Citation s : Pavlov CS et al. July 18, New York. Surgery, General. Pensacola, Florida. Gainesville, Florida. Springfield, Missouri. Family Medicine. Family Medicine Physician. Vernon, Illinois. By continuing to use our site, you accept the use of these cookies.
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In summary, early liver transplant is effective in the management of patients with severe AH who failed steroid treatment. Patient selection remains extremely controversial and needs to be further determined. The patients should be selected based on strict criteria, and it should be emphasized that patients with severe AH who do not respond to steroids have a very short-term mortality rate without liver transplantation.
As discussed in this review summarized in Fig. Use of corticosteroids can be associated with significant risk, such as infection, especially in this sick population of patients. In addition, the long-term benefit of steroids is still not established. Therefore, effective new pharmacologic therapies with more favorable side effect profiles are greatly needed for the treatment of AH patients. One of the challenges of drug discovery in the field is the lack of ideal animal models that entirely mimic human disease.
Here, we will briefly discuss some of the most important therapeutic targets. Alcohol disrupts the intestinal epithelial barrier, resulting in increased gut permeability to microbiota. The bacterial endotoxin lipopolysaccharide LPS increases in portal circulation and activates toll-like receptor 4 TLR4 , leading to activation of the innate immune system and release of various cytokines.
Blockage of these pathways could have therapeutic implications for the treatment of AH. Disruption of the intestinal epithelial barrier results in increased gut permeability, and has been suggested as an essential pathway in the pathophysiology of AH.
Patients were randomized to receive 5 days of Bifidobacterium bifidum and Lactobacillus plantarum 8PA3 versus standard therapy alone, abstinence plus vitamins. After 5 days of probiotic therapy in alcoholic patients, those who were treated with probiotics had significantly lower AST, ALT, gamma glutamyl-transpeptidase GGT , and total bilirubin levels than those treated with standard therapy alone. Activation of the innate immune system is one of the main steps in the development of AH.
Another key cytokine, IL, was suggested alone or in combination with steroids to be a potential therapeutic option to ameliorate ALD, due to its multiple beneficial properties, including its antioxidant, antiapoptotic, antisteatotic, antimicrobial, and proliferative properties. Therefore, IL might be useful in treating patients with AH.
Additionally, side effects due to IL22 may be minimal, as ILR expression is restricted expression to epithelial cells, such as hepatocytes. Apoptosis is a prominent feature in the pathophysiology of AH. The caspase inhibitor GS was shown to be effective in the treatment of patients with nonalcoholic steatohepatitis NASH. FXR is a nuclear receptor for bile acids, and its activation has been shown to be essential in the treatment of primary biliary cirrhosis PBC.
Challenges remain for developing therapeutic approaches targeting ALD, including AH, partly because of the lack of human-relevant model systems to study the effect of alcohol on the liver. Moreover, human iPSCs retain the same genetic information of the donor i. The human iPSC-hepatic differentiation technology has allowed us to establish effective large-scale drug screening and drug discovery studies using an iPSC-based liver disease model, which is critical for translating the iPSC technology into novel therapies for untreatable liver diseases.
Pathogenesis research using patient-relevant iPSC models of AH will aid in the discovery of better cellular and molecular targets for drug development. Regenerative therapy using iPSCs will require in vivo functional testing of these cells.
Perhaps a more immediate use of human iPSC-derived cells is the in vitro screening of candidate drugs, as improving and evaluating the in vivo function for most iPSC-derived cell types is still in the future. Although there are many technical hurdles to overcome before establishing iPSC-based tailored therapy for ALD patients, the potential of pluripotent stem cell therapy is great.
Together with continued improvements in current therapies, iPSC technology provides an additional new therapy, but much more work needs to be done to demonstrate their true value in the clinic. ALD remains one of the leading causes of liver disease in the United States. The clinical and pathological spectrum of disease includes alcoholic fatty liver, alcoholic hepatitis and alcoholic cirrhosis. In general, diagnosis of AH solely based on clinical and laboratory data might be challenging, as there is significant overlap between various forms of ALD.
Liver biopsy remains the gold standard when the diagnosis is unclear, especially when steroids are being considered. The most important predictor for determining long-term survival in AH patients is alcohol abstinence. Steroids have some short term benefit in treatment of severe AH, but long term effect is unclear.
