Trends in mortality from gastrointestinal, hepatic, and pancreatic cancers in the United States: A comprehensive analysis (1999-2020).

Background and Aim: This study investigates temporal trends in gastrointestinal cancer-related mortality in the United States between 1999 and 2020, focusing on differences by sex, age, and race. Methods: We investigated the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research multiple causes of death database (Years 1999-2020) for gastrointestinal cancer-related mortality with a focus on the underlying cause of death. Results: A total of 3 115 243 gastrointestinal cancer-related deaths occurred from 1999 to 2020. The overall age-adjusted mortality rate decreased from 46.7 per 100 000 in 1999 to 38.4 per 100 000 in 2020. The average annual percent change (AAPC) for the study period was -0.9% (95% CI: -1.0%, -0.9%, P < 0.001), with no significant difference in AAPC between the sexes but some difference between races and related to individual cancers. African Americans and Asian Americans, and Pacific Islanders experienced a greater decrease in mortality compared with Whites. Mortality rates for American Indian and Alaskan Native populations also decreased significantly from 1999 to 2020 (P < 0.001). There were significant declines in esophageal, stomach, colon, rectal, and gallbladder cancer-related mortality but increases in the small bowel, anal, pancreatic, and hepatic cancer-related mortality (P < 0.001), with variation across different sexes and racial groups. Conclusion: While overall gastrointestinal cancer-related mortality declined significantly in the United States from 1999 to 2020, mortality from some cancers increased. Furthermore, differences between sexes and racial groups underscore crucial differences in gastrointestinal cancer mortality, highlighting areas for future research.

Liver toxicity in oncology trials and beyond: a simplified concept for management of hepatocellular drug-induced liver injury in patients with abnormal baseline liver tests.

BACKGROUND: Management of side effects in clinical trials has to balance generation of meaningful data with risk for patients. A toxicity area requiring detailed management guidelines is drug-induced liver injury (DILI). In oncology trials, patients are often included despite baseline liver test abnormalities, for whom there is no consensus yet on levels of liver test changes that should trigger action, such as drug interruption or discontinuation. METHODS: We provide an innovative approach to manage hepatocellular DILI in oncology trials for patients with abnormal baseline alanine aminotransferase (ALT) levels. The algorithm proposed is based on mathematical derivation of action thresholds from those generally accepted for patients with normal baselines. RESULTS: The resulting algorithm is grouped by level of baseline abnormality and avoids calculation of baseline multiples. Suggested layered action levels are 4, 6, and 11 × Upper Limit of Normal (ULN) for patients with baseline ALT between 1.5 and 3 × ULN, and 6, 8, and 12 × ULN for patients with baseline ALT between 3 and 5 × ULN, respectively. CONCLUSIONS: Our concept and resulting algorithm are consistent, transparent, and easy to follow, and the method for derivation from consensus-based thresholds may also be applicable to other drug toxicity areas.

Size Matters! Anti-HBs Titer and HBV Reactivation During Anti-TNF Therapy.

BACKGROUND AND AIMS: We and others have previously described that hepatitis B surface antibody (anti-HBs) seems to protect against clinically significant HBV reactivation in cohort studies of patients undergoing anti-tumor necrosis factor (TNF) therapy. However, there were too few cases of HBV reactivation within cohort studies to assess the role of anti-HBs titer on reactivation. The purpose of this study was to systematically review the correlation between anti-HBs titer and the degree of clinically relevant HBV reactivation in patients undergoing anti-TNF therapy. METHODS AND RESULTS: We systemically reviewed all studies discussing anti-TNF therapy in patients with resolved HBV infection, defined as hepatitis surface antigen (HBsAg) negative and hepatitis B core antibody (anti-HBc) positive. We identified a total of 48 cases of reactivation from 5 cohort studies and 10 case reports or case series; 21 were anti-HBs negative, 7 were only reported as anti-HBs positive, 16 were anti-HBs positive with titer below 100, and 4 were anti-HBs positive with titer above 100. HBsAg sero-reversion was dominantly seen in patients with negative, low and/or declining anti-HBs titers. There was a significant trend toward less clinically relevant form of reactivation with increase in baseline anti-HBs titer (p = 0.022). CONCLUSION: Anti-HBs titers greater than 100 iU/L protect against clinically relevant HBV reactivation, while patients with low anti-HBs titers or negative anti-HBs had more clinically relevant HBV reactivation and higher rates of HBsAg sero-reversion. This suggests the importance of baseline quantitative anti-HBs prior to starting anti-TNF therapy and consideration vaccination for boosting anti-HBs titers prior to and/or during therapy.

