Medical manslaughter is involuntary manslaughter by gross negligence where patient death has resulted from a grossly negligent (but otherwise lawful) act or omission.1 Although related prosecutions remain uncommon, the emergence of recent cases in Hong Kong presents an opportunity to reflect upon whether criminal sanctions are justifiable and effective at dealing with substandard medical practices. This paper begins with an examination of the underlying legal principles, followed by a discussion on how the current direction of travel might impact patient care and the medical profession.

The applicable legal offence in medical manslaughter is that of gross negligence manslaughter (GNM).1 As for civil claims in medical negligence, the legal test to satisfy is that the affected party is owed a duty of care and that a breach of that duty has occurred and caused the injury at issue.2 In addition, it must be further established in GNM that the degree of negligence has gone:

The legal test was affirmed in the landmark case of Adomako, in which an anaesthesiologist failed to respond to a disconnection of the oxygen supply during general anaesthesia, whereby the jury had to decide whether “the degree of negligence is so great that a criminal penalty is warranted”.4 It is ultimately about the transformation of a private wrong into a public one.

Medical manslaughter cases have historically been rare, but a rising trend has been observed in recent years. In the UK, 85 doctors were charged between 1795 and 2005,5 while 11 cases have already materialised between 2006 and 2013.6 A similar situation has occurred in the United States, where over 50 prosecutions have been brought since 1990.7 The majority of UK cases involved obstetrics and errors in the prescription or administration of drugs.5 Tables 1 and 2 outline the two recent and controversial cases of Mr David Sellu8 and Dr Hadiza Bawa-Garba,9 respectively.

The first case in Hong Kong involved the misuse of sedative drugs during an illegal abortion for which the doctor was jailed for 2 years in 2003 (Table 3).10 A hiatus followed. The highly publicised “DR Group” case saw the conviction of a beauty clinic’s owner and technician in 2017; the third defendant, a doctor who gave the treatment, is awaiting a re-trial (Table 4).11 In March 2018, a general practitioner was charged after her patient died following a liposuction 4 years prior.12 Presently, the family of a 73-year-old man is alleging criminal responsibility on the part of a group of nurses13 and a doctor14 who were already found guilty of professional misconduct in connection with his death.

The central and hotly debated question is whether criminal law intervention is justified in cases of fatal medical incidents.15 On the one hand, a doctor’s license to practice has a legal foundation. Criminal sanctions serve an important punitive function and a symbolic role in restoring public trust when that foundation is not being respected. By holding individuals publicly accountable, criminal sanctions may ensure compliance with professional standards and deter poor and dangerous practices.16 In France, for example, a range of criminal offences is available to punish medical mistakes, even when they are non-fatal. Jail terms are uncommon; the ultimate force of deterrence lies in the stigma of the charge or conviction itself.17

On the other hand, it can be argued that the criminal law is supposed to punish those who cause damages with a morally blameworthy state of mind, whereas misjudgement, inadvertence, or sheer incompetence may be the reasons for a doctor failing to meet standards of care.18 Criminal sanctions presume, if not forcibly embed, the role of choice in situations where no choice or decision has been consciously made. This overlooks the notion of blameworthiness as the foundation of the criminal law, and prosecutions were arguably unjustified in at least some cases.19 At issue is the appropriateness of the legal test and the threshold for prosecution.

The term “gross negligence” has not been defined, and the legal test established in Adomako has been criticised for its circularity, in that an act or omission constitutes a crime if the jury finds it a crime.7 The determination of “grossness” is one for the jury, as directed by the judge; it is a question of law and not for medical experts to address. However, medical experts have occasionally employed their varied understanding of the legal term and provided opinions that could potentially usurp the jury’s role.20 In the UK, the conviction of Mr David Sellu was reversed because the trial judge had failed to direct the jury properly with regard to the determination of “grossness” and the weight given to the expert opinions on that issue (Table 1).8 Clearer guidance has since become available; how this will affect judicial practice and outcomes within the UK and other common law jurisdictions, such as Hong Kong, remains to be discovered.

Another contentious aspect of the existing law concerns the mens rea (or “guilty mind”) requirement for GNM. A detailed discussion on this highly complex topic is beyond the scope of this paper, and readers are referred to previous works by legal scholars.18 21 22 23 It suffices to say that the culpable mental state in GNM is one of indifference. This can be understood as a state of “wilful blindness” or a high degree of negligence in considering and avoiding obvious risks.18 It is (arguably) distinguishable from recklessness, which is acting in the face of subjectively known risks, but less readily so from what is commonly regarded as “inadvertence” or “absent-mindedness” by lay people.23

Take for example a hypothetical scenario in which a patient died from septicaemia following a transfusion procedure. While those who consciously disregarded standard safety procedures in preparing the blood product should probably be held criminally liable, it is debatable whether the doctor who gave the transfusion should be so treated. Did the doctor know or suspect the risk of contamination? If not, should he or she have been aware of or considered the possibility of that risk? Was he or she “indifferent”? What is the level of due diligence reasonably expected from a doctor administering a treatment passed to him or her by someone else? How much checking is needed, and how should “grossness” be determined in a situation like this? And from an ethical point of view, should the severity of the consequence alone (ie, patient death) transform a common human failing such as “inattention” into a crime? If so, what could this mean in daily clinical practice?

There is no ready answer, and the concept of liability in criminal negligence remains controversial, especially in the medical context.23 In the UK, charges against two pharmacists, whose dispensing of a defective medicine caused a child’s death, were dropped because of the absence of malicious intent to cause harm,24 whereas two junior doctors who inadvertently injected vincristine into a patient’s spine were convicted on the grounds that criminal liability may be found not at the time of the injection but when they had “chosen” not to be more careful before acting.25 The distinction between these individuals’ corresponding mental states is not overly clear, and the legal bar for gross negligence remains disputable.14

The situation is further complicated by the fact that a defendant’s mental state may be judged either objectively (ie, what a reasonably competent doctor should have been thinking at the time) or subjectively (ie, what the doctor in question was actually thinking at the time).18 In the sensationalised case of Dr Conrad Murray, convicted for causing the death of the singer Michael Jackson, it was sufficient for the prosecution to prove that the doctor “should have been aware” of the risks associated with using Propofol outside of a hospital setting, not whether he had actual knowledge of those risks (ie, an objective test).26 In contrast, the High Court of Hong Kong had consciously departed from the established English authorities and applied the subjective test in a recent non-medical case.27 The debate continues.28

A charge of GNM even without conviction can be devastating for the doctor involved. In principle, prosecution is brought when it is in the public interest to do so and when there is a realistic prospect of success, but the loosely defined concept of gross negligence affords prosecutors considerable discretion.29 Importantly, the criteria for distinguishing between honest mistakes and conscious violations of professional standards are “tests unknown to the criminal law”.30 As a result, doctors (or even lawyers) can have little confidence in knowing what kinds of behaviour will attract the attention of the criminal law.

Indeed, prosecutors in the UK have been criticised for prosecuting many doctors who should not have been charged in the first place.19 Such prosecutions have caused significant disruptions to the personal and professional lives of innocent individuals and negative feelings within the medical community.31 The small number of cases in Hong Kong does not permit a valid assessment, but a reasonable, consistent, and transparent threshold for prosecution would certainly be welcomed. The principle reaffirmed in Mr David Sellu’s successful appeal is that a prosecution should not be brought unless the conduct of the doctor involved was “truly exceptionally bad”. The mere commission of an error, even if fatal, does not begin to satisfy that test.

From the public’s point of view, an important question is whether criminalisation improves patient safety. There is no empirical evidence to show that it does, and the current understanding of the nature of human error challenges the premise that punishment can prevent mistakes.32 Again, a distinction can be made between errors and violations.

Human errors are by nature unintentional. Even the most able and conscientious clinician can commit errors in a complex hospital environment; inexperience, exhaustion, lack of supervision, or systemic failures may be responsible.33 Because errors are committed without awareness of the associated risks, they are unlikely to respond positively to the threat of criminal prosecution.34 This is particularly the case where health care delivery involves multiple disciplines and professionals whose roles and responsibilities, and hence their duties of care and liabilities, cannot be easily delineated. Moreover, human error is often the last part of a chain of events leading up to an adverse outcome; the proper response should be the adoption of a culture of open disclosure, learning, risk management, and system improvement measures.32 A case in point is that of Dr Bawa-Garba, in which system factors such as understaffing, lack of supervision, and hardware malfunction are thought to be at least partially responsible for a tragic patient outcome (Table 2).

In contrast, violations are associated with deliberate disregard for patient safety and unjustified risk taking. Adverse outcomes occur primarily because of individual doctors’ autonomous decisions rather than the cumulative effects of system and latent factors. The predominance of human agency renders system improvement measures ineffective if not irrelevant; deterrence targeting individuals’ attitudes and mental states is needed.22 Criminal sanctions in these situations can potentially discourage some doctors’ “couldn’t care less” attitude and promote a greater sense of responsibility and carefulness. The conduct of Dr Sudirman and the two convicted individuals in the “DR Group” case in Hong Kong fall squarely into this category (Table 3 and 4).

Admittedly, the distinction between error and violation is not always straightforward, especially when there are questions about clinical competency. Clinical competency involves a range of human qualities, from skills and knowledge to conscientiousness and ethical standards, only some of which are influenced by threat of criminal penalties. It is notable that criminal sanctions in the early vincristine-related cases did not prevent a recurrence: numerous cases have occurred since.33

It has been suggested that the wider use of the criminal law in the present context represents an attempt by the public to exact retribution rather than a desire to improve patient safety.35 In the UK, findings from several public inquiries, such as the Bristol Royal Infirmary Report36 and the Francis Report,37 revealed widespread unethical and substandard practices within the National Health Service. Public dissatisfaction and a deepening blame culture have allegedly created a greater tendency to hold individuals criminally responsible, turning what was once a private matter of civil litigation into a public act of criminal prosecution by the state.38

There has at the same time been a gradual but fundamental shift in the way that the medical profession is perceived by society.39 Better access to medical information and a stronger emphasis on patients’ rights means that doctors are no longer held as high priests of the mysterious art and science of healing but partners in patient journey or providers of services to which taxpayers are entitled. Mistakes are not deemed acceptable simply because medical peers say so; society expects to have the final word. When society thinks that certain behaviours are unacceptable, criminal sanctions can be seen as a ready and legitimate solution.40

The medical profession has not taken this well. In the UK, the initial conviction of Mr David Sellu was met with fervent protests.31 This surgeon had an otherwise unblemished track record, was held in high regard by his peers and patients, and the penalty imposed on him was seen by some as unjustifiable and disproportionate (Table 1). Similarly, as mentioned previously, the court in Dr Bawa-Garba’s case has been strongly criticised for its failure to give due consideration to system factors.41 The insistence of the General Medical Council on removing Dr Bawa-Garba from its register caused such an outcry that the UK government decided to launch a national review into the application of the existing law to medical cases (Table 2).42 The loss of mutual trust between the medical profession, its regulatory body and the criminal justice system encapsulated in these cases is probably the most damaging effect of the prevailing climate of blame and fear. Patient care may also suffer as doctors become reluctant to disclose their mistakes. Instead of promoting high-quality care, criminalisation could in fact encourage the practice of defensive medicine, stifle compassionate care, alienate the medical profession, and hamper the promotion of a safety culture.43

Reactions from medical peers in Hong Kong towards the two convictions in the “DR Group” case have been restrained. Few appear to condone the negligent practices in that case or disapprove of the penalties imposed (Table 4). There is arguably a sense of detachment, as the circumstances in this case (ie, the preparation of an experimental blood product) are far removed from those commonly experienced by most doctors. As such, we have not seen the kind of emotional responses from within our medical sector that have been found in the UK, where doctors perform routine duties with the knowledge that jail sentences could arise from a single missed diagnosis or a few hours’ delay in performing life-saving surgery.

