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DESCRIPTION: The purpose of this American Gastroenterological Association (AGA) Institute Clinical Practice Update is to review the available published evidence and expert advice regarding the clinical management of patients with pregnancy-related gastrointestinal and liver disease. METHODS: This expert review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership and underwent internal peer review by the Clinical Practice Updates Committee and external peer review through the standard procedures of Gastroenterology. This article provides practical advice for the management of pregnant patients with gastrointestinal and liver disease based on the best available published evidence. The Best Practice Advice statements were drawn from a review of the published literature and from expert opinion. Because formal systematic reviews were not performed, these Best Practice Advice statements do not carry formal ratings regarding the quality of evidence or strength of the presented considerations. Best Practice Advice Statements BEST PRACTICE ADVICE 1: To optimize gastrointestinal and liver disease before pregnancy, preconception and contraceptive care counseling by a multidisciplinary team should be encouraged for reproductive-aged persons who desire to become pregnant. BEST PRACTICE ADVICE 2: Procedures, medications, and other interventions to optimize maternal health should not be withheld solely because a patient is pregnant and should be individualized after an assessment of the risks and benefits. BEST PRACTICE ADVICE 3: Coordination of birth for a pregnant patient with complex inflammatory bowel disease, advanced cirrhosis, or a liver transplant should be managed by a multidisciplinary team, preferably in a tertiary care center. BEST PRACTICE ADVICE 4: Early treatment of nausea and vomiting of pregnancy may reduce progression to hyperemesis gravidarum. In addition to standard diet and lifestyle measures, stepwise treatment consists of symptom control with vitamin B6 and doxylamine, hydration, and adequate nutrition; ondansetron, metoclopramide, promethazine, and intravenous glucocorticoids may be required in moderate to severe cases. BEST PRACTICE ADVICE 5: Constipation in pregnant persons may result from hormonal, medication-related, and physiological changes. Treatment options include dietary fiber, lactulose, and polyethylene glycol-based laxatives. BEST PRACTICE ADVICE 6: Elective endoscopic procedures should be deferred until the postpartum period, whereas nonemergent but necessary procedures should ideally be performed in the second trimester. Pregnant patients with cirrhosis should undergo evaluation for, and treatment of, esophageal varices; upper endoscopy is suggested in the second trimester (if not performed within 1 year before conception) to guide consideration of nonselective ß-blocker therapy or endoscopic variceal ligation. BEST PRACTICE ADVICE 7: In patients with inflammatory bowel disease, clinical remission before conception, during pregnancy, and in the postpartum period is essential for improving outcomes of pregnancy. Biologic agents should be continued throughout pregnancy and the postpartum period; use of methotrexate, thalidomide, and ozanimod must be stopped at least 6 months before conception. BEST PRACTICE ADVICE 8: Endoscopic retrograde cholangiopancreatography during pregnancy may be performed for urgent indications, such as choledocholithiasis, cholangitis, and some cases of gallstone pancreatitis. Ideally, endoscopic retrograde cholangiopancreatography should be performed during the second trimester, but if deferring the procedure may be detrimental to the health of the patient and fetus, a multidisciplinary team should be convened to decide on the advisability of endoscopic retrograde cholangiopancreatography. BEST PRACTICE ADVICE 9: Cholecystectomy is safe during pregnancy; a laparoscopic approach is the standard of care regardless of trimester, but ideally in the second trimester. BEST PRACTICE ADVICE 10: The diagnosis of intrahepatic cholestasis of pregnancy is based on a serum bile acid level >10 µmol/L in the setting of pruritus, typically during the second or third trimester. Treatment should be offered with oral ursodeoxycholic acid in a total daily dose of 10-15 mg/kg. BEST PRACTICE ADVICE 11: Management of liver diseases unique to pregnancy, such as pre-eclampsia; hemolysis, elevated liver enzymes, and low platelets syndrome; and acute fatty liver of pregnancy requires planning for delivery and timely evaluation for possible liver transplantation. Daily aspirin prophylaxis for patients at risk for pre-eclampsia or hemolysis, elevated liver enzymes, and low platelets syndrome is advised beginning at week 12 of gestation. BEST PRACTICE ADVICE 12: In patients with chronic hepatitis B virus infection, serum hepatitis B virus DNA and liver biochemical test levels should be ordered. Patients not on treatment but with a serum hepatitis B virus DNA level >200,000 IU/mL during the third trimester of pregnancy should be considered for treatment with tenofovir disoproxil fumarate. BEST PRACTICE ADVICE 13: In patients on immunosuppressive therapy for chronic liver diseases or after liver transplantation, therapy should be continued at the lowest effective dose during pregnancy. Mycophenolate mofetil should not be administered during pregnancy.
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Continuing medical education (CME) is essential to increase the knowledge, skills, and professional performance of health care providers. To keep the content of CME relevant and balanced, conflict of interest (COI) determination and mitigation is essential. While the Accreditation Council for Continuing Medical Education provides oversight and guidelines, each organization that sponsors CME programs has its own protocol for COI. To standardize and simplify the American Association for the Study of Liver Diseases' approach to COI, we propose a standardized COI disclosure scoring system for all CME programs to notify the audience of any conflicts and how such conflicts can be mitigated.
