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1.
Medicine (Baltimore) ; 99(2): e18696, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914071

RESUMO

RATIONALE: Severe alcoholic hepatitis (AH) has a very high mortality rate. Current guidelines recommend oral corticosteroids as first-line agents in individuals with severe AH to reduce short-term mortality. However, systemic corticosteroids have serious adverse effects. In individuals with AH, infection, which is one of the complications of steroid use, can result in serious outcomes, such as acute-on-chronic liver failure. Pneumocystis pneumonia (PCP) is a life-threatening opportunistic infection which may occur when high-dose corticosteroids are prescribed for more than 1 month. Therefore, when high-dose corticosteroids are used, providing PCP prophylaxis is warranted. Although trimethoprim-sulfamethoxazole (TMP-SMX) is the drug of choice for the prophylaxis of PCP, its hepatotoxicity limits its use in patients with severe AH who are on high-dose corticosteroids. Moreover, there is a lack of consensus on which drugs should be used for PCP prophylaxis in individuals with severe AH who are on glucocorticoid treatment. Herein, we report a case of a 43-year-old male with fatal PCP that occurred after the use of corticosteroids for severe AH. PATIENT CONCERNS: A 43-year-old alcoholic man presented with a hematoma on his right leg. His liver function was poor, and he was he was diagnosed with severe AH and treated with oral corticosteroids for 26 days. After glucocorticoid treatment, he developed a productive cough. DIAGNOSES: A sputum PCR test was positive for Pneumocystis jirovecii. INTERVENTIONS: He was initially treated with TMP-SMX and required artificial ventilation. OUTCOMES: He developed disseminated intravascular coagulation and multi-organ failure, and died 10 days after starting TMP-SMX. LESSONS: To date, prevention of PCP in individuals with severe AH who are on corticosteroids has been overlooked. This case illustrates the need for prophylaxis of PCP in individuals with severe AH taking corticosteroids.


Assuntos
Hepatite Alcoólica/complicações , Hepatite Alcoólica/tratamento farmacológico , Metilprednisolona/uso terapêutico , Pneumonia por Pneumocystis/etiologia , Adulto , Humanos , Masculino , Metilprednisolona/efeitos adversos , Infecções Oportunistas , Pneumocystis carinii , Pneumonia por Pneumocystis/tratamento farmacológico , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico
3.
Cochrane Database Syst Rev ; 4: CD001511, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30964545

RESUMO

BACKGROUND: Alcoholic hepatitis is a form of alcoholic liver disease characterised by steatosis, necroinflammation, fibrosis, and complications to the liver. Typically, alcoholic hepatitis presents in people between 40 and 50 years of age. Alcoholic hepatitis can be resolved if people abstain from drinking, but the risk of death will depend on the severity of the liver damage and abstinence from alcohol. Glucocorticosteroids have been studied extensively in randomised clinical trials to assess their benefits and harms. However, the results have been contradictory. OBJECTIVES: To assess the benefits and harms of glucocorticosteroids in people with alcoholic hepatitis. SEARCH METHODS: We identified trials through electronic searches in Cochrane Hepato-Biliary's (CHB) Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS, and Science Citation Index Expanded. We looked for ongoing or unpublished trials in clinical trials registers and pharmaceutical company sources. We also scanned reference lists of the studies retrieved. The last search was 18 January 2019. SELECTION CRITERIA: Randomised clinical trials assessing glucocorticosteroids versus placebo or no intervention in people with alcoholic hepatitis, irrespective of year, language of publication, or format. We considered trials with adults diagnosed with alcoholic hepatitis, which could have been established through clinical or biochemical diagnostic criteria or both. We defined alcoholic hepatitis as mild (Maddrey's score less than 32) and severe (Maddrey's score 32 or more). We allowed cointerventions in the trial groups, provided they were similar. DATA COLLECTION AND ANALYSIS: We followed Cochrane methodology, performing the meta-analyses using Review Manager 5. We presented the results of dichotomous outcomes as risk ratios (RR) and of continuous outcomes as mean difference (MD), with 95% confidence intervals (CI). We used both the fixed-effect and the random-effects models for meta-analyses. Whenever there were significant discrepancies in the results, we reported the more conservative point estimate of the two. We considered a P value of 0.01 or less, two-tailed, as statistically significant if the required information size was reached for our three primary outcomes (all-cause mortality, health-related quality of life, and serious adverse events during treatment) and our post hoc decision to include analyses of mortality at more time points. We presented heterogeneity using the I² statistic. If trialists used intention-to-treat analysis to deal with missing data, we used these data in our primary analysis; otherwise, we used the available data. We assessed the bias risk of the trials using bias risk domains and the certainty of the evidence using GRADE. MAIN RESULTS: Sixteen trials fulfilled our inclusion criteria. All trials but one were at overall high risk of bias. Fifteen trials (one of which was an abstract) provided data for analysis (927 participants received glucocorticosteroids and 934 participants received placebo or no intervention). Glucocorticosteroids were administered orally or parenterally for a median 28 days (range 3 days to 12 weeks). The participants were between 25 and 70 years old, had different stages of alcoholic liver disease, and 65% were men. Follow-up, when reported, was up to the moment of discharge from the hospital, until they died (median of 63 days), or for at least one year. There was no evidence of effect of glucocorticosteroids on all-cause mortality up to three months following randomisation (random-effects RR 0.90, 95% CI 0.70 to 1.15; participants = 1861; trials = 15; very low-certainty evidence) or on health-related quality of life up to three months, measured with the European Quality of Life - 5 Dimensions - 3 Levels scale (MD -0.04 points, 95% CI -0.11 to 0.03; participants = 377; trial = 1; low-certainty evidence). There was no evidence of effect on the occurrence of serious adverse events during treatment (random-effects RR 1.05, 95% CI 0.85 to 1.29; participants = 1861; trials = 15; very low-certainty evidence), liver-related mortality up to three months following randomisation (random-effects RR 0.89, 95% CI 0.69 to 1.14; participants = 1861; trials = 15; very low-certainty evidence), number of participants with any complications up to three months following randomisation (random-effects RR 1.04, 95% CI 0.86 to 1.27; participants = 1861; very low-certainty evidence), and number of participants of non-serious adverse events up to three months' follow-up after end of treatment (random-effects RR 1.99, 95% CI 0.72 to 5.48; participants = 160; trials = 4; very low-certainty evidence). Based on the information that we collected from the published trial reports, only one of the trials seems not to be industry-funded, and the remaining 15 trials did not report clearly whether they were partly or completely funded by the industry. AUTHORS' CONCLUSIONS: We are very uncertain about the effect estimate of no difference between glucocorticosteroids and placebo or no intervention on all-cause mortality and serious adverse events during treatment because the certainty of evidence was very low, and low for health-related quality of life. Due to inadequate reporting, we cannot exclude increases in adverse events. As the CIs were wide, we cannot rule out significant benefits or harms of glucocorticosteroids. Therefore, we need placebo-controlled randomised clinical trials, designed according to the SPIRIT guidelines and reported according to the CONSORT guidelines. Future trials ought to report depersonalised individual participant data, so that proper individual participant data meta-analyses of the effects of glucocorticosteroids in subgroups can be conducted.


