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Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 28, 2017; 23(36): 6549-6570
Published online Sep 28, 2017. doi: 10.3748/wjg.v23.i36.6549
Treatment options for alcoholic and non-alcoholic fatty liver disease: A review
Sukhpreet Singh, Natalia A Osna, Kusum K Kharbanda, Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
Natalia A Osna, Kusum K Kharbanda, Department of Internal Medicine, Nebraska Medical Center, Omaha, NE 68198, United States
Kusum K Kharbanda, Department of Biochemistry and Molecular Biology, Nebraska Medical Center, Omaha, NE 68198, United States
ORCID number: Sukhpreet Singh (000000021982876X); Natalia A Osna (0000000174980556); Kusum K Kharbanda (0000000177598889).
Author contributions: All authors equally contributed to this paper with conception, literature review, drafting and critical revision, editing, and approval of the final version.
Supported by Merit Review grants BX001155 from the Department of Veterans Affairs, Office of Research and Development (Biomedical Laboratory Research and Development) to Kharbanda KK.
Conflict-of-interest statement: No potential conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Kusum K Kharbanda, PhD, Professor, Veterans Affairs Nebraska-Western Iowa Health Care System, Research Service (151), 4101 Woolworth Avenue, Omaha, NE 68105, United States.
Telephone: +1-402-9953752 Fax: +1-402-9954600
Received: May 13, 2017
Peer-review started: May 16, 2017
First decision: June 22, 2017
Revised: July 25, 2017
Accepted: September 5, 2017
Article in press: September 5, 2017
Published online: September 28, 2017


Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are serious health problems worldwide. These two diseases have similar pathological spectra, ranging from simple steatosis to hepatitis to cirrhosis and hepatocellular carcinoma. Although most people with excessive alcohol or calorie intake display abnormal fat accumulation in the liver (simple steatosis), a small percentage develops progressive liver disease. Despite extensive research on understanding the pathophysiology of both these diseases there are still no targeted therapies available. The treatment for ALD remains as it was 50 years ago: abstinence, nutritional support and corticosteroids (or pentoxifylline as an alternative if steroids are contraindicated). As for NAFLD, the treatment modality is mainly directed toward weight loss and co-morbidity management. Therefore, new pathophysiology directed therapies are urgently needed. However, the involvement of several inter-related pathways in the pathogenesis of these diseases suggests that a single therapeutic agent is unlikely to be an effective treatment strategy. Hence, a combination therapy towards multiple targets would eventually be required. In this review, we delineate the treatment options in ALD and NAFLD, including various new targeted therapies that are currently under investigation. We hope that soon we will be having an effective multi-therapeutic regimen for each disease.

Key Words: Alcoholic liver disease, Non-alcoholic fatty liver disease, Treatment options, Glucocorticoids, Liver transplantation

Core tip: Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are serious health problems worldwide. Despite extensive research on understanding the pathophysiology of both these diseases there are still no targeted therapies available. In this review, we delineate the treatment options in ALD and NAFLD, including various new targeted therapies that are currently under investigation.


Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are serious health issues whose incidences are on the rise with each passing decade. Alcohol is responsible for approximately 4% of all deaths annually and 5% of all disabilities worldwide[1]. The Centers for Disease Control and Prevention in 2013 have estimated that in the United States acute deaths from alcohol attributable causes have outnumbered deaths from chronic diseases (44000 to 35000) ( Motor vehicle accidents have been considered the leading cause of acute death from alcohol-attributable injuries. While the incidence and prevalence of NAFLD is on the rise with each passing decade. Presently, 25%-35% and 5%-15% of the general population of Western and Asian countries, respectively, are affected by this disease[2]. This proportion is even higher in people with type 2 diabetes (60%-70%), and in those who are obese or morbidly obese (75%-92%) compared to the general population[3-5]. The prevalence of obesity in the United States has increased from 10% to 60% of the total population in the last three decades and is considered to be one of the main factors for the increasing prevalence of NAFLD[6].

The risk factors for both these diseases are well known. Patients with ALD consume an excessive amount of alcohol while NAFLD patients are usually obese; have insulin resistance and/or metabolic syndrome. Available data from various studies show that NAFLD may be the hepatic manifestation of metabolic syndrome[7]. The spectrum of both diseases ranges from benign steatosis to hepatitis to cirrhosis and hepatocellular carcinoma. Most patients with NAFLD or ALD have hepatic steatosis which is usually asymptomatic; only 20%-35% of these patients’ progress to steatohepatitis or cirrhosis[8]. The role of genetic polymorphism, mainly the patatin-like phospholipase domain containing 3 (PNPLA3) gene (rs738409 variant), has also recently been shown to be a risk factor for progression to advanced liver disease in both NAFLD and ALD that could explain why only a subset of patients who are chronic alcohol abusers or have high caloric intake present with progressive liver injury. Evidence from recent studies has shown this variability may be related to PNPLA3 variant (rs738409). The single nucleotide polymorphism rs738409 variant within the PNPLA3 causes a substitution of methionine for isoleucine at position 148. The GG phenotype of this PNPLA3 variant, rs738409, predicts a greater risk of progression to cirrhosis and HCC than the GC and CC phenotype which have shown to have a smaller risk for progression[9-12]. Despite an increased understanding of the pathophysiology and risk factors for ALD and NAFLD, we still do not have an appropriate therapeutic regimen for either disease.

The treatment options of ALD have not changed in the last four decades, and abstinence is still the cornerstone of treatment. This is supported by nutrition therapy and steroids[13,14]. Unfortunately, alcoholic hepatitis, which is the most serious manifestation of ALD, has a short term mortality of up to 50% in patients who are unresponsive to corticosteroid treatment[15]. Furthermore, limited treatment options are available for patients who are steroid non-responders or have contraindications to steroid usage (upper gastrointestinal bleed, impaired renal functions and sepsis). While the treatment for NAFLD is mainly directed toward attenuating the risk factor such as gradual weight loss by lifestyle modification with a focus on nutrition and exercise[16,17], other therapies utilizing insulin sensitizers (thiazolidinediones) and antioxidants (vitamin E) also have been found to be useful. However, their long-term safety and adverse effects have not been rigorously evaluated.

Thus, effective and safe therapeutic regimens are needed for these liver diseases. In this review, we present the current therapies as well as upcoming potential new approaches and treatment strategies for both diseases.

General management

For the last 50 years, abstinence has remained the primary therapy for ALD treatment. However, serious symptoms develop with the abrupt cessation of alcohol. Treating the alcohol withdrawal syndrome is thus extremely important and requires administration of fluid, calories, vitamins and minerals. Unstable patients need to be admitted to a critical care unit and airway protection is often required in patients with hepatic encephalopathy. Table 1 summarizes the treatment options and potential new options for ALD and ASH (alcoholic steatohepatitis).

Table 1 Treatment options for alcoholic liver disease and alcoholic steatohepatitis.
General management
Nutritional support
Anti-TNF therapy
Liver transplantation
Potential new therapies
Probiotics and antibiotics
Targeting various chemokines and interleukins
Endocannabinoids antagonists
Osteopontin inhibition
Stem cell therapy

Alcohol withdrawal syndrome: This syndrome is characterized by symptoms that occur 6-24 h after abrupt cessation of alcohol in patients who drink consistently and excessively. Long acting benzodiazepines like chlordiazepoxide or diazepam are administered for prevention of seizures while intermediate acting benzodiazepines like lorazepam are recommended in withdrawal patients who are elderly or have had recent head trauma or liver or respiratory failure[18]. Antiepileptic like carbamazepine can also be used as a benzodiazepine substitute for preventing seizures. Antipsychotics like haloperidol can be used if patients have excess agitation or psychotic symptoms[18]. Alcoholics are usually malnourished and deficient in vitamins, especially vitamin B1 (thiamine), thus putting them at risk of developing Wernicke encephalopathy, so all such patients should be given thiamine[19]. Parenteral thiamine is preferred over oral thiamine because in addition to impaired gastrointestinal absorption in alcoholics, oral thiamine has poor bioavailability that does not allow for attaining a sufficient concentration in cerebrospinal fluid. However, parenteral thiamine has a short half-life, thus multiple high-dosing is required to achieve sufficient concentration for active and passive diffusion through the blood brain barrier[20-22]. An IV dose of 500 mg (three times daily for two consecutive days) is recommended, followed by 500 mg of IV or IM thiamine for five more days if a response to the therapy is seen[23-25]. Another dosing regimen is 500 mg of IV thiamine (three times daily for 2-3 d), followed by 250 mg of IV thiamine for the next 2-3 d. The intravenous regimen is then followed by oral thiamine treatment indefinitely[26,27]. Thiamine should be given before fluids containing glucose to prevent neurological damage.

Abstinence: The first step towards treatment requires the patient to accept the fact that they are dependent and addicted to alcohol. Abstinence can resolve alcoholic fatty liver disease and can improve the survival rate of cirrhotic or decompensated liver failure patients. Thus, motivating the patients to abstain from alcohol and follow the proper treatment regime are major steps. However, preventing relapse in such patients has always been a big challenge. Patients can participate in Alcoholics Anonymous group meetings for self-control and motivation. Psychological support by an addiction specialist can also help in maintaining sobriety. Recognizing and treating any associated psychiatric conditions can be helpful in such patients[28]. Pharmacotherapy also helps in maintaining sobriety; drugs like naltrexone and acamprosate assist in reducing alcohol intake in heavy drinkers[29,30]. Topiramate has found to be effective in decreasing craving and withdrawal symptoms in alcoholics[31]. Disulfiram, an acetaldehyde dehydrogenase inhibitor, is also being used. It causes accumulation of serum acetaldehyde, which produces unpleasant sensations of nausea, vomiting, abdominal pain and dizziness. Such sensations deter patients from consuming alcohol[32]. Baclofen, a γ-amino butyric acid agonist, has also been found effective in promoting abstinence[33]. Most of these drugs (disulfiram, acamprosate, naltrexone, topiramate and baclofen), are used only for treatment of alcohol dependence[34] but are not FDA approved for ALD treatment. Of these, only baclofen has been studied for its safety and efficacy in clinical trials that compared placebo and baclofen treatment for ALD patients. In this trial, baclofen (10 mg or 20 mg twice daily) was more effective than placebo in maintaining abstinence. A 53% reduction in the number of drinks per day in the 10 mg baclofen group (P < 0.0001) and a 68% reduction in the number of drinks per day in the 20 mg baclofen group was reported, thus demonstrating a dose response effect of baclofen[35]. Naltrexone and disulfiram should be avoided in patients with liver problems because of hepatotoxicity[36]. Moreover, naltrexone should also be avoided in patients with renal failure due to its active tubular secretion[37]. Acamprosate, topiramate and baclofen were found to be safe in such patients[33,38,39]. Another drug which can help to maintain abstinence and reduce craving is metadoxine (MTD). Although not available in the United States, MTD is approved for use in several European countries. Apart from sustaining abstinence, oral MTB is also useful in acute ethanol intoxication since it is rapidly absorbed and augments alcohol metabolism by enhancing acetaldehyde dehydrogenase activity[39]. In a clinical trial with ASH patients, MTX improved liver function tests in 1 mo compared to the placebo[40]. In another trial, improved 3-6 mo survival of severely ill ASH patients who received the combination therapy with MTX compared to those that received monotherapy with either steroids or pentoxifylline (PTX) was observed. The survival rate was higher of the MTD-treated groups at 3 mo (PTX + MTD 59.4% vs PTX 33.3%, P = 0.04; steroids + MTD 68.6% vs steroids 20%, P = 0.0001) and at 6 mo (PTX + MTD 50% vs PTX 18.2%, P = 0.01; steroids + MTD 48.6% vs steroids 20%, P = 0.003) than in the non-MTD treated groups. Furthermore, the patients receiving MTD maintained greater abstinence than those not on MTD (74.5% vs 59.4%, P = 0.02)[41].

Smoking and obesity are independent risk factor for the progression of ALD[42,43]. Hence, lifestyle modifications like weight loss and smoking cessation are also helpful. Hepatitis C virus (HCV) is another independent risk factor for ALD progression due to synergistic deleterious effects of both agents in promoting liver injury and HCC development[44,45]. The main mechanisms of this effect are that both alcohol and HCV alter cellular immunity, increase free radical oxidative damage, and in the case of alcohol exposure, promote replication of HCV. Thus, the combination often result in the presence of advanced liver disease with severe histological features at a much younger age and a decreased survival[46,47]. It has been reported that alcoholic patients with HCV infection have a 30 fold increased risk of getting cirrhosis[48] and two to eight fold increased risk of all-cause mortality compared with those without the HCV infection[49,50]. Thus, all ALD patients should be screened for HCV before starting treatment and all HCV patients should be advised to stop or reduce alcohol consumption[51].

Nutritional support: Most patients with ALD are malnourished, and disease severity often correlates with the degree of malnutrition[52]. Most of the complications of ALD are strongly associated with protein calorie malnutrition[53]. Thus, nutrition support is one of the important steps in ALD treatment. Vitamins (like folate, vitamin B6, vitamin B12[54,55], vitamin A and thiamine[56] and minerals (like selenium, zinc, copper, and magnesium) are often found to be altered in ALD and some believe that these alterations play a role in initiation and progression of liver injury[57]. Especially, zinc levels are decreased in ALD patients and in animal models, and its supplementation has been shown to improve ALD[58]. A major study has also shown that enteral nutrition reduces infectious complications and improves 1-year mortality in such patients[59,60].

The American College of Gastroenterology and the American Association for the Study of Liver Diseases guidelines recommend 1.2 to 1.5 g/kg per d of protein intake and 35 to 40 kcal/kg per d of body weight for energy intake in patients with ALD[61]. This type of malnourished patient is often predisposed to infections so empiric antibiotic treatment is also advised.

Glucocorticosteroids: There have been various clinical trials on the use of corticosteroids for treating ALD patients[62-64]. Despite mixed outcomes, corticosteroids are overall beneficial for survival of these patients. Unfortunately, 40% of patients are unresponsive to corticosteroid with virtually no other treatment options. Hence, new target oriented therapies are critically required for the management of such patients[15].

A meta-analysis which pooled data from 3 randomized control trials, found that patients with modified DF ≥ 32 or MELD score ≥ 21 treated with prednisolone at 40 mg/d for 28 d and then a tapered dose over 2-4 wk (Class I, level A), conferred a 28-d survival benefit of glucocorticoids (85%) vs placebo (65%), with mortality decreasing from 35% in controls to 15% in patients on steroids[64]. Early changes in bilirubin levels (at day 7 of treatment) and the Lille score were used to predict the prognosis following steroid administration[65]. A Lille’s score greater than 0.45 on the 7th d after initiation of the treatment indicated that the patient was unresponsive to steroid therapy and predicted a lower survival rate of 25% at 6 mo. Recently this score has been re-classified as complete responders (score ≤ 0.16), partial responders (score 0.16-0.56), and null responders (score ≥ 0.56), and is associated with the 28-d survival rate of 91%, 79% and 53%, respectively, with P < 0.0001[13]. Steroids have been found to have a significant beneficial effect in complete and partial responders but not in null responders, hence discontinuation of steroid therapy is recommended for non-responders[66]. In addition to non-responders, steroids are generally avoided in patients with active infection, gastrointestinal bleeding, chronic hepatitis B virus infection or hepatorenal syndrome (HRS) because of adverse effects in these patient populations[67]. Steroids are relatively contraindicated in severe AH patients with coexistent sepsis. Thus, such patients may be treated with second line drug PTX[68]. Patients should also be screened for any infection before starting steroids and for infective complications while on steroids. Occurrence of sepsis and infective complications while the patient is on steroids is a poor prognostic sign[69]. It has been reported that patients infected after initiation of steroids had a significant lower 2-mo survival than patients with no infection (46.4% ± 6.9% vs 77.5% ± 3.2%, P < 0.00001). Thus, it is very important to differentiate infection at admission from that which occurs after starting the steroid treatment, as survival rates differ significantly. Overall, infection was more common in steroid null responders than responders[70].

PTX: Steroids are generally used as the first line of treatment in severe alcoholic hepatitis patients with DF ≥ 32, except in those with renal failure or HRS or contraindication to steroids[71]. PTX (400 mg 3 times per day for 28 d) is a substitute in such cases (Class I, level B). PTX decreases pro-inflammatory cytokines like TNF-α, has anti-fibrotic properties[72] and confers a mortality benefit by reducing the incidence of HRS[73]. A pilot study in ASH patients using PTX demonstrated reduced mortality and HRS incidence when compared to patients given a placebo[74]. These findings were later confirmed in a double-blind placebo controlled trial, where PTX decreased the 28-d mortality compared to placebo (24.5% vs 46%). Also, 50% of those who died in the PTX group developed HRS, while 91.7% who died in the placebo group developed HRS, confirming that PTX reduces the incidence of HRS in such patients[75]. A study in ASH patients comparing PTX and prednisolone have shown a better survival rate of 35.29% in the PTX group vs 14.71% on steroids. This reduced mortality was presumably because of a decrease in incidence of HRS and gastrointestinal bleeding in the PTX group. However, this study was underpowered[76]. To date, no other study has shown any additional survival benefit of the combined PTX and corticosteroid treatment[77,78]. A recently conducted randomized, multicenter, double-blind trial (STOPAH) across 65 hospitals in the United Kingdom that recruited more than a thousand patients revealed no impact of PTX on survival or disease progression in severe non-alcoholic steatohepatitis (NASH) patients in comparison to placebo[79,80]. However, because of a lack of other treatment options, PTX is being used in some centers.

Anti-TNF therapy: Intestinal gut permeability is increased in chronic alcoholics that promotes the translocation of gut luminal antigens especially endotoxin to reach the liver and enhance TNF-α production[81]. TNF-α has been found to correlate with disease severity in severe alcoholic hepatitis patients[82], and also play a vital role in alcohol induced liver injury in various animal models of alcoholic liver injury[83]. Further, mice deficient in TNF receptor 1 do not develop liver injury when administered alcohol[83]. Based on these considerations, various human studies were undertaken using anti-TNF therapy. While initial studies were found to be promising, the results could not be duplicated in larger clinical trials. A large randomized controlled trial comparing prednisolone alone with a combination of prednisolone and infliximab had to be stopped before completion because of an increase in infection rate in the prednisolone and infliximab combination group[84]. Further, patients had to be screened for tuberculosis and nocardia infection prior to participation in the study, thus limiting its clinical utility[85].

Antioxidants: Alcohol causes oxidative stress by increasing reactive oxygen species (ROS), and decreasing endogenous antioxidant levels[86]. But to date, all trials examining antioxidants (such as lecithin, β-carotene, vitamin C, vitamin E, allopurinol, desferrioxamine, and N-acetylcysteine) either alone or in combination with steroids have been disappointing[87,88].

Liver transplantation: Liver transplantation remains the definitive therapy for end stage decompensated cirrhosis due to ALD. Severe alcoholic hepatitis patients nonresponsive to steroids have a 3 mo mortality rate of 70% and with HRS the mortality rate is ≥ 90% unless the patients get liver transplantation[89,90]. At present, there are very few options for treating severe alcoholic hepatitis patients who are non-responsive to steroids and have a Lille score > 0.56. Thus, liver transplantation remains the only hope for such patients, but the issue of transplantation in alcoholics has always remained controversial. Concerns include the risk of recidivism, poor compliance with postoperative care, and ALD being a self-inflicted disease[91]. Recidivism following transplantation is a major challenge, which occurs at a rate of 10%-50%[92,93]. A meta-analysis reviewing factors responsible for recidivism found 3 major variables: a poor social support system, a family history of alcohol abuse/dependence and pre-transplant abstinence of 6 mo or less[94]. Thus, we need a multidisciplinary approach including the presence of an Alcohol Addiction Unit which can significantly contribute in reducing alcohol relapse after transplantation. Also, there should be psychological evaluation for any mental illness to determine patient suitability for transplantation.

Most transplant programs require the patients to undergo a 6-mo period of abstinence prior to transplantation[95]. Studies over the years have provided data both for and against the 6-mo abstinence rule. One report suggested that the 6-mo period of abstinence would allow the liver to recover with medical treatment and possibly there would be no need for transplantation[96]. Another study revealed that some recovery in liver function can take place within 3 mo of abstinence while many patients may die during the 6 mo of waiting period. This led to the suggestion of possibly reducing the period of abstinence to 3 mo[97]. Yet another study has also challenged the 6-mo abstinence rule by showing beneficial effects of early liver transplantation in steroid non-responding severe alcoholic hepatitis patients. In this study patients (with Lille score of 0.88) after 13 d of being unresponsive to steroids were put on the transplant list and it was found that the 6-mo survival rate was higher in patients who received early transplantation than those who did not (77% vs 23%, P < 0.001)[98].

However, patients who have received liver transplantation show a high incidence of de novo cancer[99,100], lymphoproliferative disorder and skin cancer. In some cases, squamous cell carcinoma of the oropharynx or esophagus has also been detected, likely due to the cumulative effects of smoking and post-transplant immunosuppressive drugs. Also, liver transplantation due to ALD is associated with a high rate of cardiovascular complications[101].

Potential new therapeutic options in ALD

Advances in basic science have helped to gain better insights into the pathophysiology of ALD that have provided new treatment options as discussed below.

Role of probiotics and antibiotics: Healthy intestinal flora is critically important for our well-being. An alcohol-induced change in the gut microflora plays a major role in the pathogenesis of alcoholic hepatitis. Equally important in liver disease progression is the alcohol-induced increased intestinal permeability that allows for the gut luminal antigens, including endotoxin/LPS (component of the cell wall of gram negative bacteria), to reach the liver and promote the synthesis and secretion of several inflammatory cytokines[102]. Various studies have proposed the use of probiotics in restoring the normal bowel flora in patients with ALD[103]. In a study performed on patients with ALD it was shown that using probiotics (Bifidobacterium or Lactobacillus) for 4 wk enhances and normalizes neutrophil phagocytic capacity and helps in reducing endotoxin-driven elevation in cytokine levels[104]. A similar study revealed significant improvement in AST, ALT and γ-glutamyl transferase levels in ALD patients administered probiotics (Bifidobacterium or Lactobacillus) for 5 d[105]. Rifaximin, a biochemical derivative of Rifamycin, the drug for hepatic encephalopathy, given for 28 d in a clinical trial decreased systemic endotoxin levels[106]. Indeed, blood LPS levels help in predicting response to steroids and mortality of alcoholic hepatitis patients[107]. Thus, modifying the gut microbe flora by probiotics and antibiotics could be a potential therapeutic approach for treating ALD which is being actively pursued.

Role of S-adenosylmethionine and betaine: S-adenosylmethionine (SAM) is a key methyl donor that is involved in many methylation reactions critical for normal liver function. SAM also acts as an antioxidant by activating the pathway for GSH synthesis. Decreased SAM levels have been reported in ALD patients; thus, elevating SAM levels could be a potential therapy. Various animal studies have shown liver injury can be reversed by preventing a decrease in SAM levels[108]. Also, SAM administration decreases oxidative stress and hepatic stellate cell activation[109]. A randomized controlled trial using SAM or placebo for 2 years in alcohol cirrhotic patients found that the mortality and liver transplantation rates were higher in the placebo group than in the SAM group (29% vs 12%)[110]. Thus, there is need for long-term, high quality trials in the future to establish its effectiveness.

Along the same line as SAM, betaine treatment has been very effective in improving liver injury in various animal models[111,112]. By remethylation homocysteine to generate methionine, betaine not only removes the toxic metabolites homocysteine and S-adenosylhomocysteine, but also generates SAM and normalizes the methylation potential[113]. Betaine is hepato-protective and prevents alcohol-induced steatosis, oxidative stress, apoptosis and abnormal protein accumulation[111,112], and breakdown of sulphur containing amino acid[114]. Clinical trials using betaine should be conducted.

Role of targeting various chemokines and interleukins: Chemokines play a pivotal role in the pathogenesis of alcoholic hepatitis. Studies have shown that various chemokines and their subfamily members, including CXCL5, CXCL6, CXCL10 and CCL20, are notably high in ASH livers compared to normal control livers and higher levels correlate with worse prognosis and outcomes[115,116]. Of these, CCL20 is the most elevated chemokine in ASH livers that attracts lymphocytes, monocytes, Th17 (Helper T17) cells, and dendritic cells. The consequent production of more chemokines and inflammatory mediators ultimately causes heavy neutrophilic infiltration and liver damage[117,118]. Additional studies in the future are required to determine if targeting CCL20 and other chemokines can be an effective and safe therapeutic approach for ALD patients.

IL-8 is one of the most important chemoattractant of neutrophils, which further causes hepatic infiltration as well as increased portal pressure[115]. A higher level of IL-8 in alcoholic hepatitis patients is associated with worse prognosis[115]. A therapeutic approach towards counteracting IL-8 levels should be considered as it will decrease neutrophil infiltration of the liver and prevent progressive liver damage.

IL-22 plays a critical role in bacterial infections and tissue repair. It is a part of the IL-10 family which decreases the production of various pro-inflammatory cytokines[119]. IL-22 has been found to have anti-apoptotic, antimicrobial, antioxidant and anti-steatotic effects, thus it can be used as a therapeutic option in ALD patients. It has been found that levels of T helper cells producing IL-22 correlate with improvement in alcoholic hepatitis patients[120]. Recombinant IL-22 administration showed improvement of liver injury in ethanol-fed mice[121] and in an animal model of acute hepatitis while blocking the IL-22 receptor led to worsening of the disease[122]. Thus, up regulating IL-22 levels can be a potential therapy for ALD.

IL-17 increases chemotaxis of neutrophils and various other chemokines and its levels are found to be increased in alcoholic hepatitis[123]. Secukinumab, an anti-IL-17 monoclonal antibody has shown favorable results in clinical trials of rheumatoid arthritis, psoriasis and uveitis[124]. Up until now, no study has been done in patients with liver disease using this monoclonal antibody, which can be a potential therapy.

Role of endocannabinoids: Endocannabinoids signalling through cannabinoid receptors, CB-1 and CB-2, has been implicated in the pathogenesis of ALD[125]. Studies using animal models of alcoholic liver injury revealed that CB1-deficient mice are resistant, whereas CB2-deficient mice are more susceptible to fatty liver damage[126,127]. These findings suggested that therapy targeting CB1 and CB2 receptors should be utilized as an alternative for the management of ALD.

Role of osteopontin: There is substantial evidence suggesting that osteopontin (OPN) plays a notable role in wound healing in response to injury in many organs[128]. It is an extracellular matrix protein with pro-fibrogenic properties, and is found to be highly expressed in alcoholic hepatitis patients[129]. One study demonstrated attenuation of alcohol mediated liver disease in mice lacking OPN[130]. More studies should be conducted to assess OPN as a potential therapeutic target.

Stem cell therapy: Hematopoietic stem cell transplant ion is an evolving field. Though limited research has been performed in this area, it could be a promising therapeutic approach in the future. Recent studies have suggested that stem cell transplantation may reduce liver inflammation and improve fibrosis in patients with liver cirrhosis[131]. Mesenchymal stem cells (MSC) directly inhibit the activation of hepatic stellate cells and may also induce apoptosis of hepatic stellate cells[132]. They have also been reported to stimulate proliferation of endogenous hepatocytes[133,134]. A pilot study performed on 12 patients with ALD to assess the regenerative capacity of the liver after infusion of bone marrow derived-MSC through the hepatic artery showed improvement in the histological grading with an overall decrease in TGF-β, type 1 collagen and smooth muscle actin[135]. A significant improvement in the Child-Pugh score and albumin levels was noted in another similar study on 9 cirrhotic patients given bone marrow derived stem cells via the portal vein[136]. Liver function was also reported to be better after stem cell therapy in cirrhotic patients[137]. Results of these studies are encouraging and stem cell therapy could serve as a potential breakthrough treatment for ALD. However, the benefits and safety of stem cells should be examined in a large sized RCT.


Like ALD there is no effective treatment to date for NAFLD. In the absence of a proven effective therapy, we must follow a multi-disciplinary approach in NAFLD treatment, where a combination of drugs and factors are taken into consideration to counter multiple pathological risk factors involved in NAFLD. These are summarized in Table 2 and are further discussed below.

Table 2 Treatment options for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.
Lifestyle changesWeight loss
Dietary changes
Insulin sensitizersThiazolidinedione’s
Lipid lowering agentsStatins
Hepatoprotective agentsUDCA
AntioxidantsVitamin E
Incretin analoguesGLP-1 agonists
DPP-IV inhibitors
Anti-inflammatory agentsPTX
Angiotensin receptor blockers
Endocannabinoid antagonists
Bariatric surgery
Liver transplantation
Potential new therapeutic optionsCaspases inhibitors
ASK1 inhibitors
p38 MAPK inhibitors
PPAR- alpha and delta agonists
FXR agonists
NOX-1/4 inhibitors
Galectin-3 antagonists
Acetyl CoA carboxylase inhibitors
FGF-21 and FGF-19 analogues
CCR2 and CCR5 inhibitors
SCD-1 inhibitors
Lysyl oxidase-like 2 inhibitors
Weight loss, dietary modification and changes in lifestyle

Treatment is mainly directed towards weight loss and risk factor reduction, as most patients are obese or have metabolic syndrome[138]. A weight loss of 3%-5% reduces steatosis while a ≥ 5%-7% drop in weight has been shown to resolve NASH. Greater reductions in weight (i.e., ≥ 10%) may also improve hepatic fibrosis. Weight loss is mainly due to diet modification and exercise. However, the shortcoming of this approach is the lack of adherence and non-compliance with time[139]. Various studies have shown the benefit of weight loss in NAFLD[140]. Dietary modification also plays a key role since a carbohydrate-rich diet, especially with high fructose, is the major cause of obesity, insulin resistance and NAFLD development[141]. Thus, sugar consumption should be kept below 10% of total caloric intake in a day and a fructose-rich diet should be avoided in such patients. Food rich in omega-3 fatty acid should be included and those rich in saturated fat and omega-6 fatty acid should be excluded from the diet[142]. An omega-3 fatty acid rich diet promotes fatty acid oxidation and decreases fatty acid synthesis, thus improving the lipid profile. Fish and fish oil consumption should be promoted as they are rich in omega-3 fatty acid[143]. Thus, diet and moderate exercise are preferred methods of natural weight loss. A study also revealed that a combination of diet changes and exercise lowered ALT levels better in NAFLD patients than insulin sensitizers or other hypoglycaemic drugs[144]. Weight loss is also beneficial as it improves the cardiovascular risk profile[145]. Nevertheless, it should be noted that weight loss should be gradual, as very rapid weight loss has been associated with a worsening of steatohepatitis and an increased risk for liver failure[146] and gallstones[147].

Apart from natural weight loss, drugs like Orlistat and Sibutramine are also being used for controlling weight. Orlistat is a lipase inhibitor, that prevents fat absorption in the liver and intestine, thus causing weight loss. Sibutramine on the other hand is a serotonin reuptake antagonist which suppresses appetite. Both agents have shown to reduce serum transaminase levels and hepatic steatosis[148,149].

Insulin sensitizers

Since NAFLD is closely associated with obesity and metabolic syndrome, and both conditions cause insulin resistance, treatment strategies invariably include agents which enhance insulin sensitivity.

Thiazolidinedione: Thiazolidinediones (TZDs) are peroxisome proliferator activated receptor (PPAR)-γ agonists, which improve hepatic and peripheral insulin sensitivity[150] via increasing plasma adiponectin levels[151]. In addition, adiponectin is also shown to have anti-fibrotic and anti-inflammatory properties. Thus, multiple factors involved in pathogenesis of NAFLD such as high insulin resistance, low adiponectin levels and high pro-inflammatory cytokines are all targeted by these drugs. First generation TZDs (troglitazone) have shown improvement in steatohepatitis but had to be stopped due to hepatotoxicity[152]. However, it paved the way for second generation TZDs (rosiglitazone and pioglitazone) which are not hepatotoxic and showed improvement in insulin resistance, hepatic steatosis and aminotransferases levels[153,154]. A long-term therapy with second generation TZDs may be required as their benefits tend to reverse on discontinuation; however long term therapy is associated with various adverse effects like congestive heart failure, weight gain, peripheral oedema, anaemia and osteoporosis[155,156]. Also, it has been found that TZD therapy alone without nutrition and lifestyle changes is often not effective[154]. Thus, we need additional studies on a larger population with a combination of other drugs to find safe and efficacious treatment options.

Metformin: Metformin, a hypoglycaemic drug, is used for treatment of type 2 diabetes mellitus. Metformin improves hepatic and peripheral insulin resistance by decreasing hepatic gluconeogenesis, lipogenesis and glucose reabsorption from the gut and increasing fatty acid oxidation[157]. While metformin does not cause weight gain as TZDs, it can cause some minor gastrointestinal adverse effects and sometimes lactic acidosis is seen in patients with renal impairment. Various studies have documented an improved insulin sensitivity, cholesterol and aminotransferase levels in NASH patients on metformin but the results are mixed when assessing biopsy-guided improvement in steatosis and NASH activity score (NAS)[158]. Thus, while its effectiveness as a monotherapy is debatable, metformin could be a part of a multi-therapeutic regimen for the management of NAFLD patients.

Lipid lowering agents

NAFLD is often associated with obesity and metabolic syndrome which is characterized by hypercholesterolemia and hypertriglyceridemia. Therefore, the use of lipid lowering agents could be beneficial. While, clofibrate did not show any beneficial effect on the liver tests or the histological scores[159], gemfibrozil showed improvement in ALT levels in NAFLD patients compared to the placebo[160]. Statins have also been tried but have shown variable effects. Nevertheless, lipid-lowering agents should be given as most NAFLD patients are hyperlipidemic and thus have a high risk of developing cardiovascular issues.

Ezetimibe, a drug that inhibits the reabsorption of lipids from the intestine, reduces serum TNF-α levels[161], hepatic lipid content and ALT levels in a mouse model of NAFLD[162]. Human studies for this drug are awaited.


This drug has hepatoprotective properties and has been studied in various clinical trials for NAFLD treatment. Initial small studies revealed an improvement in liver enzyme levels and hepatic steatosis[159], but a subsequent RCT showed no improvement in liver histology or aminotransferases[163]. Thus, UDCA is not approved as a monotherapy but is part of a drug combination regime in various trials on NAFLD in progress.

Vitamin E

ROS generation plays an important part in the progression of NASH[164]. Vitamin E and C decrease oxidative stress and thus have been evaluated in patients with NASH. Various clinical trials with vitamin E have revealed an improvement in liver test functions and reduction in oxidative stress markers but significantly less improvement in the histological grading of the disease has been noted[165,166]. A recent trial using a combination of vitamins E and C for 6 mo showed that these were no better than placebo for treating patients with NASH[167]. One study with a three arm trial involving placebo, UDCA and Vitamin E/UDCA combination showed improvement in histology only in the Vitamin E/UDCA combination arm[168]. Another trial comparing a combination of pioglitazone and vitamin E with vitamin E alone over a period of 6 mo showed a decrease in serum ALT in both groups, but a significant histological improvement was only seen in the combination group[169]. A meta-analysis involving high-dose vitamin E supplementation has shown an increase in all-cause mortality and cardiovascular deaths, thus decreasing the enthusiasm for vitamin E therapy[170].

Incretin analogues

Glucagon-like peptide 1 agonists: Glucagon-like peptide 1 (GLP-1) is an incretin hormone that is produced by intestinal mucosa L cells. GLP-1 has a short half-life, as it is rapidly degraded by dipeptidyl-peptidase IV (DPP-IV). GLP-1 agonists are resistant to DPP-IV and are useful since they lower blood glucose levels by decreasing glucagon secretion, delay gastric emptying and stimulate pancreatic β cells to increase insulin secretion. Furthermore, these agonists have a central appetite suppressive effect and promote weight loss which are favorable outcomes for obese NAFLD/NASH patients[171]. In an obese mouse model, it has shown to improve insulin sensitivity and reduce hepatic steatosis[172].

In various clinical trials, liraglutide has proven to be an effective therapeutic drug for type 2 diabetics producing a good glycemic control and significant weight loss in such patients. Since diabetes is an important component of metabolic syndrome and associated NAFLD development, the effective glycemic control and weight loss makes liraglutide a suitable therapeutic option for NAFLD[173]. In a phase 2 clinical trial study (LEAN study) with 52 NASH subjects using liraglutide compared to placebo, 39% of patients using liraglutide vs 9% using placebo attained the primary endpoint (histological resolution of NASH without worsening of fibrosis). Two (9%) of 23 patients in the liraglutide group vs eight (36%) of 22 patients in the placebo group had progression of fibrosis. The trial was designed using A’Hern’s single-group method, which required eight (38%) of 21 successes in the liraglutide group for the effect of liraglutide to be considered clinically significant. The liraglutide treatment group has also shown improved insulin sensitivity, reduced hepatic glucose production and lipogenesis ( Thus, liraglutide was safe, well-tolerated, and led to histological resolution of NASH, warranting longer term studies in such patients[174,175].

DPP-IV inhibitor: DPP-IV inactivates both incretin hormones (GIP, GLP-1), therefore DPP-IV inhibitors are used in the treatment of type 2 diabetes[176]. NASH patients exhibit higher DPP-IV expression[177]. A cross sectional study on type 2 diabetics without any evident liver disease and NAFLD patients revealed a strong positive correlation of serum DPP-IV activity and insulin resistance with liver enzymes only in NAFLD patients [178]. Serum DPP-IV activity was not increased in the type 2 diabetics with no evidence of liver disease. This led the authors to postulate that the increased serum DPP-IV reported in earlier studies in type 2 diabetics may have been due to some un-diagnosed liver disease and that the excess DPP-IV found in the serum of NAFLD patients is of hepatic origin. They further suggested that serum DPP-IV should be considered as a potential liver disease biomarker[178]. This supposition was also corroborated by another study which analyzed human liver biopsy specimens and showed a strong correlation of DPP-IV expression with stages of fatty liver and NASH[179].

Furthermore, a DPP-IV inhibitor like sitagliptin, decreases hepatic steatosis and serum transaminases levels when given to diabetic NAFLD patients[180,181]. In a recent randomized, double-blind, placebo controlled study, sitagliptin was shown to be safe but no more effective than placebo in improving hepatic steatosis and fibrosis in NAFLD patients. However, in comparison to sitagliptin, an increase in hyaluronic acid levels and increase in FIBROSpect II index (measure of liver fibrosis) was reported in the placebo arm[182]. Another RCT comparing sitagliptin to placebo also revealed no improvement in fibrosis score or NAS after 24 wk of therapy, but reported that sitagliptin increased adiponectin and decreased γ-glutamyl transferase levels[183]. There have been only a few clinical trials with sitagliptin till date. However, despite the lack of convincing evidence, the efficacy of sitagliptin in improving liver fibrosis in NAFLD cannot be ruled out. This is because not only were the trials underpowered but were possibly not long enough to evaluate its effectiveness. Hence, stagliptin effect should be assessed in clinical trials of longer duration with larger number of enrolled patients with NAFLD/NASH.


PTX can be of potential benefit in NAFLD due to its effects on reducing free radical oxidative stress, TNF-α levels, and potential anti-fibrotic properties[184]. In some trials, PTX has shown improvement in steatosis, lobular inflammation and ballooning degeneration in comparison to baseline, but improvement was not clinically significant when compared to placebo[185]. In a small RCT on NASH patients, 400 mg PTX given three times per day for a period of 1 year decreased hepatic steatosis, inflammation and NAS by ≥ 2 points and modestly reduced fibrosis[186]. This favorable response was due to a reduction in free-radical-mediated lipid peroxidation[187]. In two recent small RCT evaluating the role of PTX has also shown beneficial effect by improving liver enzymes and histology in NAFLD patients[188,189]. In a recent meta-analysis it was found that only PTX and OCA improve fibrosis in NASH patients[190]. Therefore, further studies are warranted to determine its role in NAFLD/NASH treatment.


Probiotics: Like alcoholic patients, NAFLD patients also exhibit gut bacterial overgrowth, enhanced gut permeability and increased paracellular leakage of gut luminal antigens, factors that promote NASH development. Thus, probiotics can be a therapeutic option for NASH patients[191,192]. In a RCT, improvement in liver enzymes was noted in NAFLD patients on Lactobacillus bulgaricus and Streptococcus thermophilus treatment compared to placebo[193]. In another study, patients randomized to a combination of Bifidobacterium longum with fructo-oligosaccharides plus lifestyle modification (diet and exercise) or lifestyle modification alone for 24 wk[194], showed a significant decrease in steatosis, TNF-α, AST and NAS in the combination treatment group. Thus, probiotics could also be a part of a combination therapy for NAFLD patients.

Angiotensin receptor blockers: NAFLD is often associated with metabolic syndrome and hypertension is an important component of metabolic syndrome. Thus, angiotensin receptor blockers can be a part of combination therapy regimen of NAFLD. A small pilot study of patients with NASH showed improvements in necro-inflammation and fibrosis with losartan (an angiotensin II receptor antagonist) treatment[195]. Larger studies are required to explore their potential in the management of NAFLD.

Endocannabinoid antagonists: CB1 and CB2 are two receptors which mediate endocannabinoid (EC) activity. The CB1 receptor is mainly expressed in the brain and liver, while CB2 is mainly expressed in the immune cells. These receptors are found to be upregulated in various liver diseases[196]. Anandamide, a highly potent endogenous agonist, has been shown to promote diet-induced obesity and hepatic steatosis in mice via acting on the CB-1 receptors.[197] Conversely, CB-1 knockout or rimonabant (CB-1 receptor antagonist)-treated high-fat diet fed mice have less steatosis and weight gain than controls[198]. However, while rimonabant was effective in promoting weight loss of obese patients in many clinical trials, it also caused intolerable adverse effects like depression, anxiety and increased suicidal tendencies that has led to its discontinuation for routine use. Thus, novel cannabinoid type 1 receptor blockers with selectivity for peripheral receptors are required which can have favorable metabolic benefits but decreased psychiatric adverse effects[199,200].

Bariatric surgery: Steady weight loss with exercise and lifestyle modification has been found to increase insulin sensitivity and improve liver histology of NAFLD patients. But the rapid weight loss induced by bariatric surgery increases the risk of developing hepatic failure especially in the cirrhotic patients[201,202]. Bariatric surgery is mostly done in non-cirrhotic NAFLD patients who are morbidly obese. It is, however, not recommended as a primary mode of treatment in such patients as there is still a risk of developing liver failure postoperatively.

Liver transplantation: NAFLD patients with end-stage decompensated liver disease should be considered for liver transplantation. But this is not a permanent cure as NAFLD has been shown to recur in post-transplant liver[203]. This is because transplantation does not correct the multifactorial pathway alteration(s) responsible for NAFLD/NASH development. Therefore, the goals of therapy before and after transplant should be always towards weight management, proper diet consumption and adequate control of glucose and lipids.

Potential new therapeutic options in NAFLD

With advancement in the field of technology, especially bioinformatics and biogenetics, new therapies are currently being tried for managing NASH, some of which are reviewed below.

Caspase inhibition/emricasan: Caspases are enzymes which are required for completion of various apoptotic pathways and for stimulation of various cytokines and therefore, can be a potential therapeutic target. Various animal studies in the past have supported this approach[204,205]. Emricasan, a pan-caspase protease inhibitor, has been shown to inhibit apoptosis, inflammation and fibrosis in a preclinical model of NASH. A preliminary report of a phase II clinical trial showed significantly decreased serum ALT and cCK18 levels in NAFLD patients[206]. The therapeutic effects of this drug have also been examined in various other fibrotic liver diseases where it has been shown to reduce hepatic venous pressure gradient (HVPG). A phase II trial on NASH patients with fibrosis ( Identifier: NCT02686762) is ongoing to evaluate the efficacy of emricasan (10 mg and 100 mg/d for 72 wk) to improve fibrosis without worsening of NASH (primary endpoint) and to assess histological improvement or resolution of NASH (secondary endpoint).

ASK1 inhibitors/ASK1-I: Apoptosis signal regulating kinase 1/ASK1 is a MAP3 kinase (mitogen activated protein 3 kinase) which induces apoptosis and fibrosis when activated by stimuli like hyperglycaemia, TGF-β and ROS. This enzyme has been shown to be activated in patients with NASH. GS 4997, a first-in-class, oral small molecule ASK1 inhibitor, given to animals with established NASH showed a significant reduction in hepatic steatosis, fibrosis, body weight, fasting blood glucose, insulin resistance, lipogenesis, cholesterol biosynthesis, plasma AST/ALT levels, and soluble/insoluble collagen and many metabolic parameters of NASH[207-209]. GS-4997 is currently being investigated in a phase II clinical trial of patients with NASH ( Identifier: NCT02466516).

p38 MAPK inhibitors: Chronic inflammation is one risk factor that contributes to progression of NAFLD. p38 mitogen activated kinases (p38 MAPK) is a stress kinase whose activation has been shown to promote inflammation[210-212]. In mammals, four p38 MAPK isoforms have been identified: p38a, b, c and d. p38 MAPK isoforms -c and -d have recently been shown to contribute to the development of steatosis and NASH in various models of NAFLD by regulating T-cell activation, neutrophil recruitment and macrophage production of TNF-α[213,214]. Studies have shown higher liver expression of p38 protein in obese individuals with steatosis. Thus, deletion of p38 -c and -d in the myeloid cells prevents neutrophil migration to the liver, protecting these animals against diet induced steatosis and inflammation[215]. Therefore, p38 MAPK can be an effective potential target for NAFLD therapy.

PPAR-α and -δ agonists (Elafibranor): PPAR-α is mainly expressed in liver and is principally involved in lipid metabolism, while PPAR-δ is found in various tissues of the body and is involved in fatty acid oxidation and insulin sensitivity. In various animal models, PPAR has been shown to be hepato-protective via its effect on decreasing lipid accumulation, inflammation and fibrosis[216-218]. In a RCT ( NCT01694849), a daily dose of 80 or 120 mg Elafibranor or placebo was given to non-cirrhotic NASH patients for 52 wk[219]. The primary endpoint of this study (i.e. resolution of NASH without worsening of fibrosis), was not met. However, it was found that patients with an initial NAS of ≥ 4 on 120 mg/d of drug showed significant improvement in hepatic inflammation. Nevertheless, Elafibranor efficacy was described as sub-optimal. Another study is in phase 3 clinical trial to clarify Elafibranor’s (GFT505) effectiveness ( NCT02704403) to improve the histological grade and reduce all-cause mortality and liver-related outcomes in patients with NASH and fibrosis.

Farnesoid X receptor/FXR agonists (Obeticholic acid): Obeticholic acid (OCA) is a Farnesoid X receptor agonist. It is a synthetic derivative of natural bile acid chenodeoxycholic acid (CDCA), with potency 100 times more than CDCA. Farnesoid X receptor is a nuclear hormone receptor which regulates bile, cholesterol, glucose and lipid metabolism[220,221]. These receptors act via multiple pathways; they inhibit hepatic lipogenesis, gluconeogenesis, glycogenolysis and maintain cholesterol balance and improve insulin sensitivity[222,223]. In various animal models, OCA has shown anti-inflammatory and anti-fibrotic properties and also improves insulin resistance and hepatic steatosis[224]. In an animal model, OCA was shown to reduce hepatic inflammation and fibrosis and also decreased intrahepatic vascular resistance and improved portal hypertension[225]. Also in an animal model with advanced cirrhosis, treatment with OCA was shown to reduce gut bacterial translocation from 78.3% to 33.3% (P < 0.01) indicating its effect in maintaining intestinal barrier integrity. Thus, it can be used as an option to prevent bacterial infection in such patients[226]. In a small pilot trial of diabetic patients with NAFLD, it was shown to decrease weight and serum γ-glutamyl transferase levels as well as an improvement in liver fibrosis[227]. The multicenter trial (FLINT trial:NCT01265498) showed a decrease in NAS, an improvement in hepatic steatosis, and a small decrease in liver fibrosis in non-cirrhotic NAFLD patients on a daily dose of 25 mg OCA compared to placebo[228]. A phase 3, double blind RCT multicenter study is ongoing to evaluate the safety and efficacy of OCA in NASH patients ( Identifier: NCT02548351). The effect of OCA on liver histology in non-cirrhotic NASH patients with stage 2 or 3 fibrosis will be compared to placebo. 2065 patients are randomized in 1:1:1 to receive 10 mg OCA, 25 mg OCA or placebo. An interim analysis is to be done at 18 mo and the study is expected to end in 6 years. However, an increase in total cholesterol and triglycerides with a decrease in high density lipoprotein was also seen in the OCA group when compared to placebo[228]. Two phase I studies conducted in healthy individuals given OCA for 14-20 d also reported decreased HDL and increased LDL cholesterol, regardless of the dose of OCA (5, 10 or 25 mg daily)[229,230]. These pro-atherogenic effects can be a concern for NAFLD patients that already have a high risk for cardiovascular adverse events because of dyslipidemia. Therefore, combination therapies with FXR agonist and agents that prevent atherosclerosis are warranted. Apart from OCA, various other FXR agonists such as GW4064, PX20606, GS-9674 and INT-767 are being tested. GW4064, PX20606 and GS-9674 are synthetic non-steroidal FXR agonists. INT-767 is a dual agonist for FXR and TGR5 (the transmembrane G-protein bile acid receptor) while BAR502 is a dual agonist for FXR and GPBAR1 receptors. In various animal models, these agonists have been shown to improve NASH histological features, steatosis and fibrosis [231-234]. Thus, clinical trials are anticipated for these agents as well.

NOX-1/4 inhibitors: NADPH oxidase (NOX), is an enzyme which catalyzes the production of ROS[235]. In various animal models these enzymes are expressed on hepatic stellate cells and promote liver fibrosis and inflammation[236]. In a murine model, NOX 1/4 inhibitor (GKT137831) has been found to decrease ROS production and fibrotic gene expression, thus decreasing liver inflammation and fibrosis[235]. Therefore, these agents can have a beneficial effect in decreasing liver fibrosis in NASH patients but require further studies.

Galectin-3 antagonists: Galectins are proteins that bind to terminal galactose residues on glycoproteins[237]. They are usually expressed in immune cells and are at very low levels in the body but their levels are increased during inflammation and fibrosis[238,239]. Galectin-3 knockout mice show reduced hepatic fibrosis after liver injury. GR-MD-02, a galectin-3 inhibitor, has shown a decrease fibrosis, hepatic steatosis and collagen deposition in various animal models with NASH[240]. A Phase II clinical trial for evaluation of the safety and efficacy of GR-MD-02 for the treatment of liver fibrosis and associated portal hypertension in patients with NASH cirrhosis is currently underway ( Identifier: NCT02462967). This study has enrolled subjects with portal hypertension and biopsy proven NASH cirrhosis (excluding subjects with medium and large varices and those with decompensated cirrhosis). The expected primary completion date is October 2017 while the study is expected to complete in February 2018.

Acetyl CoA carboxylase inhibitor: Malonyl coenzyme A plays a key role in fatty acid metabolism that maintains a balance between lipogenesis and lipid oxidation[241]. It promotes fatty acid synthesis, and inhibits β-oxidation of lipids. Malonyl CoA is generated from acetyl CoA and the key enzyme regulating this process is acetyl CoA carboxylase (ACC). Therefore, inhibiting ACC prevents fatty acid synthesis and promotes its oxidation. In a murine model of NAFLD, inhibition of ACC has been shown to decrease hepatic steatosis, lipogenesis and increase insulin sensitivity and fatty acid oxidation[241]. Chronic administration of ND-630 (ACC isozyme 1 and 2 inhibitor) to diet-induced obese rats and Zucker diabetic fatty rats caused a reduction in hepatic steatosis, lowered haemoglobin A1C (0.9% reduction) and improved insulin sensitivity[242]. Also in a crossover, randomized, double-blind trial, administration of a single dose of NDI-010976 (a highly potent and selective inhibitor of both ACC1 and ACC2) to overweight/obese subjects inhibited de novo lipogenesis in a dose dependent manner[243]. Together, all these results suggest its usefulness in treating metabolic syndrome, type 2 diabetes mellitus, and fatty liver disease. Thus, large long term clinical trials in humans are needed.

FGF-21 and FGF-19 analogues: FGF-21 (fibroblast growth factor 21) is a hormone which is secreted mainly from the liver. It is a starvation-induced peptide hormone with pleiotropic effects whose levels are mainly increased during fasting[244,245]. While FGF-21 concentrations are elevated in human subjects with NAFLD, a lack of FGF-21 worsened the metabolic disorders in an animal model of NASH[246]. Conversely, treatment with FGF-21 analogue (BMS-986036) was found to improve insulin sensitivity, hepatic steatosis and decrease lipogenesis[247]. In another animal model of NASH, LY240531 (a FGF-21 variant) was shown to increase fatty acid oxidation by enhancing hepatic mitochondrial oxygen consumption. Also, various inflammatory markers and AST and ALT levels were reduced, suggesting an attenuation of liver injury[248]. BMS-986036 is currently being evaluated in a phase II trial of NASH patients ( Identifier: NCT02413372).

FXR activation in terminal ileum by bile acid promotes FGF-19 secretion which, in turn, decreases bile acid synthesis and gluconeogenesis[245]. It also results in the activation of the FGFR4 receptor which has a proliferative impact on hepatocytes, thus raising the potential for tumorigenesis[249]. NGM-282, a variant of FGF-19 has been shown to decrease bile acid synthesis and gluconeogenesis without having a tumorigenic effect[245]. In a preliminary pre-clinical study, NGM-282 was shown to improve hepatic steatosis and histological features of NASH in an animal model[250].

CCR2 and CCR5 inhibitor (cenicriviroc): CCR2 and CCR5 are chemokine receptors which are mainly expressed in various immune cells like monocytes, macrophages, Kupffer cells, natural killer cells, T cells and stimulate hepatic stellate cells thus promoting fibrosis. These receptors can be inhibited by cenicriviroc (CVC) which is an inhibitor of the CCR2 and CCR5 receptors. CVC has been shown to decrease fibrosis and inflammation in various animal models of diet-induced NASH or substance-induced NASH[251-254]. There is an ongoing trial ( Identifier: NCT02217475) with CVC to examine its efficacy in NASH patients with fibrosis. It will compare shorter vs longer CVC treatment and assess correlations between decreased inflammation and fibrosis[255].

SCD-1 inhibitors (aramchol): Aramchol is a synthetic lipid molecule which decreases hepatic fat accumulation by decreasing lipogenesis and increasing fatty acid oxidation by inhibiting stearoyl coenzyme A desaturase 1 (SCD1) enzyme[256]. This drug was found to decrease liver fat content significantly in 60 NAFLD patients who were given 100 or 300 mg of this drug daily for 3 mo; the effect of the drug on fibrosis was not determined[256]. A phase II clinical trial of this drug is ongoing on NASH patients with fibrosis ( Identifier: NCT02279524).

Lysyl oxidase-like 2 inhibitor (simtuzumab): Lysyl oxidase-like 2 inhibitor is an enzyme which causes cross linkage of collagen, thus preventing its degradation[257]. This enzyme has been found to promote fibrosis in liver diseases of various etiologies. A monoclonal antibody (simtuzumab) to this enzyme has been studied in various animal models and has shown to decrease fibrosis[258]. Two big trials are ongoing to examine the efficacy of this drug in decreasing fibrosis and preventing progression to cirrhosis in such patients ( Identifier: NCT01672866 and NCT01672879).