Liver transplant has shown good results in the management of AH patients who have failed medical therapy, however patient selection remains a major challenge. There are multiple ongoing clinical trials targeting novel pathways involved in the pathogenesis of AH. Human iPSCs are currently being used as a novel technology for studying the pathogenesis of ALD with potential for drug discovery. Designing the manuscript, collecting the data, drafting the article and reading and approving the final draft of the manuscript BS , designing the manuscript, collecting the data, drafting the article and reading and approving the final draft of the manuscript AD , designing the manuscript, collecting the data, drafting the article and reading and approving the final draft of the manuscript YYJ , designing the manuscript, drafting the article and reading and approving the final draft of the manuscript.
In addition contributed by revisiting the article for intellectual content AG , designing the manuscript, drafting the article and reading and approving the final draft of the manuscript, revisiting the article for intellectual content EM. All rights reserved. Download PDF.
J Clin Transl Hepatol. Author information. Journal of Clinical and Translational Hepatology ; 4 2 : - Abstract Alcohol is one of the most common etiologies of liver disease, and alcoholic liver disease overall is the second most common indication for liver transplantation in the United States. Keywords Alcoholic hepatitis, Corticosteroids, Liver transplantation, Induced pluripotent stem cell. Introduction Approximately two-thirds of the US adult population drinks alcohol each year, and 7.
Spectrum of liver disease The clinical and pathologic spectrum of ALD ranges from alcoholic fatty liver disease alcoholic steatosis to cirrhosis with various survival rates. Nutrition Malnutrition as well as obesity in alcoholic patients are well-recognized phenomena that can critically impact the development and progression of liver disease. Corticosteroids In the meta-analysis of three trials that compared the efficacy of PTX vs. Etanercept In a multicenter study by Boetticher et al.
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Accelerated improvement of alcoholic liver disease with enteral nutrition. The role of nutritional therapy in alcoholic liver disease. Nutrition in alcoholic liver disease. A randomized placebo controlled trial of vitamin E for alcoholic hepatitis. MELD accurately predicts mortality in patients with alcoholic hepatitis. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data.
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Alcoholic liver disease: proposed recommendations for the American College of Gastroenterology. The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. Effects of pentoxifylline on tumor necrosis factor production and survival during lethal E. Pentoxifylline may prevent renal impairment hepatorenal syndrome in severe acute alcoholic hepatitis.
Pentoxifylline: a first line treatment option for severe alcoholic hepatitis and hepatorenal syndrome?. Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial. Systematic review: pentoxifylline for the treatment of severe alcoholic hepatitis. Pentoxifylline for alcoholic hepatitis. Pentoxifylline does not decrease short-term mortality but does reduce complications in patients with advanced cirrhosis.
Corticosteroid plus pentoxifylline is not better than corticosteroid alone for improving survival in severe alcoholic hepatitis COPE trial. Role of pentoxifylline in treatment of severe acute alcoholic hepatitis - a randomized controlled trial. Prednisolone or pentoxifylline for alcoholic hepatitis. Pentoxifylline versus prednisolone for severe alcoholic hepatitis: a randomized controlled trial. Short-term survival in patients with severe alcoholic hepatitis treated with corticosteroid vs.
Pentoxifylline vs. Prednisolone vs. Prednisolone with vs without pentoxifylline and survival of patients with severe alcoholic hepatitis: a randomized clinical trial. Early switch to pentoxifylline in patients with severe alcoholic hepatitis is inefficient in non-responders to corticosteroids. Increased plasma tumor necrosis factor in severe alcoholic hepatitis. Plasma tumor necrosis factor alpha predicts decreased long-term survival in severe alcoholic hepatitis.
A randomized, double-blinded, placebo-controlled multicenter trial of etanercept in the treatment of alcoholic hepatitis. A double-blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis. Glucocorticoids plus N-acetylcysteine in alcoholic hepatitis. Evolving frequency and outcomes of liver transplantation based on etiology of liver disease. Liver transplantation in alcoholic liver disease current status and controversies.
Liver transplantation in acute alcoholic hepatitis: Current status and future development. Assessing priorities for allocation of donor liver grafts: survey of public and clinicians. Public and professional attitudes to transplanting alcoholic patients. Relapse after transplantation: European studies.
Evaluation and selection of the patient with alcoholic liver disease for liver transplant. Long-term survival and predictors of relapse after orthotopic liver transplantation for alcoholic liver disease. Should length of sobriety be a major determinant in liver transplant selection?. Early liver transplantation for severe alcoholic hepatitis. Outcomes after liver transplantation for alcoholic hepatitis are similar to alcoholic cirrhosis: exploratory analysis from the UNOS database.
Alcohol recidivism impairs long-term patient survival after orthotopic liver transplantation for alcoholic liver disease. Alcohol relapse after liver transplantation for alcoholic liver disease: does it matter?. Orthotopic liver transplantation for alcoholic liver disease: a retrospective analysis of survival, recidivism, and risk factors predisposing to recidivism. Gut-liver axis in alcoholic liver disease. Bacterial translocation and changes in the intestinal microbiome associated with alcoholic liver disease.
Beneficial effects of a probiotic VSL 3 on parameters of liver dysfunction in chronic liver diseases. Probiotics restore bowel flora and improve liver enzymes in human alcohol-induced liver injury: a pilot study. Alcoholic liver disease: mechanisms of injury and targeted treatment. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice.
Interleukin treatment ameliorates alcoholic liver injury in a murine model of chronic-binge ethanol feeding: role of signal transducer and activator of transcription 3. Hepatocyte apoptosis is a pathologic feature of human alcoholic hepatitis. Mechanisms and biomarkers of apoptosis in liver disease and fibrosis.
A phase 2, randomized, double-blind, placebo-controlled study of GS in subjects with nonalcoholic steatohepatitis. Recent advances in the development of farnesoid X receptor agonists. Efficacy of obeticholic Acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic Acid. Targeting the FXR nuclear receptor to treat liver disease.
Liver fibrosis: from animal models to mapping of human risk variants. Reprogramming of EBV-immortalized B-lymphocyte cell lines into induced pluripotent stem cells. In addition, steroids have the potential to suppress the cytokine-mediated inflammation that drives progressive liver dysfunction.
However, steroids also have the potential of exacerbating existing infections by suppressing immune function. Moreover, he cautioned that steroids are contraindicated in patients with gastrointestinal bleeding or pancreatitis. Importantly, patients with alcoholic hepatitis who are going to respond to steroids typically demonstrate a reduction in bilirubin within the first week, according to Dr.
He cautioned that continuing steroids in the absence of a change in bilirubin should be weighed again potential harms, including the exacerbation of liver disease or comorbidities. Even in responders, he recommended no more than 3 weeks to preserve a favorable benefit-to-risk ratio. Mullen advised, but he also suggested that the management of advanced alcoholic hepatitis may be best left to specialists. Mullen, who cautioned that this is a challenging disease. Global Academy and this news organization are owned by the same company.
Mullen had no disclosures to report. Skip to main content. Conference Coverage. Therapeutic window is narrow for steroids in alcoholic hepatitis. Kevin D. Liver Disease. Rapid core antigen HCV tests could expand accessibility The pandemic hurt patients with liver disease in many ways.
Patients discharged on corticosteroids require very careful coordination with outpatient providers as prolonged corticosteroid treatment courses can lead to serious complications and death. Critics of corticosteroid therapy in these patients often cite problems related to prolonged steroid use, especially in patients who do not respond to therapy.
Pentoxifylline, an oral phosphodiesterase inhibitor, is recommended by the ACG, especially if corticosteroids are contraindicated. This study demonstrated that patients who received pentoxifylline had decreased day mortality One small, randomized trial comparing pentoxifylline with prednisolone demonstrated that pentoxifylline was superior. The recommended dose is mg orally three times daily TID for four weeks. Common side effects are nausea and vomiting. Pentoxifylline cannot be administered by nasogastric tubes and should not be used in patients with recent cerebral or retinal hemorrhage.
Other therapies. Several studies have examined vitamin E, N-acetylcystine, and other antioxidants as treatment for alcoholic hepatitis. No clear benefit has been demonstrated for any of these drugs. Tumor necrosis factor TNF -alpha inhibitors e. Patients are not usually considered for liver transplantation until they have at least six months of abstinence from alcohol as recommended by the American Society of Transplantation.
Discharge considerations. No clinical trials have studied optimal timing of discharge. Careful outpatient follow-up and assistance with continued abstinence is very important. The patient fits the typical clinical picture of alcoholic hepatitis. Cessation of alcohol consumption is the most important treatment and is accomplished by admission to the hospital. Because of his daily alcohol consumption, folate, thiamine, multivitamins, and oral vitamin K are ordered.
