Alpha-fetoprotein Testing Research Articles

Input of serum haptoglobin fucosylation profile in the diagnosis of hepatocellular carcinoma in patients with non-cirrhotic liver disease

Haptoglobin bifucosylated tetra-antennary glycan have been identified in patients with early stage hepatocellular carcinoma, but its specificity according to the presence or not of cirrhosis has never been assessed. The aims of this study were to determine if haptoglobin bifucosylated tetra-antennary glycan (1) could be a marker of HCC in patients without cirrhosis; (2) could increase the performance of standard alpha-fetoprotein (AFP) or recent blood tests for HCC detection, i.e., lectin-reactive alpha-fetoprotein (AFP-L3), des-gamma-carboxy prothrombin (DCP) and Liver-Cancer-Risk-test (LCR1-test). We retrospectively selected patients, 102 with HCC (21 without cirrhosis), matched by stages with 140 controls without HCC (81 without cirrhosis). Haptoglobin fucosylation was assessed by MALDI-TOF. LCR-glycan algorithm was constructed combining components of the LCR-1 test (haptoglobin, gammaglutamyl-transpeptidase, apolipoproteinA1, alpha-2-macroglobulin) with AFP, AFP-L3, DCP and haptoglobin bifucosylated tetra-antennary glycan. In 102 patients without cirrhosis (21 HCC and 81 controls), the intention-to-diagnose analyses showed that haptoglobin bifucosylated tetra-antennary glycan alone had a sensitivity of 71% (15/21;95%CI 50-86), significantly better (P=0.02) than standard AFP (43%;9/21;95%CI 24-63), and a specificity of 96% (78/81;95% 90-99). The sensitivity of LCR-glycan, in patients without cirrhosis, was 86% (18/21; 95%CI 63-95) significantly better (P=0.001) than standard AFP (43%; 9/21; 95%CI 24-63), with an AUROC of 0.943 (95%CI 0.806-0.98) compared to 0.811 (95%CI 0.630-0.908) for AFP (P=0.06). Haptoglobin bifucosylated tetra-antennary glycan is associated with the presence of HCC in patients with chronic liver disease including those without cirrhosis. Its combination with existing HCC biomarkers could improve the performance of standard AFP for HCC detection.

The Correlation between Alpha-fetoprotein and Liver Function Tests

Background Serum alpha-fetoprotein (AFP) level is a good indicator of important pathological stages in patients with chronic liver diseases. This study aims to investigate the alpha-fetoprotein level in male and female patients and to correlate it with other liver functions tests (LFTs), such as ALT, AST, total albumin and total protein. Methods A total of 100 patients within the age range 20-85 years who visited Shaukat Khanum Laboratory in Lahore were recruited for this study. Automated chemiluminicence microparticle immuno assay and immulite 2000 (CMIA, siemens USA) were used to measure serum AFP level. To measure serum ALT and AST, Architect 8200 kit (Abbott, USA) was used with a reference range of 0-50 U/L, according to the manufacturer’s protocols. Results Out of the total 100 samples (55 males, 45 females), 47 samples (47%) had normal AFP level (<5IU/l) and 53 samples (53%) had high AFP level (>5IU/l). A higher frequency of elevated AFP was observed in men at 60.38%. There was no significant correlation of AFP level with ALT (p= 0.38, r2= 0.002), T.P. (P. value= 0.7635 r2= 0.002) and albumin levels (p= 0.07, r2 =0.041). However, a significant correlation was found between AFP and AST levels (p= 0.02, r2= 0.15). Conclusion Our study found a higher AFP level in older population (>60) as compared to the younger people (20-40) and a higher frequency among males (60.38%) as compared to females (39.63%). It also found that AFP level significantly correlates with AST level but does not show any association with ALT and albumin levels.

Racial disparities in alpha-fetoprotein testing and alpha-fetoprotein status associated with the diagnosis and outcome of hepatocellular carcinoma patients.

BackgroundThe use of alpha‐fetoprotein (AFP) testing for the surveillance, diagnosis, and prognosis of hepatocellular carcinoma (HCC) remains controversial. Here, we compared AFP testing rates, elevated AFP rates, factors associated with elevated AFP levels, and prognostic factors associated with overall survival (OS) in HCC patients from different ethnic groups.MethodsPatients with HCC were identified from the Surveillance, Epidemiology, and End Results registries. Race was categorized as white, black, and others. AFP testing rates and elevated AFP rates were analyzed. Multivariable logistic regression and Cox regression analyses were used to identify independent factors associated with elevated AFP levels and prognosis, respectively. All statistical tests were two sided.ResultsA proportion of 79.2% of total HCC patients had AFP testing reports; 77.3% of white, 79.7% of black, and 81.2% of other races underwent AFP testing. Compared with white and other races, black HCC patients had a higher rate of elevated AFP levels among all patients and the early‐stage HCC patient cohort. Elevated AFP level was a significant prognostic factor for all HCC patients in different race groups. Factors associated with elevated AFP level and prognostic factors associated with OS varied significantly by race.ConclusionsAFP testing, elevated AFP rates, predictors of elevated AFP level, and prognostic factors associated with OS differed significantly according to race after adjusting for AFP levels among the three groups. AFP testing for the surveillance, diagnosis, and prognosis of HCC patients is strongly recommended, although racial disparities need to be considered.