Assuntos
Glucocorticoides/uso terapêutico , Hepatite Alcoólica/tratamento farmacológico , Adulto , Idoso , Feminino , Glucocorticoides/efeitos adversos , Hepatite Alcoólica/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto
5.
Clin Liver Dis ; 23(1): 81-98, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30454835

RESUMO

Alcoholic hepatitis is a unique type of alcohol-associated liver disease characterized by acute liver inflammation caused by prolonged heavy alcohol use. Treatment is mostly supportive. The short-term prognosis of acute alcoholic hepatitis depends on liver recovery, and ranges widely from rapid improvement to grim multiorgan failure despite treatment. Refinement of scoring systems have enhanced prognostication to guide clinical decision making in alcoholic hepatitis. Recent advances in the treatment of alcoholic hepatitis have solidified corticosteroids as the cornerstone of treatment to enhance short-term survival, but not intermediate or long-term survival.


Assuntos
Alanina Transaminase/metabolismo , Aspartato Aminotransferases/metabolismo , Hepatite Alcoólica/metabolismo , Icterícia/metabolismo , Doença Aguda , Biópsia , Técnicas de Imagem por Elasticidade , Glucocorticoides/uso terapêutico , Hepatite Alcoólica/diagnóstico , Hepatite Alcoólica/tratamento farmacológico , Hepatite Alcoólica/patologia , Humanos , Fígado/patologia , Prednisolona/uso terapêutico , Prognóstico , Índice de Gravidade de Doença
6.
Trials ; 19(1): 696, 2018 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-30577864

RESUMO

BACKGROUND: Alcoholic hepatitis (AH) has the most severe presentation among alcohol-related liver diseases. Corticosteroids are the most widely recommended treatment for severe AH. However, more innovative, refined treatment measures are required because of its high mortality despite corticosteroid treatment. This study aims to determine whether granulocyte colony stimulating factor (G-CSF) treatment increases short-term survival in patients with severe AH refractory to corticosteroid treatment. METHODS/DESIGN: Patients with severe AH whose Maddrey's discriminant function (MDF) score is ≥ 32 and who will be treated with prednisolone (40 mg/day) for 1 week will be screened. Among them, 190 subjects with a partial response (PR) (Lille score 0.16-0.56), and 78 subjects with a null response (NR) (Lille score ≥ 0.56) will be enrolled. Subjects with PR will be randomized to steroid plus placebo or steroid plus 12 G-CSF injections (5 µg/kg/day for 5 days followed by every 3 days) at a ratio of 1:1. Subjects with a NR will be randomized to the placebo or G-CSF group (1:1). Study subjects in the PR group will be treated with prednisolone for 28 days followed by dose tapering for an additional 2 weeks. The primary endpoint is the 2-month survival rate in the NR group and the 6-month survival rate in the PR group. Child-Turcotte-Pugh, model for end-stage liver disease score, and the change in the proportion of peripheral circulating CD34-positive cells will be analyzed as risk factors for mortality. Preliminary safety data for the initial 10 study subjects enrolled in the PR study will be assessed to determine whether the PR study would be continued, according to the G-CSF-mobilized, peripheral-blood stem cell donor assessment protocol of the National Marrow Donor Program. DISCUSSION: We hypothesized that G-CSF would prolong short-term survival of patients with severe AH refractory to corticosteroid treatment. This is a proof-of-concept trial designed to assess the efficacy of Lille-score-guided G-CSF treatment. This trial is also designed to identify a special subgroup in whom G-CSF rescue treatment would improve liver function and prolong survival. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02442180 . Prospectively registered on 13 May 2015.


