Digestive system diseases

The increasing use of split livers for in children has effectively increased the donor organ supply

James Neuberger

Objective: To examine whether non‐medical switching of patients with inflammatory bowel disease (IBD) from originator infliximab to a biosimilar (CT‐P13, Inflectra) is safe and clinically non‐inferior to continued treatment with originator infliximab. Design: Prospective, open label, multicentre, parallel cohort, non‐inferiority study in seven Australian hospitals over 48 weeks, May 2017 – October 2019. Participants: Adults (18 years or older) with IBD receiving maintenance originator infliximab (Remicade) who had been in steroid‐free clinical remission for at least 12 weeks. Intervention: Managed program for switching patients in four hospitals from originator to biosimilar infliximab (CT‐P13); patients in three other hospitals continued to receive originator infliximab (control). Main outcome measures: Clinical disease worsening requiring infliximab dose escalation or change in therapy. Results: The switch group included 204 patients, the control group 141 patients with IBD. Ten patients in the control group (7%) and 16 patients switched to CT‐P13 (8%) experienced clinical deterioration; the adjusted risk difference (control v switch group) was –1.1 percentage points (95% CI, –6.1 to 8.2 percentage points), within our pre‐specified non‐inferiority margin of 15 percentage points. Serious adverse events leading to infliximab discontinuation were infrequent in both the switch (six, 3%) and control (six, 4%) groups. Conclusion: Switching patients with IBD from originator to biosimilar infliximab is safe and non‐inferior to continuing treatment with originator infliximab. Moreover, the introduction of biosimilar infliximab, by increasing market competition, has resulted in substantial cost savings for the Pharmaceutical Benefits Scheme.

Craig Haifer · Ashish Srinivasan · Yoon‐Kyo An · Sherman Picardo · Daniel Langenberg · Shankar Menon · Jakob Begun · Simon Ghaly · Lena Thin

To the Editor: The recent discussion on chronic liver disease and ultrasonographic surveillance is welcome.1 Over two decades ago, investigators at Westmead Hospital in Sydney showed that ultrasonographic surveillance of 232 Australian patients with chronic liver disease (most of whom had cirrhosis) was superior to α‐fetoprotein in the detection of hepatocellular carcinoma (HCC).2 In this research, we detected six HCCs with ultrasound for an annual cohort incidence of 1.4%; we calculated that each HCC detected cost $US8472 (in 1998 dollar terms). Further, the superior detection of HCCs with ultrasonography did not translate into improved survival either because of tumour multicentricity, metastases at diagnosis, or patient comorbidity factors precluding surgery. Since that time, our technical expertise in liver screening with ultrasound has grown. Nevertheless, we remain concerned by the relatively poor sensitivity compared with computed tomography or magnetic resonance imaging. In addition, specialists in diagnostic imaging understand that the distorted liver architecture from cirrhosis and the presence of regenerating nodules pose significant challenges in distinguishing HCC from benign lesions. While published meta‐analyses3,4 offer some promise, they are by their very nature highly selective in the data evaluated and seldom consider the downstream costs of false positive tests. It is perhaps unsurprising that recent appropriateness criteria guidelines from the American College of Radiology sound a note of caution on the role of ultrasound in this context.5 Despite the above, there remains a need to perform a contemporary analysis of the potential benefits and costs of screening in patients with cirrhosis in Australian settings. However, as a recent Australian HCC surveillance study6 has concluded, it is difficult to interpret survival outcomes from selective retrospective studies, and conducting a randomised controlled trial may be nigh on impossible.

