Editor: Byoung Kuk Jang, Keimyung University School of Medicine, Korea
Severe alcoholic hepatitis (SAH) remains a disease with high mortality. Steroid is the main stay and has been shown to give modest 28-day survival benefit in carefully selected patients, but no 90-day survival benefit. Since non-responders have high incidence of infections and increased mortality, it would be worthwhile to identify them before starting steroid therapy. A high and rising bilirubin, urinary acetyl carnitine >2,500 ng/mL, high asiloglycoprotein positive microparticles, and specific features in liver biopsy could predict steroid non-response at baseline. There is an ever-growing need to find new and effective therapies for SAH patients. Besides aggressive nutrition, granulocyte colony stimulating factor, fecal microbiota transplantation, and plasma exchange appear promising therapies and provide a hope for steroid ineligible or steroid non-responsive patients. Suppression of hepatic inflammation, preventing new bacterial or fungal infections, and enhancing liver regeneration will remain the key targets for next generation therapies.
The burden of alcohol-related liver diseases (ALD) is rapidly growing and is likely to increase in the coming years. With the availability of better treatment options for managing hepatitis B and C, alcoholic hepatitis (AH) related hospital admissions are adding substantial load on healthcare costs and utilization [
AH is an acute form of alcohol-induced liver injury, ranges from mild to severe, and usually presents on the background of chronic liver disease. It is clinically defined as recent onset or worsening of jaundice in a patient with chronic heavy alcohol use until at least 6 weeks prior to presentation, elevated liver enzymes with an aspartate aminotransferase to alanine aminotransferase ratio of >1.5:1, with absolute values of these enzymes not exceeding 500 IU/L and exclusion of other liver diseases [
Predominant histological lesions that characterize AH include the coexistence of steatosis, hepatocyte ballooning, and inflammatory infiltrates, mainly with neutrophils, called satellitosis [
An important part of therapy for any disease requires assessment of the severity of the disease and the appropriate time for initiation of the therapy. Assessing severity of AH can be done by using a combination of clinical and biochemical parameters. Maddrey’s discriminant function (MDF) [
In mild or moderate AH, abstinence does help to some extent. For severe AH, specific and effective therapy is required to suppress the ongoing inflammation and hepatic necrosis. Unfortunately, there are very limited options [
Since AH is considered as a severe form of inflammatory disease of the liver, prednisolone with its anti-inflammatory action, has been used for over 40 years for such patients [
In a recent study of Shasthry et al. [
Furthermore, infections are not uncommon after initiation of steroid therapy. Steroid non-response is associated with a high risk of infection and poor outcomes [
There is an unmet need to treat these large cohort of patients with severe AH with newer therapeutic strategies. Furthermore, even for the steroid-eligible patients, it would be highly desirable, if predictors of non-response to steroids could be defined prior to initiation of steroid therapy.
If steroid non-responders can be identified prior to starting steroids, several adverse effects like development of new infections, gastrointestinal hemorrhage, hyperglycemia, etc. could be prevented.
Persistently high and rising bilirubin is very suggestive of an unremitting inflammation, likely to be unresponsive to steroids.
Whether assessment of the same parameters which form the Lille score can reliably predict non-response at day 4 rather than day 7, was evaluated. The data showed that Lille score on day 4 was as good as day 7 to predict 3-month mortality and reduces unnecessary steroid exposure [
A pre-therapy liver biopsy helps in stratification of SAH patients not only to assess the severity of liver disease, but also to predict response to therapy. Liver biopsy showing ballooning hepatocytes and bilirubinostasis, indicates a poor response to steroids. In one study, non-responders had higher ballooning degeneration (BD) (mean, 3.87 [standard deviation (SD), -0.91] vs. 2.92 [SD, -1.33],
Patients with SAH have a unique metabolic phenotype, one with severe inflammatory milieu and an impaired immune status. Whether baseline metabolic phenotype could identify non-responders and those with unfavorable outcome was investigated [
Microvesicles (MVs) reflect the cellular stress and the disease conditions. In one study, pre-therapy peripheral plasma MV levels of haematopoietic stem-cells (CD45+ CD34+; 116.8 vs. 13.4 MV/μL;
Whether variation to steroid response in SAH patients has a genetic basis, is largely unknown. This was explored by investigating the hepatic transcriptome in patients originating in different countries [
Circulatory albumin is a potent ROS scavenger. However, structural modifications in albumin may modulate its antioxidant and immune‐regulatory properties. Such alterations in circulating albumin in SAH patients along with their contribution to neutrophil activation, intracellular stress, and alteration in associated molecular pathways have been assessed [