Sirtuins: Sirtuins (SIRTs) are information regulator proteins. There are various types of SIRTs found in mammals. SIRT-1, a member of this family of proteins, has anti-inflammatory effects and increases insulin secretion and sensitivity[259]. A decreased liver expression of SIRT-1 was observed in an animal model of NAFLD[260]. Since SIRT-1 activator (resveratrol) was shown to improve hepatic steatosis and insulin sensitivity[261], SIRT-1 could be a potential target for treatment of NAFLD patients’ in future clinical studies.

Betaine: A phase II clinical trial of betaine in patients with a clinical diagnosis of NAFLD is close to completion. This trial ( Identifier: NCT03073343) will evaluate the effect of two doses of oral betaine in reducing ALT levels in NAFLD patients with and without diabetes.


Both ALD and NAFLD are chronic liver diseases with similar spectrums from simple steatosis to cirrhosis with basic differences only in their etiology. Despite understanding much of the pathophysiology of both diseases, there is still no effective treatment for either disease. The treatment for ALD basically relies on alcohol abstinence, nutritional support, lifestyle modifications, steroids and symptomatic treatment of complications of cirrhosis while for NAFLD, the focus of treatment is on weight loss, exercise and the use of insulin sensitizers. Removal of the cause would be the most efficient way of treating both diseases. However, the involvement of several inter-related pathways in the pathogenesis of these diseases indicates that a single therapeutic agent is unlikely to be an effective treatment strategy. Hence, a combination therapy towards multiple targets would eventually be required. Future areas of research also include the safety, efficacy, and ethical considerations of liver transplant in severe ASH for patients who are not responding to medical therapy. Various new target-oriented therapies are under investigation for both diseases and hopefully soon we will be having an effective multi-therapeutic regimen for each disease.


Manuscript source: Invited manuscript

Specialty type: Gastroenterology and hepatology

Country of origin: United States

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P- Reviewer: Firneisz G, Marcos M, Zheng SJ S- Editor: Gong ZM L- Editor: A E- Editor: Zhang FF