The outcome of the re-trial of the third defendant in the “DR Group” case could generate more lively discussions for several reasons. First, general opinions vary more widely regarding the wrongfulness of the doctor’s conduct. Second, practising clinicians can relate more readily to the circumstances in this part of the case and see the relevance and implications of the re-trial. Third, the legal arguments involved are more complex and subject to debate with respect to the culpability of the doctor’s mental state.28 Irrespective of the outcome, the ruling will send a strong message on how similar cases will be handled in the future and raise concerns within different sectors of society one way or the other. Ahead of us could be a challenging time.

In the greater scheme of things, there are perhaps good reasons to believe that the general attitude towards the medical profession in Hong Kong has not (yet) become hostile, and that the catalogue of recent cases here is a rare exception. A previous survey showed that the majority of our patients were very satisfied with the quality of care received.44 The number of complaints submitted to the Medical Council of Hong Kong has remained steady.45 We have not had any public scandal at a comparable scale to those in the UK, and our health care professionals still enjoy a reasonable level of respect.44 There is also a handsome degree of transparency and accountability within our system, while institutional measures are in place to ensure that our medical students are properly trained, foreign graduates suitably qualified, and requirements for continuous education diligently followed.46 47 All of these factors must be acknowledged, treasured, and enhanced.

But society’s trust in us is not a given; it has to be earned and maintained. Our doctors and nurses work under challenging conditions and need to be supported.48 The recent controversy about the suspension of a doctor by the Medical Council mentioned above represents a serious trust crisis that must be addressed urgently.14 Meanwhile, we need to train our medical students and trainees well and impart a strong sense of ethical awareness and responsibility so that our patients will remain safe, and know that they are safe, in our hands.49 Public education should culture a better understanding of the nature of human error and the acknowledgment of the fact that Medicine is not a perfect science. Lastly, underpinning our right to practice and power to self-regulate is a social contract with society that is built on trust.50 The expert opinions we give, how we discuss and handle medical incidents, and the ways in which we respond to legislative efforts to improve patient safety will eventually affect how society perceives and reacts to our mistakes and failings.

The rising number of medical manslaughter charges and convictions in Hong Kong and overseas poses a concern. Criminal liability for medical negligence is an arguably unstable legal concept, and the prosecutorial threshold and legal test for GNM are imbued with uncertainty. The criminalisation of medical mistakes can potentially create a climate of blame and fear that is damaging to the medical profession and detrimental to patient welfare. From the perspectives of providing deterrence and punishment in the medical context, criminal sanctions should probably be limited to conscious violations of established standards; unintentional errors are better dealt with through professional disciplinary actions or litigation based on the ordinary civil test of negligence. However, this necessitates a fundamental jurisprudential shift that is unlikely to materialise in the near future. As we await the outcomes of ongoing cases in Hong Kong, there is much that we can do to maintain society’s trust in the medical profession by upholding standards of care and nurturing a robust culture of professionalism.

The author has made substantial contributions to the concept or design; acquisition of data; analysis or interpretation of data; drafting of the article; and critical revision for important intellectual content.

This article received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

The author has disclosed no conflicts of interest. The author had full access to the data, contributed to the paper, approved the final version for publication, and takes responsibility for its accuracy and integrity.

1. Crown Prosecution Service, UK Government. Homicide: murder and manslaughter. Available from: http://www.cps.gov.uk/legal/h_to_k/homicide_murder_and_manslaughter/#gross. Accessed 16 Mar 2018.

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4. R v Adomako [1995] 1 AC 171.

5. Ferner RE, McDowell SE. Doctors charged with manslaughter in the course of medical practice, 1795-2005: a literature review. J R Soc Med 2006;99:309-14. Crossref

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7. Quick Q. Medicine, mistakes and manslaughter: a criminal combination? Cam Law J 2010;69:186-203. Crossref

8. David Sellu v R [2016] EWCA Crim 1716.

9. Bawa Garba v R [2016] EWCA Crim 1841.

10. HKSAR v Harry Sudirman CACC 486/2003.

11. HKSAR v Chow Heung-Wing, Stephen and 2 others HCCC 437/2015.

12. Mok D. Hong Kong doctor arrested on manslaughter charge over death of dancer after beauty treatment. South China Morning Post. 2018 Mar 13. Available from: http://www.scmp.com/news/hong-kong/law-crime/article/2137050/hong-kong-doctor-arrested-manslaughter-charge-over-death. Accessed 19 Mar 2018.

13. Tsang E. Hong Kong nurses found guilty of misconduct in fatal blunder or one month. South China Morning Post. 2016 June 13. Available from: http://www.scmp.com/news/hong-kong/health-environment/article/1974286/hong-kong-nurses-found-guilty-misconduct-fatal. Accessed 16 Mar 2018.

14. Cheung E. Hong Kong doctor Wong Cheuk-yi banned for six months over death of elderly cancer patient Wang Keng-kao at Kowloon Hospital. South China Morning Post. 2018 May 9. Available from: http://www.scmp.com/news/hong-kong/health-environment/article/2145352/hong-kong-doctor-wong-cheuk-yi-found-guilty. Accessed 10 Mar 2018.

15. Edwards S. Medical manslaughter: a recent history. Ann R Coll Surg Engl 2014;96:118-9. Crossref

16. Dekker SA. Criminalization of medical error: who draws the line? ANZ J Surg 2007;77:831-7. Crossref

17. Spencer JR, Brajeux MA. Criminal liability for negligence—a lesson from across the Channel? Int Comp Law Quart 2010;59:1-24. Crossref

18. McCall Smith A. Criminal negligence and the incompetent doctor. Med Law Rev 1993;1:336-49. Crossref

19. Hubbeling D. Criminal prosecution for medical manslaughter. J R Soc Med 2010;103:216-8. Crossref

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21. Virgo G. Reconstructing manslaughter on defective foundations. Cam Law J 1995;54:14-6. Crossref

22. Horder J. Gross negligence and criminal culpability. U Toronto Law J 1997;47:495-521. Crossref

23. Smith AM. Criminal or merely human?: the prosecution of negligent doctors. J Cont Health Law Policy 1996;12:131-46.

24. March PJ. Boots pharmacist and trainee cleared of baby’s manslaughter, but fined for dispensing a defective medicine. Pharmaceutical J 2000;264:390-2.

25. R v Prentice, R v Adomako [1995] 1 AC 171.

26. Kim CJ. The trial of Conrad Murray: prosecuting physicians for criminally negligent over-prescription. Am Crim Law Rev 2014;51:517-40.

27. HKSAR v Lai Shui Yin HCCC 29/2011.

28. Leung JA, Liu HT. Gross negligence manslaughter after Lai Shui Yin. Hong Kong Law J 2014;44:709-17.

29. Quick O. Prosecuting ‘gross’ medical negligence: manslaughter, discretion, and the crown prosecution service. J Law Soc 2006;33:421-50. Crossref

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37. UK Government Report of the Mid Staffordshire NHS foundation trust public inquiry. London: The Stationery Office; 2013.

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39. Edwards N, Komacki MJ, Silversin J. Unhappy doctors: what are the causes and what can be done? BMJ 2002;324:835-8. Crossref

40. Leung GK. If we do not take charge of ourselves, some else would (have to). Surg Pract 2016;20:141. CrossRef

41. Cohen D. Back to blame: the Bawa-Garba case and the patient safety agenda. BMJ 2017;359:j5534. Crossref

42. Donnelly L. Hunt orders review of medical malpractice amid doctors’ outcry over manslaughter case. The Telegraph. 6 Feb 2018. Available from: https://www.telegraph.co.uk/news/2018/02/06/hunt-orders-review-medical-malpractice-amid-doctors-outcry-manslaughter/. Accessed 26 Mar 2018.

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Jaundice is caused by the accumulation of bilirubin in the blood. It can be a result of overproduction of or failure to metabolise and excrete bilirubin. The incidence of infantile jaundice is approximately 1 in 2500 to 5000 live births1 2 with a variety of underlying diagnoses ranging from self-limiting breast milk jaundice to aggressive life-threatening diseases such as biliary atresia (BA) and liver failure. Although the clinical features of certain diseases are obvious, some may have more subtle presentations that necessitate a high index of suspicion for diagnosis. In general, the differential diagnoses of jaundice in infancy follow those of adults and can broadly be divided into pre-hepatic, hepatic, and post-hepatic causes. In some cases, specific treatment may not be necessary but more often timely management is required for an optimal outcome. In this article, we highlight several medical and surgical diagnoses of infantile jaundice and a diagnostic strategy based on current evidence.

Breast milk jaundice was first described more than 50 years ago, with benign unconjugated hyperbilirubinaemia associated with breastfeeding.3 4 5 It is the most common cause of prolonged jaundice in an otherwise healthy breastfed infant born at term. It usually presents in the first 2 to 3 weeks of life (incidence has been reported as 34%),6 and can persist for as long as 12 weeks before spontaneous resolution. Total serum bilirubin levels in breast milk jaundice alone do not exceed 200 μmol/L. Diagnosis of breast milk jaundice requires the exclusion of other possible pathological causes. Table 1 shows the essential clinical features of breast milk jaundice.

The aetiology of breast milk jaundice is not clear. Animal models suggest that mature breast milk may enhance bilirubin uptake in the gastrointestinal tract, thus increasing enterohepatic circulation and unconjugated bilirubin levels.7 8 Higher levels of epidermal growth factor both in the serum and breast milk of affected infants may offer a plausible mechanism for breast milk jaundice in the same way.9 Activity of beta-glucuronidase (which deconjugates intestinal bilirubin) that is higher in human milk than formula milk will again increase the serum bilirubin level by increasing enterohepatic circulation.10

Severity and duration of breast milk jaundice may be affected by a concurrent neonatal manifestation of Gilbert syndrome which will be discussed later.

Infants with breast milk jaundice require no treatment provided they are clinically well and the total serum bilirubin concentration remains below the recommended phototherapy level. The interruption of breastfeeding is not advised. If total serum bilirubin exceeds 200 μmol/L, further investigation is required. In case of a negative workup, the possibility of the additional presence of a mutation of the hepatic enzyme UGT1A1 (uridine diphosphate glucuronosyltransferase 1A1) conjugating bilirubin in the hepatocyte, ie, Gilbert syndrome, should be considered. Follow-up (every 2 weeks) should be offered preferably until a decreasing trend of jaundice becomes evident.

Glucose-6-phosphate dehydrogenase (G-6-PD) is an enzyme found in all cells of the body. Reactive oxygen species (ROS) are continually formed in the body causing tissue oxidation, disruption of lipid membranes, destruction of cell enzyme functions, alteration of DNA structure, and eventually cell death. Glucose-6-phosphate dehydrogenase plays a major role in neutralising the ROS and offers protection against tissue oxidative damage. Red blood cells are particularly susceptible to oxidative stress so the major effect of G-6-PD deficiency is haematological.

Glucose-6-phosphate dehydrogenase deficiency is a genetic condition with an X-linked recessive inheritance. Males are more likely to be affected. In Hong Kong, there is routine cord blood screening for G-6-PD deficiency and an incidence of around 4.5% in males and 0.5% in females.11

Glucose-6-phosphate dehydrogenase deficiency– associated neonatal hyperbilirubinaemia can manifest in two forms: severe jaundice resulting from acute haemolysis or gradual onset jaundice. Some G-6-PD–deficient neonates may develop severe haemolysis that results in rapidly rising serum total bilirubin levels, with the potential to develop kernicterus, with or without the identification of a known trigger of haemolysis.12 13 In contrast to the severe haemolytic jaundice, gradual onset jaundice is less severe and is associated with a slower increase in total serum bilirubin concentration.

Apart from haemolysis (as evidenced by a falling haemoglobin with elevated reticulocyte count), diminished bilirubin clearance plays a role in the pathogenesis of jaundice in G-6-PD deficiency infants. Serum conjugated bilirubin studies indicate diminished bilirubin conjugation in G-6-PD–deficient neonates,14 with impaired excretion of conjugated bilirubin into the small intestine in bile.