Though he has no symptoms of alcohol withdrawal, a note is added about potential withdrawal to the handoff report. An infectious workup is completed by ordering blood and urine cultures, a chest X-ray, and performing paracentesis to exclude spontaneous bacterial peritonitis. A dietary consult with calorie count is given, along with a plan to discuss with the patient the importance of consuming at least 2, calories a day is made.
Tube feedings will be considered if the patient does not meet this goal in 48 hours. If he is actively bleeding or infected, pentoxifylline mg TID for 28 days is favored due to its lower-side-effect profile. Due to the severity of his illness, a gastroenterology consultation is recommended. Alcoholic hepatitis is a serious disease with significant short-term mortality. Treatment options are limited but include abstinence from alcohol, supplemental nutrition, and, for select patients, pentoxifylline or corticosteroids.
Because most transplant centers require six months of abstinence, these patients usually are not eligible for urgent liver transplantation. Skip to main content. Medicolegal Issues. The Hospitalist. Rush Pierce Jr. Key Points Alcoholic hepatitis is a severe form of alcohol-related liver disease associated with significant short-term mortality. The diagnosis of alcoholic hepatitis is usually made on the basis of typical clinical and laboratory features. Fever is common in alcoholic hepatitis but should prompt an evaluation for infection.
Treatment should include abstinence from alcohol and supplemental nutrition in all patients with alcoholic hepatitis. Prognostic prediction models are used to select patients for treatment with prednisolone or pentoxifylline. Typical clinical and laboratory features of alcoholic hepatitis. Common scoring systems used to predict prognosis in alcoholic hepatitis. Treatment considerations in alcoholic hepatitis. Several prognostic scoring systems, to date, have been developed and validated for use in those with AH[ 5 - 10 ].
However, despite the sudden onset of the clinical presentation, this term seems to fade into the mists of history now that AH is usually associated with extensive fibrosis or cirrhosis and often follows a protracted natural course. ASH is a pathologic disease entity, defined as the coexistence of steatosis, hepatocellular ballooning, neutrophilic infiltration, and perisinusoidal fibrosis[ 11 ].
ASH is not exclusively accompanied by AH but can be superimposed on any different stages of ALD comprising steatosis, steatohepatitis, fibrosis, and cirrhosis[ 12 , 13 ]. In addition, the true incidence and prevalence of ASH or AH among alcohol abusers remain unclear due to the uncertainties behind a clinical diagnosis of AH and the limited number of studies with liver biopsy to ascertain a histologic diagnosis of ASH.
Recently, the updated practice guidelines for management of ALD have been released from the European Association for the Study of the Liver[ 14 ] as well as the American Association for the Study of Liver Diseases[ 15 ]. Herein, we attempt to address some issues regarding different types of alcohol-induced liver failure, new prognostic scoring systems, general therapeutic measures, and potential specific therapies in patients with severe ASH from a clinical perspective.
Traditionally, there are two different types of liver failure, which have different prognoses and call for different therapeutic approaches. One is acute liver failure ALF , which occurs suddenly in patients without previous any liver disease. The other is chronic liver failure CLF due to chronic hepatic decompensation CHD , which is found in those with end-stage liver cirrhosis as a result of slow progression of underlying liver disease.
Since the advent of albumin dialysis, a new subtype of CLF, that is, acute-on-chronic liver failure ACLF has been widely recognized and highlighted in the field of clinical practice[ 16 - 18 ]. This new entity is characterized by an acute and rapid deterioration within several weeks on the top of underlying compensated liver disease, mostly cirrhosis, leading to deep jaundice, renal impairment, hepatic encephalopathy, and multi-organ failure in the early stage[ 19 ].
Currently, an excessive pro-inflammatory response to bacterial components such as gut microbiota and lipopolysaccharide LPS seems to play an important role in ACLF, linking the gut, liver, and portal to systemic circulation[ 21 ]. The most critically ill patients with alcohol-induced liver failure are some people suffering from severe ASH, mostly superimposed on alcoholic cirrhosis, and secondly those with decompensated cirrhosis.
Precipitating events such as variceal hemorrhage, infection, and hepatitis B viral reactivation are usually crucial for the onset of ACLF, given that the rapid and aggressive control of these triggers can allow a complete reversal of ACLF. In this regard, an early use of transjugular intrahepatic portosystemic shunt effectively prevented the development of ACLF in patients with high-risk varices[ 22 ].