Conceptually, the approach to manage SAH includes attempts to abrogate the severe inflammation and necrosis due to alcohol-induced injury, removal of the toxic metabolites produced due to severe inflammation in AH, stimulate liver regeneration despite a toxic milieu of a failing liver using endogenous or exogenous growth factors and modulation of gut bacteria to availability of appropriate nutrition and immune modulation. (
G-CSF (also known as CSF3) is a colony stimulating factor which stimulates bone-marrow precursor cells to produce granulocytes and stem cells, and release them into the blood [
Inflammation and impaired liver repair and regeneration are the major factors responsible for liver failure in patients with AH. A state of hyper-inflammatory response leading to progressive hepatocyte damage is accompanied by skewed and deficient immune system in SAH patients. Agents that can ameliorate gut-derived infection and inflammation, and enhance native liver regeneration including bone marrow response are needed. The maximal level of CD34+ cells are released on day 5 after daily G-CSF administration, and the levels fall rapidly on subsequent days despite a continued rise in white blood cell counts [
G-CSF regulates innate immune cell response by modulating the production, maturation, migration, and function of neutrophils, monocytes and dendritic cells (DCs). Excessive alcohol consumption impairs this granulopoiesis and the functionality of granulocytes resulting in defects in immune defense and susceptibility to serious infections [
Locally produced G-CSF within the injured tissue also affects the function of recruited neutrophils and DCs. The frequencies of intrahepatic myeloid DCs and plasmacytoid DCs are lower in non-survivors compared to survivors. Intravenously given G-CSF has been shown to enhance the recruitment of plasmacytoid DCs, nearly 12-folds, resulting in reduction in the intrahepatic gamma interferon production and amelioration of hepatic injury (
G-CSF mobilizes bone marrow hematopoietic stem cells into the circulation by reduced C-X-C motif chemokine ligand 12 levels and adhesive action and facilitates their release into the circulation. G-CSF also stimulates the peripheral sympathetic nervous system, increasing catecholamine concentrations [
In a randomized trial of patients with acute-on-chronic liver failure, mostly due to alcohol, G-CSF was able to reduce the incidence of new infections, hepatorenal syndrome and hepatic encephalopathy with an improved 28-day survival compared to placebo (69% vs. 29%,
G-CSF (given as 5 mg/kg, twice daily for 5 days) in another study on 46 SAH patients with a mean MDF of 85, was found to improve CD34+ cells in peripheral blood at the end of therapy along with improved 90-day survival (78.3% vs. 30.4%,
These reports are mainly from Asian countries. In one study [
For steroid non-responders, there are few choices. In the only available study, G-CSF was evaluated in steroid non-responsive SAH patients. Shasthry et al. [
Patients with severe AH, not amenable to steroids treatment or steroid non-responders can be considered for G-CSF administration. However, as noted in most of the RCTs, patients with MDF >90, hemoglobin <8 g/dL, high ferritin levels, macrophage activation syndrome (MAS), evidence of iron overload, hypersplenism, ascites, total leucocyte count of >40,000/mm3, infections, culture positive sepsis, acute kidney injury [
The gut microbiome (GM) plays a major role in liver disease. A chronically altered and unhealthy microbiome contributes to the development and perpetuation of liver disease, and this is probably true for SAH. The GM digests the ingested alcohol, with an increase in acetaldehyde concentrations in the gut lumen, and disruption of the mucosal barrier, permitting translocation of viable bacteria and their products, into portal circulation. Locally in the gut, the overgrowth of pathogenic species changes the bile acid composition, enteral metabolites, and entero-hepatic circulation [
Patients with AH, have a pathobiont of their own [
Quantitative and qualitative variations in fecal lipid metabolites like the short-chain fatty acids butyrate and propionate have been reported in rats following chronic ethanol administration [
AH-related dysbiosis is associated with an increase in
Alteration in the GM of a patient can be achieved by using probiotics, FMT or using genetically altered bacteria [
Probiotics have been shown in a small randomized trial to be of benefit in cirrhotic patients, including those with hepatic encephalopathy [
FMT has been used in multiple clinical conditions in gastroenterology. Its use was evaluated in a pilot study of eight steroidineligible SAH patients, and was compared to anecdotal controls. FMT showed significant survival benefit at day 90 with the donor microbiota co-existing in the recipients till 12 months [
It is known that subjects in the same household, living and eating the same food, generally share common bacterial taxa. We therefore preferred using FMT material from a related healthy individual living in the same household, with a presumption that the bacteria could adapt readily in the patient.
Recently, concerns have been raised about the safety of FMT therapy as fecal instillate may serve as a medium to carry pathogens [
We have completed a large study on 112 SAH patients, comparing the safety and efficacy in 90 day-survival in those receiving steroids with healthy donor FMT. We serially assessed the recipients for the improvement in clinical and biochemical parameters, changes in their GM, occurrence of adverse events, new complications, and infections. Since Lille score has been validated only for steroid therapy, new scores for assessing the therapeutic response to emerging therapies have also been developed. The initial results of the FMT in SAH patients are quite encouraging. Attempts have been made to inhibit the effects of pro-inflammatory IL-1 by using antagonist to its receptor, anakinra. In a clinical trial comparing anakinra efficacy in combination with pentoxyfylline and zinc against methylprednisolone, the results suggest that long term survival was similar between the two groups (66.8%, anakinra group vs. 52.8%, prednisolone group,
The goals of nutrition therapy are briefly summarized in the
There is also a growing realization of the benefits of immunonutrition in critical illnesses. Administration of omega-3 FAs, contained in fish oil has been shown to reduce morbidity and mortality in both, postoperative and critically ill patients, without undesired side effects. Sepsis is common in SAH patients and can develop within the first few days of the illness [
Patients with SAH have insulin resistance fulfilling three dominant criteria: low high-density lipoprotein cholesterol, high triglycerides, and high fasting blood sugar. The study [
Extracorporeal liver support procedures, with potential to remove toxic and highly oxidative metabolites and circulating molecules may be of help in patients with SAH. However, artificial liver support, using different liver dialysis devices have shown limited benefits [
Plasma exchange has been shown to clear damage-associated molecular patterns, improve SIRS and survival in patients with acute liver failure in a large multi-centric RCT [
Although oxidative stress has been implicated in the pathogenesis of AH [
This technique involves removal of up to 60% of activated granulocytes and monocytes from circulating blood. It has been found to be well tolerated and of some benefit in patients responding to steroids [
Besides being compared for its anti-inflammatory potential against steroid, anakinra has also been tested for treatment of MAS, a common presentation of very sick SAH patients [
Severe AH remains to be a disease with a high mortality, and there is an ever-growing need to find effective therapies to treat the patients early or delay mortality. From the many therapeutic options discussed above, it is unlikely that a single therapy would be an all-effective option. Given the complex molecular mechanisms varying with different stages of the disease, a combination of therapies is likely to improve efficiency. Importantly, addressing suppression of bacterial or viral infections, and hepatic inflammation, in conjunction with liver regeneration will remain the key strategy for next generation therapies.
SKS and SS, both contributed to compilation of cited works, writing of review and development of figures. SKS conceptualized the manuscript.
The authors have no conflicts to disclose.
alcoholic hepatitis
alcohol-associated liver diseases
BCL2-associated athanogene1
ballooning degeneration
confidence interval
dendritic cells
fatty acid
fibroblast growth factor
fecal microbiota transplantation
granulocyte colony stimulating factor
gut microbiome
human mercaptalbumin
human non-mercaptalbumin
interleukin
long chain-fatty acid
macrophage activation syndrome
Mallory-Denk bodies
Maddrey’s discriminant function
model for end-stage liver disease
microvesicle
N-acetylcysteine
randomized control trial
reactive oxygen species
severe alcoholic hepatitis
standard deviation
systemic inflammatory response syndrome
sequential organ failure assessment
ASGPR-positive hepatocyte MPs are increased. ASGPR, asiloglycoprotein; MPs, microparticles; NR, non-responder; HC, healthy control.
Conformationally folded GR binds to glucocorticoid (i) and shifts to nucleus, where the receptor dimerizes and binds to co-factors (e.g., NFkB) to inhibit proinflammatory gene transcription. BAG1 cleaves GR (ii) in cytoplasm and prevents its downstream suppression leaving pro-inflammatory gene transcription active. GR, glucocorticoid receptor; BAG1, BCl2-associated athanogene 1.
Rationale approaches for treating severe alcoholic hepatitis. SAH, severe alcoholic hepatitis; DAMPs, damage-associated molecular patterns; FMT, fecal microbiota transplantation; G-CSF, granulocyte colony stimulating factor; FPSA, fractional plasma separation and adsorption.
Proposed algorithm for treatment of patients with severe alcoholic hepatitis; steroid non-responders or ineligible patients could be counseled to try experimental therapies. DF, discriminent factor; G-CSF, granulocyte colony stimulating factor. *A baseline assessment of likely steroid non-response could be performed.
G-CSF increases DC population which reduces IFN-γ resulting in improved survival. Adapted from Khanam et al. [
G-CSF has multifaceted applicability in severe alcoholic hepatitis patients; reduction of inflammation, prevention of infection and hepatic regeneration. Adapted from Sarin and Choudhury [
Saturated fats could help reverse dysbiosis and revert gut leakiness. Based on Chen et al. [
Calorie intake of >25 kcal/kg/day demonstrates significant improvement over <25 kcal/kg/day nutrition supplementation. Adapted
from Kalal et al. [
Nutritional therapy/adequacy plays an important role in recovery from severe alcoholic hepatitis
Goals of nutrition support |
---|
Adequate usable calories: |
Liver regeneration |
Immune restoration |
Prevent hypoglycemia |
Positive N2 balance, treat sarcopenia |
Reduce excess NH3 production: |
Treat hepatic encephalopathy |
Improve quality of life |
Survival |