Advertisement

Determining Prognosis of ALD and Alcoholic Hepatitis

Published:November 03, 2022DOI:https://doi.org/10.1016/j.jceh.2022.10.010

      Abstract

      Alcohol-associated hepatitis has a poor prognosis in terms of short-term mortality and often presents with symptoms, such as jaundice, acute renal failure, and ascites. There are many prognostic models that have been developed to predict short-term and long-term mortality in these patients. Current prognostic models can be divided into static scores, which are measured at admission, and dynamic models, which measure baseline and after a certain amount of time. The efficacy of these models in predicting short-term mortality is disputed. Numerous studies across the world have compared prognostic models, such as the Maddrey Discriminant Function, the Model for End-Stage Liver Disease score (MELD), MELD-Na, Glasgow alcoholic hepatitis score, and the ABIC scores, to each other to determine which score is more useful for a particular context. There are also prognostic markers, such as liver biopsy, breath biomarkers, and acute kidney injury that are able to predict mortality. The accuracy of these scores is key to determining when treatment with corticosteroids is futile, since there is an increased risk of infection in those treated with it. Furthermore, although these scores are helpful in predicting short-term mortality, the only factor that is able to predict long-term mortality in patients with alcohol-related liver disease is abstinence. Numerous studies have proven that even though corticosteroids provide a treatment for alcohol-associated hepatitis, it is a temporary one, at best. The purpose of this paper is to compare the historical models to current ones in their ability to predict mortality in patients with alcohol-related liver disease by analyzing multiple studies that have examined these prognostic markers. This paper also isolates the knowledge gaps in the ability to delineate which patients would benefit from corticosteroids and patients who would not and provides potential models in the future that could narrow this gap.

      Conflict of interest statement

      The authors declare that there is no conflict of interest.

      Review

      Alcohol-associated hepatitis is a severe condition characterized by acute inflammation of the liver due to excess consumption of alcohol. Patients who are diagnosed with alcoholic liver disease consume greater than 35 units of alcohol a week, where one unit is equal to 10-12 grams. Alcohol consumption should normally be limited to 21 units for men and 14 units for women [
      • Drinane M.C.
      • Shah V.H.
      Alcoholic hepatitis: Diagnosis and prognosis.
      ]. Symptoms of alcoholic hepatitis include jaundice, due to parenchymal injury and cirrhosis, fever, encephalopathy, abdominal distress, ascites, varices, anemia, leukocytosis, coagulopathy, and an AST/ALT ratio greater than 2. Hepatomegaly, jaundice, and splenomegaly are observed on clinical exam and serum bilirubin levels are usually greater than 10 at diagnosis [

      Clinical characteristics and mortality of hospitalized alcoholic hepatitis patients in the United States - PubMed.” https://pubmed.ncbi.nlm.nih.gov/21085006/(accessed Aug. 05, 2022).

      ]. When a liver biopsy is taken, the presence of macrovesicular steatosis and mallory bodies is observed in 65% of patients with alcohol-related liver disease [
      • Drinane M.C.
      • Shah V.H.
      Alcoholic hepatitis: Diagnosis and prognosis.
      ]. The current treatment for this condition is corticosteroids and pentoxyfyllin, which has shown to improve short-term survival outcomes, however, the overall outcomes are poor and there is a lot of controversy surrounding the efficacy of corticosteroids [
      • Singal A.K.
      • Walia I.
      • Singal A.
      • Soloway R.D.
      Corticosteroids and pentoxifylline for the treatment of alcoholic hepatitis: Current status.
      ] and the need for early liver transplant consideration [
      • Rahimi E.
      • Pan J.-J.
      Prognostic models for alcoholic hepatitis.
      ].
      Alcohol-associated liver disease’s increasing prevalence and association with high mortality has generated prognostic factors to estimate mortality and determine treatment options. These prognostic scores are useful in estimating short-term mortality and are divided into static and dynamic models. The purpose of this review is to analyze the different prognostic markers for AH and ALD.

      Maddrey Discriminant Function

      One of the earliest prognostic markers for this disease is the Maddrey Discriminant Function (DF). This score was created in 1978 [
      • Rahimi E.
      • Pan J.-J.
      Prognostic models for alcoholic hepatitis.
      ], and later modified in 1989 to include the difference between the patient’s PT and the control PT to account for the differences in PT values in different labs. [
      • Rahimi E.
      • Pan J.-J.
      Prognostic models for alcoholic hepatitis.
      ]. It is based on prothrombin time and serum bilirubin concentration. A cut-off score of greater than 32 indicates severe alcohol-associated liver disease, whereas DF scores less than 32 are shown to be associated with a high 28-day mortality [
      • Rahimi E.
      • Pan J.-J.
      Prognostic models for alcoholic hepatitis.
      ]. The mDF cut-off was used to determine patients who should be treated with corticosteroids and who should not. An elevated mDF and/or encephalopathy were the defining parameters for treatment with corticosteroid therapy, and these parameters showed 6% mortality at 28 days, versus 35% mortality for those treated with a placebo [
      • Rahimi E.
      • Pan J.-J.
      Prognostic models for alcoholic hepatitis.
      ]. However, there are several drawbacks to the mDF. First, it has inadequate specificity and sensitivity for short-term mortality; it has poor diagnostic performance because it can only predict mortality 66.6% of the time [
      • Rahimi E.
      • Pan J.-J.
      Prognostic models for alcoholic hepatitis.
      ]. Second, its cut-off score of 32 is arbitrary because it has been shown that DF scores of less than 32 have a high 28 day mortality as well. 10-17% of patients with a DF score below 32 still have hepatitis-related mortality [
      • Dunn W.
      • et al.
      MELD accurately predicts mortality in patients with alcoholic hepatitis.
      ]. Finally, the mDF relies on prothrombin time, which varies and is poorly standardized across different labs. Currently, many laboratories have stopped recording prothrombin time, and the DF model was validated based on patient cohorts from several decades ago, demonstrating the outdated nature of this prognostic marker [
      • Rongey C.
      • Kaplowitz N.
      Current concepts and controversies in the treatment of alcoholic hepatitis.
      ].

      Model for End-Stage Liver Disease

      A study that examined the 2007 Nationwide inpatient sample of the Healthcare Cost and Utilization Project examined clinical characteristics and risk factors associated with mortality in hospitalized alcoholic-related hepatitis patients. Subjects were categorized based on associated symptoms, such as ascites, hepatic encephalopathy, coagulopathy, as well as complications during hospitalizations, such as sepsis, pneumonia, SBP, and acute renal failure. The study found that there is a high in-hospital mortality rate among patients who were hospitalized for this condition, and there is an even higher mortality rate of these patients who developed infections, such as sepsis or SBP, during their hospital stay [

      Clinical characteristics and mortality of hospitalized alcoholic hepatitis patients in the United States - PubMed.” https://pubmed.ncbi.nlm.nih.gov/21085006/(accessed Aug. 05, 2022).

      ]. The presence of hepatic encephalopathy, coagulopathy, and ascites were strongly associated with mortality, but the strongest predictor of mortality in hospitalized patients alcohol-associated liver disease was the presence of acute renal failure [

      Clinical characteristics and mortality of hospitalized alcoholic hepatitis patients in the United States - PubMed.” https://pubmed.ncbi.nlm.nih.gov/21085006/(accessed Aug. 05, 2022).

