|Year : 2020 | Volume
| Issue : 3 | Page : 186-193
Acute Hepatitis B or Chronic Hepatitis B with Acute Exacerbation: Differentiating Clinical, Biochemical, Immunonological, and Virological Parameters
Ravi Kant Thakur, Sunit Kumar Shukla, Vinod Kumar Dixit, Dawesh Yadav, Piyush Thakur, Tuhin Mitra
Department of Gastroenterology, Institute of Medical Sciences, Banaras Hindu University, Varanasi (IMS BHU), India
|Date of Submission||16-Oct-2020|
|Date of Decision||19-Oct-2020|
|Date of Acceptance||30-Oct-2020|
|Date of Web Publication||16-Dec-2020|
Sunit Kumar Shukla
Flat Number 512, 5th Floor, Ambrosia Apartment, Lanka, Varanasi, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Background and Aims: Acute hepatitis B virus (HBV) infection and chronic HBV infection presenting as acute illness have differing prognosis. Differentiation between acute viral hepatitis B (AVH-B) and chronic hepatitis B with an acute exacerbation (CHB-AE) is difficult if prior hepatitis B surface antigen (HBsAg) status is unknown. This prospective study was undertaken to screen various factors that could help with this differentiation. Methods: All consecutive patients presenting with AVH-B like illness were enrolled in this study and were evaluated as per predefined study protocol. Patients were divided into AVH-B and CHB-AE groups based on HBsAg status at the end of 6 months. Results: Significant differences in clinical and laboratory parameters were found between AVH-B and CHB-AE. No statistically significant difference in prodromal symptoms and jaundice was seen. Ascites (40%) and hepatic encephalopathy (10%) were seen only in patients with CHB-AE (P = 0.002 and 0.244, respectively). Anti-hepatitis B virus core antigen immunoglobulin M (IgM anti-HBc) levels ≥10.15 signal-cutoff-ratio (S/CO) had positive predictive value (PPV) and negative predictive value (NPV) of 90% for diagnosis of AVH-B. Hepatitis B virus deoxyriboNucleic acid (HBV DNA) levels ≥25032 IU/mLhas 62.5% PPV and 69% NPV for diagnosis of CHB-AE. Alpha-feto protein (AFP) at >22.5 ng/mLmL for diagnosing CHB-AE has PPV and NPV of 83% and 62%, respectively. All six mortalities were seen in CHB-AE group with median survival of 2 months. Conclusions: Differentiation of AVH-B and CHB-AE is important as management and prognosis differ. Low IgM anti-HBc levels (<10.15 S/CO), high HBV DNA levels (≥25032 IU/mLmL), and high AFP (>22.5 ng/mL) favor CHB-AE over AVH-B.
Keywords: Acute viral hepatitis-b, alpha-feto protein, chronic hepatitis b with acute exacerbation
|How to cite this article:|
Thakur RK, Shukla SK, Dixit VK, Yadav D, Thakur P, Mitra T. Acute Hepatitis B or Chronic Hepatitis B with Acute Exacerbation: Differentiating Clinical, Biochemical, Immunonological, and Virological Parameters. MAMC J Med Sci 2020;6:186-93
|How to cite this URL:|
Thakur RK, Shukla SK, Dixit VK, Yadav D, Thakur P, Mitra T. Acute Hepatitis B or Chronic Hepatitis B with Acute Exacerbation: Differentiating Clinical, Biochemical, Immunonological, and Virological Parameters. MAMC J Med Sci [serial online] 2020 [cited 2021 Jan 25];6:186-93. Available from: https://www.mamcjms.in/text.asp?2020/6/3/186/303588
Key messages: Differentiation of AVH-B and CHB with acute exacerbation is important as management, outcome, and prognosis among these groups are different. A combination of HBV DNA, IgM anti-HBc antibody, and AFP at presentation can help with this differentiation.
