Dissociative/administration & dosage , Anesthetics, Dissociative/adverse effects , Biliary Tract Diseases/complications , Biopsy , Cholangitis, Sclerosing/etiology , Humans , Ketamine/administration & dosage , Liver/pathology , Male , Substance Abuse Treatment Centers , Substance-Related Disorders/therapy , Treatment Outcome , Young AdultABSTRACT
OBJECTIVE: Assess the hepatoprotective effect of Taurine (Tau) in cases of hepatic cholestasis induced by Total Parenteral Nutrition (TPN). METHODS: We describe a retrospective series of 54 patients who received TPN, in which cholestasis was detected at an (Intermediate) point that separates the duration of TPN into 2 Phases. From this moment -Phase 2- on, and according to clinical criteria, some patients (Group A, n = 27) received amino acids with Tau (22.41 ± 3.57 mg/kg/day)(Tauramin®), while the rest (Group B, n = 27) received the standard solution without Tau. The mean TPN durations were 39.2 ± 17.1 and 36.4 ± 18.1 days respectively, with the Intermediate points on days 19.56 ± 10.51 and 17.89 ± 11.14. They all received diets that were homogeneous in terms of kcal and macronutrients. In Phase 2, 21 patients from Group A received structured lipids (SMOFlipid®); while 20 from Group B received soy MCT/LCT [ Medium Chain Triglycerides/Long Chain Triglycerides ] (physical or structured mixture). In a retrospective study, differences could not be avoided. The analytical parameters from three periods (Initial, Intermediate, and Final) were obtained from Nutridata® and Servolab®. We compared interperiod values using the Wilcoxon test SPSS® (p < 0.05). RESULTS: After introducing Taurine AST, ALT, and GGT were significantly reduced; Bilirubin was also reduced, but not significantly. The values obtained for GGT in Group A were (Mean(σ)/median): Initial 48.6 (23.1)/46; Intermediate 473.7 (276.2)/438, and Final 328.9 (190.4)/305. We stress that the mean GGT value is reduced by 30.56% after adding Taurine, while in its absence all parameters are elevated, and mean GGT increases 45.36%. CONCLUSION: These results show Taurine's hepatoprotective effect and support its use in cases of TPN-induced cholestasis. We acknowledge the possibility that the differences between SMOF and the MCT/LCT mixtures also may have influenced the results in a combined effect with taurine.