Assuntos
Corticosteroides/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Hepatite Alcoólica/tratamento farmacológico , Prednisolona/administração & dosagem , Corticosteroides/efeitos adversos , Adulto , Idoso , Método Duplo-Cego , Esquema de Medicação , Resistência a Medicamentos , Feminino , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Hepatite Alcoólica/diagnóstico , Hepatite Alcoólica/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Prednisolona/efeitos adversos , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , República da Coreia , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
7.
Clin Mol Hepatol ; 24(4): 358-366, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30360030

RESUMO

Severe acute alcoholic liver disease (SAAH) unresponsive to medical therapy shows one-year-mortality rates of up to 90%. Most transplant centers request six months of alcohol abstinence prior to transplantation, the so-called "6-month rule." This regulation is not based on strong evidence, repeatedly making it a topic of controversial debates. The majority of patients with SAAH will die before fulfilling the 6-month rule. Therefore, liver transplantation (LT) protocols are becoming more flexible towards the rigid abstinence regulation, especially concerning SAAH patients. We conducted a literature review regarding LT in SAAH and its outcomes, including post-transplant mortality and recidivism. We studied available data on PubMed from 2011 and onwards whilst including articles dealing with genetic components, medical therapy and historic snapshots of alcoholism. Emerging studies recommend LT in SAAH not responding to medical therapies even without realizing the required abstinence period, since the majority of these patients would die within 6 months. SAAH without response to medical therapy has one-year-mortality rates of up to 90%. The 6-month rule is not based on strong evidence and is repeatedly a topic of controversial debates. There is genetic linkage to alcoholism and medical therapy is not as effective as estimated, yet. The 6-months-regulation has not shown to evidently decrease the risk of recidivism post-LT, which is a lifesaving treatment in SAAH patients. Insisting on rigid sobriety rules results in excluding patients with a low risk of recidivism from being transplanted. Moreover, the genetic linkage of alcoholism must be recognized.


Assuntos
Hepatite Alcoólica/terapia , Transplante de Fígado , Álcool Desidrogenase/genética , Alcoolismo/genética , Alcoolismo/patologia , Hepatite Alcoólica/tratamento farmacológico , Humanos , Pentoxifilina/uso terapêutico , Inibidores de Fosfodiesterase/uso terapêutico , Índice de Gravidade de Doença
8.
Int J Mol Sci ; 19(8)2018 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-30060508

RESUMO

Anti-tumor necrosis factor (TNF)-α agents represent an effective treatment for chronic inflammatory diseases. However, some concerns about their potentially undesirable effects on liver function have been reported. On the other hand, evidence of their therapeutic effects on certain liver diseases is accumulating. Many data showed the safety of anti-TNF-α in patients with chronic hepatitis B and C and in liver transplanted patients even if a strict follow-up and prophylaxis are recommended in well-defined subgroups. On the other side, anti-TNF-α-induced liver injury is not a rare event. However, it is often reversible after anti-TNF-α withdrawal. Anti-TNF-α agents have been tested in advanced stages of severe alcoholic hepatitis and non-alcoholic fatty liver disease. Limited data on the efficacy of anti-TNF-α in patients with autoimmune hepatitis and primary biliary cholangitis are also available. In this review, we explored the hepatic safety concerns in patients receiving anti-TNF-α agents with and without pre-existent hepatic diseases. In addition, the available evidence on their potential benefits in the treatment of specific hepatic diseases is discussed.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Inflamação/tratamento farmacológico , Fígado/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Doença Crônica , Hepatite Alcoólica/tratamento farmacológico , Humanos , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico
9.
Clin Transl Gastroenterol ; 9(6): 160, 2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29904132