Prevention of hyperbilirubinaemia and kernicterus in G-6-PD–deficient neonates is possible. Parents of neonates affected should be counselled on the risks of jaundice. They should be advised to avoid triggers of haemolysis (Table 211). Predischarge measurement of the bilirubin level using transcutaneous bilirubin or serum total bilirubin should be performed followed by earlier and more frequent follow-up.15

Gilbert syndrome is the most common inherited disorder of bilirubin glucuronidation. The prevalence of Gilbert syndrome has been reported to be 5% to 10% in the Caucasian population,16 17 with a similar prevalence (3-7%) in Chinese.18 19 Uridine diphosphate glucuronosyltransferase 1A1 is the hepatic enzyme responsible for bilirubin conjugation. Gilbert syndrome results from a mutation in the UGT1A1 gene promotor region. It manifests only in people who are homozygous for the genetic mutation, consistent with an autosomal recessive inheritance. Such mutation may produce structural or functional enzymatic deficiencies, possibly resulting in impaired bilirubin conjugation and hyperbilirubinaemia. Such genetic mutations have been demonstrated in Asian populations.18 19 20

Patients typically present during the adolescent period (with recurrent episodes of jaundice that may be triggered by dehydration, fasting, intercurrent illness, menstruation, etc) when alterations in sex steroid concentrations affect bilirubin metabolism. Nonetheless they may also present with prolonged breast milk jaundice due to concurrent Gilbert syndrome. The diagnosis is made by excluding other causes of unconjugated hyperbilirubinaemia although genetic testing is available. No treatment is necessary. The long-term outcome is similar to that for the general population. Nonetheless the Gilbert genotype is associated with an increased severity and duration of neonatal jaundice.21 22

Among the viral aetiologies in the developing world, hepatitis A, B, and E are the most common causes of paediatric acute liver failure (PALF). In the developed world, viruses like herpes simplex virus (HSV) and enterovirus are more commonly identified as the aetiological agent.

Hepatitis A virus infection resulting in PALF is uncommon in developed countries (2.5% in a PALF registry in North America and United Kingdom).23 Nonetheless acute hepatitis A virus infection accounts for up to 80% of PALF cases in developing countries.24 Similarly, acute hepatitis B virus (HBV) infection causing PALF is uncommon in the West where HBV is not endemic. On the contrary, in areas where HBV is endemic, it accounts for up to 46% of PALF.25 Hepatitis E virus infection has rarely been identified as the cause of PALF. Pregnant women have a high risk of fulminant hepatitis associated with hepatitis E virus infection, with a particularly high risk during the third trimester of pregnancy. The risk of symptomatic hepatitis in the newborn is high if a pregnant woman acquires hepatitis E virus infection during pregnancy.

Herpes simplex virus should be considered an important and treatable cause of PALF. Herpes simplex virus most commonly affects infants and newborns. In a registry study from North America and the UK, HSV was identified in 25% of young infants (0-6 months) with PALF.23

Other viruses associated with PALF include enterovirus and Epstein-Barr virus. The Enterovirus family (including echovirus, Coxsackie A and B virus) was identified as the aetiological agent of acute liver failure in 2.7% of young infants (0-90 days of age) in a multi-centre registry in North America and the UK.26 Epstein-Barr virus is more frequently implicated in PALF in older children and adolescents.

Chinese herbs are being increasingly used in the paediatric population in certain parts of the world and some have been implicated in the development of hepatotoxicity. A recent retrospective review of Chinese herbal medicine–induced liver injury in Beijing, China revealed that Ephedra sinica and Polygonum multiflorum were the major culprit herbs.27 These ingredients are found in products such as Gan-mao soft capsules (感冒軟膠), Xiao-er-ke-chuan-ling (小兒咳喘靈) granules, and Shou-wu-yan-shou (首烏延壽丹) tablets that are used to treat upper respiratory tract infection or vitiligo. Jaundice is the most common clinical sign. Median days from herbal ingestion to appearance of presenting symptoms can be up to 30 days. Therefore, it is important to enquire about the use of traditional Chinese medicine in the weeks preceding clinical presentation.

Surgical jaundice commonly refers to obstructive jaundice and consequent impaired biliary drainage. Unlike adults, the causes of obstruction in infants are usually congenital. The differentiation from medical causes can be made by measuring the level of conjugated bilirubin (which will usually be raised in cases of obstructive jaundice) as well as examination of the biliary system by ultrasound scan. Obstructive jaundice is curable by surgery but the magnitude of surgery ranges from minor to ultra-major. The management of individual diagnoses will be discussed below.

The first description in the English language of a condition similar to BA appeared in a textbook written by Dr John Burns from the University of Glasgow in 1817.28 Nonetheless it was more than a century later before the first operation was performed by Dr William Ladd from Boston in an attempt to correct BA.29 Unfortunately, his surgery did not improve the outcome of this condition and BA was at this time regarded as ‘the darkest chapter in paediatric surgery’. In 1959, Dr Morio Kasai from Japan reported his radical surgery for BA with a higher success rate.30 It was only then that BA became a potentially curable condition and the operation that was named after Dr Kasai is now the standard surgical approach for BA.

Biliary atresia is a rare disorder with an incidence that varies widely among populations (1 in 5000 in Asians to 1 in 18 000 in Caucasians). In 10% to 20% of patients, the disease is associated with other congenital anomalies.31 The disease is characterised by inflammatory sclerosing cholangiopathy affecting the entire biliary tract. The bile duct is replaced by fibrous tissue without luminal patency (Fig 1). Its aetiology remains largely unknown and the most widely accepted theory is that unknown exogenous factors trigger a series of self-limiting inflammatory events in a genetically predisposed individual during the embryonic or perinatal period. Current evidence suggests that genetics play an important role in the pathogenesis of BA.32 A genome-wide association study conducted by a group of scientists in Hong Kong discovered a BA-associated region on chromosome 10q24.2 that could alter the expression of adducin 3 in the liver.33 Nonetheless genetic abnormality alone cannot be the sole explanation since BA is not an inherited disease.

Antenatal diagnosis is difficult and only a few small case series have been published.34 Affected babies usually present with prolonged jaundice beyond the neonatal period. Due to the absence of bile pigment in the stool, the stool is typically pale in colour (Fig 2). The passage of pale-coloured stool from a young infant should always raise the suspicion of BA. Liver function tests will reveal a cholestatic pattern that may help to differentiate from other causes of infantile jaundice. The gallbladder will be absent or small on ultrasound scan. At a later stage, the liver may demonstrate parenchymal or fibrotic changes. Although radio-isotope scan, such as a techetium-99m ethyl hepatic iminodiacetic acid scan may show impaired biliary excretion, this finding is not confirmatory. The diagnosis of BA should be confirmed by direct visualisation of the fibrotic biliary tract. If necessary, an intra-operative cholangiogram can be performed and is considered normal only if there is passage of contrast up to the intrahepatic ducts as well as down to the duodenum. This diagnostic procedure can now be performed via a laparoscopic approach.

In the majority of cases, the Kasai operation is still regarded as the operation of choice to treat BA and should be carried out in a highly specialised centre. Indeed, the outcome of Kasai operation in the UK has significantly improved following centralisation of all BA cases to three major centres after 1999.35 The operation consists of the excision of the fibrous cord at the porta and restoration of biliary drainage by portoenterostomy. Despite an uneventful operation, jaundice clearance can be achieved in only 60% to 70% of patients and the 5-year native liver survival rate is roughly 50% only.36 37 Factors that may improve the outcome including the timing of surgery, experience of the surgeon, surgical approach, and use of adjuvant medications have been studied extensively but a definitive answer is still lacking. Recurrent cholangitis has been found to be associated with a poor outcome and therefore each cholangitic episode should be treated aggressively.38 About 30% to 40% of post-Kasai patients will eventually develop end-stage liver failure and require liver transplantation as the salvage treatment.39

Alagille syndrome is an autosomal dominant disease with a variable penetrance. The disorder is believed to be caused by a defect in the Notch signalling pathway that is important for normal embryonic development.40 This syndrome may present with infantile jaundice resembling BA but it also commonly affects other systems including the cardiovascular, musculoskeletal, and ocular systems. Some patients will have a characteristic facial expression (broad forehead, deep-set eyes and pointed chin). The manifestation in the hepatobiliary system is characterised by the paucity of intrahepatic bile ducts resulting in cholestatic jaundice during infancy. The diagnosis is sometimes confused with BA. It is not uncommon for the Kasai operation to be performed on a patient with Alagille syndrome with an invariably poor outcome. Preoperative distinction from BA is possible by genetic testing for JAG1 mutations but this mutation is also found in some patients with BA, leading to the belief that Alagille syndrome and BA belong to the same spectrum of disease.41 At present, the only effective treatment to correct Alagille syndrome is liver transplantation.42

Inspissated bile syndrome describes a condition where the bile duct is obstructed due to the impaction of a thick bile plug or sludge during the neonatal or infantile period. It is sometimes associated with prematurity, cystic fibrosis, or prolonged use of total parenteral nutrition but it can occur without an obvious underlying cause. The use of fluconazole has been reported as a risk factor for developing this disorder.43 The affected patient will present with symptoms of obstructive jaundice. Ultrasound examination may occasionally reveal the presence of sludge in the biliary system and dilatation of the bile duct. When the obstruction is mild, the bile plug may dissolve with hydration and high-dose ursodeoxycholic acid. Nonetheless in severe cases with prolonged obstruction, biliary obstruction may lead to liver damage and cirrhosis. Inspection of the gallbladder and the entire biliary tract should be performed to exclude other causes of obstructive jaundice. At the same time, an operative cholangiogram can be carried out to exclude BA by showing the passage of contrast into the intrahepatic ducts as well as small bowel (Fig 3). It also serves a therapeutic purpose by dissolving the bile plug. Some surgeons advocate concomitant cholecystectomy but it is not always necessary when the diagnosis is straightforward.

Choledochal cyst is a congenital disorder characterised by cystic dilatation of the intrahepatic and/or extrahepatic bile duct. The estimated incidence is around 1 in 5000 live births and slightly more in Asians.44 The diagnosis is usually made in the first few years of life when the patient presents with jaundice or abdominal pain. In recent years, antenatal diagnosis has become more common and more cysts are detected on prenatal scans. Occasionally, the disease can remain asymptomatic until adulthood when it presents with cholangitis. Malignant transformation into cholangiocarcinoma is a rare but possible sequelae of untreated choledochal cyst and thus, surgical excision is recommended.45

Choledochal cyst is traditionally classified into five types according to the Todani classification with type I cyst being the most common.46 Apart from a stenotic opening at the distal common bile duct causing biliary obstruction, the abnormal union of the pancreatic duct with a long common channel can predispose the reflux of pancreatic juice into the bile duct. Antenatally diagnosed choledochal cyst does not require fetal intervention and asymptomatic cysts after birth can be observed for a while. Nonetheless the observation period should not be long to avoid cholangitis. Earlier surgery has been found to be associated with less liver injury as well as operative complications.47 Cholangitic episodes should be treated with potent antibiotics and biliary drainage by either percutaneous or operative means if necessary to avoid progression to life-threatening sepsis.

