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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 9  |  Issue : 1  |  Page : 55-61

Prognostic markers in acute liver failure - Alpha feto protein


1 PG Resident, Department of Medicine, Amrita Institute of Medical Sciences, Kochi, Kerala, India
2 Associate Professor, Department of Medicine, Amrita Institute of Medical Sciences, Kochi, Kerala, India
3 Assistant Professor, Department of Medicine, Amrita Institute of Medical Sciences, Kochi, Kerala, India
4 Professor and Head, Department of Medicine, Amrita Institute of Medical Sciences, Kochi, Kerala, India
5 Consultant GI Surgeon, Lakeshore Hospial and Research Sciences, Kochi, Kerala, India

Date of Submission10-Jan-2021
Date of Decision02-Jun-2021
Date of Acceptance04-Jun-2021
Date of Web Publication26-Jun-2021

Correspondence Address:
Dr. Smitha Krishnamoorthy
Associate Professor, Department of General Medicine, Amrita Institute of Medical Sciences, Kochi, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/amhs.amhs_14_21

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  Abstract 


Background and Aim: Acute liver failure is associated with high mortality and only about 40% patients survive without liver transplantation. The available prognostic models failed to predict the outcome correctly. Here, we aimed to determine if alpha-fetoprotein (AFP) can be used as a prognostic marker in acute liver failure. Materials and Methods: For this prospective observational study, sixty patients with the diagnosis of acute liver failure were allocated and serum AFP ratio was measured on days 1 and 3 of admission. AFP ratio was calculated as day 3 AFP/day 1 AFP value. Other laboratory parameters and various etiological factors of acute liver failure were also studied. Results: The average AFP ratio among survivors was 1.77 ± 0.94 and among patients who died, the average ratio was 0.68 ± 0.58. Hence, AFP ratio is an important prognostic tool in predicting mortality with a P < 0.001. Majority of patients (80.6%) of patients whose AFP ratio was <0.7 died while majority of patients whose AFP ratio was >0.7 survived (70.4%). Hence, we concluded that AFP values change dynamically during the course of acute liver failure and AFP ratio can be used as a prognostic marker in acute liver failure. AFP ratio showed statistically significant negative correlation with prothrombin time and international normalized ratio, serum globulin, and the levels of indirect bilirubin, especially on the third day after admission and the variables were significantly elevated in the patients who died. Conclusions: AFP ratio can be used as a predictor of mortality in acute liver failure patients. Higher the ratio more are the chances of survival.

Keywords: Acute liver failure, alpha-fetoprotein, prognostic marker


How to cite this article:
Gayathri P, Krishnamoorthy S, Chandra S, K Pillai M G, Menon R, Iyer MS. Prognostic markers in acute liver failure - Alpha feto protein. Arch Med Health Sci 2021;9:55-61

How to cite this URL:
Gayathri P, Krishnamoorthy S, Chandra S, K Pillai M G, Menon R, Iyer MS. Prognostic markers in acute liver failure - Alpha feto protein. Arch Med Health Sci [serial online] 2021 [cited 2021 Aug 1];9:55-61. Available from: https://www.amhsjournal.org/text.asp?2021/9/1/55/319381




  Introduction Top


Acute liver failure (ALF) is a challenging clinical syndrome with high mortality. ALF refers to the “development of severe acute liver injury with encephalopathy and impaired synthetic function (international normalized ratio [INR] of ≥1.5) in a patient without cirrhosis or preexisting liver disease.”[1] While the duration of the illness that usually differentiates acute liver failure from chronic liver failure is a duration of <26 weeks. Early recognition and intervention of patients with acute liver failure are important.[2]

The prognosticating features of acute liver failure can be made out by clinical, radiological, or biochemical parameters. Biochemical parameters till to date most often depend on hepatic degeneration, while alpha-fetoprotein (AFP) is increased when the liver regenerates. Some studies have been done in the past that used AFP as a marker prognosticating acute liver failure.[3]

AFP levels changes fluctuate during the course of acute liver failure and serially rising levels indicated a better prognosis. The most common causes of liver failure acutely in adults are viral hepatitis and drug-induced hepatitis.