Similarly, early suppression of hepatitis B viremia by tenofovir prevented those with spontaneous reactivation of hepatitis B presenting as ACLF from progressing to multi-organ failure[ 23 ]. CHD is the most frequent subtype of alcohol-induced liver failure and is characterized by the complications of portal hypertension and mild to moderate jaundice in the early stage.
The best way to reverse alcohol-induced ACLF is to detect and control severe ASH as early as possible, which is less likely to recover spontaneously. In this regard, a variety of prognostic scores have been developed primarily to select patients with severe ASH at high risk of early 1, 2, or 3 mo death[ 5 - 8 , 10 ]. MDF is still one of the most commonly used prognostic models to predict survival outcomes in patients with ASH with 32 of a cutoff value[ 10 , 25 ].
The unique findings of this model are as follows: 1 the MAGIC is the first prognostic model derived from an Asian population with AH; 2 it mainly focused on the prediction of natural outcomes of untreated patients with AH; 3 it firstly brought the prognostic role of hyperkalemia in AH to light, and most importantly; and 4 the spontaneous evolution in bilirubin levels is incorporated into this new model, emphasizing the importance of early amelioration of liver function in relation to the improvement of survival.
However, this model should be further validated in other ethnic populations with severe ASH. Corticosteroids seem to improve survival outcomes in patients with severe ASH without specific contraindications such as gastrointestinal bleeding, hepatorenal syndrome HRS , uncontrolled infection, hepatitis B virus infection, and pancreatitis[ 14 , 15 ].
On the other hand, early change in bilirubin level, in vitro resistance to steroid, and the Lille score at day 7 allow us to decide on the responsiveness to corticosteroids and whether to stop corticosteroids during steroid treatment[ 9 , 27 - 29 ]. Recently, an alcoholic hepatitis histologic score AHHS has been suggested to predict survival outcomes accurately in patients with biopsy-proven, ASH[ 30 ]. The AHHS is calculated by grading the extent of fibrosis, the degree of neutrophilic infiltration, bilirubinostasis patterns, and megamitochondria[ 30 ].
In particular, the pattern of bilirubinostasis was closely associated with the development of bacterial infections during hospitalization[ 30 , 31 ]. Alcohol abstinence is the linchpin of therapy for AH, since abstinence failure increases mortality rates among those with AH[ 32 ]. However, anti-craving drugs such as disulfiram, naltrexone, and acamprosate are not routinely recommended to patients with severe AH due to the risk of potential hepatotoxicity. Although an anti-craving medication is not promptly given to patients hospitalized for severe AH, an abstinence treatment should be considered to reduce the recurrence of alcohol use disorders after recovery of liver function.
Baclofen could effectively suppress a craving for alcohol and keep an abstinence from alcohol in patients with alcoholic cirrhosis without incurring hepatotoxicity; however, additional research is needed to prove an anti-craving efficacy in those with severe AH[ 33 ]. Patients with AH often suffer from serious malnutrition resulting from promiscuous eating habits, alcohol-related diarrhea, decreased small bowel absorption capacity, anorexia, and an excessive catabolic state, which is directly related to increased mortality[ 34 ].
Accordingly, most of them require nutritional support including the adequate calorie and protein supply as well as vitamin B and mineral repletion along with dextrose water infusion. In addition, when oral feeding is not well tolerated in patients with AH, they often need fat-soluble vitamin supplementation and enteral nutrition.
However, there was no significant difference of a 1-mo mortality rate in a previous study comparing enteral nutrition and corticosteroids in patients with severe AH[ 35 ]. Nonetheless, further studies are warranted to evaluate the impact of the combination treatment on survival, because early death was more frequent in the enteral nutrition group and late mortality was higher in the steroid-treated group. In patients with severe AH, renal impairment is a frequently accompanied symptom during hospitalization and also represents an important predictor of infection and survival.
The most common cause of acute renal dysfunction is HRS. To prevent HRS, nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs, aminoglycoside, diuretics, and contrast dye should be avoided and volume expanders including albumin and fresh frozen plasma might be administered. Thus, infection and renal failure in ASH have a major impact on survival and should be screened, prevented, or treated at all time-points.
Empirical use of antibiotics, although widely instituted, is not routinely warranted. Recent data demonstrated that corticosteroids are not contraindicated for the treatment of ASH after a complete control of infection[ 36 ]. Infection developed during steroid treatment, however, was not the result of immunosuppression by corticosteroids but that of non-response to corticosteroids suggesting severe liver impairment[ 36 ].
