Factors Influencing Time-to-diagnosis of Biliary Atresia

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LITHUANIAN UNIVERSITY OF HEALTH SCIENCES

FACULTY OF MEDICINE

DEPARTMENT OF PAEDIATRICS

Factors Influencing Time-to-diagnosis of Biliary Atresia

Student: Sharon Dsouza

Supervisor: Rūta Kučinskienė, MD

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ABSTRACT

Aim:

The purpose of this study is to review various circumstances that cause a delay in the diagnosis of Biliary Atresia.

Objectives:

 To analyze factors that cause a delay in the patient’s arrival to the doctor.

 To analyze factors that cause a delay in PCP’s ability to recognize BA and refer patients.  To analyze the role of screening programs in recognizing BA earlier.

Methods:

Search for the Literature Review was managed on Pubmed. A combination of “Biliary Atresia” OR “Neonatal cholestasis” OR “Neonatal jaundice” OR “Hyperbilirubinemia” OR “Acholic stools” OR “Liver disease” OR “Extrahepatic Biliary Atresia” OR “Persistent Jaundice” WITH “Genetic predisposition” OR “Screening” OR “Mass screening” OR “Bile acids” OR “Professional identification” OR “Early referral” OR “Stool colour card” OR “Differential Diagnosis” OR “Preoperative liver biopsy” OR “Home-based” OR “Family physicians” were used in the search.

Results:

By using the combination of the following terms, the search returned n=9222 articles. After activating filters and application of inclusion and exclusion criteria, n=62 articles were found, of which n=20 articles were used in the review.

Conclusions:

Various factors were found to cause a delay in the diagnosis of BA. Elements like lack of awareness among parents, and subsequent delay in referral to primary care physicians, absence of awareness among primary care physicians about the importance of early specialist referral and more. Different strategies to improve these outcomes are also establised. Implementation of universal screening programmes, organization of educational programmes for physicians and parents to increase awareness on the issue, and centralization for BA care can all work in synergy to improve outcomes on late referral and subsequent diagnosis and treatment of BA patients.

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ACKNOWLEDGEMENT

I would like to thank my supervisor Dr Rūta Kučinskienė, MD, for her support.

CONFLICT OF INTEREST

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ABBREVIATIONS

 BA – Biliary Atresia

 KP – Kasai Portoenterostomy  PHC – Primary Health Care  LT- Liver Transplant  SCC- Stool Colour Cards  CB- Conjugated Bilirubin

KEYWORDS

 Biliary atresia  Stool colour card  Screening programmes  Neonatal cholestasis  Hyperbilirubinemia

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INTRODUCTION

Biliary atresia is a unique and rare pathology in newborns [1]. It is also one of the most common causes of pediatric end-stage liver disease and is a leading indication for pediatric liver transplantation [2]. BA is a fibrotic disease primarily affecting the extrahepatic biliary tree. Infants appear normal at birth but very soon develop liver fibrosis, bile duct obstruction, and cholestasis [3]. The leading causes of BA are still mostly unknown. They are also multifactorial, with causes like genetic predisposition, environmental trigger and autoimmunity contributing to disease pathogenesis [4]. BA is the most prevalent cause among other causes for neonatal cholestasis, accounting for about 40% of all cases [5].

In Europe, this disorder affects between 1/14,000 and 1/20,000 live births; in Switzerland, the incidence is of 1/17,800 live births [1]. BA cases appear to be more prevalent in Southeast Asia, with an incidence around 1:5000 live births, compared to North America and Western Europe, where the incidence is about 1:10,000–15,000 births. The reason for this variation in the incidence of BA is unknown [5].

The timely diagnosis of BA is very crucial because KP done before 60 days of life gives the newborn a better chance for survival with the native liver. The most definitive diagnosis of BA requires surgery and intraoperative cholangiography to verify the absence of extrahepatic bile duct [6]. Treatment methods for BA comprise of Kasai- portoenterostomy (KP), which mainly restores bile flow. KP is followed by liver transplantation if cirrhosis progresses. BA is a leading indication for liver transplantation in children [1].

Late referral, delayed diagnosis, and untimely surgery for BA are global problems. The lack of a uniform screening tool, coupled with a generally healthy appearance of the persistently jaundiced infant, often leads to substantial delays in diagnosis. [5]. Factors that hamper such diagnosis have focused on concerns PHC practitioners face in identifying and referring infants [7].