Complete cyst excision and hepaticojejunostomy is regarded as the standard operative treatment for choledochal cyst. Since the first report of successful laparoscopic surgery in 1995,48 most centres now perform laparoscopic cyst excision (Fig 4). Previous studies have demonstrated superior outcomes compared with open surgery and it is safe and feasible in young infants. With the advances in laparoscopic techniques among paediatric surgeons, an even more minimally invasive approach by single-incision laparoscopic surgery has been adopted in some centres with satisfactory results.49

A diagnostic algorithm for infantile jaundice is summarised in Figure 5. Patients with jaundice beyond the neonatal period require a thorough evaluation for underlying causes. This should always start with recording a careful history of the antenatal and perinatal periods including prenatal ultrasonography findings, G-6-PD status, result of the newborn metabolic screen, etc. It is necessary to obtain both the child and mother’s medication history to identify any potential hepatotoxic agents. Although breast milk jaundice is a common cause of infantile jaundice, other aetiologies should be considered especially if the infant is not gaining weight, if the total bilirubin level exceeds 200 μmol/L, and in the presence of red flag symptoms. The passage of pale stool or tea-coloured urine must not be missed. Physical examination should not be limited to the abdomen and a systematic examination should be carried out to look for associated anomalies. Stool can be saved for inspection of the colour. Blood tests should include a complete blood picture (along with reticulocyte count and peripheral blood smear) to exclude haemolytic diseases. The bilirubin level is measured and it is essential to distinguish between unconjugated and conjugated hyperbilirubinaemia as they suggest different disease entities. An increased level of parenchymal enzyme aspartate aminotransferase/alanine aminotransferase may suggest liver injury due to virus-/drug-induced causes or autoimmune diseases. On the contrary, obstructive causes are suggested by an increased level of ductal enzyme alkaline phosphatase/gamma glutamyl transpeptidase. Serology and antigen of hepatitis viruses can be checked by sending blood samples to a microbiology laboratory. An ultrasound scan can detect the presence of anatomical anomalies in the biliary tract such as BA or choledochal cyst. A radioisotope scan will help to confirm the presence of biliary obstruction but does not always give clues to the underlying diagnosis. Laparoscopic examination of the biliary tract should be arranged when BA cannot be excluded from the above investigations. Nonetheless laparoscopy should also be arranged if cholestasis remains unresolved despite normal imaging to exclude the possibility of inspissated bile plug syndrome. Intra-operatively, a cholangiogram can be performed by injecting contrast into the gallbladder to confirm the patency of the biliary tract. It also serves the purpose of dissolving any bile plug that may be the cause of obstruction. A liver biopsy can be performed at the conclusion of the procedure to determine the degree of liver injury. The paucity of bile duct in a liver biopsy specimen is suggestive of Alagille syndrome.

Infantile jaundice is a common but potentially life-threatening condition. Referral to a specialist is necessary if jaundice persists beyond the neonatal period. The differentiation between medical and surgical causes should be made early on by measuring the blood level of conjugated and unconjugated bilirubin. Laparoscopy should be considered in any patient with persistent cholestatic jaundice to exclude BA that requires early intervention.

As an editor of this journal, KKY Wong was not involved in the peer review process of this article. All other authors have no conflicts of interest to disclose. All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

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12. Valaes T. Severe neonatal jaundice associated with glucose-6-phosphate dehydrogenase deficiency: pathogenesis and global epidemiology. Acta Paediatr Suppl 1994;394:58-76. Crossref

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15. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004;114:297-316. Crossref

16. Owens D, Evans J. Population studies on Gilbert’s syndrome. J Med Genet 1975;12:152-6. Crossref

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18. Long J, Zhang S, Fang X, Luo Y, Liu J. Neonatal hyperbilirubinemia and Gly71Arg mutation of UGT1A1 gene: a Chinese case-control study followed by systematic review of existing evidence. Acta Paediatr 2011;100:966-71. Crossref

19. Chang PF, Lin YC, Liu K, Yeh SJ, Ni YH. Prolonged unconjugated hyperbilirubinemia in breast-fed male infants with a mutation of uridine diphosphate-glucuronosyl transferase. J Pediatr 2009;155:860-3. Crossref

20. Maruo Y, Morioka Y, Fujito H, et al. Bilirubin uridine diphosphate-glucuronosyltransferase variation is a genetic basis of breast milk jaundice. J Pediatr 2014;165:36-41.e1. Crossref

21. Roy-Chowdhury N, Deocharan B, Bejjanki HR, et al. Presence of the genetic marker for Gilbert syndrome is associated with increased level and duration of neonatal jaundice. Acta Paediatr 2002;91:100-1. Crossref

22. Monaghan G, McLellan A, McGeehan A, et al. Gilbert’s syndrome is a contributory factor in prolonged unconjugated hyperbilirubinemia of the newborn. J Pediatr 1999;134:441-6. Crossref

23. Schwarz KB, Dell Olio D, Lobritto SJ, et al. Analysis of viral testing in nonacetaminophen pediatric acute liver failure. J Pediatr Gastroenterol Nutr 2014;59:616-23. Crossref

24. Moreira-Silva SF, Frauches DO, Almeida AL, Mendonça HF, Pereira FE. Acute liver failure in children: observations in Vitória, Espírito Santo State, Brazil. Rev Soc Bras Med Trop 2002;35:483-6. Crossref

25. Chen HL, Chang CJ, Kong MS, et al. Pediatric fulminant hepatic failure in endemic areas of hepatitis B infection: 15 years after universal hepatitis B vaccination. Hepatology 2004;39:58-63. Crossref

26. Sundaram SS, Alonso EM, Narkewicz MR, et al. Characterization and outcomes of young infants with acute liver failure. J Pediatr 2011;159:813-8.e1. Crossref

27. Zhu Y, Li YG, Wang JB, et al. Causes, features, and outcomes of drug-induced liver injury in 69 Children from China. Gut Liver 2015;9:525-33. Crossref

28. Burns J. The Principals of Midwifery: Including the Disease of Women and Children. London: Longman; 1817.

29. Ladd WE. Congenital atresia and stenosis of the bile ducts. JAMA 1928;91:1082-5. Crossref

30. Kasai M, Suzuki S. A new operation for “non-correctable” biliary atresia: hepatic portoenterostomy. Shujutsu 1959;(13):733-9.

31. Hartley JL, Davenport M, Kelly DA. Biliary atresia. Lancet 2009;374:1704-13. Crossref

32. Lakshminarayanan B, Davenport M. Biliary atresia: a comprehensive review. J Autoimmun 2016;73:1-9. Crossref

33. Cheng G, Tang CS, Wong EH, et al. Common genetic variants regulating ADD3 gene expression alter biliary atresia risk. J Hepatol 2013;59:1285-91. Crossref

34. Caponcelli E, Knisely AS, Davenport M. Cystic biliary atresia: an etiologic and prognostic subgroup. J Pediatr Surg 2008;43:1619-24. Crossref

35. Davenport M, Ong E, Sharif K, et al. Biliary atresia in England and Wales: results of centralization and new benchmark. J Pediatr Surg 2011;46:1689-94. Crossref

36. Bijl EJ, Bharwani KD, Houwen RH, de Man RA. The long-term outcome of the Kasai operation in patients with biliary atresia: a systematic review. Neth J Med 2013;71:170-3.

37. Lampela H, Ritvanen A, Kosola S, et al. National centralization of biliary atresia care to an assigned multidisciplinary team provides high-quality outcomes. Scand J Gastroenterol 2012;47:99-107. Crossref

38. Chung PH, Wong KK, Tam PK. Predictors for failure after Kasai operation. J Pediatr Surg 2015;50:293-6. Crossref

39. Wang P, Xun P, He K, Cai W. Comparison of liver transplantation outcomes in biliary atresia patients with and without prior portoenterostomy: a meta-analysis. Dig Liver Dis 2016;48:347-52. Crossref

40. McDaniell R, Warthen DM, Sanchez-Lara PA, et al. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet 2006;79:169-73. Crossref

41. Dědič T, Jirsa M, Keil R, Rygl M, Šnajdauf J, Kotalová R. Alagille syndrome mimicking biliary atresia in early infancy. PLoS One 2015;10:e0143939. Crossref

42. Spinner NB, Leonard LD, Krantz ID. Alagille Syndrome. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, et al, editors. GeneReviews^®. Seattle; 1993.

43. Brownschidle S, Zenali M, Potenta S, Sartorelli K, Sullivan J. Neonatal cholestasis due to biliary sludge—review and report of a case associated with use of Diflucan. Ann Clin Pathol 2014;2:1018.

44. Singham J, Schaeffer D, Yoshida E, Scudamore C. Choledochal cysts: analysis of disease pattern and optimal treatment in adult and paediatric patients. HPB (Oxford) 2007;9:383-7. Crossref

45. Madadi-Sanjani O, Wirth TC, Kuebler JF, Petersen C, Ure BM. Choledochal cyst and malignancy: A plea for lifelong follow-up. Eur J Pediatr Surg 2017 Dec 19. Epub ahead of print. Crossref

46. Todani T, Watanabe Y, Toki A, Morotomi Y. Classification of congenital biliary cystic disease: special reference to type Ic and IVA cysts with primary ductal stricture. J Hepatobiliary Pancreat Surg 2003;10:340-4. Crossref

47. Diao M, Li L, Cheng W. Timing of surgery for prenatally diagnosed asymptomatic choledochal cysts: a prospective randomized study. J Pediatr Surg 2012;47:506-12. Crossref

48. Farello GA, Cerofolini A, Rebonato M, Bergamaschi G, Ferrari C, Chiappetta A. Congenital choledochal cyst: video-guided laparoscopic treatment. Surg Laparosc Endosc 1995;5:354-8.

49. Son TN, Liem NT, Hoan VX. Transumbilical laparoendoscopic single-site surgery with conventional instruments for choledochal cyst in children: early results of 86 cases. J Laparoendosc Adv Surg Tech A 2014;24:907-10. Crossref

This article provides an up-to-date overview of breast cancer mammography screening and briefly discusses its history, controversies, current guidelines, practices across Asia, and future directions. An emphasis is made on shared decision-making—instead of giving just a ‘yes’ or ‘no’ answer to patients, the focus should be on providing sufficient information about the pros and cons of screening to help women make a personal, informed choice. Frontline experts, including breast surgeons, oncologists, breast radiologists, and their representative professional associations should all participate in guideline panels, with the goal of improving cancer detection, reducing mortality, and improving patient outcome.

This article provides an up-to-date overview of breast cancer mammography screening and briefly discusses its history, controversies, current guidelines, practices across Asia, and future directions. An emphasis is made on shared decision-making—instead of giving just a ‘yes’ or ‘no’ answer to patients, the focus should be on providing sufficient information about the pros and cons of screening to help women make a personal, informed choice.

The goal of mammographic screening (and other breast-cancer screening tests) is to detect breast cancer earlier than it would otherwise manifest clinically, when it is less likely to have spread. Data clearly show that detection of breast cancers at smaller sizes and lower (earlier) stages is associated with better patient outcomes, lower morbidity, and reduced breast cancer deaths.1 Reduced morbidity is likely to be related to feasibility of breast conservation and hence less extensive surgery, fewer associated complications such as lymphoedema, less chemotherapy, and hence fewer adverse effects.2 Other benefits of diagnosing screen-detected cancers at an earlier stage also include a lower cost of treatment and consequent reduced financial burden on health care resources.3

The Table summarises the mammography guidelines from selected nations.4 5 In common, all organisations emphasise that the benefits of screening outweigh the harm at all ages.3 6 They all endorse informed decision-making and the importance of informing women about both benefits and limitations of screening. However, there remain legitimate concerns about guideline differences, including the complexity of the guidelines; weak adherence to creating opportunities for informed decision-making; unreadiness of referring clinicians to discuss benefits, limitations, and harm associated with screening; and the lack of reminder systems, which results in weaker adherence to recommended screening intervals. Despite these concerns, it is widely accepted that high adherence to even the least aggressive guidelines will save more lives than the current weak adherence to regular screening programmes.4

Randomised controlled trials (RCTs) have been the gold standard for proving that early detection with mammography decreases mortality from breast cancer. Since the very first screening RCT performed in New York in the 1960s, there have been eight prospective RCTs and numerous subsequent meta-analyses published. Most well-executed RCTs demonstrated a 20% to 30% decrease in mortality from breast cancer when women were invited for screening. These results laid a solid foundation for population-based screening programmes worldwide.1 7 8

Subsequent studies that generated data from population-based screening programmes have provided further evidence of the benefits of screening mammography. The true benefit reported (in terms of mortality reduction) ranged from 38% to 49%, even higher than that shown by RCTs. This difference demonstrates that service screening studies measure the direct effect of screening on women who actually underwent mammography, and not just those who were invited to undergo mammography (as opposed to the methodology of RCTs). Service screening studies also tend to measure the effect of more recent screening practices that have benefited from improved mammography technology, better breast positioning techniques, and improved interpretive skills.1 9

One exception to the RCTs that reported unfavourable results of mammographic screening was the Canadian National Breast Screening Study (CNBSS). It was conducted between 1980 and 1985, and was divided into two parts. The first CNBSS included approximately 50 000 volunteer women aged 40 to 49 years, and determined the mortality benefit in the experimental group, who were assigned to annual screening mammography plus clinical breast examination (CBE) versus the control group who received usual care.10 The second CNBSS had almost 40 000 volunteer women aged 50 to 59 years, and compared the benefit of annual mammography plus CBE with that of yearly CBE alone.11

From the time the results were first published in 1992 and again after follow-up in 2000, 2002, and 2014, the CNBSS has been controversial, because it is the only RCT to have reported no decrease in mortality associated with an invitation to screening. The study also claimed a 22% overdiagnosis of screen-detected invasive cancer, increasing to up to 35% when cases of ductal carcinoma in situ (DCIS) were included.12 13 14 However, the credibility and scientific value of the CNBSS study have been repeatedly questioned in peer-reviewed publications.15 16 17 18 19 Most criticisms of this study are related to vulnerabilities and shortcomings in its execution, including flaws in the randomisation process, lack of statistical power, non-generalisable results, poor quality imaging, suboptimal mammographic image acquisition and interpretation by untrained personnel, and inconsistent thresholds for interpretation.

The flaws in the randomisation process principally arose from three areas. First, unlike all other RCTs, potential participants in the Canadian trials initially underwent a careful physical examination. Second, women with positive findings on physical examination, including palpable lumps, skin or nipple retraction, and even palpable axillary adenopathy, were not excluded from this ‘screening’ trial.18 Finally, randomisation was unblinded and decentralised. Because almost 80% of women with advanced palpable cancers were assigned to the screening arm in the first round of the study, there has been speculation that concerned clinicians did not follow the randomisation process, but rather assigned some symptomatic women to the study group so that they would undergo mammography.19 Whether the imbalance was due to intentional tampering or occurred by chance alone, the net effect was the same—namely, a failure to produce two equal cohorts of patients for comparison.

The CNBSS was also criticised at the time of the trial for poor quality mammography, even compared with mammographic imaging of that era.15 20 To reduce radiation dose, mammography for the trial was performed without the benefit of scatter-reducing grids despite their routine use and availability. Standard imaging for much of the trial used a straight lateral view, not a mediolateral-oblique view, which images more tissue. The combination of poor quality imaging and the investigators’ resistance to taking corrective action led two advisors’ resignation in protest. In addition, technologists who participated in the trial received no special training in performing mammography. Radiologists new to mammography also received no training in interpretation.18 There was also a lack of immediate follow-up after recommendations for biopsy had been made. Overall, about 25% of the recommended biopsies were ultimately not performed.18

The CNBSS trials are an excellent example of the need to carefully consider all facets of a large-scale screening trial before accepting its results as scientifically valid. The numerous design and execution flaws described above explain in large part why the results of the CNBSS are dramatically different from those of all other RCTs. Ultimately, on the basis of the methodology of the CNBSS, the World Health Organization excluded those results when analysing the breast-screening data in the International Agency for Research on Cancer report.21

The greatest debate on the value of breast screening arose after the publication of a highly controversial but frequently quoted meta-analysis by Gotzsche (a medical statistician and director of the Nordic Cochrane Centre) and Olsen in The Lancet in 2000. Their study concluded that there was no benefit of mortality reduction by screening, after discarding six of eight RCTs because they deemed the randomisation to be “inadequate”. The only two RCTs included in their analysis showed no benefit, including the Malmo trial and the notorious CNBSS.7 22

Gotzsche and Olsen’s critique and methodology have caused much controversy and, in turn, have been criticised heavily by leading expert breast imagers, public health clinicians, and professional bodies such as the Society of Breast Imaging.7 8 23 24 25 26 27 Gotzsche and Olsen’s use of quoted figures from cancer registries rather than actual patient data, their selective approach to studies, and in particular the ignoring of the flaws of the CNBSS, have received the harshest criticism. Many experts have commented that Gotzsche and Olsen overstated the limitations of most of the well-executed RCTs, thereby reflecting a “context-free” application of guidelines in a way that did not address the real issues relevant to the effectiveness of mammographic screening. Moreover, Gotzsche and Olsen’s recommendation to abandon screening altogether has hampered collaborative efforts to improve breast cancer detection and control.27

In February 2014, the Swiss Medical Board attempted to overturn the widespread practice of mammography screening in Switzerland by stating that new systematic mammography screening programmes should not be introduced, irrespective of women’s age, and recommended that existing programmes should be discontinued. Their main argument was that the absolute risk reduction in breast cancer mortality was low and that the adverse consequences of screening (false-positive test results, overdiagnosis, overtreatment, and high costs and expense of follow-up tests and procedures) were substantial.28 29

The Swiss Medical Board’s attempt initiated a new phase of heated arguments and debate about the benefits of screening. Expert breast cancer clinicians in both the United States and Europe (including leading cancer associations in Switzerland) rejected their report. One criticism was that the Swiss Medical Board relied heavily on the controversial work by Gotzsche and Olsen and again quoted data from the flawed CNBSS. Another criticism that attracted great attention was the questionable “expert panels” of the board: they included a medical ethicist, a clinical epidemiologist, a clinical pharmacologist, an oncology surgeon, a nurse scientist, a lawyer, and a health economist. Frontline breast imagers, with expertise in diagnosing breast diseases, were excluded from the review panels because of a “conflict of interest”.28 29

The Swiss Medical Board did not adequately consider the fact that assessment of the balance between benefit and harm involves a value judgement that each woman should make only after she is fully informed about the strengths and weaknesses of screening mammography. They also disregarded the extensive literature in support of screening mammography (RCTs and population service screening studies), making their attempt at stopping national mammography screening unjustified.

Commonly mentioned potential harms of screening include false-positive mammograms, recall for additional imaging, a false-positive biopsy, missed breast cancer, radiation dose, patient anxiety, and, above all, overdiagnosis.

Overdiagnosis is defined as the detection (and subsequent actions taken) of a cancer by screening that would not have progressed to become symptomatic in a woman’s lifetime.1 The estimation of overdiagnosis is complex, highly debated, and very difficult to measure.3 Reported figures range widely, from 0% to 50%, vary greatly in terms of methodological rigour, and testify to the inexact nature of most mathematical models.30 31 32 33 34 When appropriate adjustments for temporal trends, risk factors, and lead time are considered, the level of overdiagnosis should be low, within the range of 0% to 10%.32 Importantly, a recent study of over 5 million women (aged 50-64 years) screened by the United Kingdom’s National Health Service showed that there was a significant negative association between the detection of DCIS at screening and invasive interval cancers. In that study, Duffy and colleagues analysed the data from four consecutive screen years and the 36-month outcome after each relevant screen. For every three screen-detected cases of DCIS, there was one less interval case of invasive cancer over the next 3 years. They agreed that the policy on detection and treatment of DCIS is worthwhile and can prevent subsequent invasive cancers.35

The effect of screening on heightening a patient’s anxiety has also been long questioned by critics, but the magnitude of the effect may have been over-exaggerated. In a survey of over 1200 women with a 6-question anxiety scale to understand the short-term and long-term impact of a recall examination, women involved in the digital mammographic imaging screening trial demonstrated only a transient, limited increase in anxiety after a false-positive mammogram compared with those with a negative mammogram, and there was no difference between the two groups’ intention to undergo mammography again in the subsequent 2 years.36 Schwartz et al reported that 96% of American women who received a false-positive mammography report were glad that they underwent the test and remained supportive of screening.37 Most women agreed that the anxiety, inconvenience, and the few image-guided needle biopsies using local anaesthesia associated with a recall from screening, were minor compared with dying of breast cancer.38

To summarise, papers citing a high rate of overdiagnosis in screening (in the magnitude of 20% or higher) and claiming that false-positives are a significant cause of patient anxiety are believed by most experts to be overstating the case.

Although it is important to discuss all aspects of screening asymptomatic women (including potential harm), the harm of not attending screening is underestimated and not discussed. For instance, women who do not attend screening have significantly larger tumours, a higher stage at diagnosis, poorer overall and disease-specific survival, and higher costs of treatment.39 It has been estimated that the cost of treating advanced metastatic breast cancer exceeds US$ 250 000 per patient, and the average cost of treating advanced cancer in the first year after diagnosis is almost double that of early cancers, mainly owing to the difference in costs of chemotherapy.3 40 The cost of treatment and lost productivity each year will far exceed the cost of annual screening and, additionally, do not include the indirect value of the lives saved (as a productive member of workforce).1

The incidence of breast cancer continues to increase worldwide. It remains highest in the United States and Europe, but has been increasing substantially in Asian countries over the past three decades.41 Studies that compare invasive breast cancer data from Asia with those from the United States over a 20-year period have shown that female breast cancer incidence among Asian and Western populations is more similar than expected.42 The incidence of female breast cancer in China will continue to rise, and is expected to exceed 100 per 100 000 women by 2021, giving a total of 2.5 million cases.43

According to GLOBOCAN 2012 of the International Agency for Research on Cancer, the specialised cancer research agency of the World Health Organization, almost a quarter (24%) of all breast cancers were diagnosed within the Asia-Pacific region, with the greatest number occurring in China (46%).44 The age-standardised incidence rate was highest among Taiwanese (65.9 per 100 000), followed by Singaporeans, South Koreans, and Japanese.44 In a multiracial country such as Singapore, Chinese women have been noted to have a significantly higher risk of developing breast cancer than Malays and Indians.45

The disease burden in Hong Kong is no different. Locally, the age-standardised incidence rate was 58.8 per 100 000 in 2015, with over 3900 new cases per year.46 A study of the local trend in female breast cancer incidence from 1973 to 1999 by the University of Hong Kong showed a significant yearly increase of an average of 3.6%; the increase was most marked and continued to accelerate in the younger age-groups. It was speculated that such trend changes were related to Westernisation of lifestyle.47 All these data indicate that the disease burden in Hong Kong is increasing and comparable to that of all other civilised Asian countries and cities.

Breast screening services in Asian countries and cities are highly variable: some have advanced nationwide screening programmes and others have less developed programmes.48 South Korea and Taiwan are both well recognised for their experience in running such programmes, the former having the highest intake rate and the latter being the most well-structured.

South Korea places a very strong emphasis on screening for cancer control in general. Its national health service offers mammography and CBE every 2 years to women aged 40 or older, and at no cost to the 50% of people with the lowest incomes. Their programme is popular and widely accepted by the general public, and achieved an uptake of as high as 66% in 2014. Benefits of downstaging from screening were also observed. However, South Korea encountered a problem of potential overdiagnosis, with a noticeably higher false-positive rate when compared with other places.

Taiwan’s health authorities have been recognised for rolling-out well-organised and well-resourced screening programmes, with good support from a local randomised controlled trial showing a reduction in mortality by 40% with mammography screening.49 Since 2004, their health service has provided free breast screening to women aged 50 to 69 years, expanded in 2010 to those aged 40 to 49 years. By 2015, about 40% of the target population participated in screening. It is believed that the cause of the suboptimal participation rate was not due to capacity or outreach, but rather the Taiwanese public’s values and attitude. Nonetheless, with more resources being directed to public education and motivation, Taiwan’s health authorities are pushing their goal to 60% by 2018.