Such being the case, empirical antibiotic treatment may be more beneficial to steroid responders rather than non-responders by improving survival only in the former. The impact of corticosteroid treatment on survival in those with severe AH has been under debate for the last three decades because of heterogeneity of the study design among different studies and selection bias from ambiguous diagnostic criteria lacking histologic confirmation. Moreover, the mechanisms underlying corticosteroid treatment for AH remain largely unknown.
A recent study has carefully examined the effects of prednisolone on liver injury and regeneration in several experimental models regarding alcoholic liver injury[ 37 ]. In general, corticosteroids suppress inflammatory and immune-mediated hepatic destruction, but their marked, anti-anabolic effect may suppress regeneration and slow healing by inhibiting expression of genes i.
This study may give some new insights on prednisolone treatment for AH. Corticosteroids have now become a first-line therapy for biopsy-proven, severe ASH. Moreover, the treatment of non-severe forms of AH by corticosteroids is not recommended. Thus, the effect of corticosteroids on survival seems to be restricted to biopsy-proven, severe ASH. In patients with severe ASH receiving pentoxifylline, a 6-mo survival rate was higher than in those treated with placebo[ 38 ].
The survival benefit was attributable to a lower incidence of HRS. However, this beneficial effect was challenged by two recent meta-analyses demonstrating that pentoxifylline decreased the risk of fatal HRS but did not improve survival significantly, although it remains inconclusive[ 39 , 40 ]. Recently, a Korean multicenter study group has made a head-to-head comparison between pentoxifylline and prednisolone[ 41 ].
The results demonstrated that the efficacy of pentoxifylline was not statistically equivalent to that of prednisolone in terms of 6-mo survival, supporting prednisolone as a preferred treatment option for severe AH. However, in patients with severe AH and contraindications to corticosteroids, pentoxifylline still can be considered as an alternative therapeutic option[ 14 , 15 ].
In a recent prospective trial including patients with severe ASH, the combination of pentoxifylline and prednisolone did not bring any significant survival benefit over prednisolone alone[ 42 ]. However, a limitation of this study was that they failed to include a treatment arm receiving only pentoxifylline[ 43 ]. To overcome this limitation, a large randomized trial with a sufficient sample size is ongoing in the United Kingdom comparing pentoxifylline with corticosteroids or a combination of both in patients with severe AH[ 44 ].
Finally, in patients with severe ASH and non-response to corticosteroids based on the Lille model, an early switch to pentoxifylline did not improve the survival outcome[ 45 ]. Collectively, pentoxifylline has no additional beneficial effect in combination with corticosteroids in patients with severe ASH and also pentoxifylline alone is ineffectual in non-responders to steroids.
N -acetyl cysteine: Recently, the combination treatment with N -acetyl cysteine NAC , an antioxidant and prednisolone significantly reduced a 1-mo mortality rate compared with prednisolone alone by preventing HRS and infection, although the difference was no longer statistically significant at 3 and 6 mo[ 46 ].
However, given the trend toward improved survival in those treated with NAC, additional studies are required to determine the optimal dosing schedule and treatment duration of NAC. Presumably, prolonged or excessive TNF blockade may cause profound immunosuppression and negatively impact liver regeneration[ 49 - 51 ]. Liver transplantation: AH is not considered as a usual indication for liver transplantation LT. Recently, an early LT concept was suggested to those with a first episode of severe ASH not responding to steroids[ 53 ].
Explicit improvement of survival was observed in patients who received early LT compared to historical controls without response to steroids[ 53 ]. Obviously, early LT in ASH may be relevant only in highly selected patients with a first episode of severe ASH, a favorable addiction profile, and not responding to medical therapy.
Despite the current specific therapies against AH, the overall prognosis of severe AH remains dismal. Owing to the scarcity of available therapeutic resources, undoubtedly, there is an urgent need for novel and innovative therapies to combat against severe AH. Over the past several decades, we have made great progress in grasping the clinical course of AH but not been capable of successfully identifying therapeutic targets. The failure of most clinical trials in AH results from a poor knowledge of the key disease drivers.