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Conflito de Interesses , Educação Médica ContinuadaRESUMO
BACKGROUND AND AIMS: Alcohol-associated hepatitis (AH) poses significant short-term mortality. Existing prognostic models lack precision for 90-day mortality. Utilizing artificial intelligence in a global cohort, we sought to derive and validate an enhanced prognostic model. APPROACH AND RESULTS: The Global AlcHep initiative, a retrospective study across 23 centers in 12 countries, enrolled patients with AH per National Institute for Alcohol Abuse and Alcoholism criteria. Centers were partitioned into derivation (11 centers, 860 patients) and validation cohorts (12 centers, 859 patients). Focusing on 30 and 90-day postadmission mortality, 3 artificial intelligence algorithms (Random Forest, Gradient Boosting Machines, and eXtreme Gradient Boosting) informed an ensemble model, subsequently refined through Bayesian updating, integrating the derivation cohort's average 90-day mortality with each center's approximate mortality rate to produce posttest probabilities. The ALCoholic Hepatitis Artificial INtelligence Ensemble score integrated age, gender, cirrhosis, and 9 laboratory values, with center-specific mortality rates. Mortality was 18.7% (30 d) and 27.9% (90 d) in the derivation cohort versus 21.7% and 32.5% in the validation cohort. Validation cohort 30 and 90-day AUCs were 0.811 (0.779-0.844) and 0.799 (0.769-0.830), significantly surpassing legacy models like Maddrey's Discriminant Function, Model for End-Stage Liver Disease variations, age-serum bilirubin-international normalized ratio-serum Creatinine score, Glasgow, and modified Glasgow Scores ( p < 0.001). ALCoholic Hepatitis Artificial INtelligence Ensemble score also showcased superior calibration against MELD and its variants. Steroid use improved 30-day survival for those with an ALCoholic Hepatitis Artificial INtelligence Ensemble score > 0.20 in both derivation and validation cohorts. CONCLUSIONS: Harnessing artificial intelligence within a global consortium, we pioneered a scoring system excelling over traditional models for 30 and 90-day AH mortality predictions. Beneficial for clinical trials, steroid therapy, and transplant indications, it's accessible at: https://aihepatology.shinyapps.io/ALCHAIN/ .
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BACKGROUND AND AIMS: Immunotherapy has emerged as an effective treatment for patients with advanced-stage HCC. We aimed to investigate the efficacy of immunotherapy for advanced HCC in a nationwide cohort and racial and ethnic disparities in access to immunotherapy. APPROACH AND RESULTS: We used the US National Cancer Database to identify patients with tumor-node-metastasis stage 3 or 4 HCC between 2017 and 2018. We performed multivariable Cox regression to identify factors associated with overall survival (OS) and logistic regression to identify factors associated with receipt of immunotherapy. Of the 3,990 patients treated for advanced HCC, 3,248 (81.4%) patients received chemotherapy and 742 (18.6%) patients received immunotherapy as a first-line treatment. Immunotherapy was associated with improved OS compared with chemotherapy (adjusted HR: 0.76, 95% CI: 0.65-0.88) after adjusting for covariates. There were racial and ethnic disparities in access to immunotherapy, with Hispanic (adjusted OR [aOR]: 0.63, 95% CI: 0.46-0.83) and Black patients (aOR: 0.71, 95% CI: 0.54-0.89) less likely to receive immunotherapy compared with White patients. There was a significant interaction between race-ethnicity and facility type, with higher disparity observed in nonacademic centers (interaction p = 0.004). CONCLUSIONS: Immunotherapy was associated with improved OS compared with chemotherapy in advanced HCC. There are significant disparities in early access to immunotherapy, likely due to differential access to clinical trials and experimental therapies. A comprehensive approach to monitoring and eliminating racial-ethnic disparities in the management of advanced HCC is urgently needed.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Estados Unidos , Humanos , Etnicidade , Carcinoma Hepatocelular/patologia , Disparidades em Assistência à Saúde , Neoplasias Hepáticas/patologia , ImunoterapiaRESUMO
DESCRIPTION: The purpose of this American Gastroenterological Association (AGA) Institute Clinical Practice Update is to review the available published evidence and expert advice regarding the clinical management of patients with suspected acute kidney injury in patients with cirrhosis. METHODS: This article provides practical advice for the management of patients with cirrhosis and acute kidney injury based on the best available published evidence. This best practice document is not based on a formal systematic review. This expert review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership and underwent internal peer review by the Clinical Practice Updates Committee and external peer review through the standard procedures of Clinical Gastroenterology & Hepatology. These Best Practice Advice (BPA) statements were drawn from a review of the published literature and from expert opinion. Since systematic reviews were not performed, these BPA statements do not carry formal ratings of the quality of evidence or strength of the presented considerations. BEST PRACTICE ADVICE 1: Acute kidney injury (AKI) should be diagnosed when the serum creatinine increases by ≥0.3 mg/dL within 48 hours or is ≥50% from baseline or when the urine output is reduced below 0.5 mL/kg/h for >6 hours. BEST PRACTICE ADVICE 2: Preventive measures against the development of AKI in cirrhosis include (1) avoidance of potentially nephrotoxic medications like nonsteroidal anti-inflammatory drugs (NSAIDs), (2) avoidance of excessive or unmonitored diuretics or nonselective beta-blockade, (3) avoidance of large-volume paracentesis without albumin replacement, and (4) counseling patients to avoid alcohol use. BEST PRACTICE ADVICE 3: (A) Investigation is directed to determining the cause of AKI, which can be due to hypovolemic causes (volume responsive, and the most common cause of AKI in patients with cirrhosis); acute tubular necrosis; hepatorenal syndrome with AKI (HRS-AKI) (a functional renal failure that persists despite volume repletion); HRS with acute kidney disease, a type of functional renal failure of <3 months- duration in which criteria for HRS-AKI are not met; or postrenal, which occurs only rarely. (B) The specific type of AKI should be identified through a careful history, physical examination, blood biochemistry, urine microscopic examination, urine chemistry (Na+ and urea) and selected urinary biomarkers, and renal ultrasound. BEST PRACTICE ADVICE 4: A rigorous search for infection is required in all patients with AKI. A diagnostic paracentesis should be carried out to evaluate for spontaneous bacterial peritonitis; blood and urine cultures and chest radiograph are also required. There is no role for routine prophylactic antibiotics in patients with AKI, but broad-spectrum antibiotics should be started whenever infection is strongly suspected. BEST PRACTICE ADVICE 5: When AKI is diagnosed, diuretics and nonselective beta-blockers should be held, NSAIDs discontinued, the precipitating cause of AKI treated, and fluid losses replaced, administering albumin 1 g/kg/d for 2 days if the serum creatinine shows doubling from baseline. Urine output, vital signs, and when indicated, echocardiography or CVP (if there is a pre-existing central line) should be used to monitor fluid status. BEST PRACTICE ADVICE 6: When the serum creatinine remains higher than twice the baseline value despite these measures, treatment of HRS-AKI should be initiated with albumin at a dose of 1 g/kg intravenously on day 1 followed by 20-40 g daily along with vasoactive agents (terlipressin; if terlipressin is not available, either a combination of octreotide and midodrine; or norepinephrine, depending on institutional preferences) and continued either until 24 hours following the return of the serum creatinine level to within ≤0.3 mg/dL of baseline for 2 consecutive days or for a total of 14 days of therapy. BEST PRACTICE ADVICE 7: Terlipressin should be initiated as a bolus dose of 1 mg every 4-6 hours (total 4-6 mg/d). The dose should be increased to a maximum of 2 mg every 4-6 hours (total 8-12 mg/d) if there is no reduction in serum creatinine at day 3 of therapy by at least 25% compared to the baseline value. Alternatively, clinicians can administer terlipressin by continuous intravenous infusion at a lower starting dose of 2 mg/d, which may reduce ischemic side effects and increase the dose gradually every 24-48 hours up to a maximum dose of 12 mg/d, or reversal of HRS. As per Food and Drug Administration restrictions, terlipressin should not be used in patients with a serum creatinine ≥5 mg/dL, or oxygen saturation of <90%. BEST PRACTICE ADVICE 8: Oral midodrine when used should be initiated at doses of 7.5 mg and titrated upward to 12.5 mg 3 times daily with octreotide (starting with 100 µg and titrating upward to 200 µg subcutaneously 3 times daily). BEST PRACTICE ADVICE 9: Norepinephrine should be used as a continuous intravenous infusion at a starting dose of 0.5 mg/h and the dose increased every 4 hours by 0.5 mg/h to a maximum of 3 mg/h with the goal of increasing the mean arterial pressure by ≥10 mm Hg and/or the urine output to >50 mL/h for at least 4 hours. BEST PRACTICE ADVICE 10: The risks of ischemic side effects of terlipressin and norepinephrine include angina and ischemia of fingers, skin, and intestine. These side effects may be lowered by starting at the lowest dose and gradually titrating upward. BEST PRACTICE ADVICE 11: Fluid status should be closely monitored because of the risk of pulmonary edema with excessive use of albumin. BEST PRACTICE ADVICE 12: Renal replacement therapy (RRT) may be used in the management of (A) AKI secondary to acute tubular necrosis; (B) HRS-AKI in potential candidates for liver transplantation (that is, RRT should not be used in patients with HRS-AKI who are not candidates for liver transplantation); and (C) AKI of uncertain etiology in which the need for RRT may be considered on an individual basis. BEST PRACTICE ADVICE 13: Transjugular intrahepatic portosystemic shunts should not be used as a specific treatment of HRS-AKI. BEST PRACTICE ADVICE 14: Liver transplantation is the most effective treatment for HRS-AKI. Pharmacotherapy for HRS-AKI before proceeding with liver transplantation may be associated with better post-liver transplantation outcomes. Selected patients with HRS-AKI may require simultaneous liver kidney transplantation based on updated Organ Procurement and Transplantation Network listing criteria.
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Injúria Renal Aguda , Midodrina , Humanos , Terlipressina , Creatinina , Octreotida , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico , Cirrose Hepática/terapia , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/terapia , Albuminas , Norepinefrina , Anti-Inflamatórios não Esteroides , Diuréticos , Antibacterianos , NecroseRESUMO
INTRODUCTION: Cirrhosis is associated with cardiac dysfunction and distinct electrocardiogram (ECG) abnormalities. This study aimed to develop a proof-of-concept deep learning-based artificial intelligence (AI) model that could detect cirrhosis-related signals on ECG and generate an AI-Cirrhosis-ECG (ACE) score that would correlate with disease severity. METHODS: A review of Mayo Clinic's electronic health records identified 5,212 patients with advanced cirrhosis ≥18 years who underwent liver transplantation at the 3 Mayo Clinic transplant centers between 1988 and 2019. The patients were matched by age and sex in a 1:4 ratio to controls without liver disease and then divided into training, validation, and test sets using a 70%-10%-20% split. The primary outcome was the performance of the model in distinguishing patients with cirrhosis from controls using their ECGs. In addition, the association between the ACE score and the severity of patients' liver disease was assessed. RESULTS: The model's area under the curve in the test set was 0.908 with 84.9% sensitivity and 83.2% specificity, and this performance remained consistent after additional matching for medical comorbidities. Significant elevations in the ACE scores were seen with increasing model for end-stage liver disease-sodium score. Longitudinal trends in the ACE scores before and after liver transplantation mirrored the progression and resolution of liver disease. DISCUSSION: The ACE score, a deep learning model, can accurately discriminate ECGs from patients with and without cirrhosis. This novel relationship between AI-enabled ECG analysis and cirrhosis holds promise as the basis for future low-cost tools and applications in the care of patients with liver disease.
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Aprendizado Profundo , Doença Hepática Terminal , Inteligência Artificial , Eletrocardiografia , Humanos , Cirrose Hepática/diagnóstico , Índice de Gravidade de DoençaRESUMO
Modern medical care produces large volumes of multimodal patient data, which many clinicians struggle to process and synthesize into actionable knowledge. In recent years, artificial intelligence (AI) has emerged as an effective tool in this regard. The field of hepatology is no exception, with a growing number of studies published that apply AI techniques to the diagnosis and treatment of liver diseases. These have included machine-learning algorithms (such as regression models, Bayesian networks, and support vector machines) to predict disease progression, the presence of complications, and mortality; deep-learning algorithms to enable rapid, automated interpretation of radiologic and pathologic images; and natural-language processing to extract clinically meaningful concepts from vast quantities of unstructured data in electronic health records. This review article will provide a comprehensive overview of hepatology-focused AI research, discuss some of the barriers to clinical implementation and adoption, and suggest future directions for the field.
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Inteligência Artificial , Gastroenterologia/tendências , Hepatopatias , Gastroenterologia/métodos , Humanos , Hepatopatias/diagnóstico , Hepatopatias/terapia , Sistemas Computadorizados de Registros Médicos , Pesquisa Translacional BiomédicaRESUMO
Hepatocellular carcinoma (HCC) is among the leading causes of worldwide cancer-related morbidity and mortality. Poor prognosis of HCC is attributed primarily to tumor presentation at an advanced stage when there is no effective treatment to achieve the long term survival of patients. Currently available tests such as alpha-fetoprotein have limited accuracy as a diagnostic or prognostic biomarker for HCC. Liver biopsy provides tissue that can reveal tumor biology but it is not used routinely due to its invasiveness and risk of tumor seeding, especially in early-stage patients. Liver biopsy is also limited in revealing comprehensive tumor biology due to intratumoral heterogeneity. There is a clear need for new biomarkers to improve HCC detection, prognostication, prediction of treatment response, and disease monitoring with treatment. Liquid biopsy could be an effective method of early detection and management of HCC. Circulating tumor cells (CTCs) are cancer cells in circulation derived from the original tumor or metastatic foci, and their measurement by liquid biopsy represents a great potential in facilitating the implementation of precision medicine in patients with HCC. CTCs can be detected by a simple peripheral blood draw and potentially show global features of tumor characteristics. Various CTC detection platforms using immunoaffinity and biophysical properties have been developed to identify and capture CTCs with high efficiency. Quantitative abundance of CTCs, as well as biological characteristics and genomic heterogeneity among the CTCs, can predict disease prognosis and response to therapy in patients with HCC. This review article will discuss the currently available technologies for CTC detection and isolation, their utility in the clinical management of HCC patients, their limitations, and future directions of research.