The experience of screening programmes in Singapore and Japan is more equivocal. Despite having sufficient scientific evidence to support their role in reducing mortality and reducing invasive cancer incidence, the participation rate has remained lower than expected, mostly owing to cultural barriers and paradigms, or a lack of central governing. Singapore established its national, population-wide screening programme (BreastScreen Singapore) in 2002 and now covers women aged 40 to 69 years. The participation rate has been noted to plateau at 40% since 2010, short of the target of 70%. The health promotion board believes that apart from cultural issues, costs (as screening is paid by an individual’s medical insurance account) constitute the greatest barrier to uptake.

The study of population-based screening in Japan has been complex, with scattered data owing to the lack of a single national organisation for monitoring. The participation rate remains lower than in other comparable Asian countries in the past century, again likely because of cultural paradigms. Despite these barriers, in the past decade, Japanese health officials have started designing their own methods and protocols for screening, particularly targeting the higher incidence of cancer among younger women (aged 40-49 years) and the large proportion of patients with dense breasts. After the launch of government-funded screening programmes, a clinical trial that started in 2007 (Japan Strategic Anti-cancer Randomised Trial, J-START) of over 70 000 women undergoing adjunctive ultrasonography to supplement mammography for screening showed an increased sensitivity and detection rate for early preclinical cancers.41

In China, there is no nationwide screening programme for breast cancer. A mammographic screening programme was attempted in 2005 but was abandoned because of lack of funding and concerns about false-positive diagnoses. Despite these barriers, national guidelines established in 2007 recommend annual mammography for women aged 40 to 49 years, and every 1 to 2 years for those aged 50 to 69 years. In a Beijing study of 1.46 million women (aged 35 to 59 years) who underwent screening by ultrasonography from 2009 to 2011, the cancer detection rate was 48.0 per 100 000, including 440 cases at early stage that constituted 69.7% of cases detected. The detection rate was lower than anticipated, maybe in part owing to the young age of the screened group and omission of mammography as a screening tool. Subsequently, a second-generation screening programme was initiated in 2012, after modification of the screening methods, cohort size (6 million), and target population that included women aged 35 to 64 years. The new screening procedures include parallel CBE and breast ultrasonography; women with suspicious findings from either examination are recommended to undergo mammographic imaging.50 Although the design of this screening protocol deviates from the standard practice of other countries, we believe that the programme will bring more research data and experience, and eventually lead to more comprehensive guidelines and consensus on a screening approach in China.

The awareness of breast cancer and acceptance of screening in Hong Kong is growing, but is still inadequate. According to the latest Breast Cancer Registry Report No 8 (2016), which covers 13 453 breast cancer patients diagnosed from 2006 onwards, the mean and median age of patients at diagnosis was 52.6 and 51.3 years, respectively, and about two-thirds of patients were aged 40 to 59 years. The screening habits among these patients were poor, with over 60% never having undergone mammography screening before their cancer diagnosis.51

Although to date there has been no population-based screening for women in Hong Kong, opportunistic screening has long been practised in the private sector. The largest voluntary self-financed and self-referred opportunistic screening programme is run by the Tung Wah Group of Hospitals. In a retrospective review of their performance from 1998 to 2002 involving over 46 600 screening mammograms, a breast cancer detection rate of five cases per 1000 population was noted, which was comparable to the detection rate of Western screening programmes at that time.52

Regarding the input of expertise and quality assurance, the Hong Kong College of Radiologists issued their mammographic statement in 2006 (latest revision in 2015).53 Quoting desirable goals recommended by the United Kingdom and United States as a reference the statement sets specific benchmarks for standards of mammographic machines, quality of screening mammograms, radiation dose limits, and accreditation requirements of reporting radiologists.53 Given these guidelines, together with recent advances in mammographic technology, we believe that there should be room for further local development of large-scale quality breast-screening programmes.

When planning a breast-screening programme, it is necessary to decide whom to screen (ie, at what age and the target screening population) and how to screen (ie, screening method).

For the decision of whom to screen, we should note that the mean age at diagnosis of breast cancer in Chinese women is 45 to 55 years, considerably younger than for western women.43 Starting screening at age 40 or 45 years would likely be a better fit for Chinese women than starting at age 50 years, as recommended by some western guidelines. As for the target screening population, current data favour universal screening over risk-based screening (pre-selecting patients according to risk profile). First, one should note that 80% of women with newly diagnosed breast cancer have no family history (ie, first-degree relative) or other significant previous risk factors, and therefore risk-based screening will miss a majority of screen-detected breast cancers.3 54 Second, a recent 10-year population-based cohort study of over 1.4 million asymptomatic Taiwanese women undergoing various breast-cancer screening regimens showed that universal mammography screening based only on age and sex was more effective than other screening regimens (risk-based biennial mammography screening or annual CBE alone).49 In that study, universal biennial mammography screening was associated with a 41% reduction in mortality and a rate of overdiagnosis of only 13%. In contrast, risk-based biennial mammography (pre-selecting patients according to risk profile or risk score) did not lead to any statistically significant reduction in mortality. Moreover, among all screening regimens, only universal biennial screening was associated with a clear downstaging shift in tumours (30% reduction of stage 2+ cancers), a crucial factor that can improve patient outcome.49

Regarding methods of screening, conventional screening uses standard two-view full-field digital (two-dimensional; 2D) mammography. Multiple studies have proven that screening by digital breast tomosynthesis (DBT; also called three-dimensional mammography) can increase cancer detection rates compared with 2D mammography alone, and can reduce the recall rate for benign findings (false-positives). 1 55 A retrospective analysis of over 454 000 screens showed that use of DBT was associated with relative increases of 41% in invasive cancer detection, 49% in positive predictive value (PPV) for recall, and 21% in PPV for biopsy, in addition to a 15% reduction in the overall number of recalls.56 A recent meta-analysis by a Korean group also showed that screening with DBT increased detection of early invasive cancers of <2 cm.57 The American College of Radiology Commission on Breast Imaging now recommends that mammography and DBT are “usually appropriate” for screening of average-risk women, noting that DBT addresses some limitations of standard digital mammography.58 In Hong Kong, DBT has been increasingly adopted to replace or serve as an adjunct to 2D mammography in opportunistic screening. We anticipate that the shift to DBT screening will become a global trend.

The use of whole-breast ultrasonography to screen dense breasts is also commonly adopted in Asia, including for opportunistic screening in Hong Kong. In Japan, this practice was reinforced by a government-funded RCT (J-START) that studied the use of adjunctive ultrasonography to supplement mammography in screening over 70 000 women. The J-START study showed favourable results of increased sensitivity and detection rate for early, preclinical cancers.41

Screening for high-risk women is often considered a separate entity. According to the American College of Radiology’s Appropriateness Criteria, women at high risk due to prior mantle radiation between the ages of 10 and 30 years should start mammography 8 years after radiation therapy, but not before age 25. For women with a genetic predisposition, annual screening mammography is recommended to begin 10 years earlier than the age that an affected relative had been diagnosed, but not before age 30. Annual screening by magnetic resonance imaging is recommended in high-risk women as an adjunct to mammography.59

We believe that health care in Hong Kong should have the capability and expertise to roll out quality, large-scale population-screening programmes that are comparable to those in other developed Asian countries and cities. When we examine the common themes among available guidelines, literature, and expert reviews worldwide, the global trend is to provide women with an informed choice.

In the discussion of whether breast-cancer screening is feasible, one should bear in mind that this is an emotive issue. Apart from the critical appraisal of scientific evidence, the interpretation of literature and subsequent formulation of recommendations should always account for the socioeconomic, historical, and contextual realities. The value judgement of women should also be respected.

Frontline experts, including breast surgeons, oncologists, breast radiologists, and their representative professional associations should all participate in guideline panels, with a will to end the ‘mammography wars’. Our Holy Grail should always be focused on improving cancer detection, reducing mortality, and improving patient outcome.

1. Eby PR. Evidence to support screening women annually. Radiol Clin North Am 2017;55:441-56.

2. Society of Breast Imaging Breast Screening Leadership Group. Screening in the 40-49 Age Group. Available from: https://www.sbi-online.org/RESOURCES/BreastScreeningLeadershipGroupResources.aspx. Accessed 19 Nov 2017.

3. Ray KM, Price ER, Joe BN. Evidence to support screening women in their 40s. Radiol Clin North Am 2017;55:429-39.

4. The American College of Radiology. Guidelines for Breast Cancer Screening—An Update. SBI Breast Imaging Symposium 2016. Available from: https://www.sbi-online.org/Portals/0/Breast%20Imaging%20Symposium%202016/Final%20Presentations/4-7%20800am%20Smith%20-%20Guidelines%20for%20Breast%20Cancer%20Screening.pdf. Accessed 19 Nov 2017.

5. Shieh Y, Eklund M, Sawaya GF, et al. Population-based screening for cancer: hope and hype. Nat Rev Clin Oncol 2016;13:550-65. Crossref

6. Byrne SK. What's the Buzz: Tell me what’s happening in breast cancer screening. Asia Pac J Oncol Nurs 2017;4:122-6. Crossref

7. Freer P, Moy L, DeMartini W; the Screening Leadership Group. Breast Cancer Screening: Understanding the Randomised Controlled Trials. Available from: https://www.sbi-online.org/Portals/0/Screening%20Leaders/Breast%20Cancer%20Screening_Understanding%20the%20Randomized%20Controlled%20Trials.pdf. Accessed 19 Nov 2017.

8. Duffy SW, Chen TH, Smith RA, Yen AM, Tabar L. Real and artificial controversies in breast cancer screening. Breast Cancer Manage 2013;2:519-28. Crossref

9. Newell M, Eby PR; the Breast Screening Leadership Group. Benefits of Screening Mammography: Data from Population Service Screening. Available from: https://www.sbi-online.org/Portals/0/Screening Leaders/Benefitsof Screening Mammography_Data from PopulationService Screening.pdf. Accessed 19 Nov 2017.

10. Miller AB, Baines CJ, To T, et al. Canadian National Breast Screening Study: 2. Breast cancer detection and death rates among women aged 50 to 59 years. CMAJ 1992;147:1477-88.

11. Miller AB, Baines CJ, To T, et al. Canadian National Breast Screening Study: 1. Breast cancer detection and death rates among women aged 40 to 49 years. CMAJ 1992;147:1459-76.

12. Miller AB, To T, Baines CJ, et al. Canadian National Breast Screening Study-2: 13-year results of a randomized trial in women aged 50-59 years. J Natl Cancer Inst 2000;92:1490-9. Crossref

13. Miller AB, To T, Baines CJ, et al. The Canadian National Breast Screening Study-1: breast cancer mortality after 11 to 16 years of follow-up. A randomized screening trial of mammography in women age 40 to 49 years. Ann Intern Med 2002;137:305-12. Crossref

14. Miller AB, Wall C, Baines CJ, et al. Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial. BMJ 2014;348:g366. Crossref

15. Kopans DB, Feig SA. The Canadian National Breast Screening Study: a critical review. AJR Am J Roentgenol 1993;161:755-60. Crossref

16. Burhenne LJ, Burhenne HJ. The Canadian National Breast Screening Study: a Canadian critique. AJR Am J Roentgenol 1993;161:761-3. Crossref

17. Kopans D. Breast Imaging. 3rd ed. Lippincott Williams & Wilkins: Philadelphia; 2007.

18. Heywang-Köbrunner SH, Schreer I, Hacker A, et al. Conclusions for mammography screening after 25-year follow-up of the Canadian National Breast Cancer Screening Study (CNBSS). Eur Radiol 2016;26:342-50. Crossref

19. Boyd NF. The review of randomization in the Canadian National Breast Screening Study. Is the debate over? CMAJ 1997;156:207-9.

20. Baines CJ, Miller AB, Kopans DB, et al. Canadian National Breast Screening Study: assessment of technical quality by external review. AJR Am J Roentgenol 1990;155:743-7; discussion 8-9. Crossref

21. International Agency for Cancer on Research (IARC), World Health Organization. IARC Handbooks of Cancer Prevention. Volume 7: Breast Cancer Screening. IARC Press; 2002. Available from: http://www.iarc.fr/en/publications/pdfs-online/prev/handbook7/Handbook7_Breast-4.pdf. Accessed 15 Mar 2018.

22. Gotzsche PC, Olsen O. Is screening for breast cancer with mammography justifiable? Lancet 2000;355:129-34. Crossref

23. Tabár L, Dean PB, Cen TH, et al. The impact of mammography screening on the diagnosis and management of early-phase breast cancer. In: Francescatti D, Silverstein M, editors. Breast Cancer: A New Era in Management. Springer New York; 2014: 31-78. Crossref

24. Bock K, Borisch B, Cawson J, et al. Effect of population-based screening on breast cancer mortality. Lancet 2011;378:1775-6. Crossref

25. Patnick J, Perry N, de Wolf C. Effect of population-based screening on breast cancer mortality—Authors’ reply. Lancet 2012;379:1298.

26. Mcneil DG. Confronting cancer: scientist at work—Peter Gotzsche; A career that bristles with against-the-grain conclusions. Available from: http://www.nytimes.com/2002/04/09/science/confronting-cancer-scientist-work-peter-gotzsche-career-that-bristles-with.html. Accessed 19 Nov 2017.

27. Cuzick J. Breast cancer screening—time to move forward. Lancet 2012;379:1289-90. Crossref

28. Chiolero A, Rodondi N. Lessons from the Swiss Medical Board recommendation against mammography screening programs. JAMA Intern Med 2014;174:1541-2. Crossref

29. Biller-Andorno N, Juni P. Abolishing mammography screening programs? A view from the Swiss Medical Board. N Engl J Med 2014;370:1965-7. Crossref

30. Helvie MA, Chang JT, Hendrick RE, et al. Reduction in late-stage breast cancer incidence in the mammography era: Implications for overdiagnosis of invasive cancer. Cancer 2014;120:2649-56. Crossref

31. Kopans DB, Smith RA, Duffy SW. Mammographic screening and “overdiagnosis”. Radiology 2011;260:616-20. Crossref

32. Puliti D, Duffy SW, Miccinesi G, et al. Overdiagnosis in mammographic screening for breast cancer in Europe: a literature review. J Med Screen 2012;19 Suppl 1:42-56. Crossref

33. Duffy SW, Agbaje O, Tabar L, et al. Overdiagnosis and overtreatment of breast cancer: estimates of overdiagnosis from two trials of mammographic screening for breast cancer. Breast Cancer Res 2005;7:258-65. Crossref

34. Bleyer A, Welch HG. Effect of three decades of screening mammography on breast-cancer incidence. N Engl J Med 2012;367:1998-2005. Crossref

35. Duffy SW, Dibden A, Michalopoulos D, et al. Screen detection of ductal carcinoma in situ and subsequent incidence of invasive interval breast cancers: a retrospective population-based study. Lancet Oncol 2016;17:109-14. Crossref

36. Tosteson AN, Fryback DG, Hammond CS, et al. Consequences of false-positive screening mammograms. JAMA Intern Med 2014;174:954-61. Crossref

37. Schwartz LM, Woloshin S, Fowler FJ, Jr, et al. Enthusiasm for cancer screening in the United States. JAMA 2004;291:71-8. Crossref

38. Kopans DB. An open letter to panels that are deciding guidelines for breast cancer screening. Breast Cancer Res Treat 2015;151:19-25. Crossref

39. Duffy SW, Chen TH, Smith RA, Yen AM, Tabar L. Real and artificial controversies in breast cancer screening. Breast Cancer Manage 2013;2:519-28. Crossref

40. Montero AJ, Eapen S, Gorin B, et al. The economic burden of metastatic breast cancer: a U.S. managed care perspective. Breast Cancer Res Treat 2012;134:815-22. Crossref

41. Ohuchi N, Ishida T, Kawai M, et al. Randomized controlled trial on effectiveness of ultrasonography screening for breast cancer in women aged 40-49 (J-START): research design. Jpn J Clin Oncol 2011;41:275-7. Crossref

42. Sung H, Rosenberg PS, Chen WQ, et al. Female breast cancer incidence among Asian and Western populations: more similar than expected. J Natl Cancer Inst 2015;107. Crossref

43. Fan L, Strasser-Weippl K, Li JJ, et al. Breast cancer in China. Lancet Oncol 2014;15:e279-89. Crossref

44. Youlden DR, Cramb SM, Yip CH, et al. Incidence and mortality of female breast cancer in the Asia-Pacific region. Cancer Biol Med 2014;11:101-15.

45. Singapore Health Promotion Board. National Registry of Diseases Office. Singapore Cancer Registry Interim Annual Report: Trends in cancer incidence in Singapore 2010-2014. Available from: https://www.nrdo.gov.sg/docs/librariesprovider3/default-document-library/cancer-trends-2010-2014_interim-annual-report_final-%28public%29.pdf?sfvrsn=0. Accessed 19 Nov 2017.

46. Hospital Authority, Hong Kong. Hong Kong Cancer Registry. Available from: http://www3.ha.org.hk/cancereg/. Accessed 19 Mar 2018.

47. Leung GM, Thach TQ, Lam TH, et al. Trends in breast cancer incidence in Hong Kong between 1973 and 1999: an age-period-cohort analysis. Br J Cancer 2002;87:982-8. Crossref

48. Breast cancer in Asia—The Challenge and Response. A Report from the Economist Intelligence Unit. Available from: https://www.eiuperspectives.economist.com/sites/default/files/EIU Breast Cancer in Asia_Final.pdf. Accessed 19 Nov 2017.

49. Yen AM, Tsau HS, Fann JC, et al. Population-based breast cancer screening with risk-based and universal mammography screening compared with clinical breast examination: a propensity score analysis of 1 429 890 Taiwanese women. JAMA Oncol 2016;2:915-21. Crossref

50. Song QK, Wang XL, Zhou XN, et al. Breast cancer challenges and screening in China: lessons from current registry data and population screening studies. Oncologist 2015;20:773-9. Crossref

51. A Hong Kong Breast Cancer Foundation Initiative. Hong Kong Breast Cancer Registry Report No. 8, 2016. Available from: http://www.hkbcf.org/download/bcr_report8/hkbcf_report_2016_full_report.pdf. Accessed 19 Nov 2017.

52. Lui CY, Lam HS, Chan LK, et al. Opportunistic breast cancer screening in Hong Kong; a revisit of the Kwong Wah Hospital experience. Hong Kong Med J 2007;13:106-13.

53. Hong Kong College of Radiologists Mammography Statement. Available from: https://www.hkcr.org/templates/OS03C00336/case/lop/HKCR MammographyStatement_rev20150825.pdf. Accessed 19 Nov 2017.

54. Destounis SV, Arieno AL, Morgan RC, et al. Comparison of breast cancers diagnosed in screening patients in their 40s with and without family history of breast cancer in a community outpatient facility. AJR Am J Roentgenol 2014;202:928-32. Crossref

55. Rafferty EA, Rose SL, Miller DP, et al. Effect of age on breast cancer screening using tomosynthesis in combination with digital mammography. Breast Cancer Res Treat 2017;164:659-66. Crossref

56. Friedewald SM, Rafferty EA, Rose SL, et al. Breast cancer screening using tomosynthesis in combination with digital mammography. JAMA 2014;311:2499-507. Crossref

57. Yun SJ, Ryu CW, Rhee SJ, et al. Benefit of adding digital breast tomosynthesis to digital mammography for breast cancer screening focused on cancer characteristics: a meta-analysis. Breast Cancer Res Treat 2017;164:557-69. Crossref

58. Monticciolo DL, Newell MS, Hendrick RE, et al. Breast cancer screening for average-risk women: recommendations from the ACR commission on breast imaging. J Am Coll Radiol 2017;14:1137-43. Crossref

59. Expert Panel on Breast Imaging; Mainiero MB, Moy L, Baron P, et al. ACR Appropriateness Criteria Breast Cancer Screening. J Am Coll Radiol 2017;14:S383-90. Crossref

Childhood lead poisoning is a major public health concern in many countries as it may result in serious health consequences. In general, children absorb a greater percentage of lead from the gastrointestinal tract than adults.1 2 Fasting, iron deficiency, and calcium deficiency may further increase gastrointestinal absorption of lead.1 2 In Hong Kong, food safety has become a major public concern in recent years. In 2015, the Hong Kong SAR Government and its citizens faced a major public health crisis due to the presence of lead in the drinking water of a number of public housing estates. Fortunately, no child was diagnosed with lead poisoning and hence did not require chelation therapy.

This review discusses the possible sources of lead exposure and poisoning in children, public health implications, medical management, and neurodevelopmental outcomes with a focus on the situation in Hong Kong. References were searched in January 2017 using keywords: ((“toxicity”) OR (“poisoning”) AND “lead”) AND ((“lead toxicity”) OR (“lead poisoning”) AND “Hong Kong”) in PubMed, limited to ‘human’, with no filters for article type or date of publication. Discussion is based on, but not limited to, the search results.

According to the World Health Organization, lead is a ubiquitous, naturally occurring material that exists in air, dust, soil, and water. It is also widely present in industrial products including petrol, paints, ceramics, food cans, candies, cosmetics, traditional remedies, batteries, solder, stained glass, crystal vessels, ammunition, ceramic glazes, jewellry, and toys.3 4 5 6 7 It is also found in human breast milk.8 In the US, lead-containing paint in old houses is one of the main sources of lead exposure or poisoning in children. In many industrialising countries including China, smelters, refineries, mines, soil contamination, and use of lead gasoline are important sources of lead exposure.

Water supply can be contaminated with lead.9 10 11 12 A recent example is the drinking water crisis that occurred in the post-industrial city of Flint in Michigan, US.11 In this situation, lead in drinking water is absorbed to a greater extent than lead in food and may account for more than 50% of the lead ingested by children.13 The US Environmental Protection Agency recommended taking actions when lead in drinking water exceeds 15 parts per billion, including taking further steps to optimise their corrosion-control treatment (for water systems serving 50 000 people who have not fully optimised their corrosion control), educating the public about lead in drinking water and actions consumers can take to reduce their exposure to lead, replacing the portions of lead service lines (lines that connect distribution mains to customers) under the water system’s control.14 Most incidents of lead contamination of household water were caused by copper plumbing with lead solder. Occasionally, lead pipes may also be responsible although they are now rarely used.

No review article about lead toxicity in Hong Kong was found on MEDLINE/PubMed at the time of writing. Nevertheless discrete reports from different institutes about local lead toxicity are available, with the earliest report dated 1969, when 121 Gurkha soldiers investigated for ‘epidemic myalgia’ were found to have lead poisoning due to curry powder contaminated with lead chromate.5 Later in 1977, a 4-month-old girl presented with a grand mal seizure after ingestion of Chinese herbal medicines containing lead.3 In 1991, a case of acute lead poisoning with cerebral oedema and death was reported in a 2-month-old girl.15 Two other case reports described a total of four adult patients who had lead poisoning following ingestion of two different Chinese herbal pills. They had variable clinical presentations ranging from relatively asymptomatic to end-organ complications.16 17 In 2014, a middle-aged woman who presented with motor neuron disease was found to have a raised blood lead level after consumption of ashes from burnt Chinese talismans (Dao religious handwriting believed to have the power to expel evil).18 Hong Kong is a commercialised city with very few industries and factories. The main sources of lead are contaminated food, toys, adulterated medicines, traditional remedies, and batteries. A study of children with eczema revealed that disease severity and quality of life correlated with blood lead level, and patients who had used traditional herbal remedies generally had a higher blood lead level.19 Contaminated water in public housing estates was first described in 2015 in Hong Kong.20

There is no screening programme for lead or other heavy metals in Hong Kong. Guidelines about lead screening, however, are available worldwide. In 2013, nearly 30 questionnaires were available, designed as a preliminary screening tool for paediatric lead poisoning. They showed variable sensitivity and specificity based on systematic reviews.21 22 According to the latest guideline in 2012 from the Centers for Disease Control and Prevention (CDC)’s Advisory Committee on Childhood Lead Poisoning Prevention (ACCLPP), clinicians should perform an environmental assessment before screening children for lead poisoning.13 23 This changed the practice of universal screening of all children for elevated blood lead levels2 23 24 to targeted screening after mathematical simulations suggested that such screening among 1-year-old children may not be cost-effective, especially in communities with a lower prevalence of lead poisoning.25 At the same time, with reference to the level of ‘lead toxicity’ in children, ACCLPP eliminated the term ‘level of concern’ for blood lead level (previously defined as 10 µg/dL) and replaced it with a reference level of 5 µg/dL, based on the 97.5th percentile of the population blood lead level in children aged between 1 and 5 years.2 13 24 This was supported by the American Academy of Pediatrics who acknowledged that even the lowest degree of lead exposure might harm children,13 23 26 and echoed the European Food Safety Authority who concluded that there is no known safe exposure to lead as evidenced by international studies in Europe.27 28 29 In other words, there is no safe or ‘non-toxic’ blood lead level.