| Introduction|| |
Hepatitis B virus (HBV) infection is a global health problem with significant morbidity, mortality, and health care burden. Worldwide 250 million persons are chronically infected and 600,000 persons die annually from complications of chronic HBV infection. Endemicity for chronic hepatitis B (CHB) is defined as high (>8%), intermediate (2–7%), and low (<2%) according to the percentage of population positive for hepatitis B surface antigen (HBsAg). India is considered the intermediate prevalence region but with one-fifth of world’s population residing in India, it accounts for a significant proportion of patients with HBV carrier state. CHB with acute exacerbation (CHB-AE) is defined as “Abrupt elevation of serum alanine aminotransferasse (ALT) to >5 ULN (Upper limit of normal) or a greater than three-fold increase in baseline ALT, whichever is higher” in known hepatitis B carrier., In clinical practice, it is often difficult to differentiate between true episode of acute viral hepatitis B (AVH-B) and flare of chronic HBV infection, especially if prior HBsAg status is unknown. It is of prognostic value to differentiate patients with AVH-B, (as majority will have a self-limited, benign course and not require intervention), from patients with CHB-AE who benefit from treatment with antiviral agents and might not have a benign course.
The present study was performed to assess the clinical, biochemical, and virological parameters and outcome of patients presenting with acute viral hepatitis or flare like illness and to identify the factors that could help in differentiating AVH-B and CHB-AE.
| Subjects and methods|| |
This prospective observational clinical study was carried out at the tertiary health care center in northern India in the department of gastroenterology from January 2018 to July 2019.
The study was approved by institutional ethics committee.
Patients presenting with clinical picture of acute or acute-on-chronic hepatitis like illness with a positive HBsAg report were included in this study after their consent. They were evaluated in terms of clinical presentation, treatment or drug history, etiology factors of concomitant liver disease, possible etiology of flare, set of laboratory values, complications, and clinical outcome.
Initial workup included detailed history, examination, complete blood counts, liver function tests, renal function test, prothrombin time with International Normalized Ratio (INR), alpha-feto protein (AFP), HbsAg, anti-hepatitis C virus (HCV), human immunodeficiency virus (HIV), Anti-hepatitis B virus core antigen immunoglobulin M (IgM anti-HBc), antibody of IgM type against hepatitis A virus (IgM anti-HAV), IgM anti-HEV, hepatitis B virus envelope antigen (HBeAg) and anti-HBe, Hepatitis B Virus DeoxyriboNucleic Acid (HBV DNA) (quantitative), ultrasonography of abdomen, gastroduodenoscopy (in patients presenting with features of chronicity or decompensation). Follow-up workup included Fibroscan at 6 months, liver function test (LFT) 3 monthly, HBV DNA (quantitative) and HbsAg (qualitative) at 6 months.
All patients who fulfilled the inclusion and exclusion criteria and who could be followed up for at least 6 months or reached end point of the study were included in the final analysis (consort flow diagram) [Figure 1]. CHB-AE diagnosis was made if HBsAg was positive at 6 months of initial presentation or previously diagnosed case of CHB now presenting with acute exacerbation. Those presenting with acute-on-chronic liver failure (ACLF), organ failure, hepatic decompensation, hemodynamic instability, or poor general condition were admitted for further management.
- Patients who were previously known or unknown cases of CHB, who presented with HBsAg positive report, and had clinical features along with supportive laboratory investigations suggestive of frank hepatitis/ACLF.
- Patients who did not report with initial basic workup.
- Patients in whom the reason for precipitation of hepatitis was other viral illness.
- Patients not giving consent to be included in the study.
The data were analyzed using SPSS version-24.0 statistical software (IBM Armonk, NY, USA). Data were represented in the form of number and percentage of patients who developed the concerned outcome. Comparison of continuous variables was performed by unpaired t test and discrete variables by χ2 test and Fisher exact test as required and 5% level of significance at two-tailed test was used. A P value < 0.05 was considered as statistically significant. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of various parameters were also calculated.
| Results|| |
A total of 65 patients presented with acute viral hepatitis or flare like illness with a positive HbsAg report. Out of these, 20 patients were excluded from the study as they were lost to follow-up [Figure 1]. Acute markers hepatitis A virus (HAV), hepatitis E virus (HEV), and significant current alcohol intake were seen in 2, 1, and 2 patients, respectively, and they were also excluded from final analysis [Figure 1]. CHB-AE (n = 20) and AVH-B (n = 20) were diagnosed in patients based on the results of HbsAg at 6-month follow-up. Those patients already a known case of CHB and now presenting with acute flare like illness were also given a diagnosis of CHB-AE.
