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Acute flare or exacerbation of hepatitis B: Intermittent elevations in hepatic aminotransferases that can occur in chronic hepatitis B, usually more than twice the baseline value and as high as 10 times the upper limit of normal. Anti-hepatitis B core antibody (anti-HBc), total: The antibody directed against hepatitis B core antigen - see below under Core antibody for details.
Anti-hepatitis B surface antibody (anti-HBs): The antibody directed against hepatitis B surface antigen.
Bridging fibrosis: An indicator of advanced disease characterized by fibrosis that extends to form bridges between portal-vascular structures.
Child-Turcotte-Pugh Classification System: Widely used and published scoring system for liver disease severity.
Cirrhosis: Describes a condition of the liver characterized by prominent and irreversible scarring.
Compensated versus decompensated cirrhosis: Patients with cirrhosis can be categorized as having compensated or decompensated cirrhosis.
Core promoter mutations: These mutations in the hepatitis B DNA core region can emerge spontaneously or under drug pressure resulting nucleotide substitutions in the core promoter region that effectively decrease the production of HBeAg. Direct-acting antiviral agents (DAAs): DAAs refer to the array of small-molecule compounds that have been designed and are currently being studied to target specific HCV enzymes. Encephalopathy: Describes a syndrome of global brain dysfunction characterized by confusion and cognitive impairment. FibroScan: An office-based instrument that uses an ultrasound-based technique called transient elastrography to measure the speed through which elastic shock waves pass through the liver. Genotype, HBV: There are 8 genotypes for HBV worldwide, labeled A through H, all of which have been found in the United States.
Hepatitis B c Antigen (HBcAg): HBcAg is an intracellular antigen synthesized within infected hepatocytes. Hepatitis B e antigen (HBeAg) seroconversion: Loss of HBeAg and development of anti-HBe antibody. Hepatitis B surface antigen (HBsAg): HBsAg exists as the major component of the surface (envelope) of the intact hepatitis B virion and as excess viral envelope in the form of subviral lipoprotein particles (spheres and filaments). Hepatitis E antigen (HBeAg): A precore protein secreted into the circulation by hepatitis B virus (HBV)-infected hepatocytes and generally considered a marker of HBV replication and infectivity. Histologic response: A decline in histologic activity by at least two points on a scoring scale and no worsening fibrosis on liver biopsy compared to pre-treatment biopsy, an outcome typically measured in clinical trial rather than actual practice settings. IL28B genotype: The IL28 gene encodes interleukin 28, also known as interferon lambda, a cytokine (chemical messenger) with antiviral activity. Interferon Ineligible: The American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) have established criteria for considering patients interferon ineligible.
Lead-in phase: Refers to the initial (typically 4-week) period of HCV treatment where pegylated interferon and ribavirin are started before the addition of the third agent. Model for End-Stage Liver Disease (MELD): Used to estimate the survival probability of a patient with end-stage liver disease. Necroinflammatory activity: Reflects the degree of inflammation and necrosis seen on liver biopsy in a patient with chronic viral hepatitis – the severity of this activity is characterized by a scoring system (Ishak, Knodell, Metavir are examples).
Precore mutation: These mutations occur in the precore region of the hepatitis B DNA and can emerge spontaneously or under drug pressure.
Reactivation of hepatitis B: Reappearance of active necroinflammatory disease in the liver in an individual who was known to have resolved hepatitis B or inactive carrier state. Response-guided therapy (RGT): Response-guided therapy is a strategy of following early HCV viral kinetics and adjusting the treatment duration based on the early virologic response.
Ribavirin: Ribavirin is an antiviral medication used in combination with other agents to treat HCV infection.
Sustained virologic response at week 12 (SVR12): Maintaining an undetectable HCV RNA level 12 weeks after completion of therapy. Sustained virologic response at week 24 (SVR24): Maintaining an undetectable HCV RNA level 24 weeks after completion of therapy. Undetectable viral level, HCV: HCV RNA level that is below the lower limit of detection of a sensitive molecular assay.
Virologic Breakthrough, HCV: Reappearance of HCV RNA during treatment, occurring after patient has achieved complete virologic suppression (undetectable HCV RNA level). Virologic Response, HBV: A decrease in serum HBV DNA to undetectable levels by PCR assays, and loss of HBeAg in patients who were initially HBeAg-positive.