A systematic review of the effectiveness of interventions to reduce lead exposure from consumer products and drinking water in Germany concluded that the limited quantity and quality of the evidence derived from measuring blood lead level and associated health outcomes suggested an urgent need for more robust research into the effectiveness of interventions to reduce lead exposure from consumer products and drinking water, especially for regulatory interventions.6 The dilemma is that there is no safe lead level, and it is impossible to completely eliminate lead from any city. Hence routine measurement of blood lead level is not considered useful for management.

Lead is a potent neurotoxin. Neurotoxicity is more prominent in children and infants in-utero than in adults because of the incomplete blood-brain barrier.8 30 31 Despite this, the majority of children with lead poisoning is asymptomatic. Neurological manifestations/complications of lead poisoning include acute encephalopathy, peripheral neuropathy, hearing loss, and neurobehavioural deficits such as hyperactivity, withdrawal, developmental delay, lower intelligence quotient, higher academic failure, and lower overall life achievements.32 33 34 Meta-analysis of 19 studies with a total of 8561 children suggested that lead exposure is positively related to conduct problems.35 The causal effect of lead exposure on these behavioural problems, however, cannot be proven as poor housing, poverty, and other stressors are significant confounding factors.36 According to the American Academy of Neurology, the clinical correlation of mildly elevated but non-toxic levels of blood lead with developmental status remains controversial.

Lead lines at the junction of the gums and teeth, if present, suggest severe and prolonged lead exposure. Other clinical manifestations/complications include colicky abdominal pain, constipation, growth retardation, vitamin D deficiency, anaemia, and nephropathy.1 2 24 Rarely, lead poisoning may also lead to hypertension, immunodeficiency, osteoporosis, changes in serum level of sex hormones and thyroid hormones, premature delivery, pre-eclampsia, infertility, and malignancy.30 37 38

Despite the potential harmful effects of lead on humans, lead exposure is not synonymous with lead toxicity. According to the Agency for Toxic Substances and Disease Registry, exposure is defined as contact with a substance by swallowing, breathing, or touching the skin or eyes. Exposure may be short-term (acute exposure), of intermediate duration, or long-term (chronic exposure). A toxic agent is a chemical or physical (eg radiation, heat, cold, microwaves) agent that, under certain circumstances of exposure, can cause harmful effects to living organisms (https://www.atsdr.cdc.gov/glossary.html). In other words, it is the lead toxicity per se not lead exposure that necessitates treatment. Although there is no definitive toxic level for blood lead, the affected child should be continuously monitored to ensure medical intervention if necessary.

The American Academy of Neurology suggests screening of children with developmental delay for lead toxicity. This should target those with known identifiable risk factors for excessive lead exposure, including children aged 1 to 2 years living in housing built before 1950, exposure to lead-containing folk remedies, child immigrants from countries where lead poisoning is prevalent, children with iron deficiency, children with developmental delay with pica disorder, victims of neglect, and children of low-income families.39

The CDC’s ACCLPP has updated its guidelines for blood lead screening among children eligible for Medicaid by providing recommendations to improve screening and information for health care providers, state officials, and others interested in lead-related services for Medicaid-eligible children.40 Because state and local officials are more familiar than federal agencies with local risks for elevated blood lead levels, the CDC recommends that state and local officials have the flexibility to develop blood lead screening strategies that reflect local risk. Rather than provision of universal screening to all Medicaid children, which was previously recommended, state and local officials should target screening towards specific groups of children in their area at higher risk. The updated CDC recommendations provide strategies to (1) improve screening rates of children at risk of an elevated blood lead level, (2) develop surveillance policies that are not solely dependent on blood lead level testing, and (3) assist states with evaluation of screening plans.

Neurocognitive impairment in children is a grave concern as it may be irreversible. The current policy in Hong Kong is to perform lead exposure risk assessment in citizens with a borderline raised blood lead level, and carry out developmental assessment in affected children under the age of 12 years, while continuously monitoring all citizens with raised blood lead levels. The threshold for further management for children under 18 years, pregnant women, and lactating mothers is lower than that for the general adult population. This strategy correlates with the targeted screening promoted by the ACCLPP.

The protocol of management according to blood lead level, adopted from ‘Care plan for residents of public estates with elevated lead level in drinking water’, was last updated on 28 August 2015 by the Centre for Health Protection, Hong Kong SAR.41

Management of patients with lead exposure involves not only the pharmacological management of toxicity, but also strategies for intervention and prevention of further exposure. Once an elevated lead level is found, the local health department should be notified and a home risk assessment performed to determine the need for abatement strategies. With the gradual lowering of the ‘blood lead level of concern’ by the CDC, the threshold for action has also decreased. The Pediatric Environmental Health Specialty Units have made recommendations for further evaluation and/or intervention based on the blood lead level.42

In all cases, identification and immediate removal of the source of lead exposure from the child’s environment is crucial to the successful management of the patient. Medical treatment of lead poisoning is relatively straightforward.40 43 44 45 46 There is no benefit in prescribing activated charcoal for lead ingestion since it binds lead poorly. Gastric lavage may be performed although the American Academy of Clinical Toxicology stated that there is no evidence to show that its use improves clinical outcome. Whole bowel irrigation has a theoretical benefit for decontamination of heavy metal ingestion but there are insufficient data at present to support or exclude its use.

For blood lead level between 20 and 45 µg/dL, the minimum medical management for children is to decrease their exposure to all sources of lead, to correct any iron deficiency and maintain an adequate calcium intake, and to test frequently to ensure that the child’s blood lead levels are decreasing. Although not approved by the CDC, some clinicians prescribe D-penicillamine for children within this range of blood lead level. Otherwise the patient should have a confirmatory venous blood lead level measured within 1 to 4 weeks as a venous sample is subjected to less contamination than a capillary one. A capillary blood sampling protocol has also been documented by the CDC, and is more practical than venous blood sampling, especially in infants. For blood lead level of <20 µg/dL in otherwise asymptomatic children, the principle of treatment is to provide long-term neurodevelopmental follow-up and counselling as well as periodic blood sampling to ensure lead level is not increasing and to continue until the level is <5 µg/dL.40 43 44 45 46 For symptomatic patients with blood lead level of <20 µg/dL, sequential measurements of blood lead level along with review of the child’s clinical status should be done at least every 3 months. Iron deficiency should be treated promptly. Children with blood lead levels in this range should be referred for environmental investigation and management. Identifying and eradicating all sources of excessive lead exposure is the most important intervention for decreasing blood lead levels.

Chelation therapy is recommended if the patient has a blood lead level of ≥45 µg/dL. Before starting therapy, the blood lead measurement must be repeated immediately for confirmation but treatment should not be delayed while awaiting the result if encephalopathy is suspected. Chelation therapy, especially in the setting of encephalopathy, can be complicated. The patient must be admitted to a hospital with at least a physician who has proficiency with chelation therapy and management of childhood lead poisoning. The decision as to which agent should be used depends on the blood lead level, the symptomatology, and the environmental lead burden. Intravenous fluids should be given if necessary to ensure adequate urine output to permit chelation and excretion of lead in the body.2 47 Fluid intake and output should be monitored to permit early detection of inappropriate antidiuretic hormone secretion.

Succimer (dimercaptosuccinic acid) is a water-soluble, oral chelating agent that is appropriate for asymptomatic children with a blood lead level of 45 to 69 µg/dL. The recommended dose is 10 mg/kg or 350 mg/m² three times per day.47 D-penicillamine is a second-line oral chelating agent because of its potential for significant side-effects (thromobocytopenia, leukopaenia, urticaria, angioedema, abnormal liver function, Stevens-Johnson syndrome, and nephrotic syndrome).47

Calcium disodium edetate (CaNa₂ EDTA) is a chelating agent that is preferably given by continuous intravenous infusion. The recommended dose is 35 to 50 mg/kg/day or 1000 to 1500 mg/m²/day.47 It should not be used as the sole agent in patients who manifest features of lead encephalopathy, because it does not cross the blood-brain barrier and can potentially lead to exacerbation of lead encephalopathy. Rather, dimercaprol (also referred to as British anti-Lewisite), which does cross the blood-brain barrier, should be used in combination with CaNa₂ EDTA. Dimercaprol is a parenteral chelating agent of choice for patients with lead encephalopathy; the recommended dose is 3 to 5 mg every 4 hours given by deep intramuscular injection. Combination therapy with CaNa₂ EDTA and dimercaprol or succimer should be instituted in symptomatic children with blood lead level of 45 to 69 µg/dL.2 47 Children whose blood lead level is ≥70 µg/dL should be treated as medical emergencies, preferably with intravenous therapy. A combination of intramuscular dimercaprol and intravenous CaNa₂ EDTA should be used for children with blood lead level of 70 to 99 µg/dL if there are features of lead encephalopathy or with a blood lead level of ≥100 µg/dL even in the absence of features of lead encephalopathy. Features of lead encephalopathy include persistent lethargy, persistent vomiting, headache, afebrile seizures, or coma.

Chelation therapy has its own limitations. With chronic lead ingestion, lead can be incorporated into the skeletal system and can be an endogenous reservoir of lead exposure that is hard to eliminate.2 47

Lead poisoning in childhood produces long-term problems with learning, intelligence, and earning power.48 Asymptomatic lead poisoning has a far better prognosis. Given that there is no safe blood lead level, the CDC stresses the importance of regular follow-up of children with elevated blood lead levels. A monitoring programme should include nutritional support (such as ensuring sufficient intake of calcium, vitamin D, vitamin C) to minimise lead absorption, preventive measures to avoid household lead exposure, and education of caregivers about sources of lead exposure, prevention of exposure, and ways to decrease intestinal absorption.40 44 45 46 Affected children should be followed up continuously at least until environmental sources of lead have been identified and eliminated, and thereafter until blood lead level has declined to <15 µg/dL for at least 6 months, while other objectives of the management plan are achieved. Long-term neurodevelopmental monitoring is also advised after a case is closed, in view of many of the neurological deficits that manifest late in life. Any surveillance should be continued until a child reaches 6 years of age, an age of critical learning transition points and elevated risk exposure, although the definitive duration of follow-up is unclear.40 43 44 45 46 Likewise, no end-point of follow-up is recommended by the Centre of Health Protection in Hong Kong.

It has been established that even low-level lead exposure can significantly impair the learning and educational attainment and neurodevelopment of a child.49 50 51 52 53 54 In-utero exposure to lead can adversely affect the infant’s neurodevelopment, independent of postnatal blood lead level. With no safe limit of blood lead level, rigorously reducing the amount of lead in the environment is imperative for young children and unborn babies.13

All authors have disclosed no conflicts of interest.

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