George Larcos

Objective: To assess long term graft and patient survival after donor liver retransplantation in children in Australia and New Zealand during 1986–2017; to determine the factors that influence survival. Design: Retrospective cohort analysis (registry data). Setting, participants: Australia and New Zealand Liver Transplant Registry data for all liver retransplantations in children (under 18 years of age), 1986–2017, in all four paediatric and six adult liver transplantation centres in the two countries. Main outcome measures: Graft and patient survival at one, 5, 10 and 15 years. Results: 142 liver retransplantations were undertaken in children (59 during 1986–2000, 83 during 2001–2017). Kaplan–Meier survival analysis indicated that survival was significantly greater during 2001–2017 than 1986–2000 (P < 0.001). During 2001–2017, graft survival one year after retransplantation was 84%, at 5 years 75%, at 10 years 70%, and at 15 years 54%; patient survival was 89% at one year, 87% at 5 years, 87% at 10 years, and 71% at 15 years. Median time between transplantations was 0.2 years (IQR, 0.03–1.4 years) during 1986–2000, and 1.8 years (IQR, 0.1–6.8 years) during 2001–2017 (P = 0.002). The proportion of graft failures that involved split grafts was larger during 2001–2017 (35 of 83, 42%) than 1986–2000 (10 of 59, 17%). Graft type, cause of graft failure, and number of transplants did not influence survival following retransplantation. Conclusion: Survival for children following retransplantation is excellent. Graft survival is similar for split and whole grafts. Children on the liver waiting list requiring retransplantation should have the same access to donor grafts as children requiring a first transplant.

Angus W Jeffrey · Gary P Jeffrey · Michael Stormon · Gordon Thomas · Edward O'Loughlin · Albert Shun · Winita Hardikar · Robert Jones · John McCall · Helen Evans · Graham Starkey · Peter Hodgkinson · Looi C Ee · David Moore · Catherine Mews · Geoff W McCaughan · Peter W Angus · Alan J Wigg · Michael Crawford · Jonathan Fawcett

A 48-year-old man presented with a 3-month history of increasing diarrhoea 8–10 times per day, cramping abdominal discomfort and weight loss of 8kg

Andrew S Vanlint · Patricia Kaazan · Marco Kwok · Robert V Bryant · Marie Ooi · Narin Bak · Sam Costello

To the Editor: The narrative review of diverticular disease by You and colleagues1 is most welcome. While highlighting the ubiquity of the problem and factors that facilitate the development of the disease and outlining an evidence‐based strategy to assess and manage the condition, it is also important to note patient factors, such as comorbidities treated with certain medications, which may facilitate uncomplicated disease becoming complicated. Further, commencing certain medications in patients with diverticular disease may often have unappreciated risks.2,3,4,5 Patients in the prevalent age group often have comorbidities, many of which may be treated with non‐steroidal anti‐inflammatory drugs, corticosteroids, opioids2 and, occasionally, with immunosuppressive therapy. Of these medications, the risk of perforations is highest with corticosteroids.4,5 Specifically, corticosteroids used in the management of rheumatic disease may increase the risk of diverticular abscess perforation 30‐fold.5 The association between complications of diverticular disease and the administration of various medications, particularly corticosteroids, must be emphasised,2,3,4,5 as both uncomplicated and complicated disease may present with non‐specific symptoms, suggesting a broad differential diagnosis.1 Medications must not be overlooked as an iatrogenic risk for complications for both existing and new users.