Warm antibody autoimmune haemolytic anaemia, a rare disease (0.2-1 per 100,000 populations), is due to the presence of warm agglutinins that react with protein antigens on the surface of red blood cells causing their premature destruction.
Warm autoimmune haemolytic anaemia (WAIHA) results from the production of autoantibody against unspecified high frequency red cell antigen(s).1 Usually, the antibody is of the IgG isotype and causes the destruction of patient and donor red cells at body temperature.
Autoimmune hepatitis (AIH) is a chronic necroinflammatory disease of the liver, occurring in the absence of a known etiologic agent, which causes chronic hepatitis and is characterized by fluctuating alanine aminotransferase (ALT) levels in serum, marked hypergammaglobulinaemia, and circulating autoantibodies.3 These features, as well as the responsiveness to immunosuppressive therapy have led to the belief that this is an autoimmune disease in its own right, distinguishable from other liver diseases associated with hepatotropic viruses, metabolic disorders and drugs.
Herpes simplex virus type I, Epstein-Barr virus, measles virus, and hepatitis A, B, C, and D viruses are thought to play a role in the etiology of AIH.3 Viral proteins belonging to these viruses may be similar to the amino acid chain of different autoantigens in the liver.
No coincidence of WAIHA and AIH associated with asymptomatic carrier state of HBV infection has been reported to date. A 10-year old non-vaccinated girl was admitted on 25th June 2010; complaining of progressive pallor and malaise.
Physical examination revealed height 115 cm, weight 22 Kg, severe pallor, mild icterus and distended abdomen with hepatosplenomegaly. On the basis of the above findings a diagnosis of warm antibody autoimmune haemolytic anaemia and autoimmune hepatitis type   with concomitant asymptomatic carrier of hepatitis B was made.
In this case, the elevated LDH and indirect bilirubin, and raised reticulocytes count all were consistent with haemolysis. Autoimmunity, as assessed by hypergammaglobulinaemia and the presence of autoantibodies, is well recognized in chronic hepatitis C.3 Although it remains unclear whether HCV induces AIH or not, recent studies have shown a high incidence of seropositivity for anti-HCV antibodies in patients with AIH. Only a few studies have evaluated the autoimmune response in patients with chronic hepatitis B. In conclusion, HBV carrier can induce AIHA and AIH that may progress to liver insufficiency and cirrhosis or other autoimmune diseases in patients genetically susceptible to autoimmune diseases.
Written informed consent was obtained from the patient's parents for publication of this case report and any accompanying images.
This journal is a member of and subscribes to the principles of the Committee on Publication Ethics.
This information is intended for physicians and related personnel, who understand that medical information is often imperfect, and must be interpreted in the context of a patient's clinical data using reasonable medical judgment. Except where otherwise noted, this work is licensed under Creative Commons Attribution-NonCommercial 4.0 International License.
Background: Hepatitis B virus (HBV) is one of the most common chronic viral infections in the world. Results: 275 HBsAg positive patients, who had completed a 7 year follow up period, were selected. Conclusions: These data confirm and extend data from other populations showing a low incidence of significant change in chronic HBV infection in short term with good responses to currently available therapeutics. Hepatitis B virus (HBV) is one of the most common chronic viral infections in the world (1).

This longitudinal study was performed from 2003 to 2010 on a group of 275 patients aged between 9-84 years old who were diagnosed with HBs Ag over a period longer than six months. The patients were assessed six months after their first visit and then during periodic visits for the subsequent seven years.
The mean A± standard deviation (SD) was used for the description of quantitative variables. The 275 cases were selected from a total of 800 patients with positive results for HBs Ag who was referred to the Tehran Hepatitis Centre (THC) as they had completed seven years of follow up.
This threshold is relevant for both treatment and biopsy decisions when managing this infection. Total anti-HBc refers to presence of either IgG or IgM and test result does not discriminate between the subclasses. The BMI chart shows four ranges of weight: underweight, healthy weight, overweight, and obese. Physical examination or ultrasound findings may suggest a diagnosis of cirrhosis, and some non-invasive tests provide moderately accurate assessment of whether cirrhosis is present. From a clinical standpoint, patients with compensated cirrhosis have no clinical manifestations of portal hypertension.