1.  Rehm J, Mathers C, Popova S, Thavorncharoensap M, Teerawattananon Y, Patra J. Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders. Lancet. 2009;373:2223-2233.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2298]  [Cited by in F6Publishing: 2451]  [Article Influence: 175.1]  [Reference Citation Analysis (0)]
2.  Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73-84.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5322]  [Cited by in F6Publishing: 5913]  [Article Influence: 844.7]  [Reference Citation Analysis (0)]
3.  Adams LA, Angulo P, Lindor KD. Nonalcoholic fatty liver disease. CMAJ. 2005;172:899-905.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 359]  [Cited by in F6Publishing: 386]  [Article Influence: 21.4]  [Reference Citation Analysis (3)]
4.  Ballestri S, Zona S, Targher G, Romagnoli D, Baldelli E, Nascimbeni F, Roverato A, Guaraldi G, Lonardo A. Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis. J Gastroenterol Hepatol. 2016;31:936-944.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 398]  [Cited by in F6Publishing: 448]  [Article Influence: 64.0]  [Reference Citation Analysis (0)]
5.  Lonardo A, Ballestri S, Guaraldi G, Nascimbeni F, Romagnoli D, Zona S, Targher G. Fatty liver is associated with an increased risk of diabetes and cardiovascular disease - Evidence from three different disease models: NAFLD, HCV and HIV. World J Gastroenterol. 2016;22:9674-9693.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 84]  [Cited by in F6Publishing: 83]  [Article Influence: 11.9]  [Reference Citation Analysis (0)]
6.  Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends in obesity among US adults, 1999-2008. JAMA. 2010;303:235-241.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4734]  [Cited by in F6Publishing: 4959]  [Article Influence: 381.5]  [Reference Citation Analysis (0)]
7.  Rowell RJ, Anstee QM. An overview of the genetics, mechanisms and management of NAFLD and ALD. Clin Med (Lond). 2015;15 Suppl 6:s77-s82.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 20]  [Article Influence: 2.9]  [Reference Citation Analysis (0)]
8.  Poynard T, Mathurin P, Lai CL, Guyader D, Poupon R, Tainturier MH, Myers RP, Muntenau M, Ratziu V, Manns M. A comparison of fibrosis progression in chronic liver diseases. J Hepatol. 2003;38:257-265.  [PubMed]  [DOI]  [Cited in This Article: ]
9.  Anstee QM, Day CP. The Genetics of Nonalcoholic Fatty Liver Disease: Spotlight on PNPLA3 and TM6SF2. Semin Liver Dis. 2015;35:270-290.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 110]  [Cited by in F6Publishing: 117]  [Article Influence: 14.6]  [Reference Citation Analysis (0)]
10.  Chamorro AJ, Torres JL, Mirón-Canelo JA, González-Sarmiento R, Laso FJ, Marcos M. Systematic review with meta-analysis: the I148M variant of patatin-like phospholipase domain-containing 3 gene (PNPLA3) is significantly associated with alcoholic liver cirrhosis. Aliment Pharmacol Ther. 2014;40:571-581.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 53]  [Cited by in F6Publishing: 54]  [Article Influence: 6.0]  [Reference Citation Analysis (0)]
11.  Sookoian S, Pirola CJ. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology. 2011;53:1883-1894.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 643]  [Cited by in F6Publishing: 684]  [Article Influence: 57.0]  [Reference Citation Analysis (1)]
12.  Trépo E, Nahon P, Bontempi G, Valenti L, Falleti E, Nischalke HD, Hamza S, Corradini SG, Burza MA, Guyot E. Association between the PNPLA3 (rs738409 C>G) variant and hepatocellular carcinoma: Evidence from a meta-analysis of individual participant data. Hepatology. 2014;59:2170-2177.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 164]  [Cited by in F6Publishing: 175]  [Article Influence: 19.4]  [Reference Citation Analysis (0)]
13.  Mathurin P, O’Grady J, Carithers RL, Phillips M, Louvet A, Mendenhall CL, Ramond MJ, Naveau S, Maddrey WC, Morgan TR. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Gut. 2011;60:255-260.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 292]  [Cited by in F6Publishing: 304]  [Article Influence: 25.3]  [Reference Citation Analysis (0)]
14.  Fialla AD, Israelsen M, Hamberg O, Krag A, Gluud LL. Nutritional therapy in cirrhosis or alcoholic hepatitis: a systematic review and meta-analysis. Liver Int. 2015;35:2072-2078.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 77]  [Cited by in F6Publishing: 78]  [Article Influence: 9.8]  [Reference Citation Analysis (0)]
15.  Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med. 2009;360:2758-2769.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 659]  [Cited by in F6Publishing: 673]  [Article Influence: 48.1]  [Reference Citation Analysis (0)]
16.  Musso G, Gambino R, Cassader M, Pagano G. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology. 2010;52:79-104.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 416]  [Cited by in F6Publishing: 439]  [Article Influence: 33.8]  [Reference Citation Analysis (0)]
17.  Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ; American Association for the Study of Liver Diseases; American College of Gastroenterology; American Gastroenterological Association. The diagnosis and management of non-alcoholic fatty liver disease: Practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Am J Gastroenterol. 2012;107:811-826.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 270]  [Cited by in F6Publishing: 280]  [Article Influence: 25.5]  [Reference Citation Analysis (0)]
18.  Mayo-Smith MF, Beecher LH, Fischer TL, Gorelick DA, Guillaume JL, Hill A, Jara G, Kasser C, Melbourne J; Working Group on the Management of Alcohol Withdrawal Delirium, Practice Guidelines Committee, American Society of Addiction Medicine. Management of alcohol withdrawal delirium. An evidence-based practice guideline. Arch Intern Med. 2004;164:1405-1412.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 291]  [Cited by in F6Publishing: 302]  [Article Influence: 15.9]  [Reference Citation Analysis (0)]
19.  Day E, Bentham P, Callaghan R, Kuruvilla T, George S. Thiamine for Wernicke-Korsakoff Syndrome in people at risk from alcohol abuse. Cochrane Database Syst Rev. 2004;CD004033.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 48]  [Cited by in F6Publishing: 60]  [Article Influence: 3.2]  [Reference Citation Analysis (0)]
20.  Donnino MW, Vega J, Miller J, Walsh M. Myths and misconceptions of Wernicke’s encephalopathy: what every emergency physician should know. Ann Emerg Med. 2007;50:715-721.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 137]  [Cited by in F6Publishing: 146]  [Article Influence: 9.1]  [Reference Citation Analysis (0)]
21.  Thomson AD. Mechanisms of vitamin deficiency in chronic alcohol misusers and the development of the Wernicke-Korsakoff syndrome. Alcohol Alcohol Suppl. 2000;35:2-7.  [PubMed]  [DOI]  [Cited in This Article: ]
22.  Isenberg-Grzeda E, Kutner HE, Nicolson SE. Wernicke-Korsakoff-syndrome: under-recognized and under-treated. Psychosomatics. 2012;53:507-516.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 139]  [Cited by in F6Publishing: 112]  [Article Influence: 11.2]  [Reference Citation Analysis (0)]
23.  Cook CC, Hallwood PM, Thomson AD. B Vitamin deficiency and neuropsychiatric syndromes in alcohol misuse. Alcohol Alcohol. 1998;33:317-336.  [PubMed]  [DOI]  [Cited in This Article: ]
24.  Galvin R, Bråthen G, Ivashynka A, Hillbom M, Tanasescu R, Leone MA; EFNS. EFNS guidelines for diagnosis, therapy and prevention of Wernicke encephalopathy. Eur J Neurol. 2010;17:1408-1418.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 375]  [Cited by in F6Publishing: 399]  [Article Influence: 33.3]  [Reference Citation Analysis (0)]
25.  Alcohol-Use Disorders: Diagnosis, Assessment and Management of Harmful Drinking and Alcohol Dependence. Leicester (UK), 2011. .  [PubMed]  [DOI]  [Cited in This Article: ]
26.  Nishimoto A, Usery J, Winton JC, Twilla J. High-dose Parenteral Thiamine in Treatment of Wernicke’s Encephalopathy: Case Series and Review of the Literature. In Vivo. 2017;31:121-124.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 44]  [Cited by in F6Publishing: 46]  [Article Influence: 7.7]  [Reference Citation Analysis (0)]
27.  Thomson AD, Guerrini I, Marshall EJ. The evolution and treatment of Korsakoff’s syndrome: out of sight, out of mind? Neuropsychol Rev. 2012;22:81-92.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 111]  [Cited by in F6Publishing: 80]  [Article Influence: 7.3]  [Reference Citation Analysis (0)]
28.  Moos RH, King MJ, Patterson MA. Outcomes of residential treatment of substance abuse in hospital- and community-based programs. Psychiatr Serv. 1996;47:68-74.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 18]  [Cited by in F6Publishing: 21]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
29.  Roozen HG, de Waart R, van der Windt DA, van den Brink W, de Jong CA, Kerkhof AJ. A systematic review of the effectiveness of naltrexone in the maintenance treatment of opioid and alcohol dependence. Eur Neuropsychopharmacol. 2006;16:311-323.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 60]  [Cited by in F6Publishing: 51]  [Article Influence: 3.0]  [Reference Citation Analysis (0)]
30.  Mason BJ, Lehert P. Acamprosate for alcohol dependence: a sex-specific meta-analysis based on individual patient data. Alcohol Clin Exp Res. 2012;36:497-508.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 50]  [Cited by in F6Publishing: 56]  [Article Influence: 4.7]  [Reference Citation Analysis (0)]
31.  Kenna GA, Lomastro TL, Schiesl A, Leggio L, Swift RM. Review of topiramate: an antiepileptic for the treatment of alcohol dependence. Curr Drug Abuse Rev. 2009;2:135-142.  [PubMed]  [DOI]  [Cited in This Article: ]
32.  Fuller RK, Branchey L, Brightwell DR, Derman RM, Emrick CD, Iber FL, James KE, Lacoursiere RB, Lee KK, Lowenstam I. Disulfiram treatment of alcoholism. A Veterans Administration cooperative study. JAMA. 1986;256:1449-1455.  [PubMed]  [DOI]  [Cited in This Article: ]
33.  Addolorato G, Leggio L, Ferrulli A, Cardone S, Vonghia L, Mirijello A, Abenavoli L, D’Angelo C, Caputo F, Zambon A. Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study. Lancet. 2007;370:1915-1922.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 483]  [Cited by in F6Publishing: 493]  [Article Influence: 30.8]  [Reference Citation Analysis (0)]
34.  Addolorato G, Mirijello A, Leggio L, Ferrulli A, Landolfi R. Management of alcohol dependence in patients with liver disease. CNS Drugs. 2013;27:287-299.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 69]  [Cited by in F6Publishing: 76]  [Article Influence: 7.6]  [Reference Citation Analysis (0)]
35.  Addolorato G, Leggio L, Ferrulli A, Cardone S, Bedogni G, Caputo F, Gasbarrini G, Landolfi R; Baclofen Study Group. Dose-response effect of baclofen in reducing daily alcohol intake in alcohol dependence: secondary analysis of a randomized, double-blind, placebo-controlled trial. Alcohol Alcohol. 2011;46:312-317.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 144]  [Cited by in F6Publishing: 157]  [Article Influence: 13.1]  [Reference Citation Analysis (0)]
36.  Addolorato G, Russell M, Albano E, Haber PS, Wands JR, Leggio L. Understanding and treating patients with alcoholic cirrhosis: an update. Alcohol Clin Exp Res. 2009;33:1136-1144.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 20]  [Cited by in F6Publishing: 21]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
37.  Kershenobich D, Corona DL, Kershenovich R, Gutierrez-Reyes G. Management of alcoholic liver disease: an update. Alcohol Clin Exp Res. 2011;35:804-805.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5]  [Cited by in F6Publishing: 6]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
38.  Haass-Koffler CL, Leggio L, Kenna GA. Pharmacological approaches to reducing craving in patients with alcohol use disorders. CNS Drugs. 2014;28:343-360.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 55]  [Cited by in F6Publishing: 56]  [Article Influence: 6.2]  [Reference Citation Analysis (0)]
39.  Vuittonet CL, Halse M, Leggio L, Fricchione SB, Brickley M, Haass-Koffler CL, Tavares T, Swift RM, Kenna GA. Pharmacotherapy for alcoholic patients with alcoholic liver disease. Am J Health Syst Pharm. 2014;71:1265-1276.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 31]  [Cited by in F6Publishing: 33]  [Article Influence: 4.1]  [Reference Citation Analysis (0)]
40.  Caballería J, Parés A, Brú C, Mercader J, García Plaza A, Caballería L, Clemente G, Rodrigo L, Rodés J. Metadoxine accelerates fatty liver recovery in alcoholic patients: results of a randomized double-blind, placebo-control trial. Spanish Group for the Study of Alcoholic Fatty Liver. J Hepatol. 1998;28:54-60.  [PubMed]  [DOI]  [Cited in This Article: ]
41.  Higuera-de la Tijera F, Servín-Caamaño AI, Serralde-Zúñiga AE, Cruz-Herrera J, Pérez-Torres E, Abdo-Francis JM, Salas-Gordillo F, Pérez-Hernández JL. Metadoxine improves the three- and six-month survival rates in patients with severe alcoholic hepatitis. World J Gastroenterol. 2015;21:4975-4985.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 48]  [Cited by in F6Publishing: 44]  [Article Influence: 5.5]  [Reference Citation Analysis (0)]
42.  Naveau S, Giraud V, Borotto E, Aubert A, Capron F, Chaput JC. Excess weight risk factor for alcoholic liver disease. Hepatology. 1997;25:108-111.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 449]  [Cited by in F6Publishing: 465]  [Article Influence: 17.9]  [Reference Citation Analysis (0)]
43.  Klatsky AL, Armstrong MA. Alcohol, smoking, coffee, and cirrhosis. Am J Epidemiol. 1992;136:1248-1257.  [PubMed]  [DOI]  [Cited in This Article: ]
44.  Donato F, Tagger A, Chiesa R, Ribero ML, Tomasoni V, Fasola M, Gelatti U, Portera G, Boffetta P, Nardi G. Hepatitis B and C virus infection, alcohol drinking, and hepatocellular carcinoma: a case-control study in Italy. Brescia HCC Study. Hepatology. 1997;26:579-584.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 155]  [Cited by in F6Publishing: 168]  [Article Influence: 6.5]  [Reference Citation Analysis (0)]
45.  Hutchinson SJ, Bird SM, Goldberg DJ. Influence of alcohol on the progression of hepatitis C virus infection: a meta-analysis. Clin Gastroenterol Hepatol. 2005;3:1150-1159.  [PubMed]  [DOI]  [Cited in This Article: ]
46.  Befrits R, Hedman M, Blomquist L, Allander T, Grillner L, Kinnman N, Rubio C, Hultcrantz R. Chronic hepatitis C in alcoholic patients: prevalence, genotypes, and correlation to liver disease. Scand J Gastroenterol. 1995;30:1113-1118.  [PubMed]  [DOI]  [Cited in This Article: ]
47.  Chen CM, Yoon YH, Yi HY, Lucas DL. Alcohol and hepatitis C mortality among males and females in the United States: a life table analysis. Alcohol Clin Exp Res. 2007;31:285-292.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 40]  [Cited by in F6Publishing: 44]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
48.  Harris DR, Gonin R, Alter HJ, Wright EC, Buskell ZJ, Hollinger FB, Seeff LB; National Heart, Lung, and Blood Institute Study Group. The relationship of acute transfusion-associated hepatitis to the development of cirrhosis in the presence of alcohol abuse. Ann Intern Med. 2001;134:120-124.  [PubMed]  [DOI]  [Cited in This Article: ]
49.  Henry JA, Moloney C, Rivas C, Goldin RD. Increase in alcohol related deaths: is hepatitis C a factor? J Clin Pathol. 2002;55:704-707.  [PubMed]  [DOI]  [Cited in This Article: ]
50.  Tsui JI, Pletcher MJ, Vittinghoff E, Seal K, Gonzales R. Hepatitis C and hospital outcomes in patients admitted with alcohol-related problems. J Hepatol. 2006;44:262-266.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 34]  [Cited by in F6Publishing: 39]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
51.  Novo-Veleiro I, Alvela-Suárez L, Chamorro AJ, González-Sarmiento R, Laso FJ, Marcos M. Alcoholic liver disease and hepatitis C virus infection. World J Gastroenterol. 2016;22:1411-1420.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 37]  [Cited by in F6Publishing: 33]  [Article Influence: 4.7]  [Reference Citation Analysis (0)]
52.  Mendenhall C, Roselle GA, Gartside P, Moritz T. Relationship of protein calorie malnutrition to alcoholic liver disease: a reexamination of data from two Veterans Administration Cooperative Studies. Alcohol Clin Exp Res. 1995;19:635-641.  [PubMed]  [DOI]  [Cited in This Article: ]
53.  Huisman EJ, Trip EJ, Siersema PD, van Hoek B, van Erpecum KJ. Protein energy malnutrition predicts complications in liver cirrhosis. Eur J Gastroenterol Hepatol. 2011;23:982-989.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 133]  [Cited by in F6Publishing: 116]  [Article Influence: 9.7]  [Reference Citation Analysis (0)]
54.  Fragasso A, Mannarella C, Ciancio A, Scarciolla O, Nuzzolese N, Clemente R, Vitullo E, Sacco A. Holotranscobalamin is a useful marker of vitamin B12 deficiency in alcoholics. ScientificWorldJournal. 2012;2012:128182.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 7]  [Cited by in F6Publishing: 7]  [Article Influence: 0.6]  [Reference Citation Analysis (0)]
55.  Rossi RE, Conte D, Massironi S. Diagnosis and treatment of nutritional deficiencies in alcoholic liver disease: Overview of available evidence and open issues. Dig Liver Dis. 2015;47:819-825.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 49]  [Cited by in F6Publishing: 39]  [Article Influence: 4.9]  [Reference Citation Analysis (0)]
56.  McClain CJ, Barve SS, Barve A, Marsano L. Alcoholic liver disease and malnutrition. Alcohol Clin Exp Res. 2011;35:815-820.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 67]  [Cited by in F6Publishing: 66]  [Article Influence: 5.5]  [Reference Citation Analysis (0)]
57.  Halsted CH. Nutrition and alcoholic liver disease. Semin Liver Dis. 2004;24:289-304.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 82]  [Cited by in F6Publishing: 86]  [Article Influence: 4.5]  [Reference Citation Analysis (0)]
58.  Kang YJ, Zhou Z. Zinc prevention and treatment of alcoholic liver disease. Mol Aspects Med. 2005;26:391-404.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 73]  [Cited by in F6Publishing: 59]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
59.  Henkel AS, Buchman AL. Nutritional support in patients with chronic liver disease. Nat Clin Pract Gastroenterol Hepatol. 2006;3:202-209.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 90]  [Cited by in F6Publishing: 99]  [Article Influence: 5.8]  [Reference Citation Analysis (0)]
60.  Cabré E, Rodríguez-Iglesias P, Caballería J, Quer JC, Sánchez-Lombraña JL, Parés A, Papo M, Planas R, Gassull MA. Short- and long-term outcome of severe alcohol-induced hepatitis treated with steroids or enteral nutrition: a multicenter randomized trial. Hepatology. 2000;32:36-42.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 252]  [Cited by in F6Publishing: 259]  [Article Influence: 11.3]  [Reference Citation Analysis (0)]
61.  Plauth M, Cabré E, Riggio O, Assis-Camilo M, Pirlich M, Kondrup J; DGEM (German Society for Nutritional Medicine), Ferenci P, Holm E, Vom Dahl S, Müller MJ, Nolte W; ESPEN (European Society for Parenteral and Enteral Nutrition). ESPEN Guidelines on Enteral Nutrition: Liver disease. Clin Nutr. 2006;25:285-294.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 465]  [Cited by in F6Publishing: 488]  [Article Influence: 28.7]  [Reference Citation Analysis (1)]
62.  Forrest E, Mellor J, Stanton L, Bowers M, Ryder P, Austin A, Day C, Gleeson D, O’Grady J, Masson S. Steroids or pentoxifylline for alcoholic hepatitis (STOPAH): study protocol for a randomised controlled trial. Trials. 2013;14:262.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 48]  [Cited by in F6Publishing: 51]  [Article Influence: 5.1]  [Reference Citation Analysis (0)]
63.  Rambaldi A, Saconato HH, Christensen E, Thorlund K, Wetterslev J, Gluud C. Systematic review: glucocorticosteroids for alcoholic hepatitis--a Cochrane Hepato-Biliary Group systematic review with meta-analyses and trial sequential analyses of randomized clinical trials. Aliment Pharmacol Ther. 2008;27:1167-1178.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 143]  [Cited by in F6Publishing: 132]  [Article Influence: 8.8]  [Reference Citation Analysis (0)]
64.  Mathurin P, Mendenhall CL, Carithers RL Jr, Ramond MJ, Maddrey WC, Garstide P, Rueff B, Naveau S, Chaput JC, Poynard T. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis (AH): individual data analysis of the last three randomized placebo controlled double blind trials of corticosteroids in severe AH. J Hepatol. 2002;36:480-487.  [PubMed]  [DOI]  [Cited in This Article: ]
65.  Mathurin P, Abdelnour M, Ramond MJ, Carbonell N, Fartoux L, Serfaty L, Valla D, Poupon R, Chaput JC, Naveau S. Early change in bilirubin levels is an important prognostic factor in severe alcoholic hepatitis treated with prednisolone. Hepatology. 2003;38:1363-1369.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 59]  [Cited by in F6Publishing: 69]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
66.  Louvet A, Naveau S, Abdelnour M, Ramond MJ, Diaz E, Fartoux L, Dharancy S, Texier F, Hollebecque A, Serfaty L. The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. Hepatology. 2007;45:1348-1354.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 479]  [Cited by in F6Publishing: 488]  [Article Influence: 30.5]  [Reference Citation Analysis (0)]
67.  Depew W, Boyer T, Omata M, Redeker A, Reynolds T. Double-blind controlled trial of prednisolone therapy in patients with severe acute alcoholic hepatitis and spontaneous encephalopathy. Gastroenterology. 1980;78:524-529.  [PubMed]  [DOI]  [Cited in This Article: ]