RESUMO

OBJECTIVES: During alcoholic hepatitis (AH) monocytes traverse the vascular boundaries and massively invade the liver. In principle, tissue extravasation can be limited through shedding of CD18 integrins from leukocytes, including monocytes. The soluble (s) product sCD18 conceals adhesion receptors on the endothelium, which reduces monocyte extravasation. In AH, monocytes are dysfunctional, but whether this involves their self-generated anti-migration is unknown. Our aim was, therefore, to investigate monocyte CD18 dynamics in AH. METHODS: We studied 50 AH patients and 20 healthy controls. We measured monocyte expression and conformational activation of CD18, plasma (P)-sCD18, stimulated in vitro CD18 shedding and P-sCD18 in a short-term chronic-binge mouse model. RESULTS: AH-derived monocytes had a 30-60% higher expression of active CD18 receptors (p < 0.01), but the sCD18 concentration per monocyte was reduced in vivo by 30% and in vitro by 120% (p < 0.01). Ethanol reduced the in vitro shedding of CD18 in the patients only. TNFα increased sCD18 concentration per monocyte, but less so in the patients (p < 0.04). P-sCD18 per monocyte was inversely related to disease severity. In early alcoholic liver disease, P-sCD18 was decreased in the mouse model. CONCLUSIONS: The monocyte CD18 integrins are highly activated in AH and the single monocyte shedding of CD18 was decreased favoring tissue extravasation. Alcohol in itself and altered monocyte responsiveness to TNFα may explain this lowered shedding. TRANSLATIONAL IMPACT: The contribution of this mechanism to the excessive monocyte liver infiltration in AH should be further explored as it may serve as a potential therapeutic target to limit liver inflammation.


Assuntos
Antígenos CD18/sangue , Hepatite Alcoólica/imunologia , Fatores Inibidores da Migração de Leucócitos/imunologia , Monócitos/imunologia , Animais , Antígenos CD18/efeitos dos fármacos , Movimento Celular , Células Cultivadas , Etanol/farmacologia , Feminino , Hepatite Alcoólica/tratamento farmacológico , Humanos , Ativação de Macrófagos , Masculino , Camundongos , Pessoa de Meia-Idade , Pentoxifilina/farmacologia , Pentoxifilina/uso terapêutico , Fator de Necrose Tumoral alfa/farmacologia
10.
Expert Opin Pharmacother ; 19(8): 779-793, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29708448

RESUMO

INTRODUCTION: Clinicians caring for patients with alcoholic hepatitis (AH) are often confronted with the question of the best pharmacotherapy to be used. AREAS COVERED: This article covers metabolic aspects of alcohol as the basis of understanding pharmacotherapy and to facilitate choosing the drug therapeutic options for patients with severe AH. EXPERT OPINION: Alcoholic steatohepatitis (ASH) and alcoholic hepatitis (AH) as terms are often used interchangeably in scientific literature but a stringent differentiation is recommended for proper clarity. As opposed to ASH, the clinical course of AH is often severe and requires an effective drug treatment strategy, in addition to absolute alcohol abstinence and nutritional support. Drug options include corticosteroids as a first choice and pentoxifylline, an inhibitor of phosphodiesterase, as a second line therapy, especially in patients with contraindications for a corticosteroid therapy such as infections or sepsis. At seven days under corticosteroids, treatment should be terminated in non-responders, and patients must then be evaluated for liver transplantation. Pentoxifylline is not effective as a rescue therapy for these patients. Other treatments such as infliximab, propylthiouracil, N-acetylcysteine, silymarin, colchicine, insulin and glucagon, oxandrolone, testosterone, and polyunsaturated lecithin are not effective in severe AH. For liver transplantation, few patients will be eligible.


Assuntos
Fígado Gorduroso Alcoólico/patologia , Hepatite Alcoólica/patologia , Abstinência de Álcool , Álcool Desidrogenase/metabolismo , Catalase/metabolismo , Fígado Gorduroso Alcoólico/tratamento farmacológico , Fígado Gorduroso Alcoólico/metabolismo , Hepatite Alcoólica/tratamento farmacológico , Hepatite Alcoólica/metabolismo , Humanos , Transplante de Fígado , Microssomos/metabolismo , Pentoxifilina/uso terapêutico , Inibidores de Fosfodiesterase/uso terapêutico , Índice de Gravidade de Doença , Resultado do Tratamento
11.
J Hepatol ; 69(2): 534-543, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29753761

RESUMO

A 33-year-old Caucasian male was admitted to hospital with recent onset of jaundice of 2-3 weeks duration. He reported heavy use of alcohol for the last 10 years with the last drink a day prior to the onset of symptoms. At admission, he was alert and oriented to time, place, and person, and was deeply jaundiced. His laboratory profile can be summarised as follows: haemoglobin 12.1 g/dl, white blood cell count 18,700 with 81% neutrophils, serum bilirubin 33 (direct 22) mg/dl, aspartate aminotransferase 147 IU/L, alanine aminotransferase 62 IU/L, alkaline phosphatase 117 IU/L, serum albumin 2.8 gm/dl, serum creatinine 0.6 mg/dl, prothrombin time 18.3 (control 14.5) seconds, and international normalized ratio 1.48. He was diagnosed with severe alcoholic hepatitis (Maddrey discriminant function score of 50) and treated with prednisolone for 28 days with symptomatic and biochemical improvement. His Lille score at seven days was 0.4, and his serum bilirubin had decreased to 3.5 mg/dl at the end of treatment. He was also seen by the addiction team during hospitalisation; he agreed to follow through on recommendations. He was dismissed after completing a three-week inpatient rehabilitation programme but relapsed to alcohol use three months later, and was readmitted with alcohol withdrawal. He was readmitted two months later (about six months from the first episode) for a second episode of severe alcoholic hepatitis. At admission, his model for end-stage liver disease score was 32 and he was treated again with corticosteroids. His Lille score at seven days was 0.6 and steroids were discontinued. The hospital course was complicated by spontaneous bacterial peritonitis and pneumonia with development of acute kidney injury. He continued to worsen, developing multiorgan failure. After a course of one month, the family's preference was for him to receive comfort measures. This scenario raises several questions.


Assuntos
Alcoolismo/terapia , Glucocorticoides/administração & dosagem , Hepatite Alcoólica , Transplante de Fígado/métodos , Fígado/patologia , Biópsia/métodos , Hepatite Alcoólica/complicações , Hepatite Alcoólica/diagnóstico , Hepatite Alcoólica/tratamento farmacológico , Hepatite Alcoólica/fisiopatologia , Humanos , Prognóstico , Índice de Gravidade de Doença
12.
Gastroenterology ; 155(2): 458-468.e8, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29738698

RESUMO

BACKGROUND & AIMS: We performed a meta-analysis of individual patient data from 11 randomized controlled trials comparing corticosteroids, pentoxifylline, or their combination in patients with severe alcoholic hepatitis. We compared the effects of the treatments on survival for 28 days or 6 months, and response to treatment based on the Lille model. METHODS: We searched PubMed for randomized controlled trials of pharmacologic therapy for severe alcoholic hepatitis. Our final analysis comprised 11 studies, of 2111 patients. We performed 4 meta-analyses of the effects of corticosteroids vs placebo or control, corticosteroids vs pentoxifylline, corticosteroids and pentoxifylline vs corticosteroids and placebo or control, and pentoxifylline vs placebo. In each meta-analysis, the effect of treatment on the primary outcome (overall survival at 28 days, defined as the period from the first day of assigned treatment to 28 days) was estimated using a Cox proportional hazards regression model, including trials as random effect. RESULTS: Corticosteroid treatment significantly decreased risk of death within 28 days compared with controls (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.48-0.86) or to pentoxifylline (HR 0.64; 95% CI 0.43-0.95). In multiple-imputation and complete case analyses, the effect of corticosteroids compared with controls remained significant. When we compared corticosteroids vs pentoxifylline, the corticosteroid effect remained significant in the complete case analysis (HR 0.66; P = .04) but not in multiple-imputation analysis (HR 0.71; P = .08). There was no difference in 28-day mortality when patients were given a combination of corticosteroids and pentoxifylline vs corticosteroids alone or between patients given pentoxifylline vs control. In our analysis of secondary outcomes, we found no significant differences in 6-month mortality when any treatments or controls were compared. Corticosteroids were significantly associated with increased response to therapy compared with controls (relative risk 1.24; 95% CI 1.10-1.41) or pentoxifylline (relative risk 1.43; 95% CI 1.20-1.68). We found no difference in response to therapy between patients given a combination of corticosteroids and pentoxifylline vs corticosteroids alone or pentoxifylline vs controls. CONCLUSIONS: In a meta-analysis of 4 controlled trials, we found corticosteroid use to reduce risk of death within 28 days of treatment, but not in the following 6 months. This loss of efficacy over time indicates a need for new therapeutic strategies to improve medium-term outcomes.


Assuntos
Glucocorticoides/uso terapêutico , Hepatite Alcoólica/tratamento farmacológico , Pentoxifilina/uso terapêutico , Quimioterapia Combinada/métodos , Hepatite Alcoólica/mortalidade , Humanos , Placebos/uso terapêutico , Prednisolona/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento
13.
Lipids ; 53(3): 323-334, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29663389

RESUMO

Severe alcoholic hepatitis (AH) is a life-threatening condition lacking good serologic markers to tailor treatment and predict recovery. We examined the cholesterol metabolism in severe AH to explore prognostic markers and evaluate the profile of cholesterol precursors, cholestanol and phytosterols, in this context. We assessed serum cholesterol, cholesterol precursors, cholestanol, phytosterols, and biochemical markers in 24 patients with severe AH treated with prednisolone and randomized to ciprofloxacin in the ratio 1:1. Response to prednisolone was assessed with the Lille model. Evaluations were made between responders and nonresponders to corticosteroid treatment and during follow-up for 180 days. The findings were compared with those from patients with primary sclerosing cholangitis (PSC) (n = 156) and healthy individuals (n = 124). Responders to prednisolone had ~56-60% higher (p-value 0.032-0.044) serum ratios to cholesterol of phytosterols, while the lathosterol/campesterol ratio was ~76% (p = 0.031) lower compared to nonresponders. Stigmasterol/cholesterol predicted response to corticosteroid therapy. Surrogate markers of cholesterol synthesis (lathosterol and desmosterol) inversely reflected those of absorption (cholestanol and phytosterols) in PSC and controls (r-range -0.247 to -0.559, p < 0.01 for all), contrary to AH patients, among whom this reciprocal regulation was partially recovered on day 90 (lathosterol: r-range -0.733 to -0.952, p < 0.05 for all). AH patients had ~26% lower lathosterol/cholesterol, but 1.13-3.87-fold higher cholestanol/cholesterol and sitosterol/cholesterol compared to control groups (p < 0.05 for all). Median ferritin concentration at baseline was ~37% lower (p = 0.011) among the responders. Cholesterol precursors and phytosterols have a disease-specific profile in AH. Phytosterols and ferritin may serve as surrogate markers for short-term response.


Assuntos
Colangite Esclerosante/diagnóstico , Colestanol/sangue , Ferritinas/sangue , Hepatite Alcoólica/diagnóstico , Fitosteróis/sangue , Adulto , Idoso , Anti-Inflamatórios/uso terapêutico , Biomarcadores/sangue , Colangite Esclerosante/sangue , Colangite Esclerosante/tratamento farmacológico , Colangite Esclerosante/patologia , Colesterol/sangue , Ciprofloxacino/uso terapêutico , Feminino , Seguimentos , Hepatite Alcoólica/sangue , Hepatite Alcoólica/tratamento farmacológico , Hepatite Alcoólica/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prednisolona/uso terapêutico , Índice de Gravidade de Doença
14.
Virchows Arch ; 472(4): 667-675, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29516163

RESUMO

Baseline clinical and biochemical parameters fail to predict non-response to steroids in severe alcoholic hepatitis patients. Liver biopsy features have not been adequately assessed for predicting response to steroid therapy in severe alcoholic hepatitis. We aimed to identify histological parameters, which can predict steroid response in severe alcoholic hepatitis (SAH). We analyzed histological data of 107 SAH patients (71 in a derivative and 36 in a validation cohort) who presented within 4 weeks after inset of jaundice and were prospectively treated with steroids (40 mg/day). Histopathological parameters were semi-quantitatively scored in the pre-therapy biopsies in the derivative cohort, and a histological scoring system of SAH was developed which differentiated between steroid responders (Lille score < 0.45 at day 7) and non-responders. Seventeen of the 71 (24%) patients in the derivation cohort and 9 of 36 (25%) in the validation cohort were non-responders to steroids. In the derivation cohort, in comparison to responders, non-responders had higher severity of ballooning degeneration (BD) (mean 3.87 ± 0.91 versus 2.92 ± 1.33; p = 0.013) and density of Mallory-Denk bodies (MD) (mean 2.27 ± 0.79 versus. 1.69 ± 0.97; p = 0.028) on liver histology. A score derived using BD and MD (range 0-8) had high sensitivity (81%), specificity (64%), and negative predictive value (91%) in identifying patients who did not respond to steroids. The AUROC for a combined MD and BD score of > 5 for predicting steroid non-response was 0.731. Baseline histological parameters in SAH, ballooning degeneration, and Mallory-Denk bodies can reliably identify non-response to corticosteroids and help to stratify patients prior to introduction of therapy.


Assuntos
Anti-Inflamatórios/uso terapêutico , Resistência a Medicamentos , Hepatite Alcoólica/tratamento farmacológico , Hepatite Alcoólica/patologia , Prednisolona/uso terapêutico , Adulto , Biópsia , Glucocorticoides/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Sensibilidade e Especificidade
15.
Aliment Pharmacol Ther ; 47(8): 1151-1161, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29460445

RESUMO

BACKGROUND: Severe alcoholic hepatitis patients have high mortality and limited response to corticosteroids. Microvesicles reflect cellular stress and disease conditions. AIMS: To investigate whether microvesicles are associated with severity, response to steroid therapy and inflammation in severe alcoholic hepatitis. METHODS: Microvesicles originating from different cells were studied pre-therapy in 101 patients; (71 responder to corticosteroid therapy and 30 nonresponders) and 20 healthy controls. Microvesicles and cells were determined in peripheral and hepatic vein samples using flow cytometry and correlated with outcomes. Inflammatory signalling pathways and functional alterations of immune cells after stimulation with microvesicles were also investigated. RESULTS: Microvesicles mean levels were higher in nonresponders for T cells (CD3+ CD4+ ; 10.1 MV/µL vs 5.4; P = 0.06), macrophages (CD68+ CD11b+ ; 136.5 vs 121.9 MV/µL; P = 0.01), haematopoietic stem-cells (CD45+ CD34+ ; 116.8 vs 13.4 MV/µL; P = 0.0001) and hepatocytes (ASGPR+ ; 470 vs 361 MV/µL; P = 0.01); the latter two predicting steroid nonresponse in 94% patients at baseline in peripheral plasma. Microvesicle levels correlated with histological and liver disease severity indices. Whereas, in non-responders hepatic vein CD34+ cells were lower (P = 0.02), the CD34+ microvesicles there from were higher (P = 0.04), thus suggesting impaired regeneration. Also, microvesicles of 0.2-0.4 µm size were higher in nonresponders (P < 0.03) at baseline. Microvesicles from patients trigger more (P = 0.04) ROS generation, TNF-α production (P = 0.04) and up-regulate pro-inflammatory cytokine related genes in neutrophils in vitro. CONCLUSIONS: Pre-therapy peripheral plasma levels of CD34+ and ASGPR+ microvesicles are reliable non-invasive markers of steroid nonresponse and mortality in patients with severe alcoholic hepatitis.