Demographic and clinical characteristics
The mean age of presentation was 32.15 ± 11.99 and 33 ± 12.28 years in CHB-AE and AVH-B, respectively (P = 0.826) [Table 1], Figure 2]. Male to female ratio was 9:1 and 3:1 in CHB-AE and AVH-B, respectively (P = 0.204) [Table 1].
Prodromal symptoms in the form of anorexia, malaise, nausea, vomiting, and fatigue were reported in 44.4% and 50% of patients with CHB-AE and AVH-B, respectively (P = 0.376). Jaundice was the presenting complaint in 65% and 90% patients of CHB-AE and AVH-B, respectively (P = 0.064). Mean duration of symptoms was 12.85 days and 11.70 days in CHB-AE and AVH-B, respectively (P = 0.636) [Table 1]. Ascites (40%) and hepatic encephalopathy (10%) were seen only in patients with CHB-AE (P = 0.002 and 0.244, respectively). Ascites seen was grade 3 ascites in six patients and grade 2 ascites in two patients.
There were six mortalities during the study period with a median survival of 2 months. All had clinically significant ascites at presentation and were diagnosed as ACLF, and two patients among them had both ascites and hepatic encephalopathy. Past history of jaundice was present in 10% of patients in each study group (P = 0.698) [Table 1].
Risk factor analysis
History of blood transfusion was present in 5% of patients in both CHB-AE and AVH-B groups. History of tattooing was present in only 1 patient (CHB-AE). High-risk behaviour was present in one patient with AVH-B diagnosis. Two patients in CHB-AE group had CHB diagnosis of mother.
The causes of flare were spontaneous flare (45/55), noncompliance to therapy (4/55), acute HEV hepatitis (1/55), acute HAV hepatitis (2/55), active alcohol intake (2/55), and antituberculosis drug therapy (1/55).
Biochemical parameters at initial presentation
Among biochemical parameters at initial presentation, hemoglobin, platelet count, AST, ALT, bilirubin, total protein, and albumin were not statistically different between the groups [Table 2]. The mean INR was 1.71 ± 0.78 and 1.16 ± 0.15 in CHB-AE and AVH-B, respectively (P = 0.003) [Table 2]. The mean serum creatinine level was 0.90 ± 0.46 and 0.65 ± 0.16 in CHB-AE and AVH-B, respectively (P = 0.030) [Table 2].
|Table 2 Biochemical and virological parameters at initial presentation in different groups|
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AFP level was elevated (normal <20 ng/mL) in 11/20 (55%) and 3/20 (15%) in CHB-AE and AVH-B, respectively (P = 0.009) [Table 2]. The mean level of AFP level was 33.32 ± 57.01 and 6.08 ± 8.31 ng/mL in CHB-AE and AVH-B, respectively (P = 0.012). Receiver operating characteristic curve (ROC) of AFP for CHB-AE is shown in [Figure 3]. The area under the curve (AUC) is 0.73. At the cutoff of 22.5 ng/mL for diagnosis of CHB-AE, the sensitivity, specificity, PPV, negative predictive value, and accuracy were 78%, 90%, 83%, 62%, and 68%, respectively.
|Figure 3 ROC curve for AFP level in ng/mL for diagnosis of CHB-AE. AFP, alfa feto protein; CHB-AE, chronic hepatitis B- acute flare|
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| Immunologic and virological characteristics|| |
IgM anti-HBc was positive in 12/20 (60%) and 20/20 (100%) in CHB-AE and AVH-B, respectively (P = 0.020). The mean level of IgM anti-HBc was 4.23 ± 4.25 signal-cutoff-ratio (S/CO) and 12.96 ± 2.28 S/CO in CHB-AE and AVH-B, respectively (P < 0.001) [Table 2]. The ROC curve of IgM anti-HBc for AVH-B is shown in [Figure 4] (AUC = 0.95). At the cutoff of ≥10.15 S/CO, the sensitivity, specificity, PPV, NPV, and accuracy of IgM anti-HBc for diagnosis of AVH-B are 90%, 90%, 90%, 90% and 90%, respectively.