Mark H Arnold

To the Editor: Thiopurines are used in oncology, immunology and inflammatory bowel disease (IBD). In the coronavirus disease 2019 (COVID‐19) pandemic, patients taking thiopurines face uncertainty as to the risk of serious complications or death if infected. Traditionally, thiopurine use has been associated with an increased risk of opportunistic viral infections.1,2,3 A large IBD registry study found that using thiopurines and having active disease were associated with a higher risk of serious viral infection.3 However, all identified causative agents were species of the Herpesviridae genus.1,2,3 The risk associated with thiopurine use can therefore not yet be generalised to other virus genera, and indeed only corticosteroid use is associated with risk of contracting influenza in patients with IBD.4 COVID‐19 is caused by a novel coronavirus — the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) — and there are no available data from previous coronavirus strains such as SARS‐CoV or Middle East respiratory syndrome coronavirus (MERS‐CoV) to allow for estimation of risk in patients taking thiopurines.3,5 Although, intuitively, immunosuppression with thiopurines may increase the risk from COVID‐19, there are in vitro and in silico data to suggest that thiopurines constrain maturation of MERS‐CoV via inhibition of a viral protease.5 Although this study has not been replicated for COVID‐19 or progressed into animal models, it does raise the possibility that thiopurines use may not necessarily increase the risk of contracting COVID‐19. Thiopurine withdrawal is associated with a 12‐month relapse rate of 17–53% in patients with Crohn's disease and 11–77% in patients with ulcerative colitis.6 This is an important consideration in COVID‐19, as disease relapse requiring steroid use has previously been associated with increased risk of viral complications.3,4 The consequences of thiopurine withdrawal due to COVID‐19 are not yet clear and this information is eagerly awaited as many centres collect prospective data. Preliminary data from SECURE‐IBD — a COVID‐19 database for IBD — report 87 COVID‐19 cases to date in patients taking thiopurines, of whom 52 were managed as outpatients and 35 were admitted to hospital, with two reported deaths.7 These evolving data provide cautious support for the relative safety of thiopurines but cannot be interpreted conclusively in the setting of the rapidly evolving situation. Perhaps the best advice we can currently offer patients is that effective control of disease may carry less risk than poorly considered withdrawal of therapy. The Gastroenterological Society of Australia has issued recommendations that the minimum level of immunosuppression should be continued to control disease although a drug holiday may be considered in some patients with long term stable disease.8 This dilemma highlights the importance of online registries to gather vital data as we work together as a profession to provide evidence‐based advice for our patients during this pandemic.

Thomas M Goodsall · Samuel P Costello · Robert V Bryant

Early empirical evidence provides grounds for optimism about eliminating HCV by 2030

Marianne Martinello · Behzad Hajarizadeh · Gregory J Dore

Timely diagnosis of cirrhosis and HCC surveillance using ultrasound may help improve patient outcomes

Gary P Jeffrey · Louisa Gordon · Grant Ramm

Colorectal cancer is an important cause of morbidity and mortality in Australia.1 The National Bowel Cancer Screening Program (NBCSP) aims to detect the disease early by offering faecal occult blood testing (faecal immunochemical test, FIT) to people aged 50–74 years.2 The expansion of the NBCSP has been paralleled by increased numbers of FITs outside the program (community‐initiated FITs) for a number of reasons, including the presence of symptoms. We investigated whether colonoscopy services should provide endoscopies to patients with positive FIT results with the same priority, regardless of whether the test was instigated by the NBCSP, by analysing data from the Newcastle Direct Access Colonoscopy Service (DACS) for the period 2014–18. The DACS manages all patients in the same manner: a positive FIT result leads to assessment for colonoscopy.3,4 Ethics approval was granted by the Hunter New England Human Research Ethics Committee (reference, AU201608‐01). All data were recorded prospectively. Findings were categorised according to surveillance categories endorsed by the Gastroenterological Society of Australia and the Colorectal Surgical Society of Australia and New Zealand.5 Data accuracy was confirmed by reviewing the primary sources for 10% of patients. We identified 2693 patients referred for screening colonoscopy between 1 July 2014 and 30 June 2018; 1439 (53%) had had community‐initiated FITs (Box 1). After excluding 318 patients who did not attend or were lost to follow‐up (community‐initiated, 200; NBCSP, 118) and ten patients with poor bowel preparation and no follow‐up colonoscopy during the study period, 2365 complete screening colonoscopy outcomes were analysed: 1233 following community‐initiated and 1132 following NBCSP testing. With these sample sizes, the study had 80% power to detect differences in colonic neoplasia rate ranging from 16 percentage points (assumed prevalence, 50%) to two percentage points (assumed prevalence, 3%). Z‐tests were used to calculate P values, and Wald tests (two‐tailed) for calculating confidence intervals (CIs) for the differences between the two groups. Differences between the two groups in the proportion of patients with each specific finding are presented with 99% asymptotic CIs to control for multiple testing. Colