Therapeutic Role of Early In-Hospital Corticosteroid in Non-A-E Hepatitis

- This study addressed the debate regarding the role of corticosteroids and the optimum time of in-hospital corticosteroid initiation in management of acute non-A-E hepatitis.

- It is considered the first study to evaluate the effect of early corticosteroid therapy as defined by < 7 days from hospitalization in management of acute non-A-E hepatitis.

- Frequency of mortality in patients who received early corticosteroid was 40.9%, and 33.3% of late corticosteroid and higher grades of hepatic encephalopathy, the etiology of hepatitis, and low albumin were the predictors of mortality.

 -Therefore, the study showed that early corticosteroids in acute non-A-E hepatitis did not significantly improve the severity of hepatitis or the mortality.

Statistical analysis:

Table (1): Demographic, clinical, and laboratory features of the included patients on admission

DILI: drug-induced liver injury, ALF: acute liver failure, MELD: model for end-stage liver disease, WBCs: white blood cells, ALT: alanine aminotransferase, AST: aspartate aminotransferases, ALP: alkaline phosphatase, INR: international normalized ratio.*Significant p value, **highly significant p value, ^$ Others include Epstein Barr virus, vascular causes, metabolic causes.

 Table (2):        Details of the used corticosteroid therapy in the steroid group.

Table 3: Comparison between patients who received corticosteroid and those who did not receive steroid according to mortality.

ALF: acute liver failure, MELD: model for end-stage liver disease, AIH: autoimmune hepatitis, DILI: drug- induced liver injury, WBCs: white blood cells, ALT: alanine aminotransferase, AST: aspartate aminotransferases, ALP: alkaline phosphatase, INR: international normalized ratio.

*Significant p value, ** highly significant p value

Table 4: Comparison between patients with early corticosteroid and late corticosteroid according to the mortality.

ALF: acute liver failure, MELD: model for end-stage liver disease, AIH: autoimmune hepatitis, DILI: drug- induced liver injury.

* Significant p value

Table 5: Changes of liver function test and coagulation profile before and after treatment with corticosteroid according to the onset of therapy.

Two cases died before following up liver function could be obtained. Data are expressed as median (IQR) except for albumin (mean ± standard deviation). ALT: alanine aminotransferase, AST: aspartate aminotransferases, ALP: alkaline phosphatase, PT: prothrombin time, INR: international normalized ratio. MELD: model for end-stage liver disease. * Significant p value, ** highly significant p value

 Table 6: Predictors of mortality of the included patients in the study.

* Significant p value. MELD: model for end-stage liver disease

DISCUSSION

It is well known that liver transplantation is the only curative treatment for non-acetaminophen fulminant liver failure. However, it is very difficult to perform in low- or middle-income locality due to shortage of living donors, financial burden and limited resources. On the other hand, the use of corticosteroid therapy as an alternative treatment in acute hepatitis or ALF is a controversy with no available evidence-based recommendations.

The liver is considered an immune organ, and the ALF is characterized by activation of the systemic immune responses[13] and cytokines-mediated liver injury [14]. Corticosteroids play an important role in suppressing CD4+ lymphocytes humoral immune response, enhance the immunomodulating effect of Treg, and decrease CD8+ lymphocyte immunological activity with subsequent diminished cytotoxicity [15-16]. This effect will play a key role in the management of ALF.

The etiology of acute hepatitis or ALF is an important key for the treatment strategy and prognosis stratification. The majority of cases in the current study had idiopathic acute hepatitis, followed by AIH and non-acetaminophen DILI. Among these different causes, corticosteroid therapy is recommended in AIH-induced ALF and DILI [17]. Recent guidelines recommend a trial of corticosteroids therapy in AIH-induced ALF and in case of failure to improve in 7-14 days, referral to urgent transplantation will be mandatory [18].

Proper timing, dosage and clinical indications of corticosteroids in cases of ALF are the key elements for better management outcome, but the use of corticosteroid in ALF still lacks clear consensus supporting its use. Therefore, in the present study, the decision of corticosteroid therapy was judged by the physician in charge of the patient, which showed a heterogenicity in the data obtained regarding the type, dose, and the duration of the prescribed corticosteroids. Recently, ALF was thought to be generally controlled by using methylprednisolone(1-2mg/kg/d) according to different clinical studies [5].

The preferred type of corticosteroid in this study was prednisolone for conscious patients or dexamethasone for unconscious and critically ill groups. In some cases, the physicians shift from injections to oral corticosteroid after improvement in the conscious level and liver function to enable gradual tapering of the dose. Wree et al hypothesis that drug induced-ALF may have benefit from higher doses of steroid (2-20mg/kg/d) in combination with ursodesoxycholic acid[19].

Other researchers explored marginal advantage from the high dose corticosteroid with poor function due to decrease in the number of steroid receptors on hepatocytes surface with potential risk of steroid related side effects beside corticosteroids may induce liver damage themselves [5, 20]. Hence, high-dose corticosteroid could be used in ALF rather than acute-on-chronic liver failure (ACLF)[5]. High-doses of corticosteroid will suppress the humoral immunity, while low-dose suppress cellular immunity.[21]   

The definition of early corticosteroid also showed wide variations among studies. In the present study, we defined early corticosteroid by less than 7 days as the median duration between hospital admission and corticosteroid initiation was 7 days which is longer than that reported by Tellez et al which was 4 (2–8) days and subsequently they defined early corticosteroids by less than 3 days from hospital admission [22]. On the other side, other studies defined early corticosteroid by ≤2 weeks from the illness [23-24]. Patients admitted to our hospital usually undergo meticulous investigations before the cause of acute hepatitis is identified to initiate a definite treatment, otherwise corticosteroid cannot be initiated. This explains the time lag between hospital admission and corticosteroid initiation in the current study.

The present results demonstrated the effect of early corticosteroid therapy on lowering the bilirubin level, improvement of liver enzymes, and alkaline phosphatase after one week of therapy. However, improvement of serum albumin and coagulation profile after early steroid was not remarkable.

The mortality rate was relatively higher in the steroid group (37.5%) relative to the non-steroid group in our study (28.6%), which in concordance with Tellez et al who showed failure of corticosteroids in 30.5% [22]. In addition, those who received early corticosteroid showed a relatively higher mortality (40.9%) relative to the late steroid (33.3%). Poor responses to corticosteroid were observed in the current study in patients with high grade of encephalopathy, high MELD score or low albumin level which could be used as indicators of poor prognosis and are considered risk factors for mortality by regression analysis, while the use of corticosteroid was not a predictor of mortality. Similar observations were reported by Zhao et al. who demonstrated that corticosteroids should be introduced as early as possible for patients with less severe liver failure [23].

Similar to the present study, Hisanaga  et al showed no difference in the mortality between patients who received or did not receive corticosteroid therapy[25].

The etiology in this study was also a predictor of mortality. This is in concordance with a recent systematic review, which reported that corticosteroids have a beneficial effect in moderate and severe DILI but not in drug-induced fulminant ALF [26]. Another recent study demonstrated failure of corticosteroids in 50% of patients with indeterminate hepatitis induced ALF [27]. Recently, older age, high MELD score, higher grade of encephalopathy or ascites at steroid therapy initiation were considered early predictors of poor response to corticosteroids in acute severe AIH [22].

This could be explained by the occurrence of both hepatocyte degeneration and necrosis in ALF. Despite hepatocytes degeneration is reversible, hepatocyte necrosis is irreversible. Hence, massive hepatic necrosis in ALF could be a predictor of non-survival[28]. On the opposite side, presence of multilobular necrosis on liver biopsy was reported to predict benefit from corticosteroids therapy in patients with indeterminate hepatitis[27].

The age, gender and liver enzymes did not show difference between the groups of survivors and non-survivors in the present study which is in concordance with Fujiwara et al [6]. Decreased ALT level during the advanced stage of liver disease may indicate regression of cell necrosis, extensive parenchymal loss or dysfunctional ALT synthesis [29]. Additionally, lower ALT level or rapid drop in the initially elevated ALT levels is considered to be an unfavorable prognostic sign[23]. This rapid decrease in ALT level was observed in the current study in those who received early corticosteroids in comparison to the slow decrease of ALT in the late group which may also explain the difference in the mortality rate between the two groups.

On the other hand, Yasui et al considered INR level as a best marker of liver regeneration after steroid therapy and suggested not to perform emergent liver transplantation until persistent impairment of INR level despite two weeks of steroid therapy which could be considered in selected cases [30].

There are some limitations in our study, one of them is the small number of the recruited patients, however; considerations of the rarity of the disease could hinder obtaining larger samples. Another limitation is the retrospective collection of data with lack of randomization which results in heterogenicity of both the corticosteroid types, or doses, and severity. Lack of records on the observed corticosteroids side effects is also considered another limitation.

However, this study evaluated for the first time the therapeutic effect of early corticosteroids within 7 days of hospital admission. Results of the current study revealed that the use of corticosteroid should be used cautiously in cases of advanced liver failure caused by acute severe non-A-to-E hepatitis. The appropriate dose, time of initiation, and duration of corticosteroids in ALF require further multicenter large-scale studies using uniform treatment protocol.  

CONCLUSION

In conclusion, corticosteroid therapy in acute non-A-E hepatitis was associated with a significant improvement in serum bilirubin, and liver enzymes, but not the albumin, coagulopathy nor the mortality rate. Hence, corticosteroids did not prevent the disease progression. Moreover, early corticosteroid did not show a significant difference from late steroid regarding improvements of liver function or mortality. A high percentage of the non-survivors who received corticosteroid in this study had a fulminant course with high MELD score and early corticosteroids initiated in these cases with advanced liver disease did not lower the mortality rate. The etiology of non-A-to-E hepatitis had an impact on the response to corticosteroid, particularly autoimmune hepatitis. Therefore, careful evaluation of the stage of liver disease is crucial when initiating corticosteroid, including the grade of hepatic encephalopathy, and albumin levels, which represent predictors of mortality. This will necessitate early consideration of liver transplantation in these cases rather than starting corticosteroids therapy.

Statement of Ethics: The study was conducted in accordance with the Declaration of Helsinki and was approved by the Medical Ethics Board in Faculty of Medicine, Assiut University (IRB no: 17300764). Patient informed consent was waived due to the retrospective nature of the study.

Conflict of Interest Statement: The authors declare they have no competing interests.

Funding Sources:  This research did not receive any specific grant from funding agencies in the public, commercial, or non-profit sectors.

Author Contributions: We declare that all listed authors have made substantial contributions to all the following three parts of the manuscript:

- Research design, or acquisition, analysis or interpretation of data;

- drafting the paper or revising it critically;

- approving the submitted version.