In the United States, the United Kingdom, Australia, and Denmark, the commonest cause of acute liver failure is paracetamol poisoning, whereas, in Asia and parts of Europe, viral hepatitis predominates.

AFP is expressed at higher levels in the fetal liver and especially in those with congenital liver abnormalities. Serum AFP levels decline in pregnancy and postpartum period. Increased serum concentrations of AFP are seen in many patients with hepatocellular carcinoma, with modest increases observed chronic viral hepatitis patients.

In a study done by Pastor et al.,[4] it was “shown that the high levels of serum AFP observed in severe forms of hepatitis may represent active hepatocyte regeneration after extensive hepatic necrosis. Although there was no positive correlation between survival and serum concentration of AFP, the findings shown that the rise in serum of this protein in patients with massive hepatic necrosis may be considered a favorable sign that liver cells are regenerating.

After liver injury, immature regenerating hepatoblasts have features resembling those of fetal hepatocytes and a rise in AFP level seems to be associated with hepatic regeneration. Bloomer et al.[6] studied the post mortem changes in the liver in patients who died of massive hepatic necrosis and found that their AFP raised during the 8th day following illness and morphologically liver showed features of regeneration.

Liver transplantation is a crucial decision and hence predicting chance of recovery in patients with acute onset liver dysfunction is important. There is no single factor so far that can accurately predict the chances of survival. Over the past few years, many models of prognostication have been proposed such as the King' s College Criteria, MELD, APACHE II, and SOFA SCORE, but there is not a single factor that predict the outcome accurately and the decision to take up liver transplantation or do without it. In this study, our aim was to determine if a marker of liver regeneration such as AFP can be used as a favorable metabolic marker in acute liver failure.

The primary objective was to determine the role of AFP in determining the outcome severity and prognosticate patients admitted with acute liver failure.


  Materials And Methods Top


The study was approved by the Ethics Committee. Informed consent was obtained from the relatives of all patients. For this prospective cross-sectional study, all patients aged more than 18 years admitted with the diagnosis of acute hepatic failure from June 2017 to June 2019 who met the necessary criteria were enrolled into the study.

The most widely accepted definition of acute liver failure includes “evidence of coagulation abnormality, usually an INR1.5, and any degree of mental alteration (encephalopathy) in a patient without preexisting cirrhosis and with an illness of < 26 weeks duration.”

Paired AFP samples were measured on day 1 and day 3 of admission.[6] The normal AFP value is taken as 0–20 ng/mL. The AFP ratio was then calculated as the day 3 AFP/Day 1 AFP value.

Selection and description of participants

The study was carried out over a period of 2 years (2017–2019) at the Department Of General medicine, Department of Medical Gastroenterology, and Surgical Gastroenterology. During the period of study, sixty patients admitted to the hospital who met the necessary criteria for acute liver failure were enrolled into the study after a written informed consent. Patients with chronic liver disease were excluded from the study. Males and females under the age of 18 years were also excluded from the study. Patients included were who developed acute liver injury in the form of coagulopathy (defined as INR >1.5) and with any degree of hepatic encephalopathy. The degree of encephalopathy was not separately assessed in the study group.

Based on the sensitivity (95) of AFP in predicting survival of patients with acute liver failure observed in earlier publication and with 95% confidence interval and 10% allowable error, the minimum sample size is 27. As it is difficult to draw conclusions and to interpret the findings when a small sample size is used, 60 patients were enrolled into the study.

AFP levels were measured in the serum of selected patients and 1 st and 3rd day of admission and AFP ratio was calculated as day 3 AFP value/day1 AFP value. AFP was determined by the Cobas 8000 (Roche, UK) at the biochemistry laboratory of the hospital. The patients enrolled into the study were followed up to a period of 2 weeks to know the outcome. Age, sex, and routine laboratory parameters including complete blood count, liver function, renal function tests, and PT/INR were also studied. The various etiologies that lead to the condition were interpreted. The correlation of mean AFP ratio with mortality was measured statistically.