Assuntos
Corticosteroides/uso terapêutico , Micropartículas Derivadas de Células , Veias Hepáticas/patologia , Hepatite Alcoólica/tratamento farmacológico , Hepatite Alcoólica/patologia , Fígado/patologia , Adulto , Antígenos CD34/sangue , Receptor de Asialoglicoproteína/sangue , Biomarcadores/sangue , Resistência a Medicamentos , Humanos , Fígado/irrigação sanguínea , Pessoa de Meia-Idade
17.
Clin Gastroenterol Hepatol ; 16(10): 1650-1656.e2, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29391265

RESUMO

BACKGROUND & AIMS: Patients with alcoholic hepatitis (AH) have high mortality, so new therapies are needed. Administration of granulocyte colony stimulating factor (G-CSF) increases survival times of patients with AH. It is not known whether addition of N-acetyl cysteine (NAC) to G-CSF could further increase survival time. We performed a randomized controlled pilot study to compare the efficacy of standard medical therapy with pentoxifylline to treatment with a combination of G-CSF and standard medical therapy as well as to the combination of NAC, G-CSF, and standard medical therapy in patients with severe AH. METHODS: We performed an open-label, single-center study of 57 patients with severe AH admitted to a Liver Intensive Care unit in India from October 2014 through March 2017. Patients were randomly assigned to groups that received standard medical therapy (with pentoxifylline) plus G-CSF for 5 days (G-CSF group; n = 18), standard medical therapy plus G-CSF and intravenous NAC for 5 days (combination group; n = 19), or standard medical therapy alone (n = 20). Clinical data and blood samples were collected at baseline; on day 6; and 1, 2, and 3 months after the study began. CD34+ cells were measured in blood samples collected on days 0 and 6. The primary outcome was proportion of patients surviving for 90 days. Secondary outcomes were mobilization of CD34+ cells at day 6, as well as Child Turcotte Pugh, model for end-stage liver disease, and modified discriminant function scores until day 90. RESULTS: Significantly higher proportions of patients in the G-CSF group (16/18) and the combination group (13/19) survived for 90 days than in the standard medical therapy group (6/20) (P = .0001 for G-CSF group and P = .037 and combination group). The GGSF and combination groups each had increased numbers of CD34+ cells from baseline until day 6, compared with the standard medical therapy group. The G-CSF group (but not the combination group) had significantly larger median reductions in modified discriminant function scores at study months 1 (reduction of 60.36%), 2 (reduction of 75.36%), and 3 (reduction of 88.73%) vs the standard medical therapy group (P = .02; P = .05; and P = .00, respectively). The G-CSF group had a significantly larger median reduction in model for end-stage liver disease score at 3 months (reduction of 55.77%; P = .01), but not in Child Turcotte Pugh score, compared with the standard medical therapy group. All groups had similar numbers of complications. CONCLUSION: In a pilot randomized controlled trial, we found administration of G-CSF to improve liver function and increase survival times in patients with severe AH, compared with standard therapy. We found no evidence for benefit of adding NAC to G-CSF. These findings require confirmation in larger trials. ClincialTrials.gov, number: NCT02971306.


Assuntos
Acetilcisteína/administração & dosagem , Depuradores de Radicais Livres/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Hepatite Alcoólica/tratamento farmacológico , Fatores Imunológicos/administração & dosagem , Adolescente , Adulto , Idoso , Quimioterapia Combinada/métodos , Feminino , Hepatite Alcoólica/patologia , Humanos , Índia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Pentoxifilina/administração & dosagem , Projetos Piloto , Estudos Prospectivos , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
18.
Clin Mol Hepatol ; 24(1): 43-50, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29316778

RESUMO

Severe alcoholic hepatitis has very high short term mortality and corticosteroids have been the mainstay of treatment for decades. Patients with Lille score >0.45 are considered non-responders to steroids and have poor outcome. Recently Orthotopic Liver Transplantation (OLT) is being increasingly used as rescue treatment for these patients, without waiting for 6 months of abstinence. Liver transplant is the only rescue treatment which can potentially provide long term benefit for patients who are steroid non-responders. However, with scarcity of organs being a concern, all patients of severe alcoholic hepatitis cannot be chosen for transplantation in an arbitrary way. There is a need for development of predictive tools and objective protocols to select patients who can justify the use of precious liver grafts. With a stringent criteria for selection of patients receiving the graft, liver transplantation in severe alcoholic hepatitis can become a viable rescue therapeutic option conferring significant survival advantage of both short- and long-term basis. The optimal criteria for selection will also prevent misuse of the liver donor pool as well as to prevent mortality in salvageable patients. Further research needs to be done to identify subset of patients which are at low risk of recidivism and also cannot be managed with pharmacotherapy alone. We reviewed the current knowledge on role of OLT in patient with acute severe alcoholic hepatitis in the present review.