|Figure 4 ROC curve of IgM anti-HBc (S/CO) for diagnosis of AVH-B. S/CO, signal-cutoff-ratio|
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HBV DNA Level (IU/mL) at first presentation
The mean level of HBV DNA was 3787217.25 ± 6571848.84 IU/mL and 276547.85 ± 492228.45 IU/mL in CHB-AE and AVH-B, respectively (P = 0.022) [Table 2]. The ROC curve of HBV DNA level in IU/mL for diagnosis of CHB-AE is shown in [Figure 5] (AUC = 0.71). At the cutoff point of HBV DNA level ≥25032 IU/mL for diagnosis of CHB-AE, the sensitivity, specificity, PPV, NPV, and accuracy are 75%, 55%, 62.5%, 69%, and 65%, respectively.
|Figure 5 The ROC curve HBV DNA IU/mL for diagnosis of CHB-AE. HBV, hepatitis B virus|
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HBeAg and anti-HBeAb
Hepatitis B virus envelope antigen (HBeAg) was positive in 5/15 (25%) and 8/20 (40%) of patients with CHB-AE and AVH-B, respectively (P = 0.250). The hepatitis B virus envelope antigen antibody (anti-HBeAb) was positive in 15/20 (75%) and 6/20 (30%) patients of CHB-AE and AVH-B, respectively (P = 0.005) [Table 2].
A total of 6 patients expired during the follow-up at different times. A follow-up of investigations till termination of the study is summarized below.
Serum ALT Levels
The ALT was assessed at 3 monthly intervals and all surviving patients had normal ALT levels at 9 and 12 months in both the groups. At 1 month, 75% and 45% had elevated ALT levels in CHB-AE and AVH-B, respectively. The same frequencies were 31.25% and 20% at 3 months and 13.33% and 5% at 6 months, respectively, of follow-up.
The low-level viremia was still seen in 3/15 (20%) patients in the CHB-AE group at 6 months of follow-up, but all patients with AVH-B had nondetectable HBV DNA levels at 6 months. All patients had nondetectable HBV DNA at 12 months. All patients with CHB-AE were given antiviral therapy and only a few selected patients with AVH-B received antiviral therapy.
Fibroscan at 6 months
The mean liver stiffness measurement at 6 months of study was 8.99 ± 4.82 and 5.63 ± 1.01 in CHB-AE and AVH-B, respectively (P = 0.005).
| Discussion|| |
HBV infection is a global health problem despite the availability of an affordable and effective vaccine. With one-fifth of world’s population residing in India, there is tremendous health care burden of HBV-related complications. Overall HBsAg positivity rate in India has been reported to be around 2–8%, which corresponds to more than 37 million HBV carriers.,,,,
HBV infection in humans has varied clinical presentations and patients often present with AVH-B, sometimes even associated with decompensated chronic liver disease. These patients could be either acute viral hepatitis B or acute flare of chronic HBV infection. In lack of prior HBsAg status, this differentiation becomes difficult, but it is required for prognostication and treatment decision.
Although CHB-AE and AVH-B have similar clinical presentation, management and outcome differ considerably. Acute viral hepatitis has favorable prognosis and more than 95% recover spontaneously without specific antiviral therapy. Recent American Association for the study of liver diseases (AASLD) guidelines recommend treatment for AVH-B in those presenting with acute liver failure (ALF) or who have a protracted (>4 weeks), severe course, as indicated by total bilirubin >3 mg/dL, INR >1.5, encephalopathy, or ascites. However, antiviral therapy is required for CHB-AE presenting as hepatitis, ALF, decompensated liver disease, or ACLF.
This study was performed with the primary aim of identifying factors that could differentiate AVH-B versus CHB-AE and the secondary aims of identifying outcomes associated with each cohort. In high prevalence areas of HBV infection, a significant proportion of patients may present with CHB-AE simulating as AVH-B and Kumar et al. reported prevalence of CHB-AE to be 37.9% of all clinical acute presentations. In the present study, 50% of the patients had CHB-AE and AVH-B.
Although a recent study has shown that older age (mean 47.2 years) could be a predictor of chronicity of HBV infection, previous studies have shown that age and gender are unlikely to help in such differentiation., In our study, majority of patients were males in both groups, but gender distribution was not statistically different between these groups. Also, mean age difference was not statistically significant between the groups. This reflects that age could not be used as the sole criterion for chronicity in patients presenting with acute viral hepatitis like illness.
Except for ascites at presentation, none of the other clinical parameters were able to differentiate between the groups. In our study, 20% of patients already had decompensated liver disease (ascites) at presentation, all diagnosed as CHB-AE. All six mortalities were observed within 6.5 months with median survival of 2 months and were diagnosed as ACLF. Limited access to health care, inadequate vaccination, inadequate screening of relatives of index cases, and lack of awareness among public and local practitioners could be the primary reasons for late presentations of HBV infected cases.
In biochemical studies, CBC and LFT parameters were comparable between the groups, which is in contrast to the results published by Han et al. Recently, Thanage et al. reported mean albumin levels to be lower in CHB-AE group, but statistically significant difference was not observed in our study. Mean INR and creatinine levels were higher in CHB-AE, and this difference reached statistical significance probably related to decompensated disease at the time of presentation.
In AVH-B, noncytolytic processes result in elimination of the virus from hepatocytes, with the help from CD 8 cells mediated destruction of infected hepatocytes. This could explain patients with AVH-B having lower detectable HBV DNA levels,  while in patients with CHB-AE, the ongoing liver injury is due to increased levels of HBV DNA. Our study emphasizes the importance of HBV DNA levels in differentiating patients with AVH-B from those with CHB-AE. The mean level of HBV DNA was higher in CHB-AE (3787217.25 ± 6571848.84 IU/mL) as compared to AVH-B (276547.85 ± 492228.45 IU/mL) and this difference was statistically significant. Kumar et al. showed high HBV DNA levels (>0.5 pg/mL = 28751 IU/mL) had sensitivity and specificity of 86.6% and 95.9%, respectively, for the diagnosis of CHB-AE. In our study, at cutoff point of HBV DNA level ≥25032 IU/mL for diagnosis of CHB-AE, the sensitivity, specificity, PPV, NPV, and accuracy are 75%, 55%, 62.5%, 69%, and 65%, respectively. A higher HBV DNA level at initial presentation could be suggestive of CHB-AE.The importance of IgM anti-HBc positivity in high titres has been reported in several studies.,, Our study reinforces the importance of IgM anti-HBc positivity and its titres in differentiating between these two groups. IgM anti-HBc was positive in 100% and 60% of patients with AVH-B and CHB-AE, respectively. The mean level of IgM anti-HBc was significantly higher in AVH-B group with 90% of patients having high titres (≥10.15 S/CO) and only 10% of patients with CHB-AE having titres above this cutoff. At the cutoff of ≥10.15 S/CO, the sensitivity, specificity, PPV, NPV, and accuracy of IgM anti-HBc for diagnosis of AVH-B are 90%, 90%, 90%, 90% and 90% respectively. Kumar et al. have reported high IgM anti-HBc (>1:1000) titres in 77.5% of AVH-B. Anti-HBeAb was more commonly seen in the CHB-AE group.
Serum AFP levels are elevated in around 45–60% patients of CHB-AE. Han et al. reported that lower cutoff of serum AFP (<5 times of normal) improves the accuracy of IgM anti-HBc for diagnosis of AVH-B. In our study, 55% and 15% of patients had elevated AFP levels in CHB-AE and AVH-B groups, respectively. The mean level was significantly higher in the CHB-AE group. At the cutoff of 22.5 ng/mL for diagnosis of CHB-AE, the sensitivity, specificity, PPV, negative predictive value, and accuracy were 78%, 90%, 83%, 62%, and 68%, respectively.
Limitations of the study
Most of our patients travelled a long distance and had limited financial resources, and so HBV genotyping, quantitative HBsAg testing, and additional etiological agents like hepatitis D virus (HDV) superinfection were not evaluated in this study. Liver biopsy was not done in CHB-AE due to ethical concerns. Telephone enquiry revealed that some of the patients had shifted to ayurvedic medications and were unwilling for follow-up. We recommend further long-term prospective studies with a larger cohort for better understanding of the differences.
With deep sense of gratitude, I endeavour to thank my seniors, colleagues, and senior residents of the department for helping me with this research.
Financial support and sponsorship
Conflicts of interest
There are no conflict of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2]