Inadequate Hepatocellular Carcinoma Screening in Patients With Nonalcoholic Steatohepatitis Cirrhosis.

Nonalcoholic steatohepatitis (NASH) is a common cause of liver disease which can progress to cirrhosis and hepatocellular carcinoma (HCC). American Association for the Study of Liver Diseases (AASLD) guidelines recommend abdominal ultrasound, with or without serum alpha-fetoprotein, every 6 months for HCC surveillance in cirrhotic patients. Describe HCC surveillance rates in NASH cirrhosis compared with hepatitis C (HCV) cirrhosis and the impact of surveillance on tumor size, treatment, and mortality. Adults with NASH and HCV cirrhosis diagnosed with HCC from 2009 to 2016 were retrospectively evaluated. Patients were categorized into 3 mutually exclusive disease screening groups based on abdominal imaging with or without serum alpha-fetoprotein testing before HCC diagnosis. In total, 99 patients with NASH cirrhosis and 162 patients with HCV cirrhosis were evaluated. In total, 51.5% of NASH cirrhosis patients and 25.9% of HCV cirrhosis patients had no screening before HCC diagnosis. Patients with HCV cirrhosis were significantly more likely to undergo surveillance compared with patients with NASH cirrhosis (P=0.002). NASH cirrhosis patients who underwent complete screening had smaller tumors compared with those with incomplete screening and no screening (P=0.006). There were no differences in number of tumors at diagnosis or mortality between screening groups in patients with NASH cirrhosis (P=0.281 and 0.468, respectively). There is suboptimal HCC surveillance in NASH and HCV cirrhotic patients, with a greater proportion of patients with NASH cirrhosis not undergoing surveillance. Patients with NASH cirrhosis who had complete surveillance had smaller tumors at diagnosis, but there were no differences in treatment outcomes or mortality.

Alpha Feto Protein in vaginal fluid as a diagnostic marker of Premature rupture of membrane

Background : Premature Rupture of Membrane (PROM) is a significant obstetric emergency where a normal pregnancy suddenly becomes a high risk one. It can cause serious complications of mother and fetus. Patient’s history, per speculum vaginal with Nitrazine paper test and Fern test considered as gold standard for diagnosis of PROM. But these multiple tests are hazardous and time consuming. Therefore Alpha-Feto Protein (AFP) test is a single sensitive test for proper diagnosis of PROM.
 Objective : To evaluate the accuracy of Alpha-Feto protein in vaginal fluid as a diagnostic tool of PROM.
 Method : It was a cross sectional study, carried out among 120 pregnant women who had the gestational age between 28th to 40th week of pregnancy. Sample was collected purposively and divided into two groups. In group-I-62 suspected PROM patients were selected who gave the history of per vaginal watery discharge and was found positive in per speculum examination (P/S). In group-II-58 non PROM pregnant patients were selected. Then in group-I, Nitrazine paper test and Fern test were done to confirme PROM patients. Both groups AFP test was done by AxSYM auto analyzer. Finally the accuracy of AFP was evaluated against the gold standard test.
 Result : It was found that AFP concentration was significantly higher in group-I of suspected PROM patients (30- 502ng/ml) than in group-II (0-40ng/ml). Among 62 suspected PROM patients 49 were found gold standard (Nitrogen paper test and Fern test) positive. Out of these 49 confirmed PROM patients 48 was found positive in Alpha-Feto protein test. The sensitivity of AFP test was found 98%, specificity was 84.6% and accuracy was 95.1%.
 Conclusion : As Alpha-Feto protein in vaginal fluid was found highly accurate (95.1%) for diagnosis of PROM. Therefore, AFP test can be used as a single sensitive test for diagnosis of PROM.
 Northern International Medical College Journal Vol.10(1) Jul 2018: 335-338

Rationale and design of the Hepatocellular carcinoma Early Detection Strategy study: A multi-center longitudinal initiative of the National Cancer Institute’s Early Detection Research Network

BackgroundHepatocellular carcinoma (HCC) is a common malignancy with a steadily rising incidence and associated morbidity and mortality. Cirrhosis of the liver is presently the leading risk factor for developing HCC. Abdominal imaging, with or without alpha-fetoprotein (AFP) testing, every 6 months is the current surveillance strategy for patients at risk. The available biomarkers for detecting this cancer at an early stage have inadequate sensitivity and specificity. MethodsThe Hepatocellular carcinoma Early Detection Strategy (HEDS) study, a multi-center initiative of the National Cancer Institutes' (NCI) Early Detection Research Network (EDRN), launched an effort to establish what has become the nation's largest comprehensive biorepository and database on patients at high risk of developing HCC. The cohort has been developed in seven clinical centers across the USA. Subjects are enrolled for a five-year period involving data and specimen collection every six months in accordance with standard surveillance for HCC. Extensive clinical data are collected and specimens are stored at a central repository. ResultsThe database and biorepository contain longitudinally collected clinical data and serum and plasma samples from 1482 participants with cirrhosis and without evidence of HCC at baseline. Fifty-six percent are male, 85% Caucasian, 30% have a history of chronic HCV and 71% have compensated cirrhosis. ConclusionsThe HEDS cohort provides opportunities for the continued study of the incidence and course of HCC in a comprehensively followed population of patients at high risk for this malignancy. Further, the EDRN biorepository provides a distinct opportunity for the development of novel biomarkers.Trial registry URL: https://edrn.nci.nih.gov/protocols/316-hepatocellular-carcinoma-early-detection-strategy.

Predictive Markers for Hepatocellular Carcinoma Development in Patients with Chronic Hepatitis C Virus Genotype4a

Background: Egypt has the highest prevalence of hepatitis C virus worldwide. Monitoring hepatitis C-infected patients for hepatocellular carcinoma development is an important clinical issue to diagnose these patients during the potentially curable early-stage of disease. This study aims to evaluate the role of N-terminal procollagen III, matrix metalloproteinase- 2, tissue inhibitor of matrix metalloproteinase-1, alpha-fetoprotein, and conventional liver function tests as predictors of hepatocellular carcinoma development upon long-term followup of non-responding hepatitis C virus patients.Methods: The study included 850 treatment-naive hepatitis C virus genotype 4a adult patients; after treatment, 360 achieved sustained viral response while 490 did not. Nonresponding patients had a 5-year rate for hepatocarcinogenesis of 8.4% and a 10-year rate of 27.5%. N-terminal procollagen III, matrix metalloproteinase-2, tissue inhibitor of matrix metalloproteinase-1, alpha-fetoprotein, and conventional liver function tests were evaluated in all patients before and after treatment, and after hepatocellular carcinoma development. The study also included a group of 50 hepatocellular carcinoma patients who were negative for hepatitis C and hepatitis B viruses, and a group of 50 healthy subjects as controls.Results: The non-responders had significantly higher age, stage, grade, viral load, alanine aminotransferase, and aspartate aminotransferase than responders. Also N-terminal procollagen III, matrix metalloproteinase-2, tissue inhibitor of matrix metalloproteinase-1, and alphafetoprotein were significantly higher in non-responders; after treatment they decreased in responders. In non-responders they remained higher than the control. The most significant risk factors for hepatocellular carcinoma development in non-responding hepatitis C virus patients were male gender and increased age, stage, grade, aspartate aminotransferase, Nterminal procollagen III, and tissue inhibitor of matrix metalloproteinase-1. Patients with viral-hepatocellular carcinoma were of significantly lower age, higher grade, stage, γ-glutamyltransferase, N-terminal procollagen III, and matrix metalloproteinase-2 than non-viral hepatocellular carcinoma patients. Percent positive N-terminal procollagen III, tissue inhibitor of matrix metalloproteinase-1, and alpha-fetoprotein were significantly higher in viral hepatocellular carcinoma patients.Conclusion: Data suggest that high N-terminal procollagen III and tissue inhibitor of matrix metalloproteinase-1levels after treatment might be particularly important as markers of hepatitis C virus-non-responding patients who are at higher risk of developing hepatocellular carcinoma, especially in older males with high stage and grade liver disease. However, studies of larger scale are needed to verify this suggestion.

Comparison of the Duo of Insulin-Like Growth Factor Binding Protein-1/Alpha Fetoprotein (Amnioquick Duo+®) and Nitrazine Test for Diagnosing Query Rupture of Fetal Membranes

Background: premature rupture of membranes (PROM) constitutes one of the most important dilemmas in the obstetric practice. It could be defined as rupture of membranes before the onset of labour, irrespective of the gestational age. It is associated with infectious morbidity in mother and fetus, cord accidents, imminent term or preterm labour. For these reasons, its correct diagnosis is very important. A novel test used for diagnosing rupture of membranes (ROM) is Amnioquick duo+® (Biosynex, Strasbourg Cedex, France). Amnioquick duo+® is a rapid strip test with immunoassay that is simple, easy to perform, quick and noninvasive. It is an immunochromatographic test that identifies even trace amounts of both alpha fetoprotein (AFP) and insulin-like growth factor binding protein-1 (IGFBP-1). On other hand the traditional methods for diagnosis of PROM are through the patient’s history, leakage, ferning test and nitrazine test. Aim of the Work: the aim of this study is to compare the accuracy of the duo of insulin-like growth factor binding protein-1/alpha fetoprotein (Amnioquick duo+®) and nitrazine test for diagnosing query rupture of fetal membranes in pregnant women with query PROM. Patients and Methods: this comparative cross sectional study was carried out at Ain Shams University Maternity Hospital between November 2017 to June 2018. Results: a total of one hundred and thirteen pregnant women > 24 weeks of gestation were included in the study with age ranging between 18 and 42 years (mean ± SD, 27 ± 6 years). Thirty eight (33.6%) women were primigravidae and 75 (66.4%) were multigravidae. Forty (35.4%) women were primiparas while 63 (64.6%) were multiparas. Twenty five (22.1%) women experienced one or more previous abortion. The Amnioquick duo+® test was more specific and accuracy in diagnosing rupture of membranes than Nitrazine test. The sensitivity and the specificity of Amnioquick duo+® test in diagnosing PROM was 100% and 97.3% respectively as compared to Nitrazine test which was 100% and 83%. The PPV and NPV of Amnioquick duo+® test were 98.7% and 100% as compared to Nitrazine test which were 92.7% and 100%. Conclusion: this study concluded that IGFBP-1/AFP (AmnioQuick® Duo+) test is rapid reliable non-invasive, easy and accurate bedside immunoassay test, better than nitrazine test and can used as complementary test to improve the management of women with women premature fetal membranes rupture.

Comparison of the Duo of Insulin-Like Growth Factor Binding Protein-1/Alpha Fetoprotein (Amnioquick Duo+®) and Nitrazine Test for Diagnosing Query Rupture of Fetal Membranes

Background: premature rupture of membranes (PROM) constitutes one of the most important dilemmas in the obstetric practice. It could be defined as rupture of membranes before the onset of labour, irrespective of the gestational age. It is associated with infectious morbidity in mother and fetus, cord accidents, imminent term or preterm labour. For these reasons, its correct diagnosis is very important. A novel test used for diagnosing rupture of membranes (ROM) is Amnioquick duo+® (Biosynex, Strasbourg Cedex, France). Amnioquick duo+® is a rapid strip test with immunoassay that is simple, easy to perform, quick and noninvasive. It is an immunochromatographic test that identifies even trace amounts of both alpha fetoprotein (AFP) and insulin-like growth factor binding protein-1 (IGFBP-1). On other hand the traditional methods for diagnosis of PROM are through the patient’s history, leakage, ferning test and nitrazine test. Aim of the Work: the aim of this study is to compare the accuracy of the duo of insulin-like growth factor binding protein-1/alpha fetoprotein (Amnioquick duo+®) and nitrazine test for diagnosing query rupture of fetal membranes in pregnant women with query PROM. Patients and Methods: this comparative cross sectional study was carried out at Ain Shams University Maternity Hospital between November 2017 to June 2018. Results: a total of one hundred and thirteen pregnant women > 24 weeks of gestation were included in the study with age ranging between 18 and 42 years (mean ± SD, 27 ± 6 years). Thirty eight (33.6%) women were primigravidae and 75 (66.4%) were multigravidae. Forty (35.4%) women were primiparas while 63 (64.6%) were multiparas. Twenty five (22.1%) women experienced one or more previous abortion. The Amnioquick duo+® test was more specific and accuracy in diagnosing rupture of membranes than Nitrazine test. The sensitivity and the specificity of Amnioquick duo+® test in diagnosing PROM was 100% and 97.3% respectively as compared to Nitrazine test which was 100% and 83%. The PPV and NPV of Amnioquick duo+® test were 98.7% and 100% as compared to Nitrazine test which were 92.7% and 100%. Conclusion: this study concluded that IGFBP-1/AFP (AmnioQuick® Duo+) test is rapid reliable non-invasive, easy and accurate bedside immunoassay test, better than nitrazine test and can used as complementary test to improve the management of women with women premature fetal membranes rupture.

Air Pollution and Metabolomics in Maternal Serum

Background: Studies have shown that maternal exposed to air pollution can increase the risk of a variety of neurodevelopmental disorders. However, air pollution cannot be considered a well-established risk factor, partially due to a lack of valid exposure assessment methodology. Assessing environmental metabolomic profiles using high-resolution metabolomics (HRM) is a novel tool to investigate air pollution exposure history and related biological mechanism.Objectives: The aim of this study is to comprehensively profile metabolomics in the blood of women in mid-pregnancy and identify perturbations in metabolites and metabolic pathways associated with air pollution exposure by using HRM.Methods: We retrieved stored maternal serum samples from the mid-pregnancy alpha-fetoprotein testing program in California for a largely immigrant Hispanic community of women living in the Central Valley of California, a region with high particulate air pollution exposures. We developed measures of air pollution exposure at the mothers birth address. By using HRM, we identified significant metabolites and metabolic pathways within 99 exposed mothers and 62 unexposed mothers. Statistical methods include univariates analysis, multivariates analysis, and pathway enrichment analysis.Results: A set of 3917 metabolic features resulting from HRM were used for discriminant analysis and pathway analysis. We have identified 25 metabolites which can properly classify the air pollution exposure status with over 80% accuracy. Pathway analysis showed that air pollution exposure associated with leukotriene metabolism, amino acid metabolism, and pyrimidine and purine metabolism pathways.Conclusions: We found that maternal exposed to air pollution during pregnancy could potentially affect inflammation and oxidative stress-related metabolism, which may then contribute to the development of neurodevelopmental disorders in the offspring.

Noncontrast magnetic resonance imaging versus ultrasonography for hepatocellular carcinoma surveillance (MIRACLE-HCC): study protocol for a prospective randomized trial

BackgroundBiannual ultrasound (US)—with or without alpha-fetoprotein (AFP)—is recommended by current guidelines for the surveillance of hepatocellular carcinoma (HCC). However, the inadequate sensitivity of US has been a concern. Magnetic resonance imaging (MRI) is known to have high sensitivity in detecting hepatic malignancies, even without contrast enhancement. The purpose of our study is to compare US with noncontrast (unenhanced) MRI for HCC surveillance of high-risk patients.Methods/designMIRACLE-HCC (usefulness of noncontrast MagnetIc Resonance imAging versus nonContrast ultrasonography for surveiLlancE of HepatoCellular Carcinoma) is a prospective, single-center, nonblinded, balanced-randomized, parallel-group study. This study was approved by our institutional review board, and informed consent will be obtained from all participating patients. All patients with compensated liver cirrhosis will undergo noncontrast US or MRI, with serum AFP testing every 6 months. If a suspicious lesion is newly detected, or if the serum AFP level is elevated in an increasing trend for two consecutive tests, dynamic contrast-enhanced imaging will be performed to confirm the diagnosis. The primary endpoints are detection rates of very early or early stage HCC, stage distribution at the initial diagnosis, and false positive referral rates, which will be compared using Fisher’s exact or chi-square tests. The study will include 416 patients in a tertiary academic medical center in South Korea.DiscussionMIRACLE-HCC is the first prospective randomized trial to compare the effectiveness of noncontrast MRI and noncontrast US in the surveillance of HCC in at-risk patients. The results of this trial will show whether noncontrast MRI surveillance is superior to noncontrast US surveillance in the early detection of HCC. The trial will also determine whether there are fewer false referrals with noncontrast MRI than with noncontrast US and, eventually, whether there is improvement in the overall survival of HCC patients.Trial registrationThe date of trial registration (ClincalTrials.gov: NCT02514434) for this study is July 23, 2015. Enrollment of participants was finished in November 2017. No authors have relationships, conditions, or circumstances that present potential conflicts of interest.

Antineoplastic Approach of Semecarpus anacardium Leaves Against N-Nitroso Diethylamine Initiated Hepatocellular Carcinoma

Abstract: Objective: To evaluate the effect of MESA on NDEA induced hepatocellular carcinoma on Sprague Dawley rats. Methodology: Semecarpus anacardium commonly known as ‘marking nut tree’ is a rich antioxidant and in Ayurveda it has been used for treatment of various forms of cancer. Methanolic extract of leaves of Semecarpus anacardium (MESA) was studied for its potential antioxidant property both in vitro and in vivo. NDEA 200 mg/kg, single i.p was the hepatocarcinogen while 200 mg/kg and 400 mg/kg of MESA was administered daily orally for 12 weeks. Protective effect of MESA was evaluated by measuring biochemical parameters like SGOT, SGPT, ALP and LDH. Alpha fetoprotein test was performed and histopathology changes of livers were assessed. Results: Preliminary phytochemical study revealed the presence of flavonoids, tannins, steroids, alkaloids, glycosides and vitamin C. MESA restored the level of antioxidants near to normal and reduced the elevated serum level of SGOT, SGPT, AST, LDH and AFP. The histopathology changes i.e. necrosis, widened sinusoids, elevated inflammatory cell infiltrate were partly or fully prevented in animals treated with the extract. Conclusion: The result of the present study indicates MESA to be rich in antioxidants and its active constituents mediated the free radical scavenging activity. 400 mg/kg extract showed promising effect in management of primary liver cancer. Key words: Semecarpus anacardium, Hepatocellular carcinoma, N-nitroso diethylamine, Alpha fetoprotein, Liver marker enzymes.

Incidence and risk factors associated with hepatocellular carcinoma surveillance failure.

Surveillance for hepatocellular carcinoma (HCC) intends to detect tumors at an early stage to improve survival. The study aims were to assess the frequency and risk factors associated with HCC surveillance failure. The study analyzed data from 188 consecutive patients diagnosed with HCC within a surveillance program conducted among 1,242 cirrhotic patients and based on ultrasonography and alpha-fetoprotein (AFP) testing every 3 or 6months. Program failure was defined as the detection of HCC exceeding the Milan criteria. Variables recorded at entry into the program, during follow-up and at HCC diagnosis, were analyzed. At diagnosis, 50 (26.6%) HCC tumors were beyond the Milan criteria. In univariate analysis, Child-Pugh B at entry (P=0.03), development of complications of portal hypertension before tumor diagnosis (P=0.03), and failure to complete the prior screening round (P=0.02), Child-Pugh B/C (P=0.001) and AFP≥100ng/mL (P=0.03) at diagnosis, were associated with failure. In multivariate analysis, only Child-Pugh B/C (hazard ratio, 3.18; 95% confidence interval, 1.66-6.10, P<0.001) and AFP≥100ng/mL, both at diagnosis (hazard ratio, 2.80; 95% confidence interval, 1.37-5.71, P=0.005), were independently associated with failure. Survival was higher among patients with tumors within the Milan criteria than those with program failure (33.9 vs 7.6months, P<0.001). Approximately 25% of HCC cases diagnosed among patients included in a surveillance program were beyond the Milan criteria. Child-Pugh B/C and AFP≥100ng/mL at diagnosis were associated with program failure. However, Child-Pugh B at entry and development of liver-related complications during follow-up can be early predictors of failure.

An expert consensus for the management of chronic hepatitis B in Asian Americans.

SummaryBackgroundHepatitis B virus (HBV) infection is common with major clinical consequences. In Asian Americans, the HBsAg carrier rate ranges from 2% to 16% which approximates the rates from their countries of origin. Similarly, HBV is the most important cause of cirrhosis, hepatocellular carcinoma (HCC) and liver related deaths in HBsAg positive Asians worldwide.AimTo generate recommendations for the management of Asian Americans infected with HBV.MethodsThese guidelines are based on relevant data derived from medical reports on HBV from Asian countries as well as from studies in the HBsAg positive Asian Americans. The guidelines herein differ from other recommendations in the treatment of both HBeAg positive and negative chronic hepatitis B (CHB), in the approach to HCC surveillance, and in the management of HBV in pregnant women.ResultsAsian American patients, HBeAg positive or negative, with HBV DNA levels >2000 IU/mL (>104 copies/mL) and ALT values above normal are candidates for anti‐viral therapy. HBeAg negative patients with HBV DNA >2000 IU/mL and normal ALT levels but who have either serum albumin <3.5 g/dL or platelet count <130 000 mm3, basal core promoter (BCP) mutations, or who have first‐degree relatives with HCC should be offered treatment. Patients with cirrhosis and detectable HBV DNA must receive life‐long anti‐viral therapy. Indications for treatment include pregnant women with high viraemia, coinfected patients, and those requiring immunosuppressive therapy. In HBsAg positive patients with risk factors, life‐long surveillance for HCC with alpha‐fetoprotein (AFP) testing and abdominal ultrasound examination at 6‐month intervals is required. In CHB patients receiving HCC treatments, repeat imaging with contrast CT scan or MRI at 3‐month intervals is strongly recommended. These guidelines have been assigned to a Class (reflecting benefit vs. risk) and a Level (assessing strength or certainty) of evidence.ConclusionsApplication of the recommendations made based on a review of the relevant literature and the opinion of a panel of Asian American physicians with expertise in HBV treatment will inform physicians and improve patient outcomes.

Qidong hepatitis B virus infection cohort: a 25-year prospective study in high risk area of primary liver cancer

Qidong hepatitis B virus (HBV) infection cohort (QBC) is a prospective community-based study designed to investigate causative factors of primary liver cancer (PLC) in Qidong, China, where both PLC and HBV infection are highly endemic. Residents aged 20-65 years, living in seven townships of Qidong, were surveyed using hepatitis B surface antigen (HBsAg) serum test and invited to participate in QBC from June 1991 to December 1991. A total of 852 and 786 participants were enrolled in HBsAg-positive and HBsAg-negative sub-cohorts in May 1992, respectively. All participants were actively followed up in person, received HBsAg, alanine aminotransferase (ALT), alpha-fetoprotein (AFP) tests and upper abdominal ultrasonic examination, and donated blood and urine samples once or twice a year. The total response rate was 99.6%, and the number of incident PLC was 201 till the end of February 2017. The ratio of incidence rates was 12.32 (95% confidence interval[CI]=7.16-21.21, P < 0.0001) in HBsAg-positive arm compared with HBsAg-negative arm. The relative risk of PLC was 13.25 (95% CI=6.67-26.33, P < 0.0001) and 28.05 (95% CI=13.87-56.73, P < 0.0001) in the HBsAg+/HBeAg- group and the HBsAg+/HBeAg+ group, respectively, as compared to the HBsAg-/HBeAg- group. A series of novel PLC-related mutations including A2159G, A2189C and G2203W at the C gene, A799G, A987G and T1055A at the P gene of HBV genome were identified by using samples from the cohort. The mutation in hepatitis B virus (HBV) basal core promoter region of HBV genome has an accumulative effect on the occurrence of PLC. In addition, the tripartite relationship of aflatoxin exposure, P53 mutation and PLC was also investigated. Dynamic prediction model for PLC risk by using its long-term follow-up information and serial blood samples for QBC was developed. This model is expected to improve the efficiency of PLC screening in HBV infection individuals.

Combination of dual serum fluorescence, AFP and hepatic function tests is valuable to identify HCC in AFP-elevated liver diseases.

Serum alpha-fetoprotein (AFP) levels elevated in benign liver diseases (BLD) represent a challenge in hepatocellular carcinoma (HCC) diagnosis. The present study aimed to develop a simple method to identify HCC in AFP-elevated liver diseases based on combining serum fluorescence and general clinical data. Serum specimens and clinical data were collected from 201 HCC and 117 BLD (41 liver cirrhosis, 76 chronic hepatitis) patients with abnormal serum AFP levels. Dual serum fluorescence (autofluorescence and cell-free DNA-related fluorescence) intensities were sequentially measured and expressed as 6 fluorescence indicators. The diagnostic value of these fluorescence and clinical data were evaluated alone and in combination by the area under receiver operating characteristic curve (AUROC). All fluorescence indicators significantly differed between HCC and BLD and some of them were more valuable for diagnosing HCC than AFP (AUROC 0.782–0.801 vs. 0.752). The diagnostic model established with fluorescence indicators, AFP, hepatic function tests and age showed that AUROC, sensitivity, specificity and accuracy were 0.958 (95% CI 0.936–0.979), 92.0%, 88.9% and 92.3%, respectively, and positive rates in AFP-negative, early and small HCCs were 73.8%, 81.6% and 74.3%, respectively. In conclusion, the combination of dual serum fluorescence, AFP, hepatic function tests and age is simple and valuable for identifying HCC in serum AFP-elevated liver diseases.

The prognostic correlation of AFP level at diagnosis with pathological grade, progression, and survival of patients with hepatocellular carcinoma

The purpose of this study was to conduct a comprehensive study of the clinical correlation between the alpha-fetoprotein (AFP) level at diagnosis and pathological grades, progression, and survival of patients with hepatocellular carcinoma (HCC). A total of 78,743 patients in Surveillance, Epidemiology, and End Results Program (SEER)-registered HCC was analyzed. The AFP test results for patients with HCC were mainly recorded as AFP-negative and AFP-positive. Logistic regression analysis revealed that the AFP level at diagnosis was an independent risk factor of pathological grade (odds ratio [OR], 2.559; 95% confidence interval [CI], 2.075–3.157; P < 0.001), TNM-7 stage (OR, 2.794; CI, 2.407–3.242; P < 0.001), and tumor size (OR, 1.748; 95% CI, 1.574–1.941; P < 0.001). Multivariable Cox regression analyses identified AFP level as an independent predictor of survival risk of patients with HCC who did not undergo surgery (hazard ratio [HR], 1.660; 95% CI, 1.534–1.797; P < 0.001), and those who underwent surgery (HR, 1.534; 95% CI, 1.348–1.745; P < 0.001). The AFP level at diagnosis was an independent risk predictor associated with pathological grade, progression, and survival. Further, surgery may not significantly reverse the adverse effects of AFP-positive compared with AFP-negative.

Mid-trimester preterm premature rupture of membranes (PPROM): etiology, diagnosis, classification, international recommendations of treatment options and outcome.