Statistical analysis

Statistical analysis was done using IBM SPSS 20.(SPSS Inc, Chicago, USA). For all the continuous variables, the results are either given in Mean ± Standard deviation and for categorical variables as percentage. To obtain the association of categorical variables, Chi-square test was applied. To compare the mean difference of numerical variables between groups, independent two sample “t”-test was applied for parametric data. ROC curve analysis used for predict the cutoff point of AFP ratio with respect to mortality. Accuracy was used to predict mortality and P < 0.05 was considered as statistically significant.


  Results Top


Sixty patients were studied of which 23 (38.3%) were male and 37 (61.7%) were female [Table 1] and [Figure 1]. The study patients were between 20 and 60 years.
Table 1: Distribution of gender

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Figure 1: Distribution of gender

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The patients were categorically divided according to their outcome as those who survived and the ones who expired. Of the 60 patients, 35 expired and 25 survived.

Among the 25 patients who survived, eight patients underwent liver transplantation. The outcomes of liver transplantation were not studied.

The most common etiology was zinc phosphide poisoning (rhodenticide) (40%) followed by Hepatitis A (13.3%). Other etiologies for acute liver failure were autoimmune (10%), paracetamol poisoning (11.7%), dengue fever (8.3%), and antitubercular therapy (ATT) induced (3.3%). It was found that in 13.3% of patients, the etiology was unknown [Table 2] and [Figure 2].
Table 2: Distribution of etiology

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Figure 2: Distribution of etiology

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Out of 24 patients with zinc phosphide poisoning as the etiology, twenty died. Among other etiologies, the number of patients who expired was two in the Hepatitis A group (total 8), three among paracetamol group (of total 7), one of autoimmune (of total 6), five patients with dengue fever (of total 5), and five among unknown etiology (of total 8) [Figure 3]. There was no mortality in the two persons in drug-induced liver failure group (Anti Tuberculous Therapy).
Figure 3: Mortality according to etiology of liver failure

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In the sixty patients, AFP levels were measures on 1st day and 3rd day only in 58 of these patients. The other two patients expired before the 3rd day indicating the high mortality associated with the condition.

The average AFP ratio among survivors was 1.77 ± 0.94 and among patients who died, the average ratio was 0.68 ± 0.58. Hence, AFP ratio is an important prognostic tool in predicting mortality. This was also found to be significant in the statistical point of view (P < 0.001) [Table 3].
Table 3: Comparison of mean alpha-fetoprotein and mortality

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Using the receiver operating characteristics curve, AFP ratio cutoff was calculated as 0.7. Patients fared well when AFP ratio on Day 1 to Day 3 was more than 0.7 indicating hepatic regeneration.

Majority of patients (80.6%) of patients whose AFP ratio was <0.7 died, whereas majority of patients whose AFP ratio was >0.7 survived (70.4%). This was found to have an accuracy of 75% and P < 0.001 indicating that this was statistically significant [Table 4] and [Figure 4], [Figure 5].
Table 4: Association of mean alpha-fetoprotein ratio with mortality

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Figure 4: Association of cut off alpha feto protein ratio and mortality

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Figure 5: Mean alpha feto protein ratio in alive and people who died

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Among females, 56.8% expired and among males, 60.9% died indicating that gender was not an important risk factor in predicting mortality [Table 5] and [Figure 6]. The study group was followed up for a period of 2 weeks. Total duration of stay, degree of encephalopathy, or vital signs were not studied.
Table 5: Mortality among males and females

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Figure 6: Association of gender with mortality

