The Function Of Alt And The Origin Of Its Normal Range
Serum ALT is a kind of intracellular functional enzyme catalyzing amino transfer reaction, which is mainly distributed in the liver. It is one of the most sensitive indicators to measure liver function and reflect liver damage . In normal condition, as long as a small amount of ALT is released into the blood, the activity and activity of the enzyme in the serum can be significantly increased. The concentration of ALT in hepatocytes was 1,000~3,000 times higher than that in serum. As long as 1% of hepatocytes are necrotic and the activity of enzymes in blood is doubled, thus serum ALT is a sensitive marker of acute hepatocyte injury .
In fact, serum ALT detection equipment and reagents are different in different countries and regions, thus the results of normal range are not the same . The standardization of ALT normal range needs to be solved urgently. And the individualized ALT reference level may be also a new direction in the future.
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Durability And Related Factors After Hbsag Clearance
When patients with HBeAg-positive CHB achieve a satisfactory antiviral treatment endpoint , the clinical recurrence is 2040%, and the virological recurrence can be as high as 8090% after drug withdrawal . Because the safety of drug withdrawal is uncertain, HBsAg clearance is recommended as the ideal treatment endpoint for CHB patients. The accessibility and rate of HBsAg clearance was mentioned above, but the durability of HBsAg clearance after treatment cessation remains controversial.
HBeAg status should also receive attention in the pursuit of HBsAg clearance. The clearance of HBsAg in most patients is based on HBV DNA suppression and HBeAg seroconversion, but a few patients exhibit different HBsAg response patterns, such as HBsAg clearance without HBeAg seroconversion. Only HBsAg clearance based on HBV DNA suppression and HBeAg seroconversion is safe for drug withdrawal .
Chb With Normal Alt Still Had Obvious Liver Histological Abnormalities
We previously analyzed the pathological results of 141 CHB patients with normal ALT and found that 47.5% of the patients had significant inflammation and 33.3% had significant fibrosis or cirrhosis . Among HBeAg-positive patients with persistently normal ALT, the proportion of patients with significant liver inflammation or fibrosis was 27.8~49.4% . Recently, Prof. Zhuang and his colleagues also reported that 53.2% of HBeAg-negative patients with normal ALT have obvious liver fibrosis . Among them, 44.6% of patients with serum ALT > 20 U/L had obvious hepatic necrotizing inflammation and 61.0% had obvious hepatic fibrosis while only 26.5% of patients with ALT 20 U/L had obvious hepatic necrotizing inflammation and 41.7% had obvious hepatic fibrosis. These results confirmed that a considerable number of HBeAg-negative CHB patients with normal ALT had obvious liver histopathological changes, and even 46.2% of the patients with low HBV DNA level had obvious liver fibrosis. A long-term follow-up study of 1,965 untreated inactive carrier HBeAg-negative patients in Taiwan found that during an average follow-up of 11.5 years, 16% progressed to reactivation and 3% developed cirrhosis . Therefore, patients with normal ALT in inactive carrier status may also have significant liver pathological changes and high risk of liver cancer or death .
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Special Considerations During Immunosuppressive Therapy
With immunosuppressive therapy, both in the context of malignancy and rheumatologic/autoimmune diseases, reactivation of HBV infection can occur. HBV reactivation in HIV-negative people with HBsAg-positive/anti HBc-positive disease receiving immunomodulatory therapy is well described.147,148 Even among people with HBsAg-negative/anti-HBc-positive disease, HBV reactivation occurs in 8% to 18% of people receiving anti-cancer drugs149 and 1.7% of people receiving rheumatologic disease drugs.150
Candidates In The General Population
Antiviral treatment is an effective therapeutic strategy for CHB patients that efficiently suppresses HBV replication, decreases inflammatory necrosis in the liver, reduces the incidence of liver cirrhosis and related complications, and reduces the fatality rate associated with hepatocellular carcinoma and other liver diseases. In the 2019 China guidelines , HBV infection is divided into four phases: immune tolerance, immune clearance, immune control, and immune reactivity, and it is different from the 2015 version . Additionally, the 2019 China guidelines eased the restrictions on indications for antiviral therapy, and reducing the demand for HBV-DNA load. Conversely, the HBV-DNA load is considered for the performance of antiviral therapy in the 2018 guidelines updated by the 2018 AASLD guideline and the 2017 EASL guidelines . For the treatment of HBV infection with normal ALT , antiviral therapy is recommended in patients > 30-years-old with a family history of liver cirrhosis or cancer in the 2019 China guidelines. In another case > 30-years-old without a family history of liver cirrhosis or cancer, a hepatic biopsy was recommended. Although we can refer to many guidelines, there are many patients failed to fulfill the criteria for treatment at follow-up and eventually developed liver fibrosis, cirrhosis, and cancer .