      ]. This in combination with coagulopathy was the basis of developing the MELD score.
      In the early 2000s, the Model for End Stage Liver Disease (MELD) score was originally created to assess the short-term prognosis of patients with cirrhosis having elective transjugular intrahepatic portosystemic shunts [
      • Dunn W.
      • et al.
      MELD accurately predicts mortality in patients with alcoholic hepatitis.
      ], but it soon replaced the Child-Turcotte Pugh score for organ allocation of cadaveric livers for transplantation. It was subsequently determined to be a reliable measurement of short-term mortality in patients with end stage liver disease. The MELD score is calculated using serum bilirubin, creatinine, and the international normalized ratio (INR). Different studies have analyzed the use of different MELD cut-off scores at predicting in hospital, 30-day, and 90-day mortality. Figure 1 analyzes how MELD scores at admission affect 30 day mortality in patients treated with corticosteroids and patients who are not on corticosteroid treatment. MELD has been shown to be comparable to DF when looking at 30-day and 90-day mortality [
      • Morales-Arráez D.
      • et al.
      The MELD Score Is Superior to the Maddrey Discriminant Function Score to Predict Short-Term Mortality in Alcohol-Associated Hepatitis: A Global Study.
      ]–[
      • Kadian M.
      • Kakkar R.
      • Dhar M.
      • Kaushik R.M.
      Model for end-stage liver disease score versus Maddrey discriminant function score in assessing short-term outcome in alcoholic hepatitis.
      ]. However, a MELD score of 21 has been shown to have the highest sensitivity and specificity in predicting 90-day mortality [
      • Rongey C.
      • Kaplowitz N.
      Current concepts and controversies in the treatment of alcoholic hepatitis.
      ]. A study conducted by Kamath et. al validated the MELD score as a liver disease severity index in determining short-term survival in liver transplant candidates by measuring the score’s ability to rank patients according to their risk of death within 3 months [
      • Kamath P.S.
      • et al.
      A model to predict survival in patients with end-stage liver disease.
      ]. It also evaluated 1 week and 1 year survival. Because the MELD scale was developed in patients undergoing the TIPS procedure, this study examined the model’s use in patients with decompensated cirrhosis not undergoing the TIPS procedure. The C-statistic for prediction of 3-month survival by the MELD score was 0.87, and the study concluded that MELD was able to perform well among cirrhotic patients not undergoing the TIPS procedure [
      • Kamath P.S.
      • et al.
      A model to predict survival in patients with end-stage liver disease.
      ]. Furthermore, there has been minimal improvement in 3-month mortality predictions when considering portal hypertensive complications, such as ascites, encephalopathy, variceal bleeding, and spontaneous bacterial peritonitis [
      • Kamath P.S.
      • et al.
      A model to predict survival in patients with end-stage liver disease.
      ].
      Figure 1
      Figure 1The Association Between Mortality Rate at 30 Days and MELD Score at Admission in Patients Treated with Corticosteroids versus Untreated Patients.
      When comparing MELD and mDF, MELD has been shown to be better at predicting in-hospital mortality [
      • Monsanto P.
      • Almeida N.
      • Lrias C.
      • Pina J.E.
      • Sofia C.
      Evaluation of MELD score and Maddrey discriminant function for mortality prediction in patients with alcoholic hepatitis.
      ]. Even though DF also incorporates PT and bilirubin, the MELD score weighs these markers using log values to avoid extreme outliers [
      • Rongey C.
      • Kaplowitz N.
      Current concepts and controversies in the treatment of alcoholic hepatitis.
      ]. Furthermore, MELD’s inclusion of creatinine is more advantageous because it is a value that is highly associated with poor outcomes in patients with alcohol-associated hepatitis. Thus, it can discriminate patients with cirrhosis. As a result, MELD is the only independent predictor of 90-day mortality [
      • Rongey C.
      • Kaplowitz N.
      Current concepts and controversies in the treatment of alcoholic hepatitis.
      ]. It has been suggested that the incorporation of serum creatinine is responsible for this. Furthermore, the use of the INR is comparable across labs and more standardized because it accounts for the sensitivity of thromboplastin [
      • Rongey C.
      • Kaplowitz N.
      Current concepts and controversies in the treatment of alcoholic hepatitis.
      ,
      • Kamath P.S.
      • et al.
      A model to predict survival in patients with end-stage liver disease.
      ]. Finally, the DF was developed decades ago, and MELD better accounts for a more heterogenous cohort of patients [
      • Rongey C.
      • Kaplowitz N.
      Current concepts and controversies in the treatment of alcoholic hepatitis.
      ].
      As stated above, a DF score cut-off greater than 32 was used as the cut-off point for treatment with corticosteroids because of its higher adverse event profile. However, it has been shown that patients with a score less than 32 also die from this disease. It is advantageous for the cut-off to be lower, so patients could look for different therapeutic options; this is why having a MELD score cut-off of 21 is advantageous [
      • Rahimi E.
      • Pan J.-J.
      Prognostic models for alcoholic hepatitis.
      ,
      • Rongey C.
      • Kaplowitz N.
      Current concepts and controversies in the treatment of alcoholic hepatitis.
      ].

      Child-Turcotte-Pugh Score

      With the development of the MELD score, the efficacy of the Child-Turcotte-Pugh score in classifying cirrhotic patients based on severity for liver transplantation came into question [
      • Kamath P.S.
      • et al.
      A model to predict survival in patients with end-stage liver disease.
      ]. The CTP score is based on ascites, encephalopathy, serum bilirubin, albumin, and prothrombin time. Each variable has a score of 1 to 3, and patients are classified as class A (best), B (moderate), and C (worse) to determine the prognosis for cirrhotic patients undergoing surgery [

      Alcohol abstinence in patients surviving an episode of alcoholic hepatitis: Prediction and impact on long-term survival - Altamirano - 2017 - Hepatology - Wiley Online Library.” https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.29338 (accessed Aug. 05, 2022).

      ]. The CTP score was deemed not competent for determining priority in organ allocation for a few reasons. First, it has a limited discriminatory ability. There are only 8 levels of difference between transplant candidates who are the most sick and least sick. Because of the limited distinguishability of this score, there are lots of ties that are broken with arbitrary cut-offs, such as waiting time. This does not evaluate patients with abnormal laboratory parameters - patients with different labs values have the same severity of liver disease [
      • Kamath P.S.
      • et al.
      A model to predict survival in patients with end-stage liver disease.
      ]. On the other hand, MELD has no ceiling or floor in terms of grading patients based on severity. Appropriate weight is given to variables according to their importance. Another problem with the CTP is its subjective interpretation of parameters. For example, the evaluation of ascites is based on physical exam, which is subjective to the individual physician. Encephalopathy is also another factor dependent on the examiner - there is no accepted or universal definition. As a result, there are no standardized parameters for grading ascites and encephalopathy, and parameters change with treatment [
      • Kamath P.S.
      • et al.
      A model to predict survival in patients with end-stage liver disease.
      ]. While CTP relies on these two subjective parameters, MELD’s variables are objective and standardized, so there is no subjectivity bias when grading the severity of cirrhosis in patients with alcohol-related liver disease. Finally, there is a lot of variability in the measurement of laboratory parameters that the CTP does use. As opposed to MELD, the objective elements in the CTP, such as albumin and PT, are highly variable across laboratories and not standardized. MELD also incorporates serum creatinine, which is a measure of renal function in patients with liver disease and a well-recognized predictor in patients with liver disease [
      • Kamath P.S.
      • et al.
      A model to predict survival in patients with end-stage liver disease.
      ].
      A study carried out at the Himalayan Institute Hospital assessed the disease severity in patients with end-stage liver disease using the CTP score, MELD, and MELD-Na and compared prognostic scores as predictors of 3-month mortality among patients with ESLD. The study concluded that the CTP score was superior to MELD in predicting 3-month mortality, and MELD was better than the MELD-Na score [
      • Acharya G.
      • Kaushik R.M.
      • Gupta R.
      • Kaushik R.
      Child-Turcotte-Pugh Score, MELD Score and MELD-Na Score as Predictors of Short-Term Mortality among Patients with End-Stage Liver Disease in Northern India.
      ], [14, p.]. This study incorporated AUCs to examine the accuracy of all three prognostic scores. A meta-analysis of 269 studies comparing the accuracy of the CTP score to the MELD score to assess the prognosis of cirrhotic patients showed that 44 studies favored the MELD score, 16 favored the CTP score, 99 studies found both to have similar value, and 110 reported no statistically significant difference [
      • Acharya G.
      • Kaushik R.M.
      • Gupta R.
      • Kaushik R.
      Child-Turcotte-Pugh Score, MELD Score and MELD-Na Score as Predictors of Short-Term Mortality among Patients with End-Stage Liver Disease in Northern India.
      ], [
      • Peng Y.
      • Qi X.
      • Guo X.
      Child–Pugh Versus MELD Score for the Assessment of Prognosis in Liver Cirrhosis.
      ]. This study, however, did cite that different regions of the world had different results when comparing the discriminative ability of these scores. For example, studies in France and the US reported favoring MELD over the CTP score in predicting 3-month mortality in patients on the wait list for liver transplantation [
      • Acharya G.
      • Kaushik R.M.
      • Gupta R.
      • Kaushik R.
      Child-Turcotte-Pugh Score, MELD Score and MELD-Na Score as Predictors of Short-Term Mortality among Patients with End-Stage Liver Disease in Northern India.
      ]. However, for this study, the AUC was 0.93 for the CTP score, 0.86 for the MELD score, and 0.83 for the MELD-Na score, and it was found that the CTP score was superior to the MELD score in predicting 3-month mortality. Acharya et. al attributes the better performance of the CTP score over MELD or MELD-Na to the different aetiologies and clinical presentations of the patients cohorts, which vary depending on the region of the world [
      • Acharya G.
      • Kaushik R.M.
      • Gupta R.
      • Kaushik R.
      Child-Turcotte-Pugh Score, MELD Score and MELD-Na Score as Predictors of Short-Term Mortality among Patients with End-Stage Liver Disease in Northern India.
      ]. Since each prognostic score has different components, a specific score might perform better for a specific presentation. Acharya et. al state that in this study, 63.15% of the patients had ascites and 32.74% had hepatic encephalopathy, whereas in a study done in France, only 4.98% of patients had ascites and 9.96% had hepatic encephalopathy [
      • Acharya G.
      • Kaushik R.M.
      • Gupta R.
      • Kaushik R.
      Child-Turcotte-Pugh Score, MELD Score and MELD-Na Score as Predictors of Short-Term Mortality among Patients with End-Stage Liver Disease in Northern India.
      ]. In this France study, the MELD and MELD-Na scores were shown to have better prognostic accuracy than the CTP [
      • Dupont B.
      • et al.
      Retrospective evaluation of prognostic score performances in cirrhotic patients admitted to an intermediate care unit.
      ], [
      • Wiesner R.
      • et al.
      Model for end-stage liver disease (MELD) and allocation of donor livers.
      ]. Due to these differences, Acharya et. al concludes that the CTP score might be better for patients who present with ascites and hepatic encephalopathy, whereas the MELD/MELD-Na scores might be better for patients who have renal impairment with/without hyponatremia [
      • Acharya G.
      • Kaushik R.M.
      • Gupta R.
      • Kaushik R.
      Child-Turcotte-Pugh Score, MELD Score and MELD-Na Score as Predictors of Short-Term Mortality among Patients with End-Stage Liver Disease in Northern India.
      ].

      MELD-Na

      Although MELD is a better predictor of mortality in patients with alcohol-associated hepatitis, it does not take into account for hyponatremia, an independent prognostic factor in patients with cirrhosis. In patients with cirrhosis, the pathophysiology demonstrates that portal hypertension leads to systemic vasodilation, secondary neurohormonal compensation, and less renal excretion of solute-free water [
      • John S.
      • Thuluvath P.J.
      Hyponatremia in cirrhosis: Pathophysiology and management.
      ]. The more severe the portal hypertension, the greater degree of hyponatremia [
      • Goudsmit B.F.J.
      • et al.
      Validation of the Model for End-stage Liver Disease sodium (MELD-Na) score in the Eurotransplant region.
      ]. Hyponatremia is a common predictor of death in patients displaying cirrhosis. However, MELD does not take hyponatremia into account in its equation. Hyponatremia is an independent prognostic factor. This can significantly impact liver transplant candidates [
      • Kim W.R.
      • et al.
      Hyponatremia and Mortality among Patients on the Liver-Transplant Waiting List.
      ].
      A study investigated the effectiveness of the MELD-Na score in predicting 90-day mortality. The study demonstrated that 90-day mortality and transplantation rates increased as sodium levels decreased [
      • Goudsmit B.F.J.
      • et al.
      Validation of the Model for End-stage Liver Disease sodium (MELD-Na) score in the Eurotransplant region.
      ]. MELD-Na has better prognostic ability than MELD for the prediction of 90-day WL mortality [
      • Kim W.R.
      • et al.
      Hyponatremia and Mortality among Patients on the Liver-Transplant Waiting List.
      ], and the severity of hyponatremia is associated with a continuous increase in the risk of death on the WL [
      • Biggins S.W.
      • et al.
      Evidence-based incorporation of serum sodium concentration into MELD.
      ]. There is a higher reduction in the prediction error 90-day mortality compared to MELD. However, this study was done on a Eurotransplant population. In the United States, the introduction of MELD-Na based allocation reduced 90-day waiting list mortality for almost all MELD scores.
      Ascites is the most common complication of cirrhosis and increases the chances of infection, renal failure, and death [
      • Vaa B.E.
      • Asrani S.K.
      • Dunn W.
      • Kamath P.S.
      • Shah V.H.
      Influence of serum sodium on MELD-based survival prediction in alcoholic hepatitis.
      ]. There is an increased mortality rate in patients with cirrhosis than in patients who do not. Cirrhotic patients present with hyponatremia due to the activation of the vasopressin system, hypersecretion due to circulatory dysfunction, and volume overload [
      • Liamis G.L.
      • Milionis H.J.
      • Rizos E.C.
      • Siamopoulos K.C.
      • Elisaf M.S.
      Mechanisms of hyponatraemia in alcohol patients.
      ]. The lack of increased sodium uptake results in a hyper-osmolar state, which results in potomania - excessively low-osmolar fluid consumed by those addicted to alcohol [
      • Vaa B.E.
      • Asrani S.K.
      • Dunn W.
      • Kamath P.S.
      • Shah V.H.
      Influence of serum sodium on MELD-based survival prediction in alcoholic hepatitis.
      ]. The retention of water then leads to hyponatremia. When comparing MELD to MELD-Na for predicting 180-day mortality in patients with alcohol-related liver disease, MELD-Na is a better predictor of mortality in patients with ascites [
      • Vaa B.E.
      • Asrani S.K.
      • Dunn W.
      • Kamath P.S.
      • Shah V.H.
      Influence of serum sodium on MELD-based survival prediction in alcoholic hepatitis.
      ]. In patients without ascites, they are both similar predictors. C-statistics was used to quantitatively compare MELD with MELD-Na to predict 180 day mortality. The c-statistic for MELD was 0.81 and 0.79 for MELD-Na [
      • Goudsmit B.F.J.
      • et al.
      Validation of the Model for End-stage Liver Disease sodium (MELD-Na) score in the Eurotransplant region.
      ]. Serum Na is not a significant predictor of mortality when isolating patients with AH who do not present with ascites. Patients with ascites are older, have a higher serum creatinine, and a higher bilirubin. The median MELD and MELD-Na score is higher in patients with ascites. The c-statistic for MELD in examining 180-day mortality in patients with ascites was 0.90 compared to a c-statistic of 0.97 for MELD-Na [
      • Vaa B.E.
      • Asrani S.K.
      • Dunn W.
      • Kamath P.S.
      • Shah V.H.
      Influence of serum sodium on MELD-based survival prediction in alcoholic hepatitis.
      ]. Patients with low serum sodium and ascites identify patients with cirrhosis with high risk of mortality even with low MELD scores [
      • Heuman D.M.
      • et al.
      Persistent ascites and low serum sodium identify patients with cirrhosis and low MELD scores who are at high risk for early death.
      ].

      Glasgow Alcoholic Hepatitis Score

      In addition to the development of the MELD score, in 2005, the Glasgow Alcoholic Hepatitis Score was developed from a population of 241 patients from Glasgow and was validated in a separate cohort of 195 patients throughout the UK [
      • Rahimi E.
      • Pan J.-J.
      Prognostic models for alcoholic hepatitis.
      ]. It is based on age, blood urea, peripheral blood leukocyte count, serum bilirubin, and PT. The GAHS ranges in values between 5 and 12. Forrest et. al’s study separated patients with value of <9 or >/- 9 points; this study demonstrated that GAHS day 1 and 7 data had a better predictive accuracy of 28 day and 84 day outcome than mDF [
      • Forrest E.H.
      • et al.
      Analysis of factors predictive of mortality in alcoholic hepatitis and derivation and validation of the Glasgow alcoholic hepatitis score.
      ], [
      • Forrest E.H.
      • et al.
      The Glasgow alcoholic hepatitis score identifies patients who may benefit from corticosteroids.
      ]. In another study done by Forrest et al., it was determined that patients with a mDF>/- of 32 and a GAHS<9 did not benefit from treatment with corticosteroids, but those who had a GAHS score of >/-9 and mDF >/- 32 were associated with better survival with corticosteroid treatment [
      • Forrest E.H.
      • et al.
      Analysis of factors predictive of mortality in alcoholic hepatitis and derivation and validation of the Glasgow alcoholic hepatitis score.
      ], [
      • Forrest E.H.
      • et al.
      The Glasgow alcoholic hepatitis score identifies patients who may benefit from corticosteroids.
      ].

      ABIC Score

      Another prognostic score developed for these patients in 2008 is the ABIC score [
      • Dominguez M.
      • et al.
      A new scoring system for prognostic stratification of patients with alcoholic hepatitis.
      ], based on age, serum bilirubin, INR, and serum creatinine [
      • Rahimi E.
      • Pan J.-J.
      Prognostic models for alcoholic hepatitis.
      ]. Dominguez et al.’s study validated this score using a cutoff value of 6.71 and 9 and identified patients with alcohol-associated hepatitis that have a low, intermediate, and high risk of mortality at 90 days.
      The ABIC score was found to be the best independent predictor of 90-day mortality when comparing it to the MELD, mDF, and GAHS. The ABIC score was also looked at to see if it could predict 1-year mortality, which could be useful for liver transplantations. It categorizes risk of death into low, intermediate, and high [
      • Rana R.
      • Wang S.-L.
      • Li J.
      • Xia L.
      • Song M.-Y.
      • Yang C.-Q.
      A prognostic evaluation and management of alcoholic hepatitis.
      ]. It was found that the ABIC score was the only independent predictor of 1-year mortality when compared to other prognostic models. Patients in the group with an intermediate ABIC score were showing the best response to steroids when compared to the low ABIC or high ABIC scores. Furthermore, the ABIC score at 7 days had better predictive accuracy than the Lille model in predicting mortality at 6 months [
      • Rahimi E.
      • Pan J.-J.
      Prognostic models for alcoholic hepatitis.
      ].

      The Lille Model

      The Lille Model was developed in 2007 to identify patients with severe alcohol-associated hepatitis who are not responding to corticosteroid therapy. The Lille Model is based on age, renal insufficiency, albumin, PT, bilirubin, and evolution of bilirubin at day 7. It is highly predictive of death at 6 months in patients treated with corticosteroids and uses a cut-off value of 0.45. With a cut-off of 0.45, the sensitivity and specificity is 81% and 76% respectively. It was determined that patients with a score of >/- 0.45 showed a decrease in 6-month survival, compared to less than 0.45 [
      • Louvet A.
      • et al.
      The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids.
      ]. In addition to this, there was no evidential benefit to patients receiving corticosteroids after 7 days with a score greater than or equal to 0.45 (Table 1).The day 4 Lille score is as accurate as the day 7 Lille score, but the former increases safety by enabling early termination of corticosteroid treatment in patients that show a high risk of adverse outcomes [
      • Louvet A.
      • et al.
      The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids.
      ]–[
      • Garcia-Saenz-de-Sicilia M.
      • et al.
      A Day-4 Lille Model Predicts Response to Corticosteroids and Mortality in Severe Alcoholic Hepatitis.
      ].
      Table 1Description of Prognostic Markers for Alcohol-Related Hepatitis.
      SystemFactorsCut-off for Severe DiseaseSurvivalReference Range
      Maddrey Discriminant FunctionSerum bilirubin and prothrombin time≥321 month survival in untreated patients: 50-65%78, 79
      Child-Turcotte-Pugh ScoreSerum bilirubin, prothrombin time, serum albumin, ascites, and encephalopathy grade>990-day survival of ∼ 20%80
      MELD ScoreSerum bilirubin, serum creatinine and INR≥21Mortality at 90 days of 20%81
      GAHSAge, BUN, WBC, serum bilirubin, and INR≥9Survival rate at 84 days: 38% without CS treatment82
      ABIC ScoreAge, bilirubin, INR and creatinine≥9Survival rate at 90 days: 25%83
      Lille Score (dynamic)Age, labs at day 0 (SB, albumin, and PT), and change in SB at day 7≥0.45Survival rate at 6 months: 25%

      Advises for discontinuation of CS treatment
      84
      The Lille model is a dynamic model and should not be compared to static models that do not include day 4 or day 7 data [
      • Rahimi E.
      • Pan J.-J.
      Prognostic models for alcoholic hepatitis.
      ]. An international multicenter cohort study across 4 continents assessing mortality 30 days, the STOPAH trial [
      • Forrest E.
      • et al.
      Steroids or pentoxifylline for alcoholic hepatitis (STOPAH): study protocol for a randomised controlled trial.
      ], calculated static scores at admission and the Lille score at day 7 to assess the efficacy of corticosteroids in patients with alcohol-related liver disease. In patients with a DF >/- 32, lots of randomized controlled trials and analysis demonstrate that corticosteroids improve short-term survival, but novel strategies are required because 40% of patients die at 6 months. The Lille model has a high sensitivity and specificity for early identification of patients at high risk of death at 6 months. Patients with a high MELD score were treated with corticosteroids, and their responses to treatment were calculated at day 7. The ability of the Lille model to identify nonresponders to treatment allows for a greater reduction in mortality. The results of this trial demonstrated that calculating the MELD score at baseline and the Lille model at day 6 or 7 was the best way to predict 60-day and 90-day mortality [
      • KAMATH P.S.
      • THERNEAU T.
      • SHAH V.H.
      MELDing the Lille Score to More Accurately Predict Mortality in Alcoholic Hepatitis.
      ]. Using that model, researchers showed that corticosteroids are beneficial in patients with severe alcohol-associated hepatitis and MELD scores ranging from 21 to 51, with maximum benefit in those with MELD scores from 25 to 39 and moderate benefit in those with MELD scores between 22–24 and 40–44 [
      • Arab J.P.
      • Arrese M.
      • Singal A.K.
      Diagnosis of Alcohol-Associated Hepatitis: When Is Liver Biopsy Required?.
      ].
      Even though the Lille model is a dynamic model and should not be compared to static scores, it is better for other reasons. The AUROC curve is better than the dynamic evolution of DF, MELD, and Glasgow between day 0 and day 7. The dynamic evolution of those scores did not add any benefit to their diagnostic accuracy at baseline, and the Lille model has better diagnostic accuracy than the previous dynamic criterion, the ECBL [
      • Louvet A.
      • et al.
      The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids.
      ].

      TMA and Pentane Score

      Another prognostic marker associated with alcohol-related liver disease is the TMA and Pentane Score (TAP). It is a breath biomarker and found that 2-propanol, acetaldehyde, acetone, ethanol, pentane, and trimethylamine are increased in patients with liver disease. However, TMA, acetone, and pentane were much higher in this condition compared to those with acute decompensation or control subjects [
      • Hanouneh I.A.
      • et al.
      The Breathprints in Patients With Liver Disease Identify Novel Breath Biomarkers in Alcoholic Hepatitis.
      ], [
      • Khalid T.
      • Richardson P.
      • Probert C.S.
      The Liver Breath! Breath Volatile Organic Compounds for the Diagnosis of Liver Disease.
      ]. The TAP score of greater than or equal to 36 identified patients with alcohol-associated hepatitis with a 90% sensitivity and 80% specificity. Finally, acute kidney injury is associated with a drop in serum creatinine. It influences 90-day mortality in patients with the disease vs. those without it. Accurate predictors of AKI include the presence of SIRS, serum bilirubin, and elevated INR [
      • Rahimi E.
      • Pan J.-J.
      Prognostic models for alcoholic hepatitis.
      ].

      Early Change in Bilirubin Levels

      Early change in bilirubin levels is a prognostic marker that helps physicians identify non-responders to corticosteroids. One study proved that 95% of patients with ECBL (decrease in bilirubin) had improved liver function during treatment. At 6 months, survival of patients with ECBL was higher than patients without it. This study recommended that patients without ECBL should discontinue corticosteroids after 7 days [
      • Mathurin P.
      • et al.
      Early change in bilirubin levels is an important prognostic factor in severe alcoholic hepatitis treated with prednisolone.
      ]. Another study by Morris and Forrest showed that steroid responders who had a 25% decrease in serum bilirubin after 6-9 days of treatment demonstrated better outcomes than non-responders, highlighting the important prognostic value ECBL carries for identifying non-responders to corticosteroids [
      • Rahimi E.
      • Pan J.-J.
      Prognostic models for alcoholic hepatitis.
      ].

      Liver Biopsy

      Beyond prognostic markers, such as MELD and GAHS, scientists have been questioning the prognostic value of an early liver biopsy in patients with this condition [
      • Arab J.P.
      • Arrese M.
      • Singal A.K.
      Diagnosis of Alcohol-Associated Hepatitis: When Is Liver Biopsy Required?.
      ], [
      • Palmer G.
      • Singal A.K.
      Refining criteria for liver biopsy in severe alcoholic hepatitis: Moving the field forward.
      ]–[
      • Forrest E.
      • et al.
      The diagnostic and prognostic significance of liver histology in alcoholic hepatitis.
      ]. A study that aimed to systematically assess this graded the severity of ASH based on histological parameters, such as hepatocellular ballooning and lobular inflammation, and determined its prognostic value [
      • Mookerjee R.P.
      • et al.
      The role of liver biopsy in the diagnosis and prognosis of patients with acute deterioration of alcoholic cirrhosis.
      ]. The presence of SIRS and these clinical features are suggestive of ASH but predicts this histologically in only 50% of cases. In 41% of SIRS negative patients who were thought not to have ASH were diagnosed with ASH on histological grading. This demonstrates that an early liver biopsy in patients presenting with cirrhosis carries valuable prognostic and diagnostic information [
      • Mookerjee R.P.
      • et al.
      The role of liver biopsy in the diagnosis and prognosis of patients with acute deterioration of alcoholic cirrhosis.
      ]. Furthermore, liver biopsies are valuable for diagnosing alcohol-associated hepatitis in patients who are ineligible for steroids or clinical trials under consideration for an early liver transplantation via an exception pathway and for patients with an uncertain clinical diagnosis. In a combined dataset of 11 randomized clinical trials with biopsy-proven patients, the accuracy of clinical diagnosis was 84.5% and increased to 96% in patients with bilirubin of greater than 4.7 mg/dL [
      • Jophlin L.
      • Singal A.K.
      Liver Biopsy in Patients With Alcohol-Associated Liver Disease With Acute-on-Chronic Liver Failure.
      ]. The STOPAH trial also demonstrated that the accuracy of clinical diagnosis was 80% in patients with alcohol-related liver disease, but increased to 100% in patients undergoing liver biopsy exam before administration of corticosteroids and a baseline MELD of >/= 25 [
      • Jophlin L.
      • Singal A.K.
      Liver Biopsy in Patients With Alcohol-Associated Liver Disease With Acute-on-Chronic Liver Failure.
      ].
      Although liver biopsies carry high diagnostic value for these patients, there are several limitations to performing a liver biopsy. The invasiveness of the technique poses a high risk for complications in these patient cohorts, especially those who present with ascites and/or coagulopathy. A study showed that an open liver biopsy for diagnosis of alcohol-associated hepatitis had 58% mortality [
      • Jophlin L.
      • Singal A.K.
      Liver Biopsy in Patients With Alcohol-Associated Liver Disease With Acute-on-Chronic Liver Failure.
      ]. For this reason, a trans jugular approach is recommended for these patients; this approach is associated with a lower morbidity and mortality. In a review of 74 studies on 7,649 patients with liver disease and undergoing trans jugular liver biopsy, the mortality rate was 0.09% [
      • Jophlin L.
      • Singal A.K.
      Liver Biopsy in Patients With Alcohol-Associated Liver Disease With Acute-on-Chronic Liver Failure.
      ]. Even though trans jugular liver biopsies have been shown to decrease the mortality in patients with alcohol-associated hepatitis, only centers with increased expertise and infrastructure will perform these biopsies. A second limitation of liver biopsies is the interobserver variability in the detection and staging of fibrosis on liver biopsy regarding markers such as bilirubinostasis, mega mitochondria, and hepatic steatosis (Table 2). Histological findings of the disease are used to estimate disease prognosis and response to medical treatment, but liver biopsies have been shown to carry less prognostic value to non-invasive assessments, such as MELD and mDF [
      • Jophlin L.
      • Singal A.K.
      Liver Biopsy in Patients With Alcohol-Associated Liver Disease With Acute-on-Chronic Liver Failure.
      ].
      Table 2Advantages and Disadvantages of Different Prognostic Markers for Alcoholic Hepatitis.
      Prognostic ScoreAdvantagesDisadvantages
      Maddrey Discriminant Function
      • Defines parameters for corticosteroid treatment
      • Outdated
      • Cut-off for treatment is arbitrary
      • Reliant on PT, which is not standardized across labs
      MELD
      • High sensitivity and specificity in predicting 90-day mortality
      • Avoids extreme outliers by using a log scale
      • Better at predicting in-hospital mortality
      • Standardized
      • Incorporates serum creatinine, which is able to distinguish patients with cirrhosis
      • Does not take hyponatremia into consideration
      MELD-Na
      • Incorporates hyponatremia as a factor
      • Reduced prediction error in 90-day mortality predictions compared to MELD
      • Better predictor of mortality in patients with ascites
      CTP
      • Better score than MELD for patients with ascites or hepatic encephalopathy
      • Limited discriminatory ability
      • Subjective interpretation of parameters, such as encephalopathy
      • Variability in laboratory parameters
      GAHS
      • Better predictor of mortality at 28 and 84 days compared to mDF
      • Not superior to the MELD score
      ABIC
      • Best independent predictor of 90-day mortality when compared to GAHS, MELD, and mDF
      • Only independent predictor of 1 year mortality
      • Better predictor than Lille for 6 month mortality
      Lille Model
      • Dynamic model
      • Identifies nonresponders to corticosteroid treatment
      • Better diagnostic accuracy than ECBL
      • Cannot be compared to static models
      TMA and Pentane
      • High sensitivity and specificity in identifying patients with alcohol-associated hepatitis
      • Larger studies are needed to validate results
      ECBL
      • Helps identify nonresponders to corticosteroid treatment
      • Not superior to the Lille model
      Liver Biospy
      • Useful for patients with an uncertain clinical diagnosis
      • Invasive and associated with mortality
      • Interobserver variability

      Lung Infection in Patients with Alcohol Associated Hepatitis

      Although there is a consensus that corticosteroids are currently valuable in increasing survival in some patients with alcohol-associated hepatitis, incidence of infection is an important obstacle that drives short-term mortality. A study done by Wandji et. al demonstrated that 25% of patients admitted with severe alcohol-associated hepatitis have infection at baseline before using corticosteroids and another 25% of patients will develop infection in the 2 months after starting prednisolone, with a higher incidence in nonresponders [
      Lung Infection Affects Access to Treatment and Short-Term Ou....
      ]. The reason for this is multifactorial. It has been shown that factors such as bacterial overgrowth, translocation of gut-resident bacteria, increases in proinflammatory and anti-inflammatory cytokines, and impaired adaptive immunity all play a role in an increased incidence of infection in these patient cohorts. More specifically, lung infection is associated with short-term mortality during decompensated cirrhosis. A 2009 study demonstrated that pneumonia became more prevalent after steroid treatment began, and in the STOPAH trial, patients treated with prednisolone had a higher incidence of infection. The rate of pneumonia was twice as high in patients receiving corticosteroids [
      Lung Infection Affects Access to Treatment and Short-Term Ou....
      ]. Wandji et. al’s study confirms this high prevalence of infection and highlights the need for systematic screening at admission. His study observed a higher proportion of lung infections at admission than the study published in 2009 because more attention was being paid to diagnosing them. Diagnosis of lung infections at admission is critical because 50% of patients admitted with pneumonia will die before steroid initiation [
      Lung Infection Affects Access to Treatment and Short-Term Ou....
      ]. However, even if patients with a lung infection at admission have a high risk of mortality before starting prednisolone, they are still eligible to start steroids because the response rate is not different from patients without infection or who have nonrespiratory infections. This study proved that when infection at admission was controlled by antibiotics, the risk of infection after prednisolone is not any higher, meaning that steroid treatment is safe if infection is controlled with antibiotics. The results in this study emphasize the important of screening for infection in patients with alcohol-related liver disease admitted to start corticosteroid treatment [
      Lung Infection Affects Access to Treatment and Short-Term Ou....
      ].

      Long-Term Predictors of Mortality

      All of the models discussed above are associated with predicting short-term mortality in patients with alcohol-related liver disease [
      • Gholam P.M.
      Prognosis and Prognostic Scoring Models for Alcoholic Liver Disease and Acute Alcoholic Hepatitis.
      ], [
      • Pang J.X.Q.
      • et al.
      Risk factors for mortality in patients with alcoholic hepatitis and assessment of prognostic models: A population-based study.
      ], however, none of these prognostic markers calculated at accession are discriminatory in predicting survival beyond 12 months. In a study that wanted to determine the long-term outcomes in severe alcohol-associated hepatitis, sobriety was found to be the only indicator of 5-year survival [

      Alcohol abstinence in patients surviving an episode of alcoholic hepatitis: Prediction and impact on long-term survival - Altamirano - 2017 - Hepatology - Wiley Online Library.” https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.29338 (accessed Aug. 05, 2022).

      ], [45, p.], [
      • Fernandes S.R.
      • et al.
      Predicting short-term and long-term mortality of hospitalized Portuguese patients with alcoholic hepatitis.
      ]–[

      Determinants of long-term outcome in severe alcoholic hepatitis - PubMed.” https://pubmed.ncbi.nlm.nih.gov/23879720/(accessed Aug. 05, 2022).

      ]. Another study that sought to describe the outcomes following index hospitalization with SAH and identify factors associated with long-term mortality, at baseline and discharge from the hospital, found the same thing. There was no baseline clinical prognostic score in this study that was able to predict outcomes at 12, 24, or 48 months. Furthermore, this study found that medical treatment was not associated with a survival benefit in either a cox analysis or in a separate binary logistic regression of survival at 12, 24, or 48 months. In this patient cohort, half of those who survived index hospitalization died during follow-up. The 5-year survival for the whole cohort was 31.8%, and 65.1% of all deaths occurred after discharge, almost all liver-related [

      Alcohol abstinence in patients surviving an episode of alcoholic hepatitis: Prediction and impact on long-term survival - Altamirano - 2017 - Hepatology - Wiley Online Library.” https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.29338 (accessed Aug. 05, 2022).

      ]. The prevalence of recidivism was high and contributed to high overall mortality and rates of hospital readmission. The only independent predictor of long-term outcome with 5-year survival was abstinence. Survival was significantly higher in abstainers (75.3%) compared to relapsed and continued alcohol consumers (26.8% and 21% respectively). This suggests that abstinence has a positive impact on long-term mortality even in advanced forms of alcohol-associated hepatitis [

      Alcohol abstinence in patients surviving an episode of alcoholic hepatitis: Prediction and impact on long-term survival - Altamirano - 2017 - Hepatology - Wiley Online Library.” https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.29338 (accessed Aug. 05, 2022).

      ].

      Conclusion

      Although the development of these prognostic scores has improved the accuracy in predicting mortality for patients with alcohol-related liver disease, there remains a knowledge gap in delineating patients who would benefit from corticosteroid treatment from those who would not and require considerations for a liver transplant. Since there is an increased risk of infections and other serious complications associated with corticosteroids [
      • Hmoud B.S.
      • Patel K.
      • Bataller R.
      • Singal A.K.
      Corticosteroids and occurrence of and mortality from infections in severe alcoholic hepatitis: a meta-analysis of randomized trials.
      ], this information is pertinent to avoid unnecessary use of this treatment. Arab et. al’s study demonstrates that corticosteroids only improve 30-day survival in patients with MELD scores between 25 and 39 [
      • Arab J.P.
      • Arrese M.
      • Singal A.K.
      Diagnosis of Alcohol-Associated Hepatitis: When Is Liver Biopsy Required?.
      ]. In addition, the Lille model is able to determine if there is any benefit to therapy after 7 days. However, the decision to stop corticosteroids may need to be made earlier than day 7. This shows that predicting medical futility is not possible with MELD, Glasgow, and Lille. However, it could be possible with the Chronic Liver Failure Consortium Organ Failure score (CLIF). Since alcohol-associated hepatitis often devolves into ACLF, multi-organ failure, and death, a study by Kim et. al demonstrated that the CLIF score may be more useful in predicting mortality for these kinds of patients, especially since infections and SIRS play key roles in the development of the ACLF [
      • Mitra A.
      • Myers L.
      • Ahn J.
      Assessing the Severity and Prognosis of Alcoholic Hepatitis.
      ], [
      • Kim H.Y.
      • et al.
      Characterization of acute-on-chronic liver failure and prediction of mortality in Asian patients with active alcoholism.
      ]. Patients with ACLF are treated in the ICU with multiorgan support. A study done by Engelmann et. al examined whether any current prognostic scores are able to identify patients with ACLF where ICU care is futile. The study found that the CLIF score most accurately predicted 28-day mortality and that patients with a score of >/- 70 had 100% mortality within 28 days, due to elevated inflammatory markers and renal failure. These patients, after 48 hours of ICU care, may reach a threshold of futility in terms of ongoing care [
      • Engelmann C.
      • et al.
      Validation of CLIF-C ACLF score to define a threshold for futility of intensive care support for patients with acute-on-chronic liver failure.
      ].
      The pursuit of better models with more variables, limited sample size and conventional statistical methodology can run into the problem of over fitting. Our group recently developed the Mortality Index for Alcohol-Associated Hepatitis (MIAAH) [
      • Kezer C.A.
      • et al.
      The Mortality Index for Alcohol-Associated Hepatitis: A Novel Prognostic Score.
      ], based on age, BUN, albumin, bilirubin, and INR, is shown to have the unprecedented AUC of 0.86 in the derivation cohort. Unfortunately, the AUC dropped to 0.73 in the validation cohort.
      In summary, many prognostic models have been developed to estimate mortality, determine candidacy for corticosteroid treatment, potential clinical trials, and select patients for early liver transplant in alcohol-associated hepatitis. The prognostic accuracy of various model is more similar than they are different. While the dynamic models that relies on day 7 data numerically outperforms the static models, due to sample size restriction, it has been been able to demonstrate statistical superiority. MELD score also offers the benefit of precise mortality prediction and steroid response prediction based on a global consortium. There are many unexplored frontiers in the field of prognostication. For example, we do not have models to predict infection, renal failure, and models to be used after initial presentation. Improvement upon current models shall require a combination of the following elements. First, pooling of patients into a consortium such as the Global AlcHep, a BigData Network shall allow examination of addition variables, interaction, and sample size to demonstrate statistical superiority over current model. Second, the use of machine learning shall avoid overfitting. Finally, the use of novel markers such has ICU based parameters shall allow identification of futility cases.

      Uncited reference

      • Zapata-Irrisón L.
      • Jurado-Nuñez J.J.
      • Altamirano-Gómez J.T.
      [MELD or Maddrey?: comparison of two prognosis models in patients with alcohol toxic hepatitis].
      • Foncea C.G.
      • et al.
      Day-4 Lille Score Is a Good Prognostic Factor and Early Predictor in Assessing Therapy Response in Patients with Liver Cirrhosis and Severe Alcoholic Hepatitis.
      • Haiar J.
      • Singal A.K.
      Editorial: liver biopsy in alcoholic hepatitis-more clarity on when it may be needed.
      • Cuthbert J.A.
      • Arslanlar S.
      • Yepuri J.
      • Montrose M.
      • Ahn C.W.
      • Shah J.P.
      Predicting short-term mortality and long-term survival for hospitalized US patients with alcoholic hepatitis.
      • Stickel F.
      • Morgan M.Y.
      Predicting long-term prognosis in severe alcoholic hepatitis.
      .

      Acknowledgement

      Figure 1 was published in J Hepatol. 2021 Nov;75(5):1026-1033.

      References

        • Drinane M.C.
        • Shah V.H.
        Alcoholic hepatitis: Diagnosis and prognosis.
        Clin. Liver Dis. 2013; 2 (Apr): 80-83https://doi.org/10.1002/cld.164
      1. Clinical characteristics and mortality of hospitalized alcoholic hepatitis patients in the United States - PubMed.” https://pubmed.ncbi.nlm.nih.gov/21085006/(accessed Aug. 05, 2022).

        • Singal A.K.
        • Walia I.
        • Singal A.
        • Soloway R.D.
        Corticosteroids and pentoxifylline for the treatment of alcoholic hepatitis: Current status.
        World J. Hepatol. 2011; 3 (Aug): 205-210https://doi.org/10.4254/wjh.v3.i8.205
        • Rahimi E.
        • Pan J.-J.
        Prognostic models for alcoholic hepatitis.
        Biomark. Res. 2015; 3 (Jul): 20https://doi.org/10.1186/s40364-015-0046-z
        • Dunn W.
        • et al.
        MELD accurately predicts mortality in patients with alcoholic hepatitis.
        Hepatol. Baltim. Md. 2005; 41 (Feb): 353-358https://doi.org/10.1002/hep.20503
        • Rongey C.
        • Kaplowitz N.
        Current concepts and controversies in the treatment of alcoholic hepatitis.
        World J. Gastroenterol. WJG. 2006; 12 (Nov): 6909-6921https://doi.org/10.3748/wjg.v12.i43.6909
        • Morales-Arráez D.
        • et al.
        The MELD Score Is Superior to the Maddrey Discriminant Function Score to Predict Short-Term Mortality in Alcohol-Associated Hepatitis: A Global Study.
        Am. J. Gastroenterol. 2022; 117 (Feb): 301-310https://doi.org/10.14309/ajg.0000000000001596
        • Monsanto P.
        • Almeida N.
        • Lrias C.
        • Pina J.E.
        • Sofia C.
        Evaluation of MELD score and Maddrey discriminant function for mortality prediction in patients with alcoholic hepatitis.
        Hepatogastroenterology. 2013; 60 (Aug): 1089-1094https://doi.org/10.5754/hge11969
        • Zapata-Irrisón L.
        • Jurado-Nuñez J.J.
        • Altamirano-Gómez J.T.
        [MELD or Maddrey?: comparison of two prognosis models in patients with alcohol toxic hepatitis].
        Rev. Gastroenterol. Mex. 2008; 73: 57-62
        • Kadian M.
        • Kakkar R.
        • Dhar M.
        • Kaushik R.M.
        Model for end-stage liver disease score versus Maddrey discriminant function score in assessing short-term outcome in alcoholic hepatitis.
        J. Gastroenterol. Hepatol. 2014; 29 (Mar): 581-588https://doi.org/10.1111/jgh.12400
        • Kamath P.S.
        • et al.
        A model to predict survival in patients with end-stage liver disease.
        Hepatol. Baltim. Md. 2001; 33 (Feb): 464-470https://doi.org/10.1053/jhep.2001.22172
      2. Alcohol abstinence in patients surviving an episode of alcoholic hepatitis: Prediction and impact on long-term survival - Altamirano - 2017 - Hepatology - Wiley Online Library.” https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.29338 (accessed Aug. 05, 2022).

        • Acharya G.
        • Kaushik R.M.
        • Gupta R.
        • Kaushik R.
        Child-Turcotte-Pugh Score, MELD Score and MELD-Na Score as Predictors of Short-Term Mortality among Patients with End-Stage Liver Disease in Northern India.
        Inflamm. Intest. Dis. 2020; 5 (Feb): 1-10https://doi.org/10.1159/000503921
        • Peng Y.
        • Qi X.
        • Guo X.
        Child–Pugh Versus MELD Score for the Assessment of Prognosis in Liver Cirrhosis.
        Medicine (Baltimore). 2016; 95 (e2877, Mar)https://doi.org/10.1097/MD.0000000000002877
        • Dupont B.
        • et al.
        Retrospective evaluation of prognostic score performances in cirrhotic patients admitted to an intermediate care unit.
        Dig. Liver Dis. Off. J. Ital. Soc. Gastroenterol. Ital. Assoc. Study Liver. 2015; 47 (Aug): 675-681https://doi.org/10.1016/j.dld.2015.04.001
        • Wiesner R.
        • et al.
        Model for end-stage liver disease (MELD) and allocation of donor livers.
        Gastroenterology. 2003; 124 (Jan): 91-96https://doi.org/10.1053/gast.2003.50016
        • John S.
        • Thuluvath P.J.
        Hyponatremia in cirrhosis: Pathophysiology and management.
        World J. Gastroenterol. WJG. 2015; 21: 3197-3205, Marhttps://doi.org/10.3748/wjg.v21.i11.3197
        • Goudsmit B.F.J.
        • et al.
        Validation of the Model for End-stage Liver Disease sodium (MELD-Na) score in the Eurotransplant region.
        Am. J. Transplant. Off. J. Am. Soc. Transplant. Am. Soc. Transpl. Surg. 2021; 21 (Jan): 229-240https://doi.org/10.1111/ajt.16142
        • Kim W.R.
        • et al.
        Hyponatremia and Mortality among Patients on the Liver-Transplant Waiting List.
        N. Engl. J. Med. 2008; 359 (Sep): 1018-1026https://doi.org/10.1056/NEJMoa0801209
        • Biggins S.W.
        • et al.
        Evidence-based incorporation of serum sodium concentration into MELD.
        Gastroenterology. 2006; 130 (May): 1652-1660https://doi.org/10.1053/j.gastro.2006.02.010
        • Vaa B.E.
        • Asrani S.K.
        • Dunn W.
        • Kamath P.S.
        • Shah V.H.
        Influence of serum sodium on MELD-based survival prediction in alcoholic hepatitis.
        Mayo Clin. Proc. 2011; 86 (Jan): 37-42https://doi.org/10.4065/mcp.2010.0281
        • Liamis G.L.
        • Milionis H.J.
        • Rizos E.C.
        • Siamopoulos K.C.
        • Elisaf M.S.
        Mechanisms of hyponatraemia in alcohol patients.
        Alcohol Alcohol. Oxf. Oxfs. 2000; 35 (Dec): 612-616https://doi.org/10.1093/alcalc/35.6.612
        • Heuman D.M.
        • et al.
        Persistent ascites and low serum sodium identify patients with cirrhosis and low MELD scores who are at high risk for early death.
        Hepatol. Baltim. Md. 2004; 40 (Oct): 802-810https://doi.org/10.1002/hep.20405
        • Forrest E.H.
        • et al.
        Analysis of factors predictive of mortality in alcoholic hepatitis and derivation and validation of the Glasgow alcoholic hepatitis score.
        Gut. 2005; 54 (Aug): 1174-1179https://doi.org/10.1136/gut.2004.050781
        • Forrest E.H.
        • et al.
        The Glasgow alcoholic hepatitis score identifies patients who may benefit from corticosteroids.
        Gut. 2007; 56 (Dec): 1743-1746https://doi.org/10.1136/gut.2006.099226
        • Dominguez M.
        • et al.
        A new scoring system for prognostic stratification of patients with alcoholic hepatitis.
        Am. J. Gastroenterol. 2008; 103 (Nov): 2747-2756https://doi.org/10.1111/j.1572-0241.2008.02104.x
        • Rana R.
        • Wang S.-L.
        • Li J.
        • Xia L.
        • Song M.-Y.
        • Yang C.-Q.
        A prognostic evaluation and management of alcoholic hepatitis.
        Minerva Med. 2017; 108 (Dec): 554-567https://doi.org/10.23736/S0026-4806.17.05136-9
        • Louvet A.
        • et al.
        The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids.
        Hepatol. Baltim. Md. 2007; 45 (Jun): 1348-1354https://doi.org/10.1002/hep.21607
        • Foncea C.G.
        • et al.
        Day-4 Lille Score Is a Good Prognostic Factor and Early Predictor in Assessing Therapy Response in Patients with Liver Cirrhosis and Severe Alcoholic Hepatitis.
        J. Clin. Med. 2021; 10 (May): 2338https://doi.org/10.3390/jcm10112338
        • Garcia-Saenz-de-Sicilia M.
        • et al.
        A Day-4 Lille Model Predicts Response to Corticosteroids and Mortality in Severe Alcoholic Hepatitis.
        Am. J. Gastroenterol. 2017; 112 (Feb): 306-315https://doi.org/10.1038/ajg.2016.539
        • Forrest E.
        • et al.
        Steroids or pentoxifylline for alcoholic hepatitis (STOPAH): study protocol for a randomised controlled trial.
        Trials. 2013; 14 (Aug): 262https://doi.org/10.1186/1745-6215-14-262
        • KAMATH P.S.
        • THERNEAU T.
        • SHAH V.H.
        MELDing the Lille Score to More Accurately Predict Mortality in Alcoholic Hepatitis.
        Gastroenterology. 2015; 149 (Aug): 281-283https://doi.org/10.1053/j.gastro.2015.06.020
        • Arab J.P.
        • Arrese M.
        • Singal A.K.
        Diagnosis of Alcohol-Associated Hepatitis: When Is Liver Biopsy Required?.
        Clin. Liver Dis. 2021; 25 (Aug): 571-584https://doi.org/10.1016/j.cld.2021.03.003
        • Hanouneh I.A.
        • et al.
        The Breathprints in Patients With Liver Disease Identify Novel Breath Biomarkers in Alcoholic Hepatitis.
        Clin. Gastroenterol. Hepatol. 2014; 12 (Mar): 516-523https://doi.org/10.1016/j.cgh.2013.08.048
        • Khalid T.
        • Richardson P.
        • Probert C.S.
        The Liver Breath! Breath Volatile Organic Compounds for the Diagnosis of Liver Disease.
        Clin. Gastroenterol. Hepatol. 2014; 12 (Mar): 524-526https://doi.org/10.1016/j.cgh.2013.10.032
        • Mathurin P.
        • et al.
        Early change in bilirubin levels is an important prognostic factor in severe alcoholic hepatitis treated with prednisolone.
        Hepatol. Baltim. Md. 2003; 38 (Dec): 1363-1369https://doi.org/10.1016/j.hep.2003.09.038
        • Palmer G.
        • Singal A.K.
        Refining criteria for liver biopsy in severe alcoholic hepatitis: Moving the field forward.
        United Eur. Gastroenterol. J. 2020; 8: 993-994https://doi.org/10.1177/2050640620957140
        • Haiar J.
        • Singal A.K.
        Editorial: liver biopsy in alcoholic hepatitis-more clarity on when it may be needed.
        Aliment. Pharmacol. Ther. 2021; 53 (Mar): 630-631https://doi.org/10.1111/apt.16173
        • Forrest E.
        • et al.
        The diagnostic and prognostic significance of liver histology in alcoholic hepatitis.
        Aliment. Pharmacol. Ther. 2021; 53 (Feb): 426-431https://doi.org/10.1111/apt.16157
        • Mookerjee R.P.
        • et al.
        The role of liver biopsy in the diagnosis and prognosis of patients with acute deterioration of alcoholic cirrhosis.
        J. Hepatol. 2011; 55 (Nov): 1103-1111https://doi.org/10.1016/j.jhep.2011.02.021
        • Jophlin L.
        • Singal A.K.
        Liver Biopsy in Patients With Alcohol-Associated Liver Disease With Acute-on-Chronic Liver Failure.
        J. Clin. Exp. Hepatol. 2022; 12 (Mar): 544-550https://doi.org/10.1016/j.jceh.2021.08.009
      3. Lung Infection Affects Access to Treatment and Short-Term Ou....
        Official journal of the American College of Gastroenterology | ACG. 2022; (accessed)
        • Gholam P.M.
        Prognosis and Prognostic Scoring Models for Alcoholic Liver Disease and Acute Alcoholic Hepatitis.
        Clin. Liver Dis. 2016; 20 (Aug): 491-497https://doi.org/10.1016/j.cld.2016.02.007
        • Pang J.X.Q.
        • et al.
        Risk factors for mortality in patients with alcoholic hepatitis and assessment of prognostic models: A population-based study.
        Can. J. Gastroenterol. Hepatol. 2015; 29 (Apr): 131-138https://doi.org/10.1155/2015/814827
        • Cuthbert J.A.
        • Arslanlar S.
        • Yepuri J.
        • Montrose M.
        • Ahn C.W.
        • Shah J.P.
        Predicting short-term mortality and long-term survival for hospitalized US patients with alcoholic hepatitis.
        Dig. Dis. Sci. 2014; 59 (Jul): 1594-1602https://doi.org/10.1007/s10620-013-3020-3
        • Fernandes S.R.
        • et al.
        Predicting short-term and long-term mortality of hospitalized Portuguese patients with alcoholic hepatitis.
        Eur. J. Gastroenterol. Hepatol. 2017; 29 (Oct): 1141-1148https://doi.org/10.1097/MEG.0000000000000926
        • Stickel F.
        • Morgan M.Y.
        Predicting long-term prognosis in severe alcoholic hepatitis.
        Liver Int. Off. J. Int. Assoc. Study Liver. 2020; 40 (Mar): 511-513https://doi.org/10.1111/liv.14343
      4. Determinants of long-term outcome in severe alcoholic hepatitis - PubMed.” https://pubmed.ncbi.nlm.nih.gov/23879720/(accessed Aug. 05, 2022).

        • Hmoud B.S.
        • Patel K.
        • Bataller R.
        • Singal A.K.
        Corticosteroids and occurrence of and mortality from infections in severe alcoholic hepatitis: a meta-analysis of randomized trials.
        Liver Int. Off. J. Int. Assoc. Study Liver. 2016; 36 (May): 721-728https://doi.org/10.1111/liv.12939
        • Mitra A.
        • Myers L.
        • Ahn J.
        Assessing the Severity and Prognosis of Alcoholic Hepatitis.
        Clin. Liver Dis. 2021; 25 (Aug): 585-593https://doi.org/10.1016/j.cld.2021.03.004
        • Kim H.Y.
        • et al.
        Characterization of acute-on-chronic liver failure and prediction of mortality in Asian patients with active alcoholism.
        J. Gastroenterol. Hepatol. 2016; 31 (Feb): 427-433https://doi.org/10.1111/jgh.13084
        • Engelmann C.
        • et al.
        Validation of CLIF-C ACLF score to define a threshold for futility of intensive care support for patients with acute-on-chronic liver failure.
        Crit. Care Lond. Engl. 2018; 22 (Oct): 254https://doi.org/10.1186/s13054-018-2156-0
        • Kezer C.A.
        • et al.
        The Mortality Index for Alcohol-Associated Hepatitis: A Novel Prognostic Score.
        Mayo Clin. Proc. 2022; 97 (Mar): 480-490https://doi.org/10.1016/j.mayocp.2021.10.026