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Among other parameters studied, the mean hemoglobin levels among survivors were 11.9 and among nonsurvivors, it was 12.1 indicating that there was no much difference in Hb values among the two groups [Table 6] and [Figure 7]. Similarly, parameters such as total count [Table 7] and [Figure 8] and ESR [Table 8] and [Figure 9] did not vary among survivors and nonsurvivors.
Table 6: Baseline comparison of mean hemoglobin value with mortality

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Table 7: Baseline comparison of mean total count with mortality

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Table 8: Baseline comparison of mean erythrocyte sedimentation rate with mortality

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Figure 7: Comparison of mean hemoglobin value with mortality

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Figure 8: Comparison of mean total count with mortality

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Figure 9: Comparison of mean ESR with mortality

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Independent sample t-test showed significant positive correlation between day 3 postadmission, prothrombin time with INR, creatinine with outcome.

Low AFP ratio was associated with significant mortality. Low AFP ratios and high mortality rates were also associated with impaired renal function and increase in creatinine values. Prothrombin time was also high in nonsurvivors signifying the importance of acute and early decline liver coagulation functions. Serum globulin and Indirect bilirubin levels were significantly high on the 3rd day in patients who died indicating poor synthetic function, low albumin, immunologic activation and conjugation dysfunction of bilirubin.

High AFP ratio did not contribute to a transplant-free survival as one-third of patients who had a high ratio, underwent liver transplantation for survival.

There was no much difference in hemoglobin, total count, and ESR between survivors and nonsurvivors.

Original mModel for end-stage liver disease scores was calculated but did not show any significant difference in survivors and non survivors.


  Discussion Top


AFP is an integral part of mammalian fetal serum. It is synthesized by visceral endoderm of the yolk sac and fetal liver. Soon after birth AFP level in blood decreases. AFP synthesis is reactivated in liver tumors and germinogeneous teratoblastomas, in a lesser extent following chemical and mechanical liver injuries due to regeneration as seen in acute viral hepatitis.[6]

In this study, the primary objective was to determine the role of AFP in determining the severity and prognosis of patients admitted with acute liver failure. Sixty patients with the diagnosis of acute liver failure were randomly enrolled into the study and AFP values were determined on day 1 and day 3 of admission. AFP ratio was calculated as the day 3 AFP/Day 1 AFP value. In this study, the average AFP ratio among survivors was 1.77 and among died patients, the average ratio was 0.68. Hence, AFP ratio can be suggested as an important prognostic tool in predicting mortality.

It can hence be told that the values of AFP change dynamically during the course of acute liver failure. A single value of AFP is not important while predicting the mortality. However, a rising trend in value as suggested by a higher AFP ratio indicated better survival. This was thought to be because of hepatic regeneration following liver injury.

In a study by Schiodt et al.,[7] AFP in sera on 1st day was studied in two hundred and six patients prospectively enrolled in the US ALF study and paired sera on 3rd day only in one hundred and sixty-two of these patients. Rise in AFP values between day 1 and 3 indicated a better prognosis: The AFP ratio was 2.2 (0.11–22.1) in spontaneous survivors and 0.87 (0.11–16.4) in nonsurvivors.

In a study by Varshney et al.,[3] AFP levels were estimated on days 1 and 3 of hospitalization of 32 patients with ALF and the ratio (AFP day3/day1) was calculated. All patients were categorized as group A (expired) or group B (survived). The AFP ratio was 0.84 + 0.15 in group in patients who expired and (n = 20) versus 1.55 + 0.70 in group who survived (n = 10); P < 0.001.

Using the reciever operating characteristics curve, AFP Ratio cutoff was calculated as 0.7. According to Schiødt et al.,[6] the AFP cutoff ratio was 1. Among 31 patients with an AFP cutoff value <0.7, 25 of 60 patients (80.6%) died indicating that declining AFP values and hence low AFP ratio indicated high mortality. Similarly, of 27 patients with AFP ratio >0.7, 19 patients (70.4%) survived. Hence, AFP ratio can be used as a single prognostic tool in predicting mortality. There were not many studies available in the literature regarding this subject. AFP ratio helps to prognosticate the patients with acute liver failure.

In a study done by Marudanayagam et al.,[8] it was found that among 1247 patients studied, 799 acute liver failure was caused by paracetamol and other drugs.

In a study by, it was found that the discriminative power of Original MELD score was found to be inferior to INR or King's college hospital criteria.[9]

Hence, original MELD score could not be equated to AFP ratio in predicting survival in acute liver failure.

Out of sixty cases analyzed, the mean age was 34 years among survivors and among nonsurvivors, it was 32 years [Table 9] and [Figure 10].
Table 9: Comparison of age with mortality

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Figure 10: Comparison of age with mortality

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Schiodt FV et al According to Schiødt et al., age did not a significantly predict spontaneous survival in acute liver failure, especially in nonacetaminophen group in a study conducted over 1000 patients with acute liver failure. Mean age in the study group was 38 years.[10]

Hence, majority of the study population were young in the above study.

Maximum prevalence of acute liver failure was found in women; 37 of 60 patients were females that constituted 61.7%, whereas males comprised only 23 among the total 60 patients (38.3%). This was in accordance with a previous study done by Guy and Peters et al.,[11] where it was found that women were more vulnerable to liver dysfunction due to immunogenetics, drug metabolism, and sex hormones.

Among the various etiologies studied, the most common one was Ratol poisoning that accounted for 40% (24 of 60 cases) followed by Hepatitis A that comprised 8 among the total 60 patients (13.3%). Other etiologies that were found were paracetamol poisoning, autoimmune, dengue fever, and ATT induced acute liver failure in the order of decreasing prevalence. In 13% of cases, the etiology could not be identified.

However, most of the studies done in the past had paracetamol poisoning and other drug-induced acute liver injury as the most common cause. One such study done by Lee found that a large number of cases in Europe and North America are due to acetaminophen and to idiosyncratic drug reactions, whereas reports from emerging countries in Asia and Africa feature viral illnesses, particularly hepatitis B and E.[12]

However, in our study, the commonest cause was zinc phosphide poisoning and mostly the intention was as a part of suicidal attempt. This was more common in young females. Zinc phosphide was the content in the rodenticide which caused the liver injury. The lethal dose of intake and delayed presentation to hospital following intake of poison resulted in acute liver failure and mortality in majority of these patients despite standard care.

Of 60 patients, 35 patients died; 58% was the mortality. In a study conducted by Tessier et al. in Montreal, it was shown that among the 81 patients studied, 16% survived without liver transplantation, and 84% died or underwent liver transplantation. High mortality is associated with acute liver failure.[13]

Even though the mortality has decreased in recent years with the introduction of liver transplantation, it still continues to be critical with only 40% of patients surviving without liver transplantation.

Among other parameters studied, the mean hemoglobin levels among survivors were 11.9 and among nonsurvivors, it was 12.1 indicating that there was no much difference in Hb values among the two groups. Similarly, parameters like total count and ESR did not vary among survivors and nonsurvivors.

Among females, 56.8% expired and among males, 60.9% died indicating that gender was not an important risk factor in predicting mortality. However, in previous studies, it was observed that women had higher mortality rates.[11] The discrepancy noted here might be because of the small population studied.

Third-day levels of prothrombin time, creatinine, and serum globulins showed higher values in patients who died showing significance [Table 10] and [Figure 11], [Figure 12].
Table 10: Day 3 creatinine, patients with International normalized ratio, globulin levels showed significant elevation in the patients who died

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Figure 11: Prothrombin time levels on Day 3 in patients who were alive and dead

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Figure 12: Creatinine levels on Day 3 in patients who were alive and dead

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Due to the high mortality associated with the condition, two among sixty patients expired before the 3rd day and hence AFP ratio could not be calculated for these patients.

The clinical implications of these findings will have to be studies in larger groups with comparison of other biochemical markers are needed to improve predictive accuracy.