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Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/sangue , Neoplasias Hepáticas/sangue , Células Neoplásicas Circulantes/metabolismo , Carcinoma Hepatocelular/patologia , Molécula de Adesão da Célula Epitelial/análise , Molécula de Adesão da Célula Epitelial/metabolismo , Humanos , Biópsia Líquida/métodos , Neoplasias Hepáticas/patologia , PrognósticoRESUMO
BACKGROUND AND AIMS: Patients with cirrhosis on the liver transplant (LT) waiting list may die or be removed because of complications of portal hypertension (PH) or infections. von Willebrand factor antigen (vWF-Ag) and C-reactive protein (CRP) are simple, broadly available markers of these processes. APPROACH AND RESULTS: We determined whether addition of vWF-Ag and CRP to the Model for End-Stage Liver Disease-Sodium (MELD-Na) score improves risk stratification of patients awaiting LT. CRP and vWF-Ag at LT listing were assessed in two independent cohorts (Medical University of Vienna [exploration cohort] and Mayo Clinic Rochester [validation cohort]). Clinical characteristics, MELD-Na, and mortality on the waiting list were recorded. Prediction of 3-month waiting list mortality was assessed by receiver operating characteristics curve (ROC-AUC). In order to explore potential mechanisms underlying the prognostic utility of vWF-Ag and CRP in this setting, we evaluated their association with PH, bacterial translocation, systemic inflammation, and circulatory dysfunction. In the exploration cohort (n = 269) vWF-Ag and CRP both improved the predictive value of MELD-Na for 3-month waitlist mortality and showed the highest predictive value when combined (AUC: MELD-Na, 0.764; MELD-Na + CRP, 0.790; MELD-Na + vWF, 0.803; MELD-Na + CRP + vWF-Ag, 0.824). Results were confirmed in an independent validation cohort (n = 129; AUC: MELD-Na, 0.677; MELD-Na + CRP + vWF-Ag, 0.882). vWF-Ag was independently associated with PH and inflammatory biomarkers, whereas CRP closely, and MELD independently, correlated with biomarkers of bacterial translocation/inflammation. CONCLUSIONS: The addition of vWF-Ag and CRP-reflecting central pathophysiological mechanisms of PH, bacterial translocation, and inflammation, that are all drivers of mortality on the waiting list for LT-to the MELD-Na score improves prediction of waitlist mortality. Using the vWFAg-CRP-MELD-Na model for prioritizing organ allocation may improve prediction of waitlist mortality and decrease waitlist mortality.
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Proteína C-Reativa/metabolismo , Doença Hepática Terminal/metabolismo , Cirrose Hepática/metabolismo , Listas de Espera/mortalidade , Fator de von Willebrand/metabolismo , Idoso , Translocação Bacteriana , Biomarcadores , Feminino , Humanos , Hipertensão Portal/metabolismo , Inflamação/metabolismo , Cirrose Hepática/cirurgia , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Prognóstico , Índice de Gravidade de Doença , Sódio/sangueRESUMO
BACKGROUND: Although single-incision robotic cholecystectomy (SIRC) overcomes various limitations of single-incision laparoscopic cholecystectomy (SILC), it is associated with high cost. In this study, we intended to investigate if SIRC is recommendable and advantageous to patients despite its high cost. MATERIALS AND METHODS: We prospectively collected and analysed data of patients who had undergone either SILC (n = 25) or SIRC (n = 50) for benign gallbladder diseases, with identical inclusion criteria, between November 2017 and February 2019. RESULTS: SILC and SIRC showed similar operative outcomes in terms of intra- and post-operative complications and verbal numerical rating scale (VNRS) for pain. However, the SIRC group exhibited significantly longer operation time than the SILC group (83.2 ± 32.6 vs. 66.4 ± 32.8, P = 0.002). The SIRC group also showed longer hospital stay (2.4 ± 0.7 vs. 2.2 ± 0.6, P = 0.053). Although the SILC and SIRC groups showed no significant difference in VNRS, the SIRC group required a higher amount (126.0 ± 88.8 mg vs. 87.5 ± 79.7 mg, P = 0.063) and frequency (3.0 ± 2.1 vs. 2.0 ± 1.8, P = 0.033) of intravenous opioid analgesic administration. During surgery, the critical view of safety (CVS), the prerequisite for safe cholecystectomy, was identified in only 24% (n = 6) of patients undergoing SILC and in 100% (n = 50) of patients undergoing SIRC (P < 0.05). CONCLUSION: We conclude that although SILC and SIRC have similar operative outcomes, SIRC is advantageous over SILC because of its potential to markedly enhance the safety of patients by proficiently acquiring CVS.