Table 1. Comparison between 2015 and 2019 guidelines.
Table 2. Indications for chronic hepatitis B treatment in 2017 and 2018 guidelines.
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How To Define The Immune Tolerance Phase Of Hbv Infection
The immune tolerance phase of HBV infection has been defined and described in many international CHB management guidelines . Although these guidelines have some differences in the definition of immune tolerance phase of HBV infection, they also have common characteristics, such as positive HBsAg , positive HBeAg, high level of HBV-DNA , persistently normal ALT , as well as no obvious inflammation, necrosis and fibrosis in liver pathology.
At present, the inconsistent definition of immune tolerance phase in different guidelines is mainly manifested in the level of serum HBV DNA and ALT. Because of the controversy in serum HBV DNA and ALT levels, clinicians must pay attention to following details when judging a chronic HBV infection whether in the immune tolerance phase. Firstly, the guidelines require that patients serum ALT level is persistently normal, rather than a certain cross-sectional serum ALT within the normal range. Therefore, in clinical practice, we need patients to provide reliable laboratory reports of dynamic serum ALT and comprehensively evaluate various potential factors that may cause ALT level fluctuations. Secondly, on the premise of meeting other conditions, the higher the serum HBV-DNA level, the more likely the patient will be in the immune tolerance period. Because only the very high serum HBV DNA level can accurately indicate the peaceful coexistence of the virus and the host.
Clinical Guidelines For Children With Chronic Hepatitis B
In general, the clinical guidelines for children are the same as for adults – visits are usually scheduled every six months or once a year. Most children do not need drug treatment, but they still need to be monitored regularly to make sure they remain healthy and to detect any problems with their liver as soon as possible. Visits will include a physical exam, blood tests, and possibly an imaging study of the liver .
AASLD guidelines provide guidance for treating children under the Updated Recommendations on the Treatment of Patients With Chronic Hepatitis B, section 9A.
The Hepatitis B Foundation convened the first Pediatric HBV Workshop and invited the nations leading pediatric liver specialists to develop the first national recommendations for children living with hepatitis B to ensure that they receive the best care possible. These recommendations have been published in highly respected, peer-reviewed journals and provide expert guidance for the care of infected children.
Hepatitis B Foundations Clinical Guidelines for Pediatric HBV
HBF’s Pediatric HBV Screening and Monitoring Recommendations Published in Pediatrics in November 2009Haber BA, Block JM, Jonas MM, Karpen SJ, London WT, McMahon BJ, Murray KF, Narkewicz MR, Rosenthal P, Schwarz KB. Recommendations for screening, monitoring, and referral of pediatric chronic hepatitis B. Pediatrics 124:e1007-13.
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Aasld Guidelines For Treatment Of Chronic Hepatitis B
Norah A. Terrault
University of California San Francisco, San Francisco, CA
Norah A. Terrault
University of California San Francisco, San Francisco, CA
Potential conflict of interest: Dr. Jonas consults and received grants from Gilead. She received grants from Bristol-Myers Squibb and Roche. Dr. Chang advises Genentech, Alnylam, and Arbutus. Dr. Terrault consults for Bristol-Myers Squibb and received grants from Gilead. Dr. Bzowej received grants from Gilead, Synageva, and Ocera.
The funding for the development of this Practice Guideline was provided by the American Association for the Study of Liver Diseases.
This Practice Guideline was approved by the AASLD on August 1, 2015.
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- American Association for the Study of Liver Diseases
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- Grading of Recommendation Assessment, Development and Evaluation
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Mother To Child Transmission Of Hepatitis B
Antiviral therapy has been studied as an intervention to reduce perinatal HBV transmission amongst pregnant women with high HBV viral DNA levels. All newborns born to HBV infected mothers should receive HBIG and HBV vaccine within 12 h of delivery followed by completion of 2 or 3 vaccine series. AASLD suggests antiviral therapy starting at 28-32 wk to reduce perinatal HBV transmission when maternal HBV DNA is > 200000 IU/mL. Tenofovir is recommended as the preferred agent due to lack of resistance and availability of safety data and the therapy is discontinued at some point between birth and three months postpartum.
Cressey et al assessed for the first time tenofovir exposure during pregnancy and postpartum in HBV-infected HIV-uninfected women receiving TDF to prevent mother-to-child transmission of HBV. They concluded that the modest reduction in tenofovir exposures observed during pregnancy does not warrant a dose adjustment.
These studies reiterate the safety, efficacy, and practicality of Tenofovir in pregnant women at high risk for MTCT of hepatitis B. In their July 2020 guidelines on antiviral prophylaxis in pregnancy, WHO recommends that pregnant women testing positive for HBV infection with HBV DNA 5.3 log10 IU/mL receive tenofovir prophylaxis from the 28th week of pregnancy until at least birth, to prevent mother-to-child transmission of HBV. This is in addition to three-dose hepatitis B vaccination in all infants, including timely birth dose.
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Clinical Guidelines For Adults
The standard recommendation for care is to schedule visits with a liver specialist every six months, but this can be more or less depending on your medical situation. During these check-ups, the following usually occurs to monitor your health and your liver:
On July 27, 2020, the American Society of Clinical Oncology published provisional guidelines recommending that all people diagnosed with cancer be tested for hepatitis B before starting anticancer treatment. According to the ASCO statement, up to 90% of people diagnosed with cancer have at least one risk factor for hepatitis B. Cancer treatments can suppress the immune system and cause the virus to reactivate, which can lead to serious liver damage or liver failure. The guidelines discuss how to manage people undergoing cancer treatment who also have hepatitis B, to prevent viral flares.
Accessibility And Hbsag Clearance Rate
HBsAg clearance occurs spontaneously or via antiviral treatment in CHB patients. The most commonly used drugs are nucleoside analogue and pegylated interferon . NA drugs include entecavir , tenofovir disoproxil fumarate and tenofovir alafenamide fumarate . The 2018 AASLD guidelines recommend Peg-IFN, ETV, or TDF as the preferred initial therapy for adults with immune-active CHB. It also suggests that alanine transaminase levels be tested at least every 6 months for adults with immune-tolerant CHB to monitor for potential transition to immune-active or immune-inactive CHB . The 2017 EASL guideline recommends ETV, TDF and TAF as the preferred monotherapy regimens, and the extension of the duration of Peg-IFN therapy beyond week 48 may be beneficial in selected HBeAg-negative CHB patients . The potential side effects of NAs include lactic acidosis for ETV and nephropathy, osteomalacia, lactic acidosis for TDF. CHB patients should be clinically monitored. The most frequently reported side effects for Peg-IFN are flu-like syndrome, myalgia, fatigue, mood disturbances, weight loss, hair loss and local reactions at the site of injection, and these side effects may be partially managed with dose reduction . Currently, the clearance of HBsAg is based primarily on sequential or combined treatment with NA and Peg-IFN.
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Controversial Issues In Clinical Practice
Nucleoide analogs withdrawal and retreatment
Oral nucleoide analogs used in first-line treatment, such as TDF, entecavir , and tenofovir alafenamide fumarate , have strong anti-virus effects, fewer side effects, convenience, and low resistance. However, long-term duration, especially > 10 years of administration, requires intensive focus on drug safety and may result in reduced compliance in patients . Drug withdrawal can be considered in HBeAg+ patients after e-antigen seroconversion and consolidation therapy, as recommended by guidelines . Conversely, for HBeAg- patients, the 2019 China guidelines recommended drug withdrawal upon serum HBsAg disappearance and HBV DNA below the limit of detection, and the 2018 AASLD guidelines recommended at least 2 years of viral inhibition and consolidation therapy, while the 2017 EASL guidelines recommended a minimal 3-year viral inhibition. The 2015 APASL guidelines recommended drug withdrawal upon serum HBsAg disappearance, followed by 12-month consolidation therapy or undetectable HBV DNA and a minimum of 2 years of treatment.
Low level viremia
Table 3. Recommendations for salvage therapy in resistant patients in 2019 guideline.
Prognosis Improvement After Hbsag Clearance
These related studies provide clear recommendations that patients who achieve HBsAg clearance have favourable clinical outcomes compared to patients who achieve only HBV DNA suppression and HBeAg seroconversion. HBsAg clearance leads to biochemical, virological and liver histological improvements, and it significantly reduces the risk of HCC. However, HCC may occur after HBsAg seroclearance despite it being the ultimate treatment endpoint recommended by current guidelines. The risk factors associated with HCC include the presence of cirrhosis, male sex, and age50 years at the time of HBsAg clearance . Closer attention should be given to patients with one or more of these risk factors.
These high-risk patients should be re-examined in a timely manner even if HBsAg clearance is obtained. These results also suggest that achieving a functional cure early in the absence of cirrhosis results in a better prognosis .
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World Health Organization Recommendations
The 2015 WHO guidelines for the prevention, care, and treatment of persons with chronic hepatitis B infection indicates treatment priority for individuals of all ages who have chronic hepatitis B infection and clinical evidence of compensated/decompensated cirrhosis , regardless of their levels of ALT or HBV DNA, or their HBeAg status.
Treatment is recommended for adults with chronic hepatitis B infection without clinical evidence of cirrhosis , but who have all of the following features , and regardless of HBeAg status :
- Are older than 30 years
- Have persistently abnormal ALT levels
- Have evidence of high-level HBV replication .
In individuals with HBV/human immunodeficiency virus coinfection, the AASLD recommends initiating ART in all those with evidence of severe chronic liver disease, regardless of CD4 count, as well as those with a CD4 count of 500 cells/mm3 or below, regardless of their liver disease stage.
However, the AASLD does not recommend antiviral therapy, indicating it can be deferred, in individuals with all of the following , regardless of HBeAg status or age :
- No clinical evidence of cirrhosis
- Persistently normal ALT levels
- Low levels of HBV DNA replication . ]
Hepatitis B And Pregnancy
The American College of Obstetricians and Gynecologists , the US Preventive Services Task Force , and the World Health Organization recommend routine prenatal screening for hepatitis B surface antigen in all pregnant womenduring every pregnancyregardless of previous test results or vaccinations. Pregnant women at risk for hepatitis B infections should be specifically targeted for vaccination. The risk of transmission of hepatitis B associated with amniocentesis is low. WHO further recommends all pregnant women undergo testing at least once for HIV and syphilis in addition to that for HBsAg and as early as possible in the pregnancy.
It is recommended that all infants receive their first dose of hepatitis B vaccine as soon as possible after birth , followed by two or three doses to complete the primary series.
To prevent maternal-fetal HBV transmission, a conditional WHO recommendation is that HBsAg-positive gravida who have an HBV DNA 5.3 log10 IU/mL receive tenofovir prophylaxis beginning the 28th week of pregnancy until at least birth. This is in addition to the three-dose hepatitis B vaccination in all infants, including a timely birth dose. When antenatal HBV DNA testing is not available, HBeAg testing can be used as an alternative study to determine eligibility for tenofovir prophylaxis to prevent mother-to-child transmission of HBV.
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Treatment Algorithm Updated For Chronic Hbv
The recommendations address use of newer therapies and are intended to offer guidance on treating chronic hepatitis B virus infection while additional antiviral agents are in development.
Seven expert panelists reviewed the available evidence and used clinical experience and consensus opinion to update an existing treatment algorithm on managing chronic HBV infection in the United States. The guidance was last updated in 2015. The revised version was published by Clinical Gastroenterology and Hepatology on July 27.
In the absence of cirrhosis, no treatment is recommended for patients with HBV DNA levels below 2,000 IU/mL and normal ALT levels, the algorithm noted. It recommended assessing ALT levels every six to 12 months and, if levels increase, checking serum HBV DNA levels and excluding other causes of disease. Therapy should be considered if significant histologic disease is present, the algorithm said.
In patients with no cirrhosis and with normal ALT levels but HBV DNA levels of 2,000 IU/mL or greater, decisions about treatment should be based on hepatitis B e antigen status, according to the algorithm. Patients without cirrhosis but with elevated HBV DNA and ALT levels should be treated with entecavir, tenofovir alafenamide , tenofovir disoproxil fumarate , or peginterferon alfa-2a. The algorithm noted that long-term treatment may be necessary if oral agents are used.