These antibodies (anti-HBc) can be detected throughout the course of HBV infection and are a marker of natural exposure to HBV; anti-HBc is absent in those who have been vaccinated.
Patients who have these mutations can have active liver disease with high HBV DNA levels after HBeAg seroconversion.
This speed correlates directly with liver stiffness; fibrotic livers generate higher FibroScan readings.
Genotypes A and B are more responsive to interferon-based therapy compared with genotypes C or D, but initial responses to oral antiviral agents appear to be similar across genotypes. Genotype 1 (subtypes 1a and 1b) is the most commonly isolated genotype in the United States, followed by 2 and 3. In setting of decreased HBV DNA levels and normal ALT, this is usually associated with disease remission.
Investigators discovered that genetic variations of this gene are strongly associated both with spontaneous clearance and sustained virologic response to treatment of hepatitis C. The model uses the most recent laboratory tests for serum bilirubin, international normalized ratio (INR), and serum creatinine to generate a "MELD score". Necroinflammatory activity is one of the main predictors of liver disease outcome in hepatitis B; patients with a high activity score are at greater risk of rapid progression of fibrosis and cirrhosis. Response-guided therapyhas been utilized with triple-therapy regimens that include an NS34A protease inhibitor. The ribavirin mechanism of action involves one or more of the following: (1) enhanced immune clearance of HCV via shifting from Th2 to Th1, (2) inhibition of the cellular enzyme Inosine Monophosphate Dehydrogenase (IMPDH), leading to depletion of cellular levels of GTP, which is a necessary substrate for HCV replication, (3)inhibition of the HCV NS5B RNA polymerase enzyme (RdRp), (4) generation of RNA mutagenesis, which results in the creation of defective HCV particles.
Here, we present a case report of a 10 year old girl who came with features of haemolytic anaemia and history of blood transfusion since 3 years.
Primary and secondary forms of the disease exist.1 The activation of the immune system in primary cases is poorly understood.
Although the pathogenesis of AIH is not known, it is accepted as the loss of tolerance of an organism to its own liver tissue. Thus, we present our case with WAIHA and AIH with asymptomatic carrier state of HBV infection. It can be intravascular, as in infections, transfusion reactions, and paroxysmal cold haemoglobinuria, or extravascular, as in enzyme deficiencies, membranopathies, haemoglobinopathies, drug reactions or autoimmune. It can affect any age group but tends to predominate in women.3 In AIH there are several autoantibodies formed against antigens specific or nonspecific to the liver. Therefore, a diagnosis of AIHA should alert paediatricians to the possibility of an associated systemic disease. Anti-asialoglycoprotein receptor autoantibodies, detected by a capture-immunoassay, are associated with autoimmune liver diseases. Autoimmune hemolytic anemia occurred prior to evident nephropathy in a patient with chronic hepatitis C virus infection: case report.
A case of autoimmune hepatitis and autoimmune hemolytic anemia following hepatitis A infection. Iran has a low to intermediate HBV prevalence and approximately 1.5 million people are living with HBV infection.
In the Middle East, HBV infection is of an intermediate endemicity with chronic HBV carriage rate of 2-5% among the general population (2). The cases were selected from a total of 800 patients with positive results for HBs Ag referred to the Tehran Hepatitis Centre (THC: the outpatient clinic of the Baqiyatallah Research Center for Gastroenterology and Liver Diseases) and had completed seven years of follow up.
The patientsa€™ medical history, route of diagnosis of HBV infection, and family history of liver diseases including: carrier state of HBV, chronic HBV, cirrhosis, and HCC were recorded. The Student t-test and one-way ANOVA were used for comparing quantitative variables, and the chi-square test was used for comparisons involving categorical variables. The outcome of patients were assessed on 6 categories; inactive carrier state (group A), chronic hepatitis (group B), cirrhosis (group C), HCC, death, and finally negative cases. Treatment regimens were assessed in two groups; one containing Interferon and another Direct Antiviral (DAV) drugs including Lamivudine, Adefovir or combination of Lamivudine and Adefovir. One meta-analysis found that an APRI threshold of 1.0 was 76% sensitive and 72% specific for detecting hepatitis C-associated cirrhosis. Measurement of BMI may not be accurate in all persons, particuarly persons with large muscle mass (such as athletes), persons who have lean muscle mass (such as seniors), or persons shorter than 5 feet tall.
When bridging fibrosis is seen diffusely in a liver specimen, it is classified as cirrhosis. However, ultimately the diagnosis of cirrhosis is based on liver histology and the presence the bridging fibrosis (see above).
Core antibody is generally in the form of IgM during acute infection or flares of HBV and predominantly in the form of IgG during chronic or resolved infection. This test has been validated across multiple patient populations including viral hepatitis but is not currently available in the U.S. Genotypes 4, 5 and 6 are increasingly observed in the US, especially among foreign-born patients from Asia and Africa (see Map).
In patients who go on to resolve their infection, HBsAg usually becomes undetectable after 4 to 6 months. The lead-in provides the advantage of assessing interferon responsiveness and likelihood of subsequent treatment response in treatment-naive individuals. The MELD scores range from 6 (less ill) to 40 (gravely ill) and are often used to prioritize patients waiting for a liver transplant.
On admission, laboratory test revealed that she had autoimmune hepatitis type 1 and was also an asymptomatic carrier of hepatitis B virus with positive HBs Ag. Her medical history before this episode revealed that, in February 2007, she had experienced similar complaints of extreme pallor and weakness, for which she was admitted to a local public sector hospital in Quetta, where she was worked up for anaemia. Dimorphic picture, macrocytosis, anisocytosis, polychromasia, red cell clumps, spherocytosis, nucleated RBC's, occasional myelocytes and metamyelocytes were detected in blood smear. When the diagnosis of AIHA was confirmed, she was put on a regular dose of prednisolone adjusted according to her body weight.

Thus, faced with a patient with AIHA, clinical and laboratory investigations are indicated with the objective of identifying subjacent pathologies such as infectious diseases, autoimmune diseases and neoplasms as early as possible.
The impact of HBV in Iran is unknown and given the very low levels of alcohol consumption, this region provides an opportunity to examine the impact of isolated chronic HBV infection.
The patientsa€™ medical history, route of diagnosis of infection, family history, and liver diseases status including: carrier state of HBV, chronic HBV, cirrhosis, and HCC were recorded. Over seven years, the rate of inactive carriers decreased by eight percent (They turned into chronic HBV or became HBSAg negative).
Worldwide more than 400 million individuals are chronically infected with HBV, and they are at the risk of developing hepatocellular carcinoma (HCC) and cirrhosis (3). Here we describe, for the first time the outcome of a cohort of patients followed up for seven years. They had been admitted due to incidental detection of HBs Ag during blood donation, routine check-ups, and work-ups for nonliver diseases or referred from other outpatient clinics.
During each visit, Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, Blood biochemical tests [including fasting blood glucose (FBS), triglyceride (TG) and cholesterol (Chl), Complete blood count (CBC), Serological HBV markers, and physical examinations were performed.
Repeated measures analyses were performed for changes during seven years follow up in different numerical variables. Genotypes 1 and 4 HCV are associated with lower response rates to pegylated interferon and ribavirin compared with genotypes 2 and 3. In acute infection that resolves, the HBeAg is promptly cleared with subsequent development of anti-HBe antibody. At that time, laboratory examination revealed deterioration of haemogram and positive Direct Coombs test (Table-1).The patient was diagnosed as autoimmune haemolytic anaemia and had recovered after transfusion of packed red cells. A normal G6PD level, obtained after the acute phase of the illness, eliminated G6PD deficiency as a possibility. Also, the optimal treatment strategy for viral hepatitis associated with autoimmunity remains to be established. No significant association was found between HBSAg seroclearance, HBeAg seroconversion and the outcome in the end of each year of follow up.
Immunosuppressed patients (who had undergone dialysis or received immunosuppressive drugs), those with concurrent hepatitis C virus, HIV infection or other liver diseases (Wilson disease, autoimmune hepatitis, I±-1-antitrypsin deficiency) and those not willing to participate in the survey (n = 158) were excluded from the study. Logistic regression analyses were performed for assessment of effective factors on the outcome. After seven years follow up, platelets count showed a significant difference between different groups of outcome, while no other significant differences were noted.