Secondly, systemic large-scale studies are required before we can engage into targeted, therapeutic trials. Finally, all animal models used to test targets represent mild ALD but not severe liver disease that characterizes AH. Thus, to settle the aforementioned issues, we are increasingly encouraged to conduct multi-center collaborative trials that use common protocols, include biomarkers, and address the spectrum of AH. To that end, recently, National Institute on Alcohol Abuse and Alcoholism has decided to support four AH consortia, which will explore translational studies and clinical trials for AH[ 54 ].
Clinical studies will collect and bank genetic or other biologic samples and consents to allow translational studies of basic mechanisms, genetics, epigenetics, and systems biology of AH severity and of treatment response. Summary of potential molecular targets and novel targeted therapies for alcoholic hepatitis.
Scientific integration for developing new biomarkers and novel therapies for AH mainly focuses on several key elements of the pathogenesis of AH. Firstly, inflammation cascade and innate immune activation are demarcating features of severe AH compared to mild to moderate ALD[ 55 - 58 ].
The syndrome of AH results from severe inflammation and cytokine dysregulation[ 59 , 60 ]. Secondly, gut integrity is significantly altered in AH allowing pathogen-associated molecular patterns to enter the liver and systemic circulation and induce innate immune activation[ 61 , 62 ]. Gut-derived endotoxins and other bacterial products that trigger inflammation are a consequence of increased permeability and altered gut barrier function[ 62 ].
Thirdly, cell survival and death pathways contribute to liver dysfunction and the release of damage-associated molecular patterns that further fuel inflammation including hepatocellular apoptosis, sterile necrosis, and injury[ 61 ]. Finally, hepatocellular regeneration is profoundly impaired in patients with severe ASH with liver failure. In this regard, it is therapeutically important to characterize the mechanisms of the poor hepatocyte regeneration and promote the differentiation of progenitor cells into functional mature hepatocytes[ 63 - 66 ].
There is a pressing need for better definitions to distinguish AH from other clinical syndromes. The definitions need to be related to risk and outcomes, to improve clarity of taxonomy, reduce problems with basic vs clinical classification, and aid in treatment decisions. Alcohol abstinence is the sine qua non of therapy for AH, and, in the milder forms, is prerequisite to clinical recovery.
Severe ASH may progress to multi-organ failure and, in particular, renal impairment and infection are the most worrisome complications requiring screening, prevention, and treatment. Clinical prognostic scores such as MDF and MELD are useful tools to determine whether to initiate steroids and the Lille model at day 7 can be applied to assess responsiveness to steroids as stopping rules. Pentoxifylline can be alternatively used as a first-line therapy in severe ASH patients with contraindications to steroids.
However, pentoxifylline provides no additional beneficial effect to patients with severe ASH receiving corticosteroids. Early switch to pentoxifylline either does not significantly improve survival in non-responders to steroids. Convincingly, future studies should include homogenous population and direct to AH patients with intermediate severity and partial or non-responders to steroids.
Strategically, we should explore novel therapeutic targets to restore altered gut mucosal integrity, suppress inflammation based on cytokine profiles, promote hepatic regeneration, and limit innate immune responses in severe ASH. Read article at publisher's site DOI : Ann Transl Med , 8 8 , 01 Apr J Clin Invest , 4 , 01 Apr Free to read. Hepatol Int , 14 2 , 19 Dec Cited by: 0 articles PMID: Sci Rep , 8 1 , 06 Jul Hepatol Commun , 2 6 , 16 Apr To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation.
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Abstract Alcoholic hepatitis AH is an acute hepatic manifestation occurring from heavy alcohol ingestion. Free full text. World J Hepatol. Published online Oct PMID: Won Kim and Dong Joon Kim. Author information Article notes Copyright and License information Disclaimer.
Author contributions: Kim W collected data, reviewed literatures, and wrote the manuscript; Kim DJ designed this review, appraised critically and revised the manuscript. All rights reserved. This article has been cited by other articles in PMC.
Go to:. Different types of alcohol-induced liver failure Traditionally, there are two different types of liver failure, which have different prognoses and call for different therapeutic approaches. Prognostic scoring systems The best way to reverse alcohol-induced ACLF is to detect and control severe ASH as early as possible, which is less likely to recover spontaneously. Table 1 Components of clinical scoring systems to assess prognosis in alcoholic hepatitis. Open in a separate window.
General therapeutic measures Alcohol abstinence is the linchpin of therapy for AH, since abstinence failure increases mortality rates among those with AH[ 32 ].
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