Role of Hepatitis B Surface Antibodies in Risk for Hepatitis B Virus Reactivation During Anti-Tumor Necrosis Factor Therapy.

An estimated 250 million people are chronically infected with hepatitis B virus (HBV), with more than 800,000 deaths related to HBV.1 Although the prevalence of HBV has been decreasing, reactivation remains a cause for concern.2 Reactivation is defined by the resurgence of HBV DNA and/or HBV surface antigen (HBsAg) seroreversion in patients with resolved HBV or an increase in HBV viral load in chronic hepatitis.3 Anti-tumor necrosis factor (TNF) therapies have been shown to place patients at a risk for HBV reactivation.4.

A novel quantitative computer-assisted drug-induced liver injury causality assessment tool (DILI-CAT).

BACKGROUND AND AIMS: We hypothesized that a drug's clinical signature (or phenotype) of liver injury can be assessed and used to quantitatively develop a computer-assisted DILI causality assessment-tool (DILI-CAT). Therefore, we evaluated drug-specific DILI-phenotypes for amoxicillin-clavulanate (AMX/CLA), cefazolin, cyproterone, and Polygonum multiflorum using data from published case series, to develop DILI-CAT scores for each drug. METHODS: Drug specific phenotypes were made up of the following three clinical features: (1) latency, (2) R-value, and (3) AST/ALT ratio. A point allocation system was developed with points allocated depending on the variance from the norm (or "core") for the 3 variables in published datasets. RESULTS: The four drugs had significantly different phenotypes based on latency, R-value, and AST/ALT ratio. The median cyproterone latency was 150 days versus < 43 days for the other three drugs (median: 26 for AMX/CLA, 20 for cefazolin, and 20 for Polygonum multiflorum; p<0.001). The R-value for the four drugs was also significantly different among drugs (cyproterone [median 12.4] and Polygonum multiflorum [median 10.9]) from AMX/CLA [median 1.44] and cefazolin [median 1.57; p<0.001]). DILI-CAT scores effectively separated cyproterone and Polygonum multiflorum from AMX/CLA and cefazolin, respectively (p<0.001). As expected, because of phenotypic overlap, AMX/CLA and cefazolin could not be well differentiated. CONCLUSIONS: DILI-CAT is a data-driven, diagnostic tool built to define drug-specific phenotypes for DILI adjudication. The data provide proof of principle that a drug-specific, data-driven causality assessment tool can be developed for different drugs and raise the possibility that such a process could enhance causality assessment methods.

A novel phenotype-based drug-induced liver injury causality assessment tool (DILI-CAT) allows for signal confirmation in early drug development.

BACKGROUND: Drug-induced liver injury (DILI) requires accurate case adjudication, with expert opinion being the current best practice. AIM: We utilised a novel DILI causality assessment tool (DILI-CAT), which uses drug-specific liver injury phenotypes, to examine potential DILI in early phase ximelagatran clinical development. METHODS: We conducted a retrospective analysis of liver injury events from four Stroke Prevention using an ORal Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) trials, in which patients were randomised to receive oral ximelagatran or adjusted-dose warfarin. A stepwise process was used with iterative adjustments. The DILI phenotype was characterised by latency, R-value, and AST/ALT ratio. A scoring algorithm was applied to liver events to assess how closely the liver events matched the Interquatile-Range for the working phenotype for each of the three parameters. FINDINGS: Data from 3115 patients included in the SPORTIF trials as above were available. The initial ximelagatran phenotype was developed based on five liver injury cases from the ximelagatran arm and was then validated against an additional eight cases (5 ximelagatran, 3 warfarin); in these eight cases, there was a statistically significant difference in the total DILI-CAT scores of the two drugs (p = 0.016) between ximelagatran and warfarin. Together, these ten ximelagatran cases generated a second, refined ximelagatran phenotype, which was validated against an additional 75 cases (53 ximelagatran/22 warfarin)-again with statistically significant different DILI-CAT ximelagatran vs. warfarin scores (p < 0.001). CONCLUSION: DILI-CAT, a clinically intuitive, data-driven, computer-assisted scoring algorithm, is a useful tool for early detection of drug's hepatotoxicity in clinical drug development.