Some patients may have received several rounds of treatment during 7 years follow up, and that is why a total of 489 treatments are presented for a total of 275 patients. Clearance of this antigen with subsequent development of surface antibody (anti-HBs) is a major benchmark but occurs rarely (0.5% or less per year) in patients with chronic infection.
Direct antiglobulin test was negative after anaemia resolution, hepatitis B virus antigenemia persisted. She then experienced similar attacks of pallor and malaise in March 2007 and January 2008, which were managed by supportive treatment. Patient was advised for regular follow up every 6 weeks, but she did not comply with the instruction. Direct Coombs test revealed an anti-IgG antibody on the RBC's, consistent with warm autoimmune haemolytic anaemia (WAIHA).
More strict diagnostic methods that differentiate AIH from viral hepatitis are required in order to determine appropriate treatment.
Different treatment regimens did not have any statistically significant difference regarding HBeAg seroconversion.
Several factors have been identified that could influence the rate of these complications resulting from HBV infection.
The viral markers (HBs Ag, anti-HBs, HBeAg, and anti-HBe) were measured using the ELISA method (11). The family history of patients showed that 55% had a positive history of hepatitis B for at least one of their first degree relative which indicates the importance of familial transmission of HBV, in Iran. To our knowledge, warm antibody autoimmune hemolytic anaemia has not previously been described in association with autoimmune hepatitis and asymptomatic carrier state of hepatitis B virus. Blood culture was positive for Pseudomonas aerogenosa for which patient received combination of injection amikacin and syrup ciprofloxacin for a total of 10 days. These include sex with higher rates of HCC found in men than women, geographic areas with higher rates found in Eastern and South East Asia and sub-Saharan Africa (3), and environmental factors such as the presence of aflatoxin on food, ethnicity, heavy alcohol consumption, as well as smoking (4).
Medications being used in the process of treatment were conventional Interferon (IFN) and Direct Antiviral (DAV) therapies, including Lamivudine, Adefovir or combination of Lamivudine and Adefovir. Serum HBV DNA level was quantitatively assessed in Keyvan Viral Special laboratory by real Cobas Amplicor and Cobas TaqMan from Roche Diagnostics. In general, for each respective clinical situation, there was no statistically significant association between the outcome and different family history characteristics. Repeated measures analysis was performed for assessment of changes in DNA load for HBV and different Para-clinical characteristics of patients during the follow up years.
Antinuclear antibody (ANA), antimitochondrial antibody (AMA) and anti-liver kidney microsomal antibody-1 (anti LKM-1) were found negative, while anti-smooth muscle antibody (ASMA) and anti-ds DNA antibody were found positive. Despite the availability of effective vaccines and effective antiviral medications, approximately one million people die annually of acute and chronic HBV infections (5, 6). Smoking, alcohol consumption, and opium intake were assessed, and 72% of patients (198) denied such habits. Table 3 indicates Mean, SD, and 95% confidence interval of survival time for each status change. Several viral factors appear to strongly influence the outcome in HBV infection, including HBV genotype, DNA levels over time and specific HBV viral mutations (7). Mutations in the HBV surface (S), precore (PC) and basal core promoter (BCP) genes are observed frequently in patients with HBV infection , and studies show that these mutations are associated with the clinical outcomes of HBV disease. Over seven years, the rate of inactive carriers decreased by 8% (most of them turned into chronic hepatitis), while increasing rate of negative HBsAg was 2.2%. There are 8 HBV genotypes in the world and incidence rate of HCC and cirrhosis in every genotype are varied (7-9).
Genotype D is the most common genotype in Iran and according to WHO classification, Iran has a low to intermediate HBV prevalence, and it is estimated that about 1.5 million people are living with HBV infection (10). Histological assessment revealed mild and moderate hepatitis in the treated patients, and minimal hepatitis in the untreated ones. To evaluate survival of HBV infection, Kaplan-Meier survival, and COX Regression graph were used.
Echocardiography showed dilated left ventricle with mild generalized left ventricular dysfunction and aortic regurgitation.

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