Assuntos
Hepatite Alcoólica/terapia , Transplante de Fígado , Corticosteroides/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Hepatite Alcoólica/tratamento farmacológico , Hepatite Alcoólica/mortalidade , Humanos , Recidiva , Índice de Gravidade de Doença , Resultado do Tratamento
19.
Rev Med Suisse ; 14(590): 146-149, 2018 Jan 17.
Artigo em Francês | MEDLINE | ID: mdl-29341528

RESUMO

The use of N-acetylcysteine is of unknown significance when it comes to acute liver failure of other origin but for paracetamol overdose. Current data state its beneficial use when added to standard treatment for acute alcoholic hepatitis, whereas this attitude is less clear for hepatitis of variable other origin. This review of literature attends to evaluate and reveal the possible interest of adding N-acetylcysteine to standard care of acute liver failure due to alcoholism or other non-paracetamol linked causes.


Assuntos
Acetilcisteína , Antivirais , Hepatite Alcoólica , Falência Hepática Aguda , Acetaminofen , Acetilcisteína/uso terapêutico , Analgésicos não Entorpecentes/uso terapêutico , Antivirais/uso terapêutico , Overdose de Drogas , Hepatite Alcoólica/tratamento farmacológico , Humanos , Falência Hepática Aguda/tratamento farmacológico
20.
Gastroenterology ; 154(4): 965-975, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29158192

RESUMO

BACKGROUND & AIMS: Patients with severe alcoholic hepatitis (AH) have a high risk of death within 90 days. Corticosteroids, which can cause severe adverse events, are the only treatment that increases short-term survival. It is a challenge to predict outcomes of patients with severe AH. Therefore, we developed a scoring system to predict patient survival, integrating baseline molecular and clinical variables. METHODS: We obtained fixed liver biopsy samples from 71 consecutive patients diagnosed with severe AH and treated with corticosteroids from July 2006 through December 2013 in Brussels, Belgium (derivation cohort). Gene expression patterns were analyzed by microarrays and clinical data were collected for 180 days. We identified gene expression signatures and clinical data that are associated with survival without liver transplantation at 90 and 180 days after initiation of corticosteroid therapy. Findings were validated using liver biopsies from 48 consecutive patients with severe AH treated with corticosteroids, collected from March 2010 through February 2015 at hospitals in Belgium and Switzerland (validation cohort 1) and in liver biopsies from 20 patients (9 received corticosteroid treatment), collected from January 2012 through May 2015 in the United States (validation cohort 2). RESULTS: We integrated data on expression patterns of 123 genes and the model for end-stage liver disease (MELD) scores to assign patients to groups with poor survival (29% survived 90 days and 26% survived 180 days) and good survival (76% survived 90 days and 65% survived 180 days) (P < .001) in the derivation cohort. We named this assignment system the gene signature-MELD (gs-MELD) score. In validation cohort 1, the gs-MELD score discriminated patients with poor survival (43% survived 90 days) from those with good survival (96% survived 90 days) (P < .001). The gs-MELD score also discriminated between patients with a poor survival at 180 days (34% survived) and a good survival at 180 days (84% survived) (P < .001). The time-dependent area under the receiver operator characteristic curve for the score was 0.86 (95% confidence interval 0.73-0.99) for survival at 90 days, and 0.83 (95% confidence interval 0.71-0.96) for survival at 180 days. This score outperformed other clinical models to predict survival of patients with severe AH in validation cohort 1. In validation cohort 2, the gs-MELD discriminated patients with a poor survival at 90 days (12% survived) from those with a good survival at 90 days (100%) (P < .001). CONCLUSIONS: We integrated data on baseline liver gene expression pattern and the MELD score to create the gs-MELD scoring system, which identifies patients with severe AH, treated or not with corticosteroids, most and least likely to survive for 90 and 180 days.


Assuntos
Técnicas de Apoio para a Decisão , Perfilação da Expressão Gênica/métodos , Hepatite Alcoólica/diagnóstico , Hepatite Alcoólica/genética , Transcriptoma , Corticosteroides/uso terapêutico , Adulto , Área Sob a Curva , Bélgica , Biópsia , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Hepatite Alcoólica/tratamento farmacológico , Hepatite Alcoólica/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Curva ROC , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
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