68.  Singal AK, Walia I, Singal A, Soloway RD. Corticosteroids and pentoxifylline for the treatment of alcoholic hepatitis: Current status. World J Hepatol. 2011;3:205-210.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 21]  [Cited by in F6Publishing: 21]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
69.  Saberi B, Dadabhai AS, Jang YY, Gurakar A, Mezey E. Current Management of Alcoholic Hepatitis and Future Therapies. J Clin Transl Hepatol. 2016;4:113-122.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13]  [Cited by in F6Publishing: 25]  [Article Influence: 3.6]  [Reference Citation Analysis (0)]
70.  Louvet A, Wartel F, Castel H, Dharancy S, Hollebecque A, Canva-Delcambre V, Deltenre P, Mathurin P. Infection in patients with severe alcoholic hepatitis treated with steroids: early response to therapy is the key factor. Gastroenterology. 2009;137:541-548.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 233]  [Cited by in F6Publishing: 234]  [Article Influence: 16.7]  [Reference Citation Analysis (0)]
71.  O’Shea RS, Dasarathy S, McCullough AJ; Practice Guideline Committee of the American Association for the Study of Liver Diseases; Practice Parameters Committee of the American College of Gastroenterology. Alcoholic liver disease. Hepatology. 2010;51:307-328.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 837]  [Cited by in F6Publishing: 892]  [Article Influence: 68.6]  [Reference Citation Analysis (2)]
72.  Raetsch C, Jia JD, Boigk G, Bauer M, Hahn EG, Riecken EO, Schuppan D. Pentoxifylline downregulates profibrogenic cytokines and procollagen I expression in rat secondary biliary fibrosis. Gut. 2002;50:241-247.  [PubMed]  [DOI]  [Cited in This Article: ]
73.  Assimakopoulos SF, Thomopoulos KC, Labropoulou-Karatza C. Pentoxifylline: a first line treatment option for severe alcoholic hepatitis and hepatorenal syndrome? World J Gastroenterol. 2009;15:3194-3195.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 16]  [Cited by in F6Publishing: 17]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
74.  Runyon BA, Antillon MR. Ascitic fluid pH and lactate: insensitive and nonspecific tests in detecting ascitic fluid infection. Hepatology. 1991;13:929-935.  [PubMed]  [DOI]  [Cited in This Article: ]
75.  Akriviadis E, Botla R, Briggs W, Han S, Reynolds T, Shakil O. Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial. Gastroenterology. 2000;119:1637-1648.  [PubMed]  [DOI]  [Cited in This Article: ]
76.  De BK, Gangopadhyay S, Dutta D, Baksi SD, Pani A, Ghosh P. Pentoxifylline versus prednisolone for severe alcoholic hepatitis: a randomized controlled trial. World J Gastroenterol. 2009;15:1613-1619.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 105]  [Cited by in F6Publishing: 97]  [Article Influence: 6.9]  [Reference Citation Analysis (0)]
77.  Mathurin P, Louvet A, Duhamel A, Nahon P, Carbonell N, Boursier J, Anty R, Diaz E, Thabut D, Moirand R. Prednisolone with vs without pentoxifylline and survival of patients with severe alcoholic hepatitis: a randomized clinical trial. JAMA. 2013;310:1033-1041.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 151]  [Cited by in F6Publishing: 156]  [Article Influence: 15.6]  [Reference Citation Analysis (0)]
78.  Sidhu SS, Goyal O, Singla P, Gupta D, Sood A, Chhina RS, Soni RK. Corticosteroid plus pentoxifylline is not better than corticosteroid alone for improving survival in severe alcoholic hepatitis (COPE trial). Dig Dis Sci. 2012;57:1664-1671.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 52]  [Cited by in F6Publishing: 51]  [Article Influence: 4.6]  [Reference Citation Analysis (0)]
79.  Im GY, Lucey MR. Practical Concerns and Controversies in the Management of Alcoholic Hepatitis. Gastroenterol Hepatol (N Y). 2016;12:478-489.  [PubMed]  [DOI]  [Cited in This Article: ]
80.  Thursz MR, Richardson P, Allison M, Austin A, Bowers M, Day CP, Downs N, Gleeson D, MacGilchrist A, Grant A. Prednisolone or pentoxifylline for alcoholic hepatitis. N Engl J Med. 2015;372:1619-1628.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 462]  [Cited by in F6Publishing: 451]  [Article Influence: 56.4]  [Reference Citation Analysis (0)]
81.  McClain CJ, Hill DB, Barve SS. Infliximab and prednisolone: too much of a good thing? Hepatology. 2004;39:1488-1490.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9]  [Cited by in F6Publishing: 9]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
82.  Felver ME, Mezey E, McGuire M, Mitchell MC, Herlong HF, Veech GA, Veech RL. Plasma tumor necrosis factor alpha predicts decreased long-term survival in severe alcoholic hepatitis. Alcohol Clin Exp Res. 1990;14:255-259.  [PubMed]  [DOI]  [Cited in This Article: ]
83.  Yin M, Wheeler MD, Kono H, Bradford BU, Gallucci RM, Luster MI, Thurman RG. Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice. Gastroenterology. 1999;117:942-952.  [PubMed]  [DOI]  [Cited in This Article: ]
84.  Naveau S, Chollet-Martin S, Dharancy S, Mathurin P, Jouet P, Piquet MA, Davion T, Oberti F, Broët P, Emilie D; Foie-Alcool group of the Association Française pour l’Etude du Foie. A double-blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis. Hepatology. 2004;39:1390-1397.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 297]  [Cited by in F6Publishing: 321]  [Article Influence: 16.9]  [Reference Citation Analysis (0)]
85.  Ali T, Kaitha S, Mahmood S, Ftesi A, Stone J, Bronze MS. Clinical use of anti-TNF therapy and increased risk of infections. Drug Healthc Patient Saf. 2013;5:79-99.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 138]  [Cited by in F6Publishing: 154]  [Article Influence: 15.4]  [Reference Citation Analysis (0)]
86.  Dey A, Cederbaum AI. Alcohol and oxidative liver injury. Hepatology. 2006;43:S63-S74.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 398]  [Cited by in F6Publishing: 428]  [Article Influence: 25.2]  [Reference Citation Analysis (0)]
87.  Stewart S, Prince M, Bassendine M, Hudson M, James O, Jones D, Record C, Day CP. A randomized trial of antioxidant therapy alone or with corticosteroids in acute alcoholic hepatitis. J Hepatol. 2007;47:277-283.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 129]  [Cited by in F6Publishing: 136]  [Article Influence: 8.5]  [Reference Citation Analysis (1)]
88.  Nguyen TH, Jacobs P, Hanrahan A, Fraser-Lee N, Wong W, Lee B, Ohinmaa A. Health care costs of persons with newly diagnosed hepatitis C virus: a population-based, observational study. J Viral Hepat. 2008;15:634-640.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2]  [Cited by in F6Publishing: 3]  [Article Influence: 0.2]  [Reference Citation Analysis (0)]
89.  Testino G, Sumberaz A, Borro P. Comment to “liver transplantation for patients with alcoholic liver disease: an open question”. Dig Liver Dis. 2013;45:80-81.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 6]  [Cited by in F6Publishing: 6]  [Article Influence: 0.6]  [Reference Citation Analysis (0)]
90.  Testino G, Ferro C, Sumberaz A, Messa P, Morelli N, Guadagni B, Ardizzone G, Valente U. Type-2 hepatorenal syndrome and refractory ascites: role of transjugular intrahepatic portosystemic stent-shunt in eighteen patients with advanced cirrhosis awaiting orthotopic liver transplantation. Hepatogastroenterology. 2003;50:1753-1755.  [PubMed]  [DOI]  [Cited in This Article: ]
91.  Tan HH, Virmani S, Martin P. Controversies in the management of alcoholic liver disease. Mt Sinai J Med. 2009;76:484-498.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 22]  [Cited by in F6Publishing: 26]  [Article Influence: 2.2]  [Reference Citation Analysis (0)]
92.  Burra P, Mioni D, Cecchetto A, Cillo U, Zanus G, Fagiuoli S, Naccarato R, Martines D. Histological features after liver transplantation in alcoholic cirrhotics. J Hepatol. 2001;34:716-722.  [PubMed]  [DOI]  [Cited in This Article: ]
93.  Pageaux GP, Bismuth M, Perney P, Costes V, Jaber S, Possoz P, Fabre JM, Navarro F, Blanc P, Domergue J. Alcohol relapse after liver transplantation for alcoholic liver disease: does it matter? J Hepatol. 2003;38:629-634.  [PubMed]  [DOI]  [Cited in This Article: ]
94.  Dew MA, DiMartini AF, Steel J, De Vito Dabbs A, Myaskovsky L, Unruh M, Greenhouse J. Meta-analysis of risk for relapse to substance use after transplantation of the liver or other solid organs. Liver Transpl. 2008;14:159-172.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 218]  [Cited by in F6Publishing: 214]  [Article Influence: 14.3]  [Reference Citation Analysis (0)]
95.  Testino G, Burra P, Bonino F, Piani F, Sumberaz A, Peressutti R, Giannelli Castiglione A, Patussi V, Fanucchi T, Ancarani O. Acute alcoholic hepatitis, end stage alcoholic liver disease and liver transplantation: an Italian position statement. World J Gastroenterol. 2014;20:14642-14651.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 54]  [Cited by in F6Publishing: 48]  [Article Influence: 5.3]  [Reference Citation Analysis (1)]
96.  Lucey MR, Brown KA, Everson GT, Fung JJ, Gish R, Keeffe EB, Kneteman NM, Lake JR, Martin P, McDiarmid SV. Minimal criteria for placement of adults on the liver transplant waiting list: a report of a national conference organized by the American Society of Transplant Physicians and the American Association for the Study of Liver Diseases. Liver Transpl Surg. 1997;3:628-637.  [PubMed]  [DOI]  [Cited in This Article: ]
97.  Veldt BJ, Lainé F, Guillygomarc’h A, Lauvin L, Boudjema K, Messner M, Brissot P, Deugnier Y, Moirand R. Indication of liver transplantation in severe alcoholic liver cirrhosis: quantitative evaluation and optimal timing. J Hepatol. 2002;36:93-98.  [PubMed]  [DOI]  [Cited in This Article: ]
98.  Mathurin P, Moreno C, Samuel D, Dumortier J, Salleron J, Durand F, Castel H, Duhamel A, Pageaux GP, Leroy V. Early liver transplantation for severe alcoholic hepatitis. N Engl J Med. 2011;365:1790-1800.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 616]  [Cited by in F6Publishing: 614]  [Article Influence: 51.2]  [Reference Citation Analysis (0)]
99.  Herrero JI. De novo malignancies following liver transplantation: impact and recommendations. Liver Transpl. 2009;15 Suppl 2:S90-S94.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 79]  [Cited by in F6Publishing: 78]  [Article Influence: 5.6]  [Reference Citation Analysis (0)]
100.  Dumortier J, Guillaud O, Adham M, Boucaud C, Delafosse B, Bouffard Y, Paliard P, Scoazec JY, Boillot O. Negative impact of de novo malignancies rather than alcohol relapse on survival after liver transplantation for alcoholic cirrhosis: a retrospective analysis of 305 patients in a single center. Am J Gastroenterol. 2007;102:1032-1041.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 79]  [Cited by in F6Publishing: 69]  [Article Influence: 4.3]  [Reference Citation Analysis (0)]
101.  Burra P, Senzolo M, Adam R, Delvart V, Karam V, Germani G, Neuberger J; ELITA; ELTR Liver Transplant Centers. Liver transplantation for alcoholic liver disease in Europe: a study from the ELTR (European Liver Transplant Registry). Am J Transplant. 2010;10:138-148.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 233]  [Cited by in F6Publishing: 244]  [Article Influence: 18.8]  [Reference Citation Analysis (0)]
102.  Seo YS, Shah VH. The role of gut-liver axis in the pathogenesis of liver cirrhosis and portal hypertension. Clin Mol Hepatol. 2012;18:337-346.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 91]  [Cited by in F6Publishing: 99]  [Article Influence: 9.0]  [Reference Citation Analysis (0)]
103.  Zhao HY, Wang HJ, Lu Z, Xu SZ. Intestinal microflora in patients with liver cirrhosis. Chin J Dig Dis. 2004;5:64-67.  [PubMed]  [DOI]  [Cited in This Article: ]
104.  Stadlbauer V, Mookerjee RP, Hodges S, Wright GA, Davies NA, Jalan R. Effect of probiotic treatment on deranged neutrophil function and cytokine responses in patients with compensated alcoholic cirrhosis. J Hepatol. 2008;48:945-951.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 199]  [Cited by in F6Publishing: 210]  [Article Influence: 14.0]  [Reference Citation Analysis (0)]
105.  Kirpich IA, Solovieva NV, Leikhter SN, Shidakova NA, Lebedeva OV, Sidorov PI, Bazhukova TA, Soloviev AG, Barve SS, McClain CJ. Probiotics restore bowel flora and improve liver enzymes in human alcohol-induced liver injury: a pilot study. Alcohol. 2008;42:675-682.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 296]  [Cited by in F6Publishing: 320]  [Article Influence: 21.3]  [Reference Citation Analysis (0)]
106.  Vlachogiannakos J, Saveriadis AS, Viazis N, Theodoropoulos I, Foudoulis K, Manolakopoulos S, Raptis S, Karamanolis DG. Intestinal decontamination improves liver haemodynamics in patients with alcohol-related decompensated cirrhosis. Aliment Pharmacol Ther. 2009;29:992-999.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 127]  [Cited by in F6Publishing: 105]  [Article Influence: 7.5]  [Reference Citation Analysis (0)]
107.  Michelena J, Altamirano J, Abraldes JG, Affò S, Morales-Ibanez O, Sancho-Bru P, Dominguez M, García-Pagán JC, Fernández J, Arroyo V. Systemic inflammatory response and serum lipopolysaccharide levels predict multiple organ failure and death in alcoholic hepatitis. Hepatology. 2015;62:762-772.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 192]  [Cited by in F6Publishing: 193]  [Article Influence: 24.1]  [Reference Citation Analysis (0)]
108.  Lieber CS. S-Adenosyl-L-methionine and alcoholic liver disease in animal models: implications for early intervention in human beings. Alcohol. 2002;27:173-177.  [PubMed]  [DOI]  [Cited in This Article: ]
109.  Karaa A, Thompson KJ, McKillop IH, Clemens MG, Schrum LW. S-adenosyl-L-methionine attenuates oxidative stress and hepatic stellate cell activation in an ethanol-LPS-induced fibrotic rat model. Shock. 2008;30:197-205.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 46]  [Cited by in F6Publishing: 52]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
110.  Rambaldi A, Gluud C. S-adenosyl-L-methionine for alcoholic liver diseases. Cochrane Database Syst Rev. 2006;CD002235.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 34]  [Cited by in F6Publishing: 54]  [Article Influence: 3.2]  [Reference Citation Analysis (0)]
111.  Kharbanda KK. Alcoholic liver disease and methionine metabolism. Semin Liver Dis. 2009;29:155-165.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 92]  [Cited by in F6Publishing: 95]  [Article Influence: 6.8]  [Reference Citation Analysis (0)]
112.  Purohit V, Abdelmalek MF, Barve S, Benevenga NJ, Halsted CH, Kaplowitz N, Kharbanda KK, Liu QY, Lu SC, McClain CJ. Role of S-adenosylmethionine, folate, and betaine in the treatment of alcoholic liver disease: summary of a symposium. Am J Clin Nutr. 2007;86:14-24.  [PubMed]  [DOI]  [Cited in This Article: ]
113.  Kharbanda KK, Mailliard ME, Baldwin CR, Beckenhauer HC, Sorrell MF, Tuma DJ. Betaine attenuates alcoholic steatosis by restoring phosphatidylcholine generation via the phosphatidylethanolamine methyltransferase pathway. J Hepatol. 2007;46:314-321.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 141]  [Cited by in F6Publishing: 147]  [Article Influence: 9.2]  [Reference Citation Analysis (0)]
114.  Kim SJ, Jung YS, Kwon DY, Kim YC. Alleviation of acute ethanol-induced liver injury and impaired metabolomics of S-containing substances by betaine supplementation. Biochem Biophys Res Commun. 2008;368:893-898.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 49]  [Cited by in F6Publishing: 49]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
115.  Dominguez M, Miquel R, Colmenero J, Moreno M, García-Pagán JC, Bosch J, Arroyo V, Ginès P, Caballería J, Bataller R. Hepatic expression of CXC chemokines predicts portal hypertension and survival in patients with alcoholic hepatitis. Gastroenterology. 2009;136:1639-1650.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 159]  [Cited by in F6Publishing: 160]  [Article Influence: 11.4]  [Reference Citation Analysis (0)]
116.  Gao B, Xu M. Chemokines and alcoholic hepatitis: are chemokines good therapeutic targets? Gut. 2014;63:1683-1684.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 21]  [Cited by in F6Publishing: 21]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
117.  Affò S, Morales-Ibanez O, Rodrigo-Torres D, Altamirano J, Blaya D, Dapito DH, Millán C, Coll M, Caviglia JM, Arroyo V. CCL20 mediates lipopolysaccharide induced liver injury and is a potential driver of inflammation and fibrosis in alcoholic hepatitis. Gut. 2014;63:1782-1792.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 99]  [Cited by in F6Publishing: 104]  [Article Influence: 11.6]  [Reference Citation Analysis (0)]
118.  Leake I. Alcoholic hepatitis: potential role of cytokine CCL20 in alcoholic hepatitis. Nat Rev Gastroenterol Hepatol. 2014;11:76.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2]  [Cited by in F6Publishing: 2]  [Article Influence: 0.2]  [Reference Citation Analysis (0)]
119.  Horiguchi N, Wang L, Mukhopadhyay P, Park O, Jeong WI, Lafdil F, Osei-Hyiaman D, Moh A, Fu XY, Pacher P. Cell type-dependent pro- and anti-inflammatory role of signal transducer and activator of transcription 3 in alcoholic liver injury. Gastroenterology. 2008;134:1148-1158.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 130]  [Cited by in F6Publishing: 144]  [Article Influence: 9.6]  [Reference Citation Analysis (0)]
120.  Støy S, Sandahl TD, Dige AK, Agnholt J, Rasmussen TK, Grønbæk H, Deleuran B, Vilstrup H. Highest frequencies of interleukin-22-producing T helper cells in alcoholic hepatitis patients with a favourable short-term course. PLoS One. 2013;8:e55101.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 24]  [Cited by in F6Publishing: 25]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
121.  Ki SH, Park O, Zheng M, Morales-Ibanez O, Kolls JK, Bataller R, Gao B. Interleukin-22 treatment ameliorates alcoholic liver injury in a murine model of chronic-binge ethanol feeding: role of signal transducer and activator of transcription 3. Hepatology. 2010;52:1291-1300.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 316]  [Cited by in F6Publishing: 340]  [Article Influence: 26.2]  [Reference Citation Analysis (0)]
122.  Radaeva S, Sun R, Pan HN, Hong F, Gao B. Interleukin 22 (IL-22) plays a protective role in T cell-mediated murine hepatitis: IL-22 is a survival factor for hepatocytes via STAT3 activation. Hepatology. 2004;39:1332-1342.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 452]  [Cited by in F6Publishing: 482]  [Article Influence: 25.4]  [Reference Citation Analysis (0)]
123.  Lemmers A, Moreno C, Gustot T, Maréchal R, Degré D, Demetter P, de Nadai P, Geerts A, Quertinmont E, Vercruysse V. The interleukin-17 pathway is involved in human alcoholic liver disease. Hepatology. 2009;49:646-657.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 273]  [Cited by in F6Publishing: 289]  [Article Influence: 20.6]  [Reference Citation Analysis (0)]
124.  Hueber W, Patel DD, Dryja T, Wright AM, Koroleva I, Bruin G, Antoni C, Draelos Z, Gold MH; Psoriasis Study Group, Durez P, Tak PP, Gomez-Reino JJ; Rheumatoid Arthritis Study Group, Foster CS, Kim RY, Samson CM, Falk NS, Chu DS, Callanan D, Nguyen QD; Uveitis Study Group, Rose K, Haider A, Di Padova F. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med. 2010;2:52ra72.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 647]  [Cited by in F6Publishing: 694]  [Article Influence: 57.8]  [Reference Citation Analysis (0)]
125.  Tam J, Liu J, Mukhopadhyay B, Cinar R, Godlewski G, Kunos G. Endocannabinoids in liver disease. Hepatology. 2011;53:346-355.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 145]  [Cited by in F6Publishing: 149]  [Article Influence: 12.4]  [Reference Citation Analysis (0)]
126.  Jeong WI, Osei-Hyiaman D, Park O, Liu J, Bátkai S, Mukhopadhyay P, Horiguchi N, Harvey-White J, Marsicano G, Lutz B. Paracrine activation of hepatic CB1 receptors by stellate cell-derived endocannabinoids mediates alcoholic fatty liver. Cell Metab. 2008;7:227-235.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 233]  [Cited by in F6Publishing: 251]  [Article Influence: 16.7]  [Reference Citation Analysis (0)]
127.  Louvet A, Teixeira-Clerc F, Chobert MN, Deveaux V, Pavoine C, Zimmer A, Pecker F, Mallat A, Lotersztajn S. Cannabinoid CB2 receptors protect against alcoholic liver disease by regulating Kupffer cell polarization in mice. Hepatology. 2011;54:1217-1226.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 186]  [Cited by in F6Publishing: 190]  [Article Influence: 15.8]  [Reference Citation Analysis (0)]
128.  Wang KX, Denhardt DT. Osteopontin: role in immune regulation and stress responses. Cytokine Growth Factor Rev. 2008;19:333-345.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 482]  [Cited by in F6Publishing: 445]  [Article Influence: 29.7]  [Reference Citation Analysis (0)]
129.  Morales-Ibanez O, Domínguez M, Ki SH, Marcos M, Chaves JF, Nguyen-Khac E, Houchi H, Affò S, Sancho-Bru P, Altamirano J. Human and experimental evidence supporting a role for osteopontin in alcoholic hepatitis. Hepatology. 2013;58:1742-1756.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 78]  [Cited by in F6Publishing: 81]  [Article Influence: 8.1]  [Reference Citation Analysis (0)]
130.  Altamirano J, Bataller R. Alcoholic liver disease: pathogenesis and new targets for therapy. Nat Rev Gastroenterol Hepatol. 2011;8:491-501.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 203]  [Cited by in F6Publishing: 205]  [Article Influence: 17.1]  [Reference Citation Analysis (0)]
131.  Zhang Z, Wang FS. Stem cell therapies for liver failure and cirrhosis. J Hepatol. 2013;59:183-185.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 72]  [Cited by in F6Publishing: 73]  [Article Influence: 7.3]  [Reference Citation Analysis (0)]
