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Research News Updates and Blogs

Developments in Biliary Atresia Research

Recently, my life has revolved around a succession of airport hubs, hospitality lounges and the occasional overnight flight. Indeed within this nebulous half-life where time plays tricks on you I celebrated a birthday – and because I was in the departure lounge of Hong Kong International airport at the start as the clocks passed midnight and then flew back to Heathrow overnight, landing at 6 AM it lengthened the day by a full 7 hours!

All in the cause of spreading the message of what’s happening in the UK with biliary atresia and its management. One of my research fellows, Florian Friedmacher, and I recently published a paper on all the world’s published material on AB…ever [1]. This to do with illustrating output, which journals were most receptive, where the research happens etc. Figure 1 shows the exponential growth of output over the years, it’s a dramatic increase in work and does show that it’s a dynamic area of interest with plenty going on. Figure 2 shows which countries are most active. The USA is leading the field but the UK and Japan are notable for being joint 2nd in terms of published papers. What is also of interest is the remarkable resurgence up the league table that China has shown. This from almost a standing start in the 2000s. Most studies involving big numbers of patients will be from China in the coming decades.

At any one time, however, interest in the disease waxes and wanes. So, for instance at the biggest paediatric surgical meeting in the world (American Pediatric Surgical Association – APSA in Boston) there was not a single abstract on the subject presented. They seemed to be more interested in dancing robots and the experience of affirmative action in American surgical programs than real diseases. Whereas in China, they were able to hold the 2nd International Symposium on Biliary Atresia in a big 21st century auditorium in a city no one has heard of – Xiamen – and attract a crowd of up to 200 people. The big centres in Shanghai and Beijing are vying for attention and because they are the centres with the biggest throughout of affected infants in the world – with 1 to 2 newly diagnosed infants every week – things can happen. The international contingent at this meeting was; surgeon Paul Tam from the Hong Kong group, acting here as the bridge from the West to the East; Jorge Bezzera – one of the leading hepatologists of his generation from Cincinnati; Masaki Nio – the heir to Morio Kasai working in Sendai, Japan and myself from Stockport, working in Camberwell, London (FIG 3). Dr Bezzera is a dedicated researcher using the mice model of BA. He was presenting some interesting work on how the microbiological milieu and how the proportions of certain bacteria in the mother mouse might affect whether or not the offspring developed the disease when exposed to a virus. Prof. Nio is more of straightforward surgeon but as he now leads the Sendai unit he is familiar with all the adult survivors treated by Prof. Kasai. Sadly, he then told of how the longest living survivor recently died in her 60s. She actually was born with a “cystic biliary atresia” and never had an actual “Kasai” operation. Kasai has simply joined the cyst to a loop of bowel, which was good enough to clear her jaundice for many, many years but eventually had to be revised in the patient’s 50s. And though at that operation they removed all the obvious bile duct tissue, which had become scarred and filled with stones and infection, some years after that she developed cancer in the remnant and died as a result.

Part of Dr Bezzera’s talk concerned the use of novel biomarkers to differentiate BA from other liver diseases which present in infancy simply with conjugated jaundice. Together with a team from the Chinese city of Wuhan, they looked at levels of serum MMP-7 (matrix metalloproteinase) in a group 135 infants being evaluated for cholestasis [2]. Use of this test and a cut-off value of 52 ng/mL was able to discriminate those who turned out to have BA from the rest who did not – with a sensitivity of 99% which is extraordinary (FIG 4).

My presentation centred on medical or at least pharmacological methods to improve surgical results so I talked on the value of steroids after surgery and simultaneously using anti-viral therapy if the affected infant also showed exposure to the cytomegalovirus (CMV). You’ll remember that the CLDF funded the first ever randomised, placebo-controlled trial of steroids in the early 2000s [3]. Now as Jorge Bezzera actually authored the later American paper which suggested that steroids had no effect I was expecting a punch-up. As it happens, he was also unhappy with the interpretation of their own work and now (like most of the rest of the world) gives steroids to his younger patients!

One of the talking points was the role of genetics in infants born with BA. Paul Tam’s group had identified certain genes in their Han Chinese population which seemed to be more common in affected infants, and particularly in females. These so-called susceptibility genes – ADD3 is an example from these Chinese studies[4], may increase the risk of the disease although are not thought to be the cause of the disease.