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AIMS AND OBJECTIVES

In this literature review, we aim to highlight recent research (from databases) relating to factors that cause a delay in BA diagnosis as well as recognizing situations that could facilitate in early referral and treatments.

Objectives raised include:

 To analyze factors that delay a patient’s arrival to the doctor.

 To analyze factors that affect PHC practitioner's ability to recognize BA and refer patients.

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LITERATURE REVIEW

BA is a fibrosing cholangiopathy that affects the extrahepatic biliary system. This eventually leads to neonatal cholestasis with obstruction of the biliary tree and finally liver damage. BA presents with persistent neonatal jaundice. Failure to thrive, splenomegaly and ascites are late findings caused by cirrhosis and the progression of hepatic fibrosis. If left untreated, BA can lead to death by two years of age [8].

Aetiology

The aetiology of BA is still unknown at large. Many theories suggest that the causative factors could be both genetic and acquired. Some studies also suggest an inflammatory and infectious course of the disease while some other studies suggest an acquired aetiology with seasonal clustering, especially in the winter months [9].

The genetic theory is supported by the increased incidence of BA in Asia and Polynesia, where different genetic backgrounds show different incidences. In one French study, genetic factors were shown to play a role in the development of BA polysplenia syndrome, where correlations between heterozygous CFC1 mutation, left-right laterality defects, and BA with splenic malformation was found [10].

Finally, there is little evidence suggesting that BA to being genetic, and familial causes are also found rarely [11].

Clinical Forms

The main clinical hallmarks of BA are the presence of jaundice, acholic stools and dark-urine. Splenomegaly is also found, but it is a late feature of BA and would imply significant hepatic fibrosis and early cirrhosis [12]. Mostly, newborns with BA are born full-term with healthy birth weight. They present with persisting jaundice from the second day of life, which usually lasts beyond 14 days of age.It is also not unusual for patients to have acholic stools after they develop intracranial haemorrhage due to decreased intestinal bile acid concentration and vitamin K malabsorption [13] [14]. Studies suggest the presence of specific clinical forms of BA, based on the non-hepatic congenital malformations, time of disease onset and morphological analysis [15] [16]

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Perinatal Form

This is the most common form of BA, and most infants fall under this clinical form. In this type, jaundice symptoms appear after a few weeks of birth. Perinatal BA is also referred to as “Acquired BA”, as the appearance of cholestasis in a newborn could suggest a postnatal insult targeting the biliary system. A small group of these patients might also have other non-hepatic malformations like intestinal mal-rotation and cardiovascular abnormalities [16] [15].

Embryonic Form

About 10%-15% of infants usually present with this form of BA. In this form, jaundice is present at birth, and are referred to as having a congenital or prenatal form of BA. Congenital bile ducts may not be present due to the early onset of bile duct injury. These newborns show increased association with maternal diabetes and usually have worse outcomes after portoenterostomy. In about 8-12% of infants, splenic malformations are found either in isolation or in combination with one or more than one additional defect (e.g., preduodenal portal vein, interrupted inferior vena cava, intestinal mal rotation), in a variation known as Biliary Atresia Splenic Malformation (BASM) [15] [16].

Cystic Form

This is a relatively rare form of BA accounting for about 5-10% of all cases. On US, cystic BA can have a very like appearance to choledochal cysts, which is the main differential form for this type of BA [17]. These biliary cysts can sometimes be detected prenatally, and jaundice and acholic stools may be seen soon after birth [16].

Cytomegalovirus-associated BA

CMV infection is one of the most studied viruses in its relationship to BA. However, the outcomes of these researches have been mixed. Only three out of six papers supported a link between pure BA and CMV infection [18]. Patients with BA and CMV infections, liver fibrosis, appears to be more severe with a lower chance of jaundice disappearance after KP. Geographical variation in CMV- associated BA also exists. Few of these differences in studies might result from methodological differences used to study the patients [15]. All in all, it is of importance to recognize CMV-associated BA, since the early treatment of CMV can suppress the inflammatory damage of the biliary system [19].

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10 Table 1: Clinical types of Biliary atresia

(by Asai et al.) [15]

Phenotype Incidence and disease

features

Pathogenesis Perinatal form ̃80% patients, isolated

malformations, jaundice-free after birth

Type-1 cytokine response

Embryonic form Seen in 7-10% of patients, BASM*, laterality defects, presence of early-onset jaundice

Gene mutations and variants

Cystic variant 8% of patients, may co-exist with BASM*, has an inadequate response to HPE when performed after 70 days of age

Type-2 cytokine response

CMV-associated Incidence is variable based on

geography, and

methodological detection has an inadequate response to HPE*

CMV infection

BASM- Biliary atresia splenic malformation, HPE- Hepatoportoenterostomy

[13] Also, based on the extent of Biliary Tract damage, BA can be classified into three main types (

Fig 1):

 Type I BA affects the common bile duct and proximal cystic biliary duct;  Type II BA affects the common hepatic duct; and

 Type III BA, which is the most common, affects the entire extrahepatic biliary tree.

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Diagnostic Tests

The diagnosis of biliary atresia is challenging because of its uncertainty with physiological jaundice (due to immaturity of the infant's liver) and breast milk jaundice. Physiological jaundice typically lasts for 2–3 days in usual term babies, while breast milk jaundice can last for up to 4 weeks [13]. Stool cards have been widely used in some countries and have shown to reduce the number of late referrals for evaluation of symptomatic infants. Screening newborns for elevated direct or conjugated bilirubin offers the potential to identify asymptomatic babies very early in the course of the disease but has relatively low specificity and has not yet been implemented widely [3].

Liver Function Tests (LFT’s): In all infants with BA, LFT’s are abnormal. A rise in conjugated

bilirubin with a fall in serum proteins (mainly albumin) is seen [20]. Gamma-glutamyl transferase (GGT) levels are also elevated and are used to differentiate from neonatal hepatitis. GGT levels >300 IU/L has a specificity of 98.1% in the diagnosis of BA [21].

Imaging: Hepatobiliary US is usually the initial investigation of choice and has an overall

accuracy of 98%. Ultrasound is, however, greatly operator dependent. ERCP (a newer modality) has also been used, and diagnosis depends on the failure to show the biliary tree. This modality is also operator dependent, and appropriate judgment and experience are necessary [20] [21]. Radionucleotide scintigraphy (Tc99-HIDA scan) has a high sensitivity in differentiating from other causes of cholestasis, even though it requires treatment with phenobarbitone for three days prior to treatment [21].

Liver biopsy: Biopsy has a non-specific diagnosis in infants with BA. It also requires an

experienced pathologist and results overlap with neonatal cholestasis [21] [20]. A typical histological finding would be oedematous portal tracts with inflammatory changes, a proliferation of bile ducts and bile plugs. Although these features may be less apparent in younger infants than older infants. If the liver biopsy shows no changes and infants stools continue to remain acholic, endoscopic retrograde cholangiography is done to verify the patency of the bile ducts [22].

Per-operative cholangiogram: Cholangiogram is a gold standard test in the diagnosis of BA

having a diagnostic accuracy of 100%. Radio opaque contrast is injected into the gall bladder. If the contrast does not fill the intrahepatic and common bile duct, a diagnosis of BA is made. This procedure requires experienced surgeons in order to differentiate between hypoplastic ducts (Alagille syndrome) from atretic ducts in order to avoid damaging operation in the former patient [21].

MR cholangiography: MRC allows for non-invasive evaluation of biliary tree in infants and

children. It is a very reliable imaging study for BA diagnosis and therefore, can be used to aid in early referrals to specialists [10]. Reports suggest that BA can be excluded if extrahepatic ducts are visualized on MRC. In a study by Hoon et al. The diagnosis of BA using MRC resulted in the

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diagnostic accuracy of 98%with sensitivity and specificity being 100% and 96% respectively [10].

However, on the other hand, the use of MRC has not been supported in terms of cost, the need for immobilization and fluctuating results. Also, the need for sedation by general anaesthesia has been a significant concern [23].

Treatment

The current treatment methods for BA involves surgical treatment with an initial Kasai portoenterostomy (KP) and liver transplantation (for infants in whom KP failed or in whom complications of biliary cirrhosis are seen) [24] [25].

Kasai Operation (Fig 2): KP is considered to be the standard treatment for BA. The procedure

is carried out by firstly dissecting the tissues of porta hepatis, exposing residual bile ductules and finally anastomosing the jejunum with Roux-Y-fashion to porta hepatis to restore bile flow [26]. Fig 2 In many cases, diagnosis is very apparent with the presence of fibrotic liver and a small fibrotic gallbladder (Type 4: complete extrahepatic gallbladder) [25]

It is known that any delay in the diagnosis of BA negatively impacts the outcomes of KP. Best results are attained when KP is performed at or before 30 days of age. Of those that received the procedure after 90 days of age, only 14% of all such cases had native liver survival by four years of age. Often, infants present for a routine pediatric visit at ~ 60 days of age, at which point some patients have already progressed to cirrhosis and end-stage liver disease, barring them any benefit from the intervention and leading to a need for an LT [24] [5].

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METHODOLOGY

Literature search

Literature was analyzed using the following databases: PubMed

Table 1: Terms that were used in the initial search (before the application of filters)

 Biliary Atresia  Neonatal cholestasis  Neonatal jaundice  Hyperbilirubinemia  Acholic stools  Liver disease

 Extrahepatic Biliary Atresia

 Persistent jaundice

AND

 Genetic predisposition  Screening  Mass screening  Bile acids  Professional identification  Early referral

 Stool colour card

 Differential Diagnosis

 Preoperative liver biopsy

 Home-based

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Not used

 Intrahepatic BA  Intrahepatic Cholestasis  Choledochal cyst



Post-operative BA

Table 2: Filters applied

 Article types: Clinical trial, Clinical Study, Case Reports

 Publication Dates: 2000 to 2020

 Species: Human

 Age: birth-18 years



Language: English

Table 3: Inclusion and Exclusion Criteria

Inclusion Criteria

 Free text (external link)

 Full free text

Exclusion criteria

 Reviews

 Abstracts with no external links

 Meta-analysis

 Systematic reviews

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RESULTS

A combination of the following terms was used in the search: “Biliary Atresia” OR “Neonatal cholestasis” OR “Neonatal jaundice” OR “Hyperbilirubinemia” OR “Acholic stools” OR “Liver disease” OR “Extrahepatic Biliary Atresia” OR “Persistent Jaundice” WITH “Genetic predisposition” OR “Screening” OR “Mass screening” OR “Bile acids” OR “Professional identification” OR “Early referral” OR “Stool colour card” OR “Differential Diagnosis” OR “Preoperative liver biopsy” OR “Home-based” OR “Family physicians” (Table 1). With the combination of the above terms 9222 articles we found. After the application of filters (Table 2) and the inclusion and exclusion criteria (Table 3), the search narrowed down to 20 articles.

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DISCUSSION

Factors causing late referral

As is well known, the survival of BA patients with their native liver dramatically depends on the timeframe of the initial KP, i.e., <60 days. An effective KP restores bile drainage leading to clearance of jaundice, restoration of bile pigmented stools, and the normalization of serum bilirubin levels. Delayed referral of suspected BA patients is one of the leading factors for failure of surgical correction. Older age at KP, later diagnosis, and referral for surgery in due time remains a challenging task all over the world. One Canadian study stated a median of 55 days of age at referral, while an American study noted a median of 61 days [27] [28].

Various factors have been found to contribute to a late referral and delayed KP.

One such barrier is the schedule for routine care visits. As BA infants usually appear healthy, and most parents being uninformed about issues regarding long-standing jaundice and pale stools, these appearances usually would not prompt an unscheduled doctor’s visit. As a result, the jaundiced newborn may not be seen by a health care provider soon, giving only a limited timeframe for evaluation and intervention [27] [24].

Also, many families tend to interpret jaundice mainly as a physiological event and use home remedies as therapeutic measures, thereby delaying consultation with a physician. Difficulty in accessing medical care has also shown to be another factor in a delayed visit to a doctor [28]. Improving the age of diagnosis is similar to bettering the prognosis of KP. Therefore, education for parents on the signs and symptoms of BA, acholic stools especially should be of significant focus [29].

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Disease recognition and a physician’s competence

As BA is a rare disease, very few PHC practitioners come across such cases during the span of their career. Adding to this, BA might not always be suspected in infants with prolonged jaundice because often, jaundice at this age is a benign, self-resolving condition. In many cases, newborns with jaundice lasting more than two weeks are healthy infants with “breast milk jaundice”. As a result, most health care providers and families do not look for further investigations [27] [7].

Given that infants with persistent jaundice are referred to specialist care earlier, many specialists postpone these cases in order to wait for disease progression. Such a course prevents “over-testing” of cholestatic infants in whom these signs could resolve [7].

Repeated consultation to a paediatrician to evaluate physiological jaundice, inaccurate interpretation of serum bilirubin levels and a lack of general understanding among PHC practitioners about early diagnosis are some of the other factors that lead to delays in treatment of BA patients [28].

Screening

In order to improve the lifelong effects of KP, extensive research has been made worldwide to facilitate earlier diagnosis of BA [24]. Several screening programmes have been proposed such as: measuring serum bile acid, serum direct bilirubin, urinary sulfated bile acid and faecal bilirubin and fat. Nevertheless, they have not been put under extensive practice [1]. Universal Screening algorithms for BA should have a clear-cut goal: to recognize newborns early without putting too much burden on families and health care systems [2]. Serum conjugated or direct bilirubin concentrations and stool colour cards are two other screening tests that have been widely investigated.

One of the earliest indicators of BA is abnormal conjugated bilirubin concentration, for which several studies have given assuring results [2]. In one study done by Harpavat et al., 56% (34/61) newborns had their CB levels measured within 96 hours of life, and all showed elevated concentrations of CB. All patients with BA, in this case, had elevated CB levels for the first four days of life. Even though their total bilirubin concentration was below phototherapy levels, the subject’s mean CB levels were higher compared to controls. Although the check for the upper limit of normal in newborns needs to be confirmed in each hospital or region this test, universal screening for CB levels is a highly sensitive early test for BA [30] [2].

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In another study carried out in 2003, by Powell et al., an extensive community-based programme took place where CB concentrations were measured in newborns younger than 28 days of age. Out of 23415 samples, conjugated bilirubin concentrations were found elevated in 3.8% of samples (1.05 mg/dL). It was concluded that this test had a sensitivity of 100%, a specificity of 99.59% as a useful marker for neonatal liver disease. Since only two infants were expected to have BA in the full sample, the sensitivity and specificity of screening for BA might not be completely accurate. However, these observations can have great potentiality for the use of CB/DB levels as a universal screening tool [2] [31].

Although challenges do exist in the implementation of this screening method. First, birth hospitals need to collect and update site-specific reference intervals (e.g. Bilirubin levels that were abnormally high at one site may be overlooked if reference intervals were borrowed from another site). Second, this testing method requires medical centres that are willing to participate in the screening (e.g. If parents or caregivers cannot travel to a clinic). Third, newborns that have a positive screening result should be quickly tested for BA, which can sometimes be difficult during the early stages of the disease when the newborn does not show any symptoms [32]. Stemming from recommendations regarding the principles and practice of screenings placed by the World Health Organisation (WHO), screenings should diagnose disorders with quick and easily applicable tests. A Japanese research group put these principles into practice in 1994 by handing out SCC to Japanese mothers at hospitals. Statistics showed a significant improved in the time taken to diagnose BA, younger age at KP, and increased survival with the native liver. [33].

Similarly, in Taiwan, a national screening programme uses SCC for the early detection of BA among its population. After its introduction, the percentage of late referrals decreased from 9.5% to 4.9%. The average age at which KP was performed decreased from 51 to 48 days after the screening program [34] [35]. A 14-year nationwide cohort study in Taiwan reported a significant reduction in hospitalization and mortality rate, also proving to be of substantial financial benefit after the launch of SCC programme [34] [36]. A 20-year long American study also concluded that the launch of nationwide SCC is cost-effective, along with improvements in survival and transplantation rates [37] [34]. This strategy could also prove helpful in smaller centres where paediatric abdominal US scans may not always be available or where ordering blood investigations might not always be feasible [34].

In Germany, stool colour control is mandatory during early medical checkups. Although this was necessary for early diagnosis, it proved ineffective because jaundiced continued to be referred to paediatric gastroenterologists too late. For SCC programme to be effective mandatory screening with a nationwide education campaign is necessary. Home-based screening adopted by Switzerland, Japan and Taiwan is more efficient as it includes parents also in the screening process [38] [33]

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(Fig 4) In Switzerland, SCC is handed out and explained to parents after childbirth by either the midwife or the paediatrician. The SCC and the baby’s stool colour are checked at four weeks [38].

One study suggested the use of a mobile application “PoopMD”. Since individuals use smartphones for long hours during the day, this app could be used to help educate parents about acholic stools, thereby aiding quick referral to a physician. This application showed to have a sensitivity of 100% and specificity of 89%. Moreover, analysis of stool images was steady across a range of users, smartphones and lighting. As a result, PoopMD may serve as a reliable and valid way to identify acholic stools in infants (Fig 3) [39].

Fig 3: Screenshots demonstrating PoopMD analytic functionality by Franciscovich et al. (2015) [39]

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Fig 4: The Swiss SCC for biliary atresia screening published by Barbara E. Wildhaber (2011)

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Centralization

Data registries in pediatric health care play an essential role in improving patient outcomes. Specifically, for rare disorders, registries provide information that cannot be gathered from single-centre studies and clinical trials [40]. In England and Wales, the centralization of BA care proved that native liver survival and overall patient survival rates dramatically improved after BA cases were restricted to three main centres in Birmingham, London and Leeds. [40] [41]. In Finland, Centralized BA care comprised of a multidisciplinary team. It consisted of pediatric surgeons, pediatric gastroenterologists, transplant paediatricians, nutritionists and pathologists [42]. After this centralization, the rate of jaundice clearance (bilirubin <20umol/l) significantly improved from 27%-75%. Also, median serum bilirubin levels and clearance of jaundice rate at the 3rd and 6th months after KP also improved [42].

Similar models are present in Japan, Taiwan and the Netherlands. These registries have led to overall improvements in communication and education among health care workers and parents. [40].On the contrary, in France, an excellent synergistic care model is present among centres while maintaining a decentralized care model. Here, smaller centres receive consultation support from larger centres [40].

As a result, it can be very beneficial to assess such strategies to increase early referral and improve the overall survival of the patient.

CONCLUSION

Biliary atresia is a life-threatening paediatric liver disease. Early referral and diagnosis of this disease are imperative for patient survival with native liver. In this review, many causes were identified, that impede early referral and diagnosis of BA infants.

 Education for parents about the first signs of BA can play a very significant role in shortening referral time and patients arrival to the doctor.

 An overall healthy appearance of the affected infant accompanied by indistinguishable symptoms make it difficult for PHC practitioners to recognize BA, so CB should be done in all cases with prolonged neonatal jaundice.

 Execution of screening programmes like the stool colour card and/or measurement of CB levels, as well as placing a strong emphasis on public and physician awareness about this health care issue can significantly improve the time taken to diagnose BA.

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PRACTICAL RECOMMENDATIONS

 Implementation of universal screening programmes like the SCC cards and measurement of CB levels can help in faster specialist referral, thus improving long-term patient survival.

 Standardizing postnatal screening for BA and conducting education policies to raise awareness of BA among PHC practitioners can also promote early referral in infants with BA. This can then enable PHC practitioners to refer them to specialists sooner.

 Finally, strong emphasis should be placed on public and physician awareness about this health care issue. All-in-all, the application of such strategies, can speed up the overall time taken in the diagnosis of BA.

REVIEW LIMITATIONS

Only one database was used in the search. Also, the English language was used as a filter which may have limited the number the articles reviewed.

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Factors Influencing Time-to-diagnosis of Biliary Atresia

LITHUANIAN UNIVERSITY OF HEALTH SCIENCES

FACULTY OF MEDICINE

DEPARTMENT OF PAEDIATRICS

Factors Influencing Time-to-diagnosis of Biliary Atresia

Student: Sharon Dsouza

Supervisor: Rūta Kučinskienė, MD

Table of Contents

ABSTRACT

Aim:

Objectives:

Methods:

Results:

Conclusions:

ACKNOWLEDGEMENT

CONFLICT OF INTEREST

ABBREVIATIONS

KEYWORDS

INTRODUCTION

AIMS AND OBJECTIVES

LITERATURE REVIEW

Aetiology

Clinical Forms

Perinatal Form

Embryonic Form

Cystic Form

Cytomegalovirus-associated BA

Diagnostic Tests

Treatment

METHODOLOGY

Literature search

AND

Not used





RESULTS

DISCUSSION

Factors causing late referral

Disease recognition and a physician’s competence

Screening

Centralization

CONCLUSION

PRACTICAL RECOMMENDATIONS

REVIEW LIMITATIONS

REFERENCES