132.  Akiyama K, Chen C, Wang D, Xu X, Qu C, Yamaza T, Cai T, Chen W, Sun L, Shi S. Mesenchymal-stem-cell-induced immunoregulation involves FAS-ligand-/FAS-mediated T cell apoptosis. Cell Stem Cell. 2012;10:544-555.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 486]  [Cited by in F6Publishing: 521]  [Article Influence: 47.4]  [Reference Citation Analysis (0)]
133.  Aurich H, Sgodda M, Kaltwasser P, Vetter M, Weise A, Liehr T, Brulport M, Hengstler JG, Dollinger MM, Fleig WE. Hepatocyte differentiation of mesenchymal stem cells from human adipose tissue in vitro promotes hepatic integration in vivo. Gut. 2009;58:570-581.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 250]  [Cited by in F6Publishing: 266]  [Article Influence: 19.0]  [Reference Citation Analysis (0)]
134.  Kuo TK, Hung SP, Chuang CH, Chen CT, Shih YR, Fang SC, Yang VW, Lee OK. Stem cell therapy for liver disease: parameters governing the success of using bone marrow mesenchymal stem cells. Gastroenterology. 2008;134:2111-2121, 2121.e1-2121.e3.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 333]  [Cited by in F6Publishing: 365]  [Article Influence: 24.3]  [Reference Citation Analysis (0)]
135.  Jang YO, Kim YJ, Baik SK, Kim MY, Eom YW, Cho MY, Park HJ, Park SY, Kim BR, Kim JW. Histological improvement following administration of autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: a pilot study. Liver Int. 2014;34:33-41.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 126]  [Cited by in F6Publishing: 136]  [Article Influence: 15.1]  [Reference Citation Analysis (0)]
136.  Terai S, Ishikawa T, Omori K, Aoyama K, Marumoto Y, Urata Y, Yokoyama Y, Uchida K, Yamasaki T, Fujii Y. Improved liver function in patients with liver cirrhosis after autologous bone marrow cell infusion therapy. Stem Cells. 2006;24:2292-2298.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 363]  [Cited by in F6Publishing: 395]  [Article Influence: 23.2]  [Reference Citation Analysis (0)]
137.  Ismail A, Fouad O, Abdelnasser A, Chowdhury A, Selim A. Stem cell therapy improves the outcome of liver resection in cirrhotics. J Gastrointest Cancer. 2010;41:17-23.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 26]  [Cited by in F6Publishing: 33]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
138.  Harrison SA, Day CP. Benefits of lifestyle modification in NAFLD. Gut. 2007;56:1760-1769.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 171]  [Cited by in F6Publishing: 179]  [Article Influence: 11.2]  [Reference Citation Analysis (0)]
139.  Hannah WN Jr, Harrison SA. Lifestyle and Dietary Interventions in the Management of Nonalcoholic Fatty Liver Disease. Dig Dis Sci. 2016;61:1365-1374.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 76]  [Cited by in F6Publishing: 76]  [Article Influence: 10.9]  [Reference Citation Analysis (2)]
140.  Tilg H, Moschen A. Weight loss: cornerstone in the treatment of non-alcoholic fatty liver disease. Minerva Gastroenterol Dietol. 2010;56:159-167.  [PubMed]  [DOI]  [Cited in This Article: ]
141.  Ouyang X, Cirillo P, Sautin Y, McCall S, Bruchette JL, Diehl AM, Johnson RJ, Abdelmalek MF. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol. 2008;48:993-999.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 627]  [Cited by in F6Publishing: 613]  [Article Influence: 40.9]  [Reference Citation Analysis (0)]
142.  Simopoulos AP. Dietary omega-3 fatty acid deficiency and high fructose intake in the development of metabolic syndrome, brain metabolic abnormalities, and non-alcoholic fatty liver disease. Nutrients. 2013;5:2901-2923.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 91]  [Cited by in F6Publishing: 96]  [Article Influence: 9.6]  [Reference Citation Analysis (0)]
143.  Al-Gayyar MM, Shams ME, Barakat EA. Fish oil improves lipid metabolism and ameliorates inflammation in patients with metabolic syndrome: impact of nonalcoholic fatty liver disease. Pharm Biol. 2012;50:297-303.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 17]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
144.  Akyüz F, Demir K, Ozdil S, Aksoy N, Poturoğlu S, Ibrişim D, Kaymakoğlu S, Beşişik F, Boztaş G, Cakaloğlu Y. The effects of rosiglitazone, metformin, and diet with exercise in nonalcoholic fatty liver disease. Dig Dis Sci. 2007;52:2359-2367.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 33]  [Cited by in F6Publishing: 34]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
145.  Balkestein EJ, van Aggel-Leijssen DP, van Baak MA, Struijker-Boudier HA, Van Bortel LM. The effect of weight loss with or without exercise training on large artery compliance in healthy obese men. J Hypertens. 1999;17:1831-1835.  [PubMed]  [DOI]  [Cited in This Article: ]
146.  Luyckx FH, Desaive C, Thiry A, Dewé W, Scheen AJ, Gielen JE, Lefèbvre PJ. Liver abnormalities in severely obese subjects: effect of drastic weight loss after gastroplasty. Int J Obes Relat Metab Disord. 1998;22:222-226.  [PubMed]  [DOI]  [Cited in This Article: ]
147.  Weinsier RL, Wilson LJ, Lee J. Medically safe rate of weight loss for the treatment of obesity: a guideline based on risk of gallstone formation. Am J Med. 1995;98:115-117.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 86]  [Cited by in F6Publishing: 88]  [Article Influence: 3.1]  [Reference Citation Analysis (0)]
148.  Zelber-Sagi S, Kessler A, Brazowsky E, Webb M, Lurie Y, Santo M, Leshno M, Blendis L, Halpern Z, Oren R. A double-blind randomized placebo-controlled trial of orlistat for the treatment of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2006;4:639-644.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 237]  [Cited by in F6Publishing: 243]  [Article Influence: 14.3]  [Reference Citation Analysis (0)]
149.  Sabuncu T, Nazligul Y, Karaoglanoglu M, Ucar E, Kilic FB. The effects of sibutramine and orlistat on the ultrasonographic findings, insulin resistance and liver enzyme levels in obese patients with non-alcoholic steatohepatitis. Rom J Gastroenterol. 2003;12:189-192.  [PubMed]  [DOI]  [Cited in This Article: ]
150.  Yki-Järvinen H. Thiazolidinediones. N Engl J Med. 2004;351:1106-1118.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1612]  [Cited by in F6Publishing: 1649]  [Article Influence: 86.8]  [Reference Citation Analysis (0)]
151.  Bajaj M, Suraamornkul S, Piper P, Hardies LJ, Glass L, Cersosimo E, Pratipanawatr T, Miyazaki Y, DeFronzo RA. Decreased plasma adiponectin concentrations are closely related to hepatic fat content and hepatic insulin resistance in pioglitazone-treated type 2 diabetic patients. J Clin Endocrinol Metab. 2004;89:200-206.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 273]  [Cited by in F6Publishing: 281]  [Article Influence: 14.8]  [Reference Citation Analysis (0)]
152.  Caldwell SH, Hespenheide EE, Redick JA, Iezzoni JC, Battle EH, Sheppard BL. A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis. Am J Gastroenterol. 2001;96:519-525.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 295]  [Cited by in F6Publishing: 303]  [Article Influence: 13.8]  [Reference Citation Analysis (0)]
153.  Aithal GP, Thomas JA, Kaye PV, Lawson A, Ryder SD, Spendlove I, Austin AS, Freeman JG, Morgan L, Webber J. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology. 2008;135:1176-1184.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 522]  [Cited by in F6Publishing: 538]  [Article Influence: 35.9]  [Reference Citation Analysis (0)]
154.  Ratziu V, Giral P, Jacqueminet S, Charlotte F, Hartemann-Heurtier A, Serfaty L, Podevin P, Lacorte JM, Bernhardt C, Bruckert E. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology. 2008;135:100-110.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 458]  [Cited by in F6Publishing: 473]  [Article Influence: 31.5]  [Reference Citation Analysis (0)]
155.  Lutchman G, Modi A, Kleiner DE, Promrat K, Heller T, Ghany M, Borg B, Loomba R, Liang TJ, Premkumar A. The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis. Hepatology. 2007;46:424-429.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 184]  [Cited by in F6Publishing: 194]  [Article Influence: 12.1]  [Reference Citation Analysis (0)]
156.  Juurlink DN, Gomes T, Lipscombe LL, Austin PC, Hux JE, Mamdani MM. Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohort study. BMJ. 2009;339:b2942.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 109]  [Cited by in F6Publishing: 123]  [Article Influence: 8.8]  [Reference Citation Analysis (0)]
157.  Loomba R, Lutchman G, Kleiner DE, Ricks M, Feld JJ, Borg BB, Modi A, Nagabhyru P, Sumner AE, Liang TJ. Clinical trial: pilot study of metformin for the treatment of non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2009;29:172-182.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 191]  [Cited by in F6Publishing: 182]  [Article Influence: 13.0]  [Reference Citation Analysis (0)]
158.  Haukeland JW, Konopski Z, Eggesbø HB, von Volkmann HL, Raschpichler G, Bjøro K, Haaland T, Løberg EM, Birkeland K. Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol. 2009;44:853-860.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 227]  [Cited by in F6Publishing: 236]  [Article Influence: 18.2]  [Reference Citation Analysis (0)]
159.  Laurin J, Lindor KD, Crippin JS, Gossard A, Gores GJ, Ludwig J, Rakela J, McGill DB. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology. 1996;23:1464-1467.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 392]  [Cited by in F6Publishing: 396]  [Article Influence: 14.7]  [Reference Citation Analysis (0)]
160.  Basaranoglu M, Acbay O, Sonsuz A. A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis. J Hepatol. 1999;31:384.  [PubMed]  [DOI]  [Cited in This Article: ]
161.  Assy N, Grozovski M, Bersudsky I, Szvalb S, Hussein O. Effect of insulin-sensitizing agents in combination with ezetimibe, and valsartan in rats with non-alcoholic fatty liver disease. World J Gastroenterol. 2006;12:4369-4376.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 38]  [Cited by in F6Publishing: 36]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
162.  Zheng S, Hoos L, Cook J, Tetzloff G, Davis H Jr, van Heek M, Hwa JJ. Ezetimibe improves high fat and cholesterol diet-induced non-alcoholic fatty liver disease in mice. Eur J Pharmacol. 2008;584:118-124.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 122]  [Cited by in F6Publishing: 116]  [Article Influence: 7.7]  [Reference Citation Analysis (0)]
163.  Lindor KD, Kowdley KV, Heathcote EJ, Harrison ME, Jorgensen R, Angulo P, Lymp JF, Burgart L, Colin P. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology. 2004;39:770-778.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 516]  [Cited by in F6Publishing: 544]  [Article Influence: 28.6]  [Reference Citation Analysis (0)]
164.  Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006;43:S99-S112.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1756]  [Cited by in F6Publishing: 1868]  [Article Influence: 109.9]  [Reference Citation Analysis (0)]
165.  Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2003;98:2485-2490.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 505]  [Cited by in F6Publishing: 499]  [Article Influence: 25.0]  [Reference Citation Analysis (0)]
166.  Kugelmas M, Hill DB, Vivian B, Marsano L, McClain CJ. Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. Hepatology. 2003;38:413-419.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 375]  [Cited by in F6Publishing: 389]  [Article Influence: 19.5]  [Reference Citation Analysis (0)]
167.  Adams LA, Angulo P. Vitamins E and C for the treatment of NASH: duplication of results but lack of demonstration of efficacy. Am J Gastroenterol. 2003;98:2348-2350.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1]  [Cited by in F6Publishing: 5]  [Article Influence: 0.3]  [Reference Citation Analysis (0)]
168.  Dufour JF, Oneta CM, Gonvers JJ, Bihl F, Cerny A, Cereda JM, Zala JF, Helbling B, Steuerwald M, Zimmermann A; Swiss Association for the Study of the Liver. Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2006;4:1537-1543.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 256]  [Cited by in F6Publishing: 268]  [Article Influence: 15.8]  [Reference Citation Analysis (0)]
169.  Sanyal AJ, Mofrad PS, Contos MJ, Sargeant C, Luketic VA, Sterling RK, Stravitz RT, Shiffman ML, Clore J, Mills AS. A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2004;2:1107-1115.  [PubMed]  [DOI]  [Cited in This Article: ]
170.  Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005;142:37-46.  [PubMed]  [DOI]  [Cited in This Article: ]
171.  Tushuizen ME, Bunck MC, Pouwels PJ, van Waesberghe JH, Diamant M, Heine RJ. Incretin mimetics as a novel therapeutic option for hepatic steatosis. Liver Int. 2006;26:1015-1017.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 100]  [Cited by in F6Publishing: 107]  [Article Influence: 6.3]  [Reference Citation Analysis (0)]
172.  Ding X, Saxena NK, Lin S, Gupta NA, Anania FA. Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology. 2006;43:173-181.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 401]  [Cited by in F6Publishing: 423]  [Article Influence: 24.9]  [Reference Citation Analysis (0)]
173.  Ostawal A, Mocevic E, Kragh N, Xu W. Clinical Effectiveness of Liraglutide in Type 2 Diabetes Treatment in the Real-World Setting: A Systematic Literature Review. Diabetes Ther. 2016;7:411-438.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 59]  [Cited by in F6Publishing: 48]  [Article Influence: 6.9]  [Reference Citation Analysis (0)]
174.  Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, Hazlehurst JM, Guo K; LEAN trial team, Abouda G, Aldersley MA, Stocken D, Gough SC, Tomlinson JW, Brown RM, Hübscher SG, Newsome PN. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016;387:679-690.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1100]  [Cited by in F6Publishing: 846]  [Article Influence: 120.9]  [Reference Citation Analysis (1)]
175.  Armstrong MJ, Hull D, Guo K, Barton D, Hazlehurst JM, Gathercole LL, Nasiri M, Yu J, Gough SC, Newsome PN. Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis. J Hepatol. 2016;64:399-408.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 232]  [Cited by in F6Publishing: 237]  [Article Influence: 33.9]  [Reference Citation Analysis (0)]
176.  Drucker DJ. Dipeptidyl peptidase-4 inhibition and the treatment of type 2 diabetes: preclinical biology and mechanisms of action. Diabetes Care. 2007;30:1335-1343.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 274]  [Cited by in F6Publishing: 290]  [Article Influence: 18.1]  [Reference Citation Analysis (0)]
177.  Balaban YH, Korkusuz P, Simsek H, Gokcan H, Gedikoglu G, Pinar A, Hascelik G, Asan E, Hamaloglu E, Tatar G. Dipeptidyl peptidase IV (DDP IV) in NASH patients. Ann Hepatol. 2007;6:242-250.  [PubMed]  [DOI]  [Cited in This Article: ]
178.  Firneisz G, Varga T, Lengyel G, Fehér J, Ghyczy D, Wichmann B, Selmeci L, Tulassay Z, Rácz K, Somogyi A. Serum dipeptidyl peptidase-4 activity in insulin resistant patients with non-alcoholic fatty liver disease: a novel liver disease biomarker. PLoS One. 2010;5:e12226.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 87]  [Cited by in F6Publishing: 100]  [Article Influence: 7.7]  [Reference Citation Analysis (0)]
179.  Baumeier C, Saussenthaler S, Kammel A, Jähnert M, Schlüter L, Hesse D, Canouil M, Lobbens S, Caiazzo R, Raverdy V. Hepatic DPP4 DNA Methylation Associates With Fatty Liver. Diabetes. 2017;66:25-35.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 50]  [Cited by in F6Publishing: 46]  [Article Influence: 7.7]  [Reference Citation Analysis (0)]
180.  Iwasaki T, Yoneda M, Inamori M, Shirakawa J, Higurashi T, Maeda S, Terauchi Y, Nakajima A. Sitagliptin as a novel treatment agent for non-alcoholic Fatty liver disease patients with type 2 diabetes mellitus. Hepatogastroenterology. 2011;58:2103-2105.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 82]  [Cited by in F6Publishing: 92]  [Article Influence: 8.4]  [Reference Citation Analysis (0)]
181.  Itou M, Kawaguchi T, Taniguchi E, Oriishi T, Sata M. Dipeptidyl Peptidase IV Inhibitor Improves Insulin Resistance and Steatosis in a Refractory Nonalcoholic Fatty Liver Disease Patient: A Case Report. Case Rep Gastroenterol. 2012;6:538-544.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 22]  [Cited by in F6Publishing: 29]  [Article Influence: 2.6]  [Reference Citation Analysis (0)]
182.  Cui J, Philo L, Nguyen P, Hofflich H, Hernandez C, Bettencourt R, Richards L, Salotti J, Bhatt A, Hooker J. Sitagliptin vs. placebo for non-alcoholic fatty liver disease: A randomized controlled trial. J Hepatol. 2016;65:369-376.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 220]  [Cited by in F6Publishing: 223]  [Article Influence: 31.9]  [Reference Citation Analysis (0)]
183.  Joy TR, McKenzie CA, Tirona RG, Summers K, Seney S, Chakrabarti S, Malhotra N, Beaton MD. Sitagliptin in patients with non-alcoholic steatohepatitis: A randomized, placebo-controlled trial. World J Gastroenterol. 2017;23:141-150.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 104]  [Cited by in F6Publishing: 96]  [Article Influence: 16.0]  [Reference Citation Analysis (2)]
184.  Duman DG, Ozdemir F, Birben E, Keskin O, Ekşioğlu-Demiralp E, Celikel C, Kalayci O, Kalayci C. Effects of pentoxifylline on TNF-alpha production by peripheral blood mononuclear cells in patients with nonalcoholic steatohepatitis. Dig Dis Sci. 2007;52:2520-2524.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 29]  [Cited by in F6Publishing: 26]  [Article Influence: 1.6]  [Reference Citation Analysis (0)]
185.  Van Wagner LB, Koppe SW, Brunt EM, Gottstein J, Gardikiotes K, Green RM, Rinella ME. Pentoxifylline for the treatment of non-alcoholic steatohepatitis: a randomized controlled trial. Ann Hepatol. 2011;10:277-286.  [PubMed]  [DOI]  [Cited in This Article: ]
186.  Zein CO, Yerian LM, Gogate P, Lopez R, Kirwan JP, Feldstein AE, McCullough AJ. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology. 2011;54:1610-1619.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 260]  [Cited by in F6Publishing: 277]  [Article Influence: 23.1]  [Reference Citation Analysis (0)]
187.  Zein CO, Lopez R, Fu X, Kirwan JP, Yerian LM, McCullough AJ, Hazen SL, Feldstein AE. Pentoxifylline decreases oxidized lipid products in nonalcoholic steatohepatitis: new evidence on the potential therapeutic mechanism. Hepatology. 2012;56:1291-1299.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 116]  [Cited by in F6Publishing: 123]  [Article Influence: 11.2]  [Reference Citation Analysis (0)]
188.  Du J, Ma YY, Yu CH, Li YM. Effects of pentoxifylline on nonalcoholic fatty liver disease: a meta-analysis. World J Gastroenterol. 2014;20:569-577.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 70]  [Cited by in F6Publishing: 64]  [Article Influence: 7.1]  [Reference Citation Analysis (0)]
189.  Zeng T, Zhang CL, Zhao XL, Xie KQ. Pentoxifylline for the treatment of nonalcoholic fatty liver disease: a meta-analysis of randomized double-blind, placebo-controlled studies. Eur J Gastroenterol Hepatol. 2014;26:646-653.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 31]  [Cited by in F6Publishing: 33]  [Article Influence: 3.7]  [Reference Citation Analysis (0)]
190.  Singh S, Khera R, Allen AM, Murad MH, Loomba R. Comparative effectiveness of pharmacological interventions for nonalcoholic steatohepatitis: A systematic review and network meta-analysis. Hepatology. 2015;62:1417-1432.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 114]  [Cited by in F6Publishing: 121]  [Article Influence: 15.1]  [Reference Citation Analysis (0)]
191.  Solga SF, Diehl AM. Non-alcoholic fatty liver disease: lumen-liver interactions and possible role for probiotics. J Hepatol. 2003;38:681-687.  [PubMed]  [DOI]  [Cited in This Article: ]
192.  Miele L, Valenza V, La Torre G, Montalto M, Cammarota G, Ricci R, Mascianà R, Forgione A, Gabrieli ML, Perotti G. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology. 2009;49:1877-1887.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 938]  [Cited by in F6Publishing: 1002]  [Article Influence: 71.6]  [Reference Citation Analysis (0)]
193.  Aller R, De Luis DA, Izaola O, Conde R, Gonzalez Sagrado M, Primo D, De La Fuente B, Gonzalez J. Effect of a probiotic on liver aminotransferases in nonalcoholic fatty liver disease patients: a double blind randomized clinical trial. Eur Rev Med Pharmacol Sci. 2011;15:1090-1095.  [PubMed]  [DOI]  [Cited in This Article: ]
194.  Malaguarnera M, Vacante M, Antic T, Giordano M, Chisari G, Acquaviva R, Mastrojeni S, Malaguarnera G, Mistretta A, Li Volti G. Bifidobacterium longum with fructo-oligosaccharides in patients with non alcoholic steatohepatitis. Dig Dis Sci. 2012;57:545-553.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 287]  [Cited by in F6Publishing: 287]  [Article Influence: 26.1]  [Reference Citation Analysis (1)]
195.  Yokohama S, Yoneda M, Haneda M, Okamoto S, Okada M, Aso K, Hasegawa T, Tokusashi Y, Miyokawa N, Nakamura K. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatology. 2004;40:1222-1225.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 355]  [Cited by in F6Publishing: 371]  [Article Influence: 19.5]  [Reference Citation Analysis (0)]
196.  Mallat A, Lotersztajn S. Endocannabinoids and liver disease. I. Endocannabinoids and their receptors in the liver. Am J Physiol Gastrointest Liver Physiol. 2008;294:G9-G12.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 75]  [Cited by in F6Publishing: 82]  [Article Influence: 5.5]  [Reference Citation Analysis (0)]
197.  Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Bátkai S, Harvey-White J, Mackie K, Offertáler L, Wang L. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest. 2005;115:1298-1305.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 32]  [Cited by in F6Publishing: 349]  [Article Influence: 19.4]  [Reference Citation Analysis (0)]