Liver transplantation in acute liver failure is a crucial decision. Spontaneous recovery will lead to a normal life. Equally important is earlier selection of patients whose condition mandates transplantation, whereas delay will result in irreversible brain damage and their rejection as suitable candidates. AFP Ratio could not be calculated for all patients as some patients expired before 3rd day due to the high mortality associated with the condition.


  Conclusion Top


The study shows that AFP ratio can be used as a prognostic marker in acute liver failure.

Higher the ratio, more are the chances of survival, and lower ratios most commonly resulted in death.

Low AFP ratio was also associated with significantly high prothrombin time, creatinine, indirect bilirubin levels, and serum globulins. However, no correlation could be drawn between MELD scores and AFP ratio. It was noted that high AFP ratio did not contribute to a transplant-free interval.

There was no significant variation in creatinine, PT with INR, serum globulins, and indirect bilirubin levels as far as the survivors and nonsurvivors were concerned.

AFP ratio alone could not predict mortality in ALF patients.

This was particularly important as acute liver failure was a condition associated with high mortality and hence patients can be triaged depending on prognosis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Lee WM, Stravitz RD, Larzon AM. Introduction to the revised American Association for the study of liver diseases Position paper on acute liver failure 2011. Hepatology 2012;55:965-7.  Back to cited text no. 1
    
2.
Lee WM. Recent developments in acute liver failure. Best Pract Res Clin Gastroenterol 2012;26:3-16.  Back to cited text no. 2
    
3.
Varshney A, Gupta R, Verma SK, Ahamed S. Alpha Fetoprotein as a prognostic marker in acute liver failure: a pilot study. Tropical Doct 2017:47:202-5.  Back to cited text no. 3
    
4.
Pastor G, Dapelota E, Dentico P, Buongiorno R, Mallardi M, Angarno G. Prognostic value of Alpha feto protein in fulminant hepatitis. Schirald Quad Sclavo Diagn 1979;15:14-21.  Back to cited text no. 4
    
5.
Lazarevich NL. Molecular mechanisms of alpha – Fetoprotein gene expression. Biochemistry (Mosc) 2000;65:117-33.  Back to cited text no. 5
    
6.
Bloomer JR, Waldmann TA, McIntire KR, Klatskin G. Serum alpha feto protein in patients with massive hepatic necrosis. Gastroenterol 1977;72:479-92.  Back to cited text no. 6
    
7.
Schiødt FV, Ostapowicz G, Murray N, Satyanarana R, Zaman A, Munoz S, et al. Alpha feto protein and prognosis in acute liver failure. Liver Transpl 2006;12:1776-81.  Back to cited text no. 7
    
8.
Marudanayagam R, Shanmugam V, Gunson B, Mirza DF, Mayer D, Buckels J, et al. Aetiology and outcome of acute liver failure. HPB (Oxford) 2009;11:429-34.  Back to cited text no. 8
    
9.
Schiodt FV, Rochling FJ, Casey DL, Lee WM. Acetaminophen toxicity in an urban country hospital. N Eng J Med 1997;337:1112-7.  Back to cited text no. 9
    
10.
Schiødt FV, Chung RT, Schilsky ML, Hay JE, Christensen E, Lee WM. Outcome of acute liver failure in the elderly. Liver Transpl 2009;15:1481-7.  Back to cited text no. 10
    
11.
Guy J, Peters MG. Liver disease in women: The influence of gender on epidemiology, natural history, and patient outcomes. Gastroenterol Hepatol (N Y) 2013;9:633-9.  Back to cited text no. 11
    
12.
Lee WM. Etiologies of acute liver failure. Semin Liver Dis 2008;28:142-52.  Back to cited text no. 12
    
13.
Tessier G, Villeneuve E, Villeneuve JP. Etiology and outcome of acute liver failure: Experience from a liver transplantation centre in Montreal. Can J Gastroenterol 2002;16:672-6.  Back to cited text no. 13
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10]



 

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