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BACKGROUND & AIMS: Corticosteroids are the only effective therapy for severe alcohol-associated hepatitis (AH), defined by a model for end-stage liver disease (MELD) score >20. However, there are patients who may be too sick to benefit from therapy. Herein, we aimed to identify the range of MELD scores within which steroids are effective for AH. METHODS: We performed a retrospective, international multicenter cohort study across 4 continents, including 3,380 adults with a clinical and/or histological diagnosis of AH. The main outcome was mortality at 30 days. We used a discrete-time survival analysis model, and MELD cut-offs were established using the transform-the-endpoints method. RESULTS: In our cohort, median age was 49 (40-56) years, 76.5% were male, and 79% had underlying cirrhosis. Median MELD at admission was 24 (19-29). Survival was 88% (87-89) at 30 days, 77% (76-78) at 90 days, and 72% (72-74) at 180 days. A total of 1,225 patients received corticosteroids. In an adjusted-survival-model, corticosteroid use decreased 30-day mortality by 41% (hazard ratio [HR] 0.59; 0.47-0.74; p <0.001). Steroids only improved survival in patients with MELD scores between 21 (HR 0.61; 0.39-0.95; p = 0.027) and 51 (HR 0.72; 0.52-0.99; p = 0.041). The maximum effect of corticosteroid treatment (21-30% survival benefit) was observed with MELD scores between 25 (HR 0.58; 0.42-0.77; p <0.001) and 39 (HR 0.57; 0.41-0.79; p <0.001). No corticosteroid benefit was seen in patients with MELD >51. The type of corticosteroids used (prednisone, prednisolone, or methylprednisolone) was not associated with survival benefit (p = 0.247). CONCLUSION: Corticosteroids improve 30-day survival only among patients with severe AH, especially with MELD scores between 25 and 39. LAY SUMMARY: Alcohol-associated hepatitis is a condition where the liver is severely inflamed as a result of excess alcohol use. It is associated with high mortality and it is not clear whether the most commonly used treatments (corticosteroids) are effective, particularly in patients with very severe liver disease. In this worldwide study, the use of corticosteroids was associated with increased 30-day, but not 90- or 180-day, survival. The maximal benefit was observed in patients with an MELD score (a marker of severity of liver disease; higher scores signify worse disease) between 25-39. However, this benefit was lost in patients with the most severe liver disease (MELD score higher than 51).
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Consumo de Bebidas Alcoólicas/efeitos adversos , Hepatite/tratamento farmacológico , Esteroides/administração & dosagem , Fatores de Tempo , Adulto , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Consumo de Bebidas Alcoólicas/fisiopatologia , Estudos de Coortes , Feminino , Hepatite/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Esteroides/uso terapêuticoRESUMO
Vibration-controlled transient elastography (VCTE) is a non-invasive method of evaluating liver fibrosis and steatosis. It can easily be performed in the outpatient setting and has been suggested as an alternative to liver biopsy. However, VCTE and biopsy discrepancies commonly occur. Patient characteristics, procedure performance, and liver features can impact the reliability of VCTE results. We identified 82 patients who received VCTE and biopsy within one month to assess how frequently major discrepancies occur and to determine the role of the liver biopsy in this workup. In our study, 35.4% of patients had a major fibrosis discrepancy, which was defined as advanced fibrosis or cirrhosis by VCTE and no to minimal fibrosis on biopsy. This was significantly associated with increased BMI, and liver features including steatohepatitis, inflammation, congestion, and cholestasis were important contributors to discrepancies. All patients with advanced fibrosis or cirrhosis on liver biopsy were appropriately detected by VCTE (n = 28). Detection of steatosis was less sensitive as 19% (n = 4 of 21) of patients with moderate to severe steatosis on biopsy were missed by VCTE. Liver biopsy has been traditionally performed for diagnosis, but with the emergence of non-invasive tools to evaluate for liver fibrosis and steatosis, biopsies are now additionally being performed to confirm findings from noninvasive procedures. Although VCTE is a highly sensitive tool for liver fibrosis, it is not as specific, and therefore, the liver biopsy remains the gold standard for accurate fibrosis assessment.
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Fígado Gorduroso/diagnóstico , Cirrose Hepática/diagnóstico , Fígado/patologia , Adulto , Idoso , Biópsia , Índice de Massa Corporal , Técnicas de Imagem por Elasticidade , Fígado Gorduroso/patologia , Feminino , Humanos , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Adulto JovemRESUMO
A predictive biomarker of immune checkpoint inhibitor (ICI)-based treatments in hepatocellular carcinoma (HCC) has not been clearly demonstrated. In this study, we focused on the infiltration and programmed death ligand 1 (PD-L1) expression of tumor-associated macrophages (TAMs) in the tumor microenvironment of HCC. Immunohistochemistry demonstrated that PD-L1 was preferentially expressed on CD68+ macrophages in the tumor microenvironment of HCC, suggestive of its expression in TAMs rather than in T cells or tumor cells (P < 0.05). A co-culture experiment using activated T cells and M2 macrophages confirmed a significant increase in T cell functionality after the pretreatment of M2 macrophages with anti-PD-L1. Syngeneic mouse model experiments demonstrated that TAMs expressed PD-L1 and tumors treated with anti-PD-L1 showed smaller diameters than those treated with IgG. In these mice, anti-PD-L1 treatment increased activation markers in intratumoral CD8+ T cells and reduced the size of the TAM population. Regarding nivolumab-treated patients, three of eight patients responded to the anti-PD-1 treatment. The percentage of Ki-67-positive CD4+ and CD8+ T cells was higher in responders than non-responders after nivolumab. Overall, PD-L1 expression on TAMs may be targeted by immune-based HCC treatment, and ICI treatment results in the reinvigoration of exhausted CD8+ T cells in HCC.
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Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/biossíntese , Carcinoma Hepatocelular/imunologia , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia/métodos , Neoplasias Hepáticas/imunologia , Terapia de Alvo Molecular/métodos , Proteínas de Neoplasias/biossíntese , Nivolumabe/farmacologia , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/metabolismo , Animais , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Técnicas de Cocultura , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Antígeno Ki-67/biossíntese , Antígeno Ki-67/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas Experimentais/imunologia , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Nivolumabe/uso terapêutico , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Células Tumorais Cultivadas , Macrófagos Associados a Tumor/efeitos dos fármacosRESUMO
The incidence and mortality related to hepatocellular carcinoma (HCC) continue to increase in the United States, with most patients presenting at advanced stages where curative therapy and long-term survival is unlikely. Fortunately, significant progress has been made in identifying the landscape of HCC mutations due to advances in whole genome expression profiling. Drug development has also evolved in recent years with multiple first- and second-line systemic chemotherapy agents approved for HCC for the first time in over a decade. However, despite advances in molecular profiling, mutations that were identified at the highest frequency were not amenable to drug development, and curative therapy for advanced HCC remains elusive. This review focuses on the current understanding of HCC genomics and the limitations of translating the current HCC molecular profiling into clinical practice and examines the effectiveness and benefits of approved systemic therapies for advanced HCC.
Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Genômica , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologiaRESUMO
Disorders of the mesenteric, portal, and hepatic veins and mesenteric and hepatic arteries have important clinical consequences and may lead to acute liver failure, chronic liver disease, noncirrhotic portal hypertension, cirrhosis, and hepatocellular carcinoma. Although literature in the field of vascular liver disorders is scant, these disorders are common in clinical practice, and general practitioners, gastroenterologists, and hepatologists may benefit from expert guidance and recommendations for management of these conditions. These guidelines represent the official practice recommendations of the American College of Gastroenterology. Key concept statements based on author expert opinion and review of literature and specific recommendations based on PICO/GRADE analysis have been developed to aid in the management of vascular liver disorders. These recommendations and guidelines should be tailored to individual patients and circumstances in routine clinical practice.
Assuntos
Gastroenterologia , Circulação Hepática , Hepatopatias/etiologia , Guias de Prática Clínica como Assunto , Circulação Esplâncnica , Doenças Vasculares/terapia , Humanos , Fígado/irrigação sanguínea , Hepatopatias/fisiopatologia , Mesentério/irrigação sanguínea , Sociedades Médicas , Estados Unidos , Doenças Vasculares/complicaçõesRESUMO
GOAL: The goal of this study was to describe potential key differences in thromboelastography (TEG) variables in hospitalized cirrhotics compared with a healthy population, identify patterns of hematologic disturbance with disease progression, and assess the value of traditional tests such as international normalized ratio (INR) and platelet count to determine coagulopathy in cirrhotics. BACKGROUND: TEG, a functional assay of coagulation, has emerged as a useful tool for predicting bleeding risk in cirrhosis. STUDY: Hospitalized cirrhotics who received a TEG before any blood products between January 2017 and February 2018 at a liver transplant center were included. Reaction time (r-time), coagulation time (k-time), angle-rate of clot polymerization (α) and maximum clot strength (maximum amplitude) were measured with kaolin-activated citrated blood TEG assays. RESULTS: A total of 106 cirrhotic patients (Child-Turcotte-Pugh A, B, C; n=25, 25, 56) were identified for comparison against data from 53 healthy controls. TEG parameters in cirrhotics were statistically different from controls. Mean INR and platelet count for all cirrhotics were largely outside the normal reference range, contrary to TEG parameters which demonstrated parameters mostly within the normal reference ranges. The r-time, k-time, and α values in the cirrhotics progressively increased and maximum amplitude values progressively decreased as the liver disease progressed. Regression analysis showed no significant correlations between INR and r-time across any Child-Turcotte-Pugh class (r=0.01, 0.18, 0.23; P=0.95, 0.39, 0.08, respectively). CONCLUSIONS: Although cirrhotics had TEG parameters within normal ranges, there was a propensity for decreased clot formation as liver function worsened. Importantly, the INR did not correlate with TEG parameters in cirrhotic patients, and given the precarious hemostatic balance in these patients, a TEG may be a better predictor of bleeding risk.
Assuntos
Hemostáticos , Tromboelastografia , Coagulação Sanguínea , Criança , Humanos , Coeficiente Internacional Normatizado , Cirrose Hepática/complicaçõesRESUMO
This paper aims to validate if intrapancreatic injection of penicillin G can enhance hardness and suture holding capacity (SHC) of the pancreas through prompting the fibrosis process. Soft pancreatic texture is constantly mentioned as one of the most contributory predictors of postoperative pancreatic fistula (POPF). Soft pancreas has poor SHC and higher incidence of parenchymal tearing, frequently leading to POPF. From a library of 114 antibiotic compounds, we identified that penicillin G substantially enhanced pancreatic hardness and SHC in experimental mice. Specifically, we injected penicillin G directly into the pancreas. On determined dates, we measured the pancreatic hardness and SHC, respectively, and performed molecular and histological examinations for estimation of the degree of fibrosis. The intrapancreatic injection of penicillin G activated human pancreatic stellate cells (HPSCs) to produce various fibrotic materials such as transforming growth factor-ß1 (TGF-ß1) and metalloproteinases-2. The pancreatic hardness and SHC were increased to the maximum at the second day after injection and then it gradually subsided demonstrating its reversibility. Pretreatment of mice with SB431542, an inhibitor of the TGF-ß1 receptor, before injecting penicillin G intrapancreatically, significantly abrogated the increase of both pancreatic hardness and SHC caused by penicillin G. This suggested that penicillin G promotes pancreatic fibrosis through the TGF-ß1 signaling pathway. Intrapancreatic injection of penicillin G promotes pancreatic hardness and SHC by enhancing pancreatic fibrosis. We thus think that penicillin G could be utilized to prevent and minimize POPF, after validating its actual effectiveness and safety by further studies.
Assuntos
Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Pâncreas/efeitos dos fármacos , Pâncreas/cirurgia , Fístula Pancreática/prevenção & controle , Penicilina G/administração & dosagem , Complicações Pós-Operatórias/prevenção & controle , Animais , Antibacterianos/administração & dosagem , Benzamidas/farmacologia , Dioxóis/farmacologia , Modelos Animais de Doenças , Fibrose , Humanos , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fístula Pancreática/etiologia , Células Estreladas do Pâncreas/efeitos dos fármacos , Células Estreladas do Pâncreas/metabolismo , Período Pós-Operatório , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Hereditary hemochromatosis (HH) is one of the most common genetic disorders among persons of northern European descent. There have been recent advances in the diagnosis, management, and treatment of HH. The availability of molecular diagnostic testing for HH has made possible confirmation of the diagnosis for most patients. Several genotype-phenotype correlation studies have clarified the differences in clinical features between patients with the C282Y homozygous genotypes and other HFE mutation patterns. The increasing use of noninvasive tests such as MRI T2* has made quantification of hepatic iron deposition easier and eliminated the need for liver biopsy in most patients. Serum ferritin of <1,000 ng/mL at diagnosis remains an important diagnostic test to identify patients with a low risk of advanced hepatic fibrosis and should be used routinely as part of the initial diagnostic evaluation. Genetic testing for other types of HH is available but is expensive and generally not useful in most clinical settings. Serum ferritin may be elevated among patients with nonalcoholic fatty liver disease and in those with alcoholic liver disease. These diagnoses are more common than HH among patients with elevated serum ferritin who are not C282Y homozygotes or C282Y/H63D compound heterozygotes. A secondary cause for liver disease should be excluded among patients with suspected iron overload who are not C282Y homozygotes. Phlebotomy remains the mainstay of therapy, but emerging novel therapies such as new chelating agents may have a role for selected patients.
Assuntos
Hemocromatose/genética , Biomarcadores/sangue , Quelantes/uso terapêutico , Ferritinas/sangue , Testes Genéticos , Genótipo , Hemocromatose/diagnóstico , Hemocromatose/terapia , Humanos , Fenótipo , FlebotomiaRESUMO
BACKGROUND: Although methyl-tertiary butyl ether (MTBE) is the only clinical topical agent for gallstone dissolution, its use is limited by its side effects mostly arising from a relatively low boiling point (55 °C). In this study, we developed the gallstone-dissolving compound containing an aromatic moiety, named 2-methoxy-6-methylpyridine (MMP) with higher boiling point (156 °C), and compared its effectiveness and toxicities with MTBE. METHODS: The dissolubility of MTBE and MMP in vitro was determined by placing human gallstones in glass containers with either solvent and, then, measuring their dry weights. Their dissolubility in vivo was determined by comparing the weights of solvent-treated gallstones and control (dimethyl sulfoxide)-treated gallstones, after directly injecting each solvent into the gallbladder in hamster models with cholesterol and pigmented gallstones. RESULTS: In the in vitro dissolution test, MMP demonstrated statistically higher dissolubility than did MTBE for cholesterol and pigmented gallstones (88.2% vs. 65.7%, 50.8% vs. 29.0%, respectively; P < 0.05). In the in vivo experiments, MMP exhibited 59.0% and 54.3% dissolubility for cholesterol and pigmented gallstones, respectively, which were significantly higher than those of MTBE (50.0% and 32.0%, respectively; P < 0.05). The immunohistochemical stains of gallbladder specimens obtained from the MMP-treated hamsters demonstrated that MMP did not significantly increase the expression of cleaved caspase 9 or significantly decrease the expression of proliferation cell nuclear antigen. CONCLUSIONS: This study demonstrated that MMP has better potential than does MTBE in dissolving gallstones, especially pigmented gallstones, while resulting in lesser toxicities.