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To assess the feasibility of screening for cholestatic hepatobiliary disease and extrahepatic biliary atresia by using tandem mass spectrometry to measure conjugated bile acids in dried blood spots obtained from newborn infants at 7-10 days of age for the Guthrie test.
Three tertiary referral clinics and regional neonatal screening laboratories.
Un...
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Context 1
... of all four bile acid types were significantly raised and the TriOH/DiOH ratio was sig- nificantly higher in the cholestatic group (table 3). No significant difference in the glycine:taurine conjugate Idiopathic neonatal hepatitis subgroup-Although concentrations of all four bile acid species were signifi- cantly raised in this group (n = 52), the increases were less distinct than in other cholestatic disorders (table 3). ...
Context 2
... of all four bile acid types were significantly raised and the TriOH/DiOH ratio was sig- nificantly higher in the cholestatic group (table 3). No significant difference in the glycine:taurine conjugate Idiopathic neonatal hepatitis subgroup-Although concentrations of all four bile acid species were signifi- cantly raised in this group (n = 52), the increases were less distinct than in other cholestatic disorders (table 3). Twenty seven cases (52%) had total bile > 33 mol/l. ...
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Purpose of Review
Biliary atresia is a serious neonatal liver disease due to obstructed bile ducts that has better outcomes when detected and treated in the first 30–45 days of life. This review examines different methods to screen newborns for biliary atresia as well as discusses observations from ongoing screening programs implemented in parts of...
Citations
... Metabolites should be used at the time of abnormality for accurate analysis. 8,15,[22][23][24][25] Metabolites produced in various diseases can serve as indicators of diagnosis and treatment efficacy. 24) Metabolite analysis by LC/MS/MS is widely used for chemical diagnostics in various single-gene disorders, [26][27][28][29] and efforts continue to develop diagnostic biomarkers in combination with metabolites and other modalities for multifactorial diseases such as cancer and dyslipidemia. ...
Analysis of endogenous metabolites in various diseases is useful for searching diagnostic biomarkers and elucidating the molecular mechanisms of pathophysiology. The author and collaborators have developed some LC/tandem mass spectrometry (LC/MS/MS) methods for metabolites and applied them to disease-related samples. First, we identified urinary conjugated cholesterol metabolites and serum N-palmitoyl-O-phosphocholine serine as useful biomarkers for Niemann–Pick disease type C (NPC). For the purpose of intraoperative diagnosis of glioma patients, we developed the LC/MS/MS analysis methods for 2-hydroxyglutaric acid or cystine and found that they could be good differential biomarkers. For renal cell carcinoma, we searched for various biomarkers for early diagnosis, malignancy evaluation and recurrence prediction by global metabolome analysis and targeted LC/MS/MS analysis. In pathological analysis, we developed a simultaneous LC/MS/MS analysis method for 13 steroid hormones and applied it to NPC cells, we found 6 types of reductions in NPC model cells. For non-alcoholic steatohepatitis (NASH), model mice were prepared with special diet and plasma bile acids were measured, and as a result, hydrophilic bile acids were significantly increased. In addition, we developed an LC/MS/MS method for 17 sterols and analyzed liver cholesterol metabolites and found a decrease in phytosterols and cholesterol synthetic markers and an increase in non-enzymatic oxidative sterols in the pre-onset stage of NASH. We will continue to challenge themselves to add value to clinical practice based on cutting-edge analytical chemistry methodology.
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... Phase-contrast CT therefore captured the morphological alterations of the infarcts on a 3D level, which might give more insight about the disease procession as compared to conventional 2D histology 7 or fluorescence microscopy 12 on a comparable scale. Elevated levels of serum bile acids are a primary characteristic of biliary obstruction in humans 22,23 and rodents 24 , but the cause is controversial. Several routes of leakage of bile acids from the bile system into the blood have been reported: cholehepatic shunting 25 , vesicular regurgitation of bile acids from bile canaliculi through intact hepatocytes to sinusoids, and leakage through tight junctions [26][27][28] . ...
Bile infarct is a pivotal characteristic of obstructive biliary disease, but its evolution during the disease progression remains unclear. Our objective, therefore, is to explore morphological alterations of the bile infarct in the disease course by means of multiscale X-ray phase-contrast CT. Bile duct ligation is performed in mice to mimic the obstructive biliary disease. Intact liver lobes of the mice are scanned by phase-contrast CT at various resolution scales. Phase-contrast CT clearly presents three-dimensional (3D) images of the bile infarcts down to the submicron level with good correlation with histological images. The CT data illustrates that the infarct first appears on day 1 post-BDL, while a microchannel between the infarct and hepatic sinusoids is identified, the number of which increases with the disease progression. A 3D model of hepatic acinus is proposed, in which the infarct starts around the portal veins (zone I) and gradually progresses towards the central veins (zone III) during the disease process. Multiscale phase-contrast CT offers the comprehensive analysis of the evolutionary features of the bile infarct in obstructive biliary disease. During the course of the disease, the bile infarcts develop infarct-sinusoidal microchannels and gradually occupy the whole liver, promoting the disease progression.
... Seventeen papers were suitable for a meta-analysis on the sensitivity and specificity in detecting BA. Included studies were retrospective cohort studies (n=4), 12-15 prospective cohort studies (n=12), 6 7 16-25 cross-sectional studies (n=7), [26][27][28][29][30][31][32] case-control studies (n=2) 33 34 and cost-benefit analyses (n=2). 35 36 Two studies were conducted in the USA, 22 27 two in Canada, 7 25 seven in China, 13 15 20 28 29 31 32 six in Japan, 16 17 19 26 30 33 six in Taiwan 6 12 14 18 21 23 and two in the UK. ...
Objective
The aim of this study was to investigate tested methods of population-based biliary atresia (BA) screening.
Design
We searched 11 databases between 1 January 1975 and 12 September 2022. Data extraction was independently done by two investigators.
Main outcome measures
Our primary outcomes were: sensitivity and specificity of screening method in BA detection, age at Kasai, BA associated morbidity and mortality, cost-effectiveness of screening.
Results
Six methods of BA screening were evaluated: stool colour charts (SCCs), conjugated bilirubin measurements, stool colour saturations (SCSs), measurements of urinary sulfated bile acids (USBAs), assessments of blood spot bile acids and blood carnitine measurements.
In a meta-analysis, USBA was the most sensitive and specific, with a pooled sensitivity and specificity of 100.0% (95% CI 2.5% to 100.0%) and 99.5% (95% CI 98.9% to 99.8%) (based on one study). This was followed by conjugated bilirubin measurements: 100.0% (95% CI 0.0% to 100.0%) and 99.3% (95% CI 91.9% to 99.9%), SCS: 100.0% (95% CI 0.00% to 100.0%) and 92.4% (95% CI 83.4% to 96.7%), and SCC: 87.9% (95% CI 80.4% to 92.8%) and 99.9% (95% CI 99.9% to 99.9%).
SCC reduced the age of Kasai to ~60 days, compared with 36 days for conjugated bilirubin. Both SCC and conjugated bilirubin improved overall and transplant-free survival. The use of SCC was considerably more cost-effective than conjugated bilirubin measurements.
Conclusion
Conjugated bilirubin measurements and SCC are the most researched and demonstrate improved sensitivity and specificity in detecting BA. However, their use is expensive. Further research into conjugated bilirubin measurements, as well as alternative methods of population-based BA screening, is required.
PROSPERO registration number
CRD42021235133.
... If successful, this would allow BA screening to be conducted alongside each state's standard newborn screen for inborn metabolic conditions. In the initial study, bile acid levels measured by tandem mass spectrometry failed to distinguish between healthy newborns and those with liver disease [28]. A more recent study found that taurocholate levels in dried blood spots collected 3-4 days after birth were significantly elevated in patients with BA (n = 8) compared to that of jaundiced (non-cholestatic) infants (n = 17) and normal healthy infants (n = 292) [29]. ...
Purpose of Review
Biliary atresia is a serious neonatal liver disease due to obstructed bile ducts that has better outcomes when detected and treated in the first 30–45 days of life. This review examines different methods to screen newborns for biliary atresia as well as discusses observations from ongoing screening programs implemented in parts of the United States.
Recent Findings
Screening strategies for biliary atresia include detecting persistent jaundice, examining stool color, testing fractionated bilirubin levels, or measuring bile acid levels from dried blood spot cards. The stool color card program is the most widely used screening strategy worldwide. An alternative approach under investigation in the United States measures fractionated bilirubin levels, which are abnormal in newborns with biliary atresia. Fractionated bilirubin screening programs require laboratories to derive reference ranges, nurseries to implement universal testing, and healthcare systems to develop infrastructure that identifies and acts upon abnormal results.
Summary
Biliary atresia meets the disease-specific criteria for newborn screening. Current studies focus on developing a strategy which also meets all test-specific criteria. Such a strategy, if implemented uniformly, has the potential to accelerate treatment and reduce biliary atresia’s large liver transplant burden.
... Several serum metabolites or proteins, like hyaluronic acid, 12 apolipoprotein C3, 13 interleukin 6, and interleukin 8, 14,15 have been reported to change in BA. Other screening programs for BA, including serum bile acid, 16 serum direct bilirubin, 17 urinary sulfated bile acid, 18 fecal bilirubin, and fat, 19 have also been found to be altered in BA. Stool anomalies have also been consistently reported and may serve as a means to evaluate and manage BA. ...
Background and aim:
Biliary atresia (BA) is a progressive fibro-inflammatory cholangiopathy with an unclear etiology. Various liver disorders are associated with an altered microbiome. However, gut microbiome in BA remains unknown. Here we performed a controlled study to investigate the gut microbiota in BA.
Methods:
A cross-sectional analysis was first conducted for 34 BA patients and 34 healthy controls. Then, we investigated the shift in gut microbiota 2 weeks post-Kasai procedure in 16 BA patients. Gut microbiome was initially analyzed using 16S ribosome RNA gene sequencing and further validated by metagenomic sequencing. Fecal bile acids were determined using ultra-high performance liquid chromatography.
Results:
Compared with healthy controls, BA showed lower diversity and significant structural segregation in the microbiome. At phylum level, Proteobacteria numbers increased, whereas those of Bacteroidetes decreased in BA. At genus level, several potential pathogens such as Streptococcus and Klebsiella thrived in BA; while numbers for Bifidobacterium and several butyrate-producing bacteria declined. The microbiome was also disturbed after Kasai procedure. Operational taxonomic units responding to BA showed significant correlation with liver function. Furthermore, the abundance ratio of Streptococcus/Bacteroides showed great promise in distinguishing BA from healthy controls. Intestinal bile acids were dramatically decreased in BA and Clostridium XIVa positively correlated with the ratio of primary/secondary bile acids.
Conclusions:
Gut microbial dysbiosis, may be caused by decreased bile acids, was associated with liver function and had a good diagnostic potential for BA. Therefore, further exploration of gut microbiota may provide important insights into their potential diagnostic and therapeutic benefits.
... Кроме того, он выгодно отличается от других инструментальных методов неинвазивностью, безболезненностью, атравматичностью, отсутствием противопоказаний к применению [27]. Существует ряд ультразвуковых ОБЗОРЫ ЛИТЕРАТУРЫ детской хирургии, анестезиологии и реаниматологии РОССИЙСКИЙ ВЕСТНИК признаков, характерных для атрезии желчных ходов в периоде новорожденности [28,29,30]: отсутствие желчного пузыря или его просвета, размеры желчного пузыря менее 19 мм, отсутствие сократительной способности желчного пузыря в ответ на прием пищи, наличие фиброзного конуса (фиброзного треугольника) в воротах печени. Также при БА отмечается увеличение соотношения диаметра воротной вены к печеночной артерии, возможно проявление полисплении, предуоденальной портальной вены, situs inversus [31]. ...
The review of literature deals with the current classification of the biliary atresia, presents the authors’ opinion considering a technique of theKasaiprocedure, and displays modern modifications of portoenteroanastomosis estimating their effectiveness. PubMed database and Google Scholar search system were used to search for primary terms. Survival of children with this pathology was analyzed depending on theKasaitechnique, anatomical form, terms of portoenteroanastomosis and importance of early diagnosis of this pathology.
... Несмотря на разработанные в настоящее время различные методы скрининговых исследований для диагностики БА, каждый из них имеет свои недостатки и оптимального метода для диагностики БА не существует [114,17,126,124,161]. ...
The monograph presents modern ideas about congenital cholestatic diseases in children,
The features of the clinical picture of such diseases as biliary atresia, progressive family intrahepatic cholestasis, Alagill's syndrome, hereditary type 1 tyrosinemia, which exemplifies the manifestations of cholestasis in metabolic diseases. The algorithm of differential diagnosis of cholestatic diseases in infants from the perspective of evidence-based medicine is presented. The criteria for differential diagnosis using hepatobiliary scintigraphy are determined. Much attention is paid to the approaches to the treatment of cholestatic diseases in children. The methodical manual is recommended for general practitioners, pediatricians, neonatologists, gastroenterologists and abdominal surgeons.
... The screening methods were developed using tandem mass spectrometry to measure bile acids in DBS. However, the sensitivity and specificity were 79 and 96%, respectively [30], which were lower ...
Early diagnosis followed by proper KP is essential for the improvement of long-term prognosis for patients with BA. It is increasingly accepted that KP at ≤ 30 days of age significantly improves native liver survival rate. Published analyses in English and Japanese indicate that screening by SCC and DB/CB is potentially feasible. Screening with SCC has been implemented in Tochigi Prefecture, Japan, since 1994. The concept of SCC was introduced from Japan to Taiwan and resulted in nationwide screening with SCC for the first time in Taiwan in 2004, followed by Japan in 2012. Home-based screening using SCC is easy and cost-effective; however, it may cause some difficulties for families in case of stools with intermediate colors. Laboratory-based screening using DB/CB may detect the suspected cases earlier, resulting in an increase in the number of patients with BA who undergo KP at ≤ 30 days of age; however, the recall rate is 1% and may be beyond an acceptable range. Further studies are needed to assess the feasibility and cost-effectiveness of both home-based (SCC) and laboratory-based (DB/CB) screening for BA.
... The problem of late referral of biliary atresia has been well documented in the literature [1][2][3][4][5][6][7][8][9][10][11]. The need for early recognition and treatment of BA has been addressed in the developed countries by various screening methodologies [5,10,[12][13][14][15][16][17][18][19][20]]. The healthcare system in India has seen huge advances in the management of BA and many other causes of neonatal cholestasis including metabolic disorders, with the availability of liver transplantation across the country. ...
Objectives
To define the recognition, age at admission, referral time and referral pattern of neonatal cholestasis in India. Methods
This prospective, observational study was conducted from February 2015 through March 2016 in the Pediatric gastroenterology unit of JIPMER, Pondicherry in infants with cholestasis < 6 mo of age. ResultsAmong 64 infants, median age of admission was 52 d (IQR 28–63 d). Fifty of sixty four infants (78.1%) came with parent-reported cholestasis-related symptoms of either jaundice alone (57.8%) or bleeding manifestations (20.3%). In 21.9% infants, jaundice was detected by physicians at a median age of 45 d (IQR 38.5–53.2 d). Two infants had intracranial bleed. Only 34% infants with pale stools were identified by the mother. The median healthcare-seeking time was 5.5 d (IQR 2.5–12 d). Among infants presenting to primary healthcare physicians (PHPs) with cholestasis-related symptoms, median time to referral was 5 d (IQR 2.5–12 d). The first point of healthcare contact in 54.7% was a PHP; 17.1% PHPs had reassured the parents. Herbal preparations were prescribed by 14.3%. Only 11.8% of those with jaundice as the only problem were given vitamin K before referral. Biliary atresia (BA) was missed in neonatal intensive care units in 9 cases. Conclusions
The above issues need to be accounted for before evaluating or implementing screening strategies in India.
... Various screening methods other than stool charts have been studied, but none are effective as a simple, cost effective and useful tool in screening general population. Serum bile acid, direct bilirubin, Apo CⅡ/CⅢ proteins, urine sulfated bile acid, fecal bilirubin and fat [91][92][93][94][95] were some of the biomarkers used in the literature for screening of Biliary atresia. ...
The pathway from clinical suspicion to establishing the diagnosis of biliary atresia in a child with jaundice is a daunting task. However, investigations available help to point towards the correct diagnosis in reasonable time frame. Imaging by Sonography has identified several parameters which can be of utility in the diagnostic work up. Comparison of Sonography with imaging by Nuclear medicine can bring out the significant differences and also help in appropriate imaging. The battery of Biochemical tests, available currently, enable better understanding of the line-up of investigations in a given child with neonatal cholestasis. Management protocols enable standardized care with optimal outcome. The place of surgical management in biliary atresia is undisputed, although Kasai procedure and primary liver transplantation have been pitted against each other. This article functions as a platform to bring forth the various dimensions of biliary atresia.