198.  Gary-Bobo M, Elachouri G, Gallas JF, Janiak P, Marini P, Ravinet-Trillou C, Chabbert M, Cruccioli N, Pfersdorff C, Roque C. Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic syndrome in obese Zucker fa/fa rats. Hepatology. 2007;46:122-129.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 245]  [Cited by in F6Publishing: 256]  [Article Influence: 16.0]  [Reference Citation Analysis (0)]
199.  Rimonabant: suicide and depression. Depression and suicidal tendencies are about twice as frequent with rimonabant as with placebo. Prescrire Int. 2007;16:250.  [PubMed]  [DOI]  [Cited in This Article: ]
200.  Christopoulou FD, Kiortsis DN. An overview of the metabolic effects of rimonabant in randomized controlled trials: potential for other cannabinoid 1 receptor blockers in obesity. J Clin Pharm Ther. 2011;36:10-18.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 77]  [Cited by in F6Publishing: 82]  [Article Influence: 6.8]  [Reference Citation Analysis (0)]
201.  Stephen S, Baranova A, Younossi ZM. Nonalcoholic fatty liver disease and bariatric surgery. Expert Rev Gastroenterol Hepatol. 2012;6:163-171.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 25]  [Cited by in F6Publishing: 26]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
202.  Grimm IS, Schindler W, Haluszka O. Steatohepatitis and fatal hepatic failure after biliopancreatic diversion. Am J Gastroenterol. 1992;87:775-779.  [PubMed]  [DOI]  [Cited in This Article: ]
203.  Charlton M, Kasparova P, Weston S, Lindor K, Maor-Kendler Y, Wiesner RH, Rosen CB, Batts KP. Frequency of nonalcoholic steatohepatitis as a cause of advanced liver disease. Liver Transpl. 2001;7:608-614.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 185]  [Cited by in F6Publishing: 198]  [Article Influence: 9.0]  [Reference Citation Analysis (0)]
204.  Anstee QM, Concas D, Kudo H, Levene A, Pollard J, Charlton P, Thomas HC, Thursz MR, Goldin RD. Impact of pan-caspase inhibition in animal models of established steatosis and non-alcoholic steatohepatitis. J Hepatol. 2010;53:542-550.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 119]  [Cited by in F6Publishing: 121]  [Article Influence: 9.3]  [Reference Citation Analysis (0)]
205.  Witek RP, Stone WC, Karaca FG, Syn WK, Pereira TA, Agboola KM, Omenetti A, Jung Y, Teaberry V, Choi SS. Pan-caspase inhibitor VX-166 reduces fibrosis in an animal model of nonalcoholic steatohepatitis. Hepatology. 2009;50:1421-1430.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 185]  [Cited by in F6Publishing: 191]  [Article Influence: 13.6]  [Reference Citation Analysis (0)]
206.  Shiffman M, Freilich B, Vuppalanchi R, Watt K, Burgess G, Morris M, Sheedy B, Schiff E. LP37: A placebo-controlled, multicenter, double-blind, randomised trial of emricasan in subjects with non-alcoholic fatty liver disease (NAFLD) and raised transaminases. J Hepatol. 2015;62:S282.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 25]  [Cited by in F6Publishing: 23]  [Article Influence: 2.9]  [Reference Citation Analysis (0)]
207.  Karnik S, Charlton M, Popov Y, Goodman ZD, Nash M, Sulfab M, Barry V, Huntzicker EG, French D, LI K. Pharmacological inhibition of apoptosis signal-regulating kinase 1 (ASK1) in a murine model of NASH with pre-existing disease blocks fibrosis, steatosis, and insulin resistance. Hepatology. 2014;60:570A.  [PubMed]  [DOI]  [Cited in This Article: ]
208.  Karnik S, Charlton MR, Li L, Nash M, Sulfab M, Newstrom D, Huntzicker EG, French D, Goodman ZD, Shafizadeh T. Efficacy of an ASK1 Inhibitor to Reduce Fibrosis and Steatosis in a Murine Model of NASH is Associated with Normalization of Lipids and Hepatic Gene Expression and a Reduction in Serum Biomarkers of Inflammation and Fibrosis. Hepatology. 2015;62:877A.  [PubMed]  [DOI]  [Cited in This Article: ]
209.  Xiang M, Wang PX, Wang AB, Zhang XJ, Zhang Y, Zhang P, Mei FH, Chen MH, Li H. Targeting hepatic TRAF1-ASK1 signaling to improve inflammation, insulin resistance, and hepatic steatosis. J Hepatol. 2016;64:1365-1377.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 100]  [Cited by in F6Publishing: 102]  [Article Influence: 14.6]  [Reference Citation Analysis (0)]
210.  Sabio G, Davis RJ. cJun NH2-terminal kinase 1 (JNK1): roles in metabolic regulation of insulin resistance. Trends Biochem Sci. 2010;35:490-496.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 118]  [Cited by in F6Publishing: 122]  [Article Influence: 9.4]  [Reference Citation Analysis (0)]
211.  Sabio G, Davis RJ. TNF and MAP kinase signalling pathways. Semin Immunol. 2014;26:237-245.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 378]  [Cited by in F6Publishing: 435]  [Article Influence: 48.3]  [Reference Citation Analysis (0)]
212.  Sabio G, Kennedy NJ, Cavanagh-Kyros J, Jung DY, Ko HJ, Ong H, Barrett T, Kim JK, Davis RJ. Role of muscle c-Jun NH2-terminal kinase 1 in obesity-induced insulin resistance. Mol Cell Biol. 2010;30:106-115.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 115]  [Cited by in F6Publishing: 120]  [Article Influence: 9.2]  [Reference Citation Analysis (0)]
213.  González-Terán B, Cortés JR, Manieri E, Matesanz N, Verdugo Á, Rodríguez ME, González-Rodríguez Á, Valverde ÁM, Martín P, Davis RJ, Sabio G. Eukaryotic elongation factor 2 controls TNF-α translation in LPS-induced hepatitis. J Clin Invest. 2013;123:164-178.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 77]  [Cited by in F6Publishing: 78]  [Article Influence: 7.1]  [Reference Citation Analysis (0)]
214.  Risco A, del Fresno C, Mambol A, Alsina-Beauchamp D, MacKenzie KF, Yang HT, Barber DF, Morcelle C, Arthur JS, Ley SC. p38γ and p38δ kinases regulate the Toll-like receptor 4 (TLR4)-induced cytokine production by controlling ERK1/2 protein kinase pathway activation. Proc Natl Acad Sci USA. 2012;109:11200-11205.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 84]  [Cited by in F6Publishing: 84]  [Article Influence: 7.6]  [Reference Citation Analysis (0)]
215.  González-Terán B, Matesanz N, Nikolic I, Verdugo MA, Sreeramkumar V, Hernández-Cosido L, Mora A, Crainiciuc G, Sáiz ML, Bernardo E. p38γ and p38δ reprogram liver metabolism by modulating neutrophil infiltration. EMBO J. 2016;35:536-552.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 45]  [Article Influence: 6.4]  [Reference Citation Analysis (0)]
216.  Staels B, Rubenstrunk A, Noel B, Rigou G, Delataille P, Millatt LJ, Baron M, Lucas A, Tailleux A, Hum DW. Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology. 2013;58:1941-1952.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 297]  [Cited by in F6Publishing: 303]  [Article Influence: 30.3]  [Reference Citation Analysis (0)]
217.  Montagner A, Polizzi A, Fouché E, Ducheix S, Lippi Y, Lasserre F, Barquissau V, Régnier M, Lukowicz C, Benhamed F. Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD. Gut. 2016;65:1202-1214.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 397]  [Cited by in F6Publishing: 395]  [Article Influence: 56.4]  [Reference Citation Analysis (0)]
218.  Piccinin E, Moschetta A. Hepatic-specific PPARα-FGF21 action in NAFLD. Gut. 2016;65:1075-1076.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 12]  [Cited by in F6Publishing: 12]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
219.  Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, Romero-Gomez M, Boursier J, Abdelmalek M, Caldwell S. Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Gastroenterology. 2016;150:1147-1159.e5.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 677]  [Cited by in F6Publishing: 700]  [Article Influence: 100.0]  [Reference Citation Analysis (0)]
220.  Pellicciari R, Costantino G, Camaioni E, Sadeghpour BM, Entrena A, Willson TM, Fiorucci S, Clerici C, Gioiello A. Bile acid derivatives as ligands of the farnesoid X receptor. Synthesis, evaluation, and structure-activity relationship of a series of body and side chain modified analogues of chenodeoxycholic acid. J Med Chem. 2004;47:4559-4569.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 138]  [Cited by in F6Publishing: 147]  [Article Influence: 7.7]  [Reference Citation Analysis (0)]
221.  Ballestri S, Nascimbeni F, Romagnoli D, Baldelli E, Lonardo A. The Role of Nuclear Receptors in the Pathophysiology, Natural Course, and Drug Treatment of NAFLD in Humans. Adv Ther. 2016;33:291-319.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 60]  [Cited by in F6Publishing: 51]  [Article Influence: 7.3]  [Reference Citation Analysis (0)]
222.  Fuchs M. Non-alcoholic Fatty liver disease: the bile Acid-activated farnesoid x receptor as an emerging treatment target. J Lipids. 2012;2012:934396.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 72]  [Cited by in F6Publishing: 81]  [Article Influence: 6.8]  [Reference Citation Analysis (0)]
223.  Makri E, Cholongitas E, Tziomalos K. Emerging role of obeticholic acid in the management of nonalcoholic fatty liver disease. World J Gastroenterol. 2016;22:9039-9043.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 27]  [Cited by in F6Publishing: 28]  [Article Influence: 4.0]  [Reference Citation Analysis (1)]
224.  Ali AH, Carey EJ, Lindor KD. Recent advances in the development of farnesoid X receptor agonists. Ann Transl Med. 2015;3:5.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 91]  [Reference Citation Analysis (0)]
225.  Verbeke L, Mannaerts I, Schierwagen R, Govaere O, Klein S, Vander Elst I, Windmolders P, Farre R, Wenes M, Mazzone M. FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis. Sci Rep. 2016;6:33453.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 131]  [Cited by in F6Publishing: 138]  [Article Influence: 19.7]  [Reference Citation Analysis (0)]
226.  Úbeda M, Lario M, Muñoz L, Borrero MJ, Rodríguez-Serrano M, Sánchez-Díaz AM, Del Campo R, Lledó L, Pastor Ó, García-Bermejo L, Díaz D, Álvarez-Mon M, Albillos A. Obeticholic acid reduces bacterial translocation and inhibits intestinal inflammation in cirrhotic rats. J Hepatol. 2016;64:1049-1057.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 104]  [Cited by in F6Publishing: 109]  [Article Influence: 15.6]  [Reference Citation Analysis (0)]
227.  Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU, Kipnes M, Adorini L, Sciacca CI, Clopton P, Castelloe E. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology. 2013;145:574-582.e1.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 656]  [Cited by in F6Publishing: 681]  [Article Influence: 68.1]  [Reference Citation Analysis (0)]
228.  Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, Chalasani N, Dasarathy S, Diehl AM, Hameed B. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385:956-965.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1569]  [Cited by in F6Publishing: 1538]  [Article Influence: 192.3]  [Reference Citation Analysis (0)]
229.  Pencek R, Marmon T, Roth JD, Liberman A, Hooshmand-Rad R, Young MA. Effects of obeticholic acid on lipoprotein metabolism in healthy volunteers. Diabetes Obes Metab. 2016;18:936-940.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 51]  [Cited by in F6Publishing: 49]  [Article Influence: 7.0]  [Reference Citation Analysis (0)]
230.  Ghosh Laskar M, Eriksson M, Rudling M, Angelin B. Treatment with the natural FXR agonist chenodeoxycholic acid reduces clearance of plasma LDL whilst decreasing circulating PCSK9, lipoprotein(a) and apolipoprotein C-III. J Intern Med. 2017;281:575-585.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 40]  [Cited by in F6Publishing: 37]  [Article Influence: 6.2]  [Reference Citation Analysis (0)]
231.  Carino A, Cipriani S, Marchianò S, Biagioli M, Santorelli C, Donini A, Zampella A, Monti MC, Fiorucci S. BAR502, a dual FXR and GPBAR1 agonist, promotes browning of white adipose tissue and reverses liver steatosis and fibrosis. Sci Rep. 2017;7:42801.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 70]  [Cited by in F6Publishing: 74]  [Article Influence: 12.3]  [Reference Citation Analysis (0)]
232.  Gege C, Kinzel O, Steeneck C, Schulz A, Kremoser C. Knocking on FXR’s door: the “hammerhead”-structure series of FXR agonists - amphiphilic isoxazoles with potent in vitro and in vivo activities. Curr Top Med Chem. 2014;14:2143-2158.  [PubMed]  [DOI]  [Cited in This Article: ]
233.  Haga S, Yimin , Ozaki M. Relevance of FXR-p62/SQSTM1 pathway for survival and protection of mouse hepatocytes and liver, especially with steatosis. BMC Gastroenterol. 2017;17:9.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 12]  [Cited by in F6Publishing: 12]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
234.  Schwabl P, Hambruch E, Seeland BA, Hayden H, Wagner M, Garnys L, Strobel B, Schubert TL, Riedl F, Mitteregger D. The FXR agonist PX20606 ameliorates portal hypertension by targeting vascular remodelling and sinusoidal dysfunction. J Hepatol. 2017;66:724-733.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 102]  [Cited by in F6Publishing: 106]  [Article Influence: 17.7]  [Reference Citation Analysis (0)]
235.  Aoyama T, Paik YH, Watanabe S, Laleu B, Gaggini F, Fioraso-Cartier L, Molango S, Heitz F, Merlot C, Szyndralewiez C. Nicotinamide adenine dinucleotide phosphate oxidase in experimental liver fibrosis: GKT137831 as a novel potential therapeutic agent. Hepatology. 2012;56:2316-2327.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 230]  [Cited by in F6Publishing: 240]  [Article Influence: 21.8]  [Reference Citation Analysis (0)]
236.  Paik YH, Iwaisako K, Seki E, Inokuchi S, Schnabl B, Osterreicher CH, Kisseleva T, Brenner DA. The nicotinamide adenine dinucleotide phosphate oxidase (NOX) homologues NOX1 and NOX2/gp91(phox) mediate hepatic fibrosis in mice. Hepatology. 2011;53:1730-1741.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 152]  [Cited by in F6Publishing: 160]  [Article Influence: 13.3]  [Reference Citation Analysis (0)]
237.  Yang RY, Rabinovich GA, Liu FT. Galectins: structure, function and therapeutic potential. Expert Rev Mol Med. 2008;10:e17.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 515]  [Cited by in F6Publishing: 541]  [Article Influence: 36.1]  [Reference Citation Analysis (0)]
238.  Di Lella S, Sundblad V, Cerliani JP, Guardia CM, Estrin DA, Vasta GR, Rabinovich GA. When galectins recognize glycans: from biochemistry to physiology and back again. Biochemistry. 2011;50:7842-7857.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 195]  [Cited by in F6Publishing: 202]  [Article Influence: 16.8]  [Reference Citation Analysis (0)]
239.  Henderson NC, Sethi T. The regulation of inflammation by galectin-3. Immunol Rev. 2009;230:160-171.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 342]  [Cited by in F6Publishing: 358]  [Article Influence: 25.6]  [Reference Citation Analysis (0)]
240.  Traber PG, Zomer E. Therapy of experimental NASH and fibrosis with galectin inhibitors. PLoS One. 2013;8:e83481.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 125]  [Cited by in F6Publishing: 135]  [Article Influence: 13.5]  [Reference Citation Analysis (0)]
241.  Foster DW. Malonyl-CoA: the regulator of fatty acid synthesis and oxidation. J Clin Invest. 2012;122:1958-1959.  [PubMed]  [DOI]  [Cited in This Article: ]
242.  Harriman G, Greenwood J, Bhat S, Huang X, Wang R, Paul D, Tong L, Saha AK, Westlin WF, Kapeller R. Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats. Proc Natl Acad Sci USA. 2016;113:E1796-E1805.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 169]  [Cited by in F6Publishing: 172]  [Article Influence: 24.6]  [Reference Citation Analysis (0)]
243.  Stiede K, Miao W, Blanchette HS, Beysen C, Harriman G, Harwood HJ Jr, Kelley H, Kapeller R, Schmalbach T, Westlin WF. Acetyl-coenzyme A carboxylase inhibition reduces de novo lipogenesis in overweight male subjects: A randomized, double-blind, crossover study. Hepatology. 2017;66:324-334.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 80]  [Cited by in F6Publishing: 83]  [Article Influence: 13.8]  [Reference Citation Analysis (0)]
244.  Inagaki T. Research Perspectives on the Regulation and Physiological Functions of FGF21 and its Association with NAFLD. Front Endocrinol (Lausanne). 2015;6:147.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 37]  [Cited by in F6Publishing: 35]  [Article Influence: 4.4]  [Reference Citation Analysis (0)]
245.  Nies VJ, Sancar G, Liu W, van Zutphen T, Struik D, Yu RT, Atkins AR, Evans RM, Jonker JW, Downes MR. Fibroblast Growth Factor Signaling in Metabolic Regulation. Front Endocrinol (Lausanne). 2016;6:193.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 46]  [Cited by in F6Publishing: 65]  [Article Influence: 8.1]  [Reference Citation Analysis (0)]
246.  Liu X, Zhang P, Martin RC, Cui G, Wang G, Tan Y, Cai L, Lv G, Li Y. Lack of fibroblast growth factor 21 accelerates metabolic liver injury characterized by steatohepatities in mice. Am J Cancer Res. 2016;6:1011-1025.  [PubMed]  [DOI]  [Cited in This Article: ]
247.  Mu J, Pinkstaff J, Li Z, Skidmore L, Li N, Myler H, Dallas-Yang Q, Putnam AM, Yao J, Bussell S. FGF21 analogs of sustained action enabled by orthogonal biosynthesis demonstrate enhanced antidiabetic pharmacology in rodents. Diabetes. 2012;61:505-512.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 130]  [Cited by in F6Publishing: 130]  [Article Influence: 11.8]  [Reference Citation Analysis (0)]
248.  Lee JH, Kang YE, Chang JY, Park KC, Kim HW, Kim JT, Kim HJ, Yi HS, Shong M, Chung HK. An engineered FGF21 variant, LY2405319, can prevent non-alcoholic steatohepatitis by enhancing hepatic mitochondrial function. Am J Transl Res. 2016;8:4750-4763.  [PubMed]  [DOI]  [Cited in This Article: ]
249.  Wu X, Ge H, Lemon B, Vonderfecht S, Weiszmann J, Hecht R, Gupte J, Hager T, Wang Z, Lindberg R. FGF19-induced hepatocyte proliferation is mediated through FGFR4 activation. J Biol Chem. 2010;285:5165-5170.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 121]  [Cited by in F6Publishing: 127]  [Article Influence: 9.1]  [Reference Citation Analysis (0)]
250.  Luo J, Ko B, To C, Ling L, Rossi S, DePaoli A, Tian H. P0932: Treatment with NGM282 significantly improves liver histopathology in a mouse model of non-alcoholic steatohepatitis (NASH). J Hepatol. 2015;62:S694.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 6]  [Cited by in F6Publishing: 6]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
251.  Hong F, Chou HI, Friedman SL. Significant Anti-Fibrotic Activity of Cenicriviroc, A Dual CCR2/CCR5 Antagonist, in a Rat Model of Thioacetamide-Induced Liver Fibrosis and Cirrhosis. Hepatology. 2013;.  [PubMed]  [DOI]  [Cited in This Article: ]
252.  Lefebvre DR, Hashiguchi T, Jenkins H, Nabhan A, Yoneyama H, Friedman S, Wolfgang GH. Anti-Fibrotic and Anti-Inflammatory Activity of the Dual CCR2 and CCR5 Antagonist Cenicriviroc in a Mouse Model of NASH. Hepatology. 2013;58:221A-222A.  [PubMed]  [DOI]  [Cited in This Article: ]
253.  Lefebvre E, Moyle G, Reshef R, Richman LP, Thompson M, Hong F, Chou HL, Hashiguchi T, Plato C, Poulin D. Antifibrotic Effects of the Dual CCR2/CCR5 Antagonist Cenicriviroc in Animal Models of Liver and Kidney Fibrosis. PLoS One. 2016;11:e0158156.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 197]  [Cited by in F6Publishing: 210]  [Article Influence: 30.0]  [Reference Citation Analysis (0)]
254.  Seki E, de Minicis S, Inokuchi S, Taura K, Miyai K, van Rooijen N, Schwabe RF, Brenner DA. CCR2 promotes hepatic fibrosis in mice. Hepatology. 2009;50:185-197.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 306]  [Cited by in F6Publishing: 329]  [Article Influence: 23.5]  [Reference Citation Analysis (0)]
255.  Friedman S, Sanyal A, Goodman Z, Lefebvre E, Gottwald M, Fischer L, Ratziu V. Efficacy and safety study of cenicriviroc for the treatment of non-alcoholic steatohepatitis in adult subjects with liver fibrosis: CENTAUR Phase 2b study design. Contemp Clin Trials. 2016;47:356-365.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 146]  [Cited by in F6Publishing: 151]  [Article Influence: 21.6]  [Reference Citation Analysis (0)]
256.  Safadi R, Konikoff FM, Mahamid M, Zelber-Sagi S, Halpern M, Gilat T, Oren R; FLORA Group. The fatty acid-bile acid conjugate Aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2014;12:2085-2091.e1.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 182]  [Cited by in F6Publishing: 192]  [Article Influence: 21.3]  [Reference Citation Analysis (0)]
257.  Moon HJ, Finney J, Ronnebaum T, Mure M. Human lysyl oxidase-like 2. Bioorg Chem. 2014;57:231-241.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 82]  [Cited by in F6Publishing: 86]  [Article Influence: 9.6]  [Reference Citation Analysis (0)]
258.  Barry-Hamilton V, Spangler R, Marshall D, McCauley S, Rodriguez HM, Oyasu M, Mikels A, Vaysberg M, Ghermazien H, Wai C. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med. 2010;16:1009-1017.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 618]  [Cited by in F6Publishing: 640]  [Article Influence: 49.2]  [Reference Citation Analysis (0)]
259.  Morris BJ. Seven sirtuins for seven deadly diseases of aging. Free Radic Biol Med. 2013;56:133-171.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 281]  [Cited by in F6Publishing: 293]  [Article Influence: 29.3]  [Reference Citation Analysis (0)]
260.  Colak Y, Ozturk O, Senates E, Tuncer I, Yorulmaz E, Adali G, Doganay L, Enc FY. SIRT1 as a potential therapeutic target for treatment of nonalcoholic fatty liver disease. Med Sci Monit. 2011;17:HY5-HY9.  [PubMed]  [DOI]  [Cited in This Article: ]
261.  Li L, Hai J, Li Z, Zhang Y, Peng H, Li K, Weng X. Resveratrol modulates autophagy and NF-κB activity in a murine model for treating non-alcoholic fatty liver disease. Food Chem Toxicol. 2014;63:166-173.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 94]  [Cited by in F6Publishing: 98]  [Article Influence: 9.8]  [Reference Citation Analysis (0)]