As you know BA is a complex, mysterious disease but one thing we do know Is that there is more than one type or variant. We characterised one of these variants back in 1992 and named it as the Biliary Atresia Splenic Malformation syndrome, a bit of a mouthful, and therefore always shortened to BASM [5]. It has always been likely to have a significant genetic component as there is involvement of other

developing organs such as the spleen but previous work has not really been conclusive. So, recently the big American consortium, ChilLDren, funded a research project to try and identify such a gene [6]. They found that mutations in a gene called PKD1L1 were present in about 5% of their BASM infants. Interestingly this gene seems to play a significant role in embryonic life by controlling the cilia of certain cells. These cilia are hair-like processes on the outside of cell walls which are capable of movement and can beat rhythmically. This actually provides a connection with one of the other components of the BASM syndrome, that of situs inversus. In this condition the abdominal organs are the wrong-way round or have a mirror image relationship with the normal situation. So, for example the liver is on the left, not the right and the stomach is on the right not the left. It is thought that the normal beating of cilia very early on in gestation determines which side of the body each organ is on. Failure to beat properly leaves it to chance and therefore the possibility of situs inversus.

One demonstration of the power and size of this American research consortium was the way this research was splashed to the media (FIG 5a b). It is fine work no doubt but it is not the first gene to be associated and it certainly ain’t the cause in the rest of the population with BA. It was found in only 5% of a variant that accounts for only 10% of all those born here in the UK. This kind of spin is all to common and is driven by a desire to expose your work as rapidly as possible to try and generate funds (and salaries) for the next big project.

My last overseas adventure just a day after returning from China was as an invitee to a big adult-centred surgical conference on hepato-biliary-pancreatic disease in Amsterdam. As one might imagine this was centred largely on liver and pancreatic cancer in the elderly but the new technology involving robot surgery was interesting -not that we will be able to afford it in Kings of course! Anyway, I was invited, probably as the token paediatric surgeon, to address a smaller sub-meeting. My content was largely on the lessons and virtues of centralisation of resources, something which the CLDF backed in the 1990s resulting in todays arrangements. In fact, following our lead: Switzerland, The Netherlands, Denmark, Norway, Finland and now Sweden have all centralised their practice. Do you know we in

the UK have the lowest median time to Kasai operation in the world – its 49 days. This is lower even than in those countries which screen for the disease using stool colour charts. We also have the 2nd best outcomes in terms of clearance of jaundice – now around 65-70%. The Japanese still are 5% or so better than that.

What’s on the horizon? We are in the final stages of planning of the 2nd International BARD (BA and related diseases) Conference. This will be held to follow the BAPS (British Association of Paediatric Surgeons) conference in the delightful Belgian mediaeval city of Bruges on the 10th and 11th July 2020. Anyone with any interest in biliary atresia, parent, specialist nurse, clinician, researcher is welcome to attend and details will follow shortly. CLDF will certainly be there!

Prof Mark Davenport ChM FRCS (Paeds)

Consultant Surgeon, Kings College Hospital, London Mark.davenport@nhs.net

Instagram: profmarkdav

References:

1. Friedmacher F, Ford K, Davenport M. Biliary atresia: a scientometric analysis of the global research architecture and scientific developments. J Hepatobiliary Pancreat Sci. 2019; 26:201-210

2. Yang L, Zhou Y, Xu PP, et al. Diagnostic accuracy of Serum Matrix Metalloproteinase-7 for biliary atresia. Hepatology. 2018; 68: 2069-2077.

3. Davenport M, Stringer MD, Tizzard SA, McClean P, Mieli-Vergani G, Hadzic N. Randomized, double-blind, placebo-controlled trial of corticosteroids after Kasai portoenterostomy for biliary atresia. Hepatology. 2007; 46: 1821-7.

4. Cheng G, Chung PH, Chan EK, et al. Patient complexity and genotype-phenotype correlations in biliary atresia: a cross-sectional analysis. BMC Med Genomics. 2017 ;10:22.

5. Davenport M, Savage M, Mowat AP, Howard ER. Biliary atresia splenic malformation syndrome: an etiologic and prognostic subgroup. Surgery. 1993; 113: 662-8.

6. Berauer JP, Mezina AI, Okou DT, et al (ChiLDReN). Identification of Polycystic Kidney Disease 1 Like 1 Gene Variants in Children With Biliary Atresia Splenic Malformation Syndrome. Hepatology. 2019 Jan 21. doi: 10.1002/hep.30515. [Epub ahead of print]

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