Mid-trimester preterm premature rupture of membranes (PPROM), defined as rupture of fetal membranes prior to 28 weeks of gestation, complicates approximately 0.4%-0.7% of all pregnancies. This condition is associated with a very high neonatal mortality rate as well as an increased risk of long- and short-term severe neonatal morbidity. The causes of the mid-trimester PPROM are multifactorial. Altered membrane morphology including marked swelling and disruption of the collagen network which is seen with PPROM can be triggered by bacterial products or/and pro-inflammatory cytokines. Activation of matrix metalloproteinases (MMP) have been implicated in the mechanism of PPROM. The propagation of bacteria is an important contributing factor not only in PPROM, but also in adverse neonatal and maternal outcomes after PPROM. Inflammatory mediators likely play a causative role in both disruption of fetal membrane integrity and activation of uterine contraction. The "classic PPROM" with oligo/an-hydramnion is associated with a short latency period and worse neonatal outcome compared to similar gestational aged neonates delivered without antecedent PPROM. The "high PPROM" syndrome is defined as a defect of the chorio-amniotic membranes, which is not located over the internal cervical os. It may be associated with either a normal or reduced amount of amniotic fluid. It may explain why sensitive biochemical tests such as the Amniosure (PAMG-1) or IGFBP-1/alpha fetoprotein test can have a positive result without other signs of overt ROM such as fluid leakage with Valsalva. The membrane defect following fetoscopy also fulfils the criteria for "high PPROM" syndrome. In some cases, the rupture of only one membrane - either the chorionic or amniotic membrane, resulting in "pre-PPROM" could precede "classic PPROM" or "high PPROM". The diagnosis of PPROM is classically established by identification of nitrazine positive, fern positive watery leakage from the cervical canal observed during in specula investigation. Other more recent diagnostic tests include the vaginal swab assay for placental alpha macroglobulin-1 test or AFP and IGFBP1. In some rare cases amniocentesis and infusion of indigo carmine has been used to confirm the diagnosis of PPROM. The management of the PPROM requires balancing the potential neonatal benefits from prolongation of the pregnancy with the risk of intra-amniotic infection and its consequences for the mother and infant. Close monitoring for signs of chorioamnionitis (e.g. body temperature, CTG, CRP, leucocytes, IL-6, procalcitonine, amniotic fluid examinations) is necessary to minimize the risk of neonatal and maternal complications. In addition to delayed delivery, broad spectrum antibiotics of penicillin or cephalosporin group and/or macrolide and corticosteroids have been show to improve neonatal outcome [reducing risk of chorioamnionitis (average risk ratio (RR)=0.66), neonatal infections (RR=0.67) and abnormal ultrasound scan of neonatal brain (RR=0.67)]. The positive effect of continuous amnioinfusion through the subcutaneously implanted perinatal port system with amniotic fluid like hypo-osmotic solution in "classic PPROM" less than 28/0 weeks' gestation shows promise but must be proved in future prospective randomized studies. Systemic antibiotics administration in "pre-PPROM" without infection and hospitalization are also of questionable benefit and needs to be further evaluated in well-designed randomized prospective studies to evaluate if it is associated with any neonatal benefit as well as the relationship to possible adverse effect of antibiotics on to fetal development and neurological outcome.

Building Classification Models with Combined Biomarker Tests: Application to Early Detection of Liver Cancer

Early detection of hepatocellular carcinoma (HCC) is critical for the effective treatment. Alpha fetoprotein (AFP) serum level is currently used for HCC screening, but the cutoff of the AFP test has limited sensitivity (~50%), indicating a high false negative rate. We have successfully demonstrated that cancer derived DNA biomarkers can be detected in urine of patients with cancer and can be used for the early detection of cancer (Jain et al., 2015; Lin et al., 2011; Song et al., 2012; Su, Lin, Song, & Jain, 2014; Su, Wang, Norton, Brenner, & Block, 2008). By combining urine biomarkers (uBMK) values and serum AFP (sAFP) level, a new classification model has been proposed for more efficient HCC screening. Several criterions have been discussed to optimal the cutoff for uBMK score and sAFP score. A joint distribution of sAFP and uBMK with point mass has been fitted using maximum likelihood method. Numerical results show that the sAFP data and uBMK data are very well described by proposed model. A tree-structured sequential test can be optimized by selecting the cutoffs. Bootstrap simulations also show the robust classification results with the optimal cutoff.

An assessment of benefits and harms of hepatocellular carcinoma surveillance in patients with cirrhosis.

Over one fourth of patients with cirrhosis experience physical harm for false-positive or indeterminate surveillance tests-more often related to ultrasound than AFP. Interventions are needed to reduce surveillance-related harm to increase the value of HCC screening programs in clinical practice. (Hepatology 2017;65:1196-1205).