Value of liver biopsy in the diagnosis of drug-induced liver injury.

BACKGROUND & AIMS: The utility of liver biopsy in diagnosing or staging idiosyncratic drug-induced liver injury (DILI) is unclear. The aim of this study was to determine whether liver histology impacted causality assessment in suspected DILI using a novel simulation model. METHODS: Fifty patients enrolled in the DILI Network (DILIN) who had liver biopsies performed within 60 days of DILI onset were randomly selected. All had standard DILIN consensus causality scoring using a 5-point scale (1=definite, 2=highly likely, 3=probable, 4=possible, 5=unlikely) based on 6-month post-injury data. Three experienced hepatologists independently performed a causality assessment using redacted case records, with the biopsy and selected post-biopsy laboratory data removed. The 3 hepatologists also reviewed the liver histology with a hepatopathologist and then repeated causality assessment for each case. RESULTS: Of the 50 cases, there were 42 high causality DILI cases (1, 2 or 3) and 8 low causality cases (4 and 5). The hepatologists judged that liver biopsy was indicated in 62% of patients; after histology review, biopsy was judged to have been helpful in 70% of patients. Histology review changed the causality score in 68% of patients, with an increase in DILI likelihood in 48% and a decrease in 20%. Biopsy results changed diagnostic certainty from less certain (3 or 4) to highly certain (1, 2 or 5) in 38% of patients. CONCLUSIONS: Liver histologic findings may help clarify the diagnosis of DILI. Histology appears to be particularly helpful in cholestatic or equivocal cases of DILI (possible or probable), shifting assessment toward a greater or lower certainty of a DILI diagnosis. LAY SUMMARY: The utility of liver biopsy in diagnosing or staging idiosyncratic drug-induced liver injury (DILI) is unclear. Herein, we show that, in patients with suspected DILI, a liver biopsy can help physicians diagnose DILI or other causes of liver injury with more certainty.

Garcinia cambogia, Either Alone or in Combination With Green Tea, Causes Moderate to Severe Liver Injury.

BACKGROUND & AIMS: Garcinia cambogia, either alone or with green tea, is commonly promoted for weight loss. Sporadic cases of liver failure from G cambogia have been reported, but its role in liver injury is controversial. METHODS: Among 1418 patients enrolled in the Drug-Induced Liver Injury Network (DILIN) from 2004 to 2018, we identified 22 cases (adjudicated with high confidence) of liver injury from G cambogia either alone (n = 5) or in combination with green tea (n = 16) or Ashwagandha (n = 1). Control groups consisted of 57 patients with liver injury from herbal and dietary supplements (HDS) containing green tea without G cambogia and 103 patients from other HDS. RESULTS: Patients who took G cambogia were between 17 and 54 years, with liver injury arising 13-223 days (median = 51) after the start. One patient died, one required liver transplantation, and 91% were hospitalized. The liver injury was hepatocellular with jaundice. Although the peak values of aminotransferases were significantly higher (2001 ± 1386 U/L) in G cambogia group (P < .018), the median time for improvement in total bilirubin was significantly lower compared with the control groups (10 vs 17 and 13 days; P = .03). The presence of HLA-B∗35:01 allele was significantly higher in the G cambogia containing HDS (55%) compared with patients because of other HDS (19%) (P = .002) and those with acute liver injury from conventional drugs (12%) (P = 2.55 × 10-6). CONCLUSIONS: The liver injury caused by G cambogia and green tea is clinically indistinguishable. The possible association with HLA-B∗35:01 allele suggests an immune-mediated mechanism of injury. CLINICAL TRIALS: gov number: NCT00345930.

Hepatitis B surface antibody titres and hepatitis B reactivation with direct-acting antiviral therapy for hepatitis C.

HBV reactivation can occur while undergoing direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV). The role of hepatitis B surface antibody (HBsAb) has not been systematically explored. Therefore, the purpose of this systematic review was to explore the role of the presence of HBsAb on the risk of HBV reactivation related to DAA therapy. We reviewed MEDLINE, CINAHL, EMBASE and Cochrane Central for studies on DAA therapy and data on HBsAb in patients with resolved hepatitis B (hepatitis B surface antigen-negative and hepatitis B core antibody-positive). We identified twenty-nine reports: thirteen case reports with HBV reactivation (10 HBsAb-negative and 3 HBsAb-positive patients) and sixteen cohort studies totalling 2528 patients with resolved HBV infection (1429 HBsAb negative, 1099 HBsAb positive). Reactivation was found in 12 (0.8%) HBsAb-negative and 7 (0.6%) HBsAb-positive individuals of cohort studies. All but two HBV reactivation occurred in patients with HBsAb titre <30 iU/L. The presence of HBsAb showed a trend towards delayed reactivation (median 12 weeks vs 9.5 weeks; P = .07). Importantly, with the exception of a patient with escape variant and an HIV-infected individual, no HBsAb-positive individual demonstrated clinical reactivation. HBsAb presence seems to protect from clinical HBV reactivation related to DAA therapy. The most pronounced prevention for reactivation may require titres greater than 30 iU/L.

HLA-B*35:01 and Green Tea-Induced Liver Injury.

BACKGROUND AND AIMS: Herbal supplements, and particularly multi-ingredient products, have become increasingly common causes of acute liver injury. Green tea is a frequent component in implicated products, but its role in liver injury is controversial. The aim of this study was to better characterize the clinical features, outcomes, and pathogenesis of green tea-associated liver injury. APPROACH AND RESULTS: Among 1,414 patients enrolled in the U.S. Drug-Induced Liver Injury Network who underwent formal causality assessment, 40 cases (3%) were attributed to green tea, 202 to dietary supplements without green tea, and 1,142 to conventional drugs. The clinical features of green tea cases and representation of human leukocyte antigen (HLA) class I and II alleles in cases and control were analyzed in detail. Patients with green tea-associated liver injury ranged in age from 17 to 69 years (median = 40) and developed symptoms 15-448 days (median = 72) after starting the implicated agent. The liver injury was typically hepatocellular (95%) with marked serum aminotransferase elevations and only modest increases in alkaline phosphatase. Most patients were jaundiced (83%) and symptomatic (88%). The course was judged as severe in 14 patients (35%), necessitating liver transplantation in 3 (8%), but rarely resulting in chronic injury (3%). In three instances, injury recurred upon re-exposure to green tea with similar clinical features, but shorter time to onset. HLA typing revealed a high prevalence of HLA-B*35:01, found in 72% (95% confidence interval [CI], 58-87) of green tea cases, but only 15% (95% CI, 10-20) caused by other supplements and 12% (95% CI, 10-14) attributed to drugs, the latter rate being similar to population controls (11%; 95% CI, 10.5-11.5). CONCLUSIONS: Green tea-related liver injury has distinctive clinical features and close association with HLA-B*35:01, suggesting that it is idiosyncratic and immune mediated.

Signatures in drug-induced liver injury.

PURPOSE OF REVIEW: Drug-induced liver injury (DILI) can be induced by a myriad of drugs. Assessing whether the patient has DILI and assessing which drug is the most likely culprit are challenging. There has been too little attention paid to the concept that certain drugs appear to have unique clinical features or 'phenotypes'. RECENT FINDINGS: Several case series of DILI because of various drugs have been published, and analysis of these case series points to the fact that individual drugs have characteristic DILI signatures. These clinical phenotypes can be characterized by latency, biochemical features (R-value), as well as clinical symptoms and signs. Several drugs, including isoniazid, amoxicillin-clavulanic acid, anabolic steroids, ß-interferon and others, have highly unique clinical features. Such unique properties may be able to be used to improve adjudication processes. SUMMARY: Individual drugs have unique clinical DILI phenotypes or signatures. Furthermore, these may be able to be used to improve adjudication.

Tools for causality assessment in drug-induced liver disease.

PURPOSE OF REVIEW: There are three liver-specific causality assessment tools currently available to guide clinical diagnosis of Drug-Induced Liver Injury (DILI): Roussel-Uclaf Causality Assessment Method (RUCAM), Digestive-Disease-Week Japan 2004 scale (DDW-J), and Clinical Diagnostic Scale (CDS). The purpose of this review is to assess these tools and discuss how to improve the causality assessment process as a whole. RECENT FINDINGS: Existing DILI-specific causality assessment tools are surprisingly similar and exhibit only minor differences in point allocation. But difference in threshold for likelihood of being DILI. We reviewed the literature on currently used causality assessment tools, identified areas for future improvement, and herein propose approaches for refinement. Opportunities to improve current models, as well as the assessment process, in general, include in particular provision of more precise clinical detail and to perhaps add new components to scoring systems. For example, the incorporation of drug-specific clinical signature patterns, accounting for a drug's inherent hepatotoxicity potential, and/or incorporation of other drug properties to scoring systems may allow enhancement. Further, more systemic exclusion of competing diagnoses is needed. Finally, causality assessment processes will likely benefit from a data-driven and computer-assisted approach. SUMMARY: Current tools used for DILI adjudication are imperfect. Avenues to improve these tools are described.

Current state-of-the-art pharmacotherapy for the management of hepatitis B infection.

INTRODUCTION: Hepatitis B virus (HBV) infection remains a global challenge with several hundred million infected individuals. Disease activity can be controlled, and adverse outcomes prevented when treatment can be provided. Frequently life-long therapy is required instead of defined treatment periods such as with the case of Hepatitis C Virus (HCV) infection. AREAS COVERED: In this review, the authors provide an overview of current start of the art therapy for HBV and indicate where variation from the current guidelines could be considered. Certain patients may be eligible for treatment with suboptimal therapies when their baseline viral load is low. Identifying ideal candidates for interferon therapy will result in good sustained responses for some patients. EXPERT OPINION: The biggest challenge remains linking patients to care and therapy. Patients can nowadays be sufficiently treated before the disease advances to a more progressed phase. However, future therapies must be extremely safe and ideally limit the required treatment period. Given Hepatitis D Virus's dependence on HBV and being a disease with an unmet clinical need, HDV may be the best target group for the development of a functional cure for hepatitis B.

Importance of Hepatitis C Virus RNA Testing in Patients with Suspected Drug-Induced Liver Injury.

BACKGROUND AND AIMS: The aims were to review the diagnosis, testing and presentation of acute hepatitis C (HCV) in patients initially diagnosed to have drug-induced liver injury (DILI) enrolled in the US DILI Network. METHODS: All patients with suspected DILI underwent testing for competing causes of liver injury and returned for 6-month follow-up. Causality was adjudicated by consensus expert opinion. RESULTS: Between 2004 and 2016, 1518 patients were enrolled and adjudicated and underwent 6 months of follow-up. Initial locally acquired anti-HCV results were available in 1457 (96%), but HCV RNA in only 795 (52%). Stored sera were available for repeat testing, so that results were available on all 1518 patients (1457 for anti-HCV and 1482 for HCV RNA). A total of 104 subjects (6.9%) had evidence of HCV infection-10 positive for HCV RNA alone, 16 for anti-HCV alone and 78 for both. All 104 HCV-positive cases were reviewed, and 23 cases were adjudicated as acute HCV. All presented with acute hepatocellular injury with median ALT 1448 U/L, alkaline phosphatase 232 U/L and total bilirubin 10.8 mg/dL. Twenty-two (96%) patients were jaundiced. While all 23 cases initially had been suspected of having DILI, 19 were adjudicated as acute HCV and not DILI at the 6-month follow-up; while 4 were still considered DILI. CONCLUSIONS: Twenty-three of 1518 (1.5%) cases of suspected DILI were due to acute HCV infection. We recommend that initial and follow-up HCV RNA testing should be performed to exclude HCV in patients with acute hepatocellular injury and suspected DILI.

Injury pattern recognition to discriminate competing causes of liver injury.

BACKGROUND: Competing causes of liver injury may be difficult to discriminate. Characterization of the typical phenotype of each injury defined by latency, time to improvement and biochemical pattern, could be helpful to identify the most likely of competing causes. METHODS: Liver injury characteristics of both bortezomib-associated drug-induced liver injury (DILI) and hepatitis B virus (HBV) reactivation associated with bortezomib are derived from PubMed listed publications. RESULTS: Bortezomib-associated DILI has very short latency of days and AP is found elevated, while liver injury due to HBV reactivation occurs after several months of bortezomib therapy. Therefore, a patient's liver injury pattern occurring 3 months into bortezomib therapy should be attributed to HBV reactivation. DISCUSSION: Identification of liver injury characteristics for competing causes of liver injury can be helpful to identify the most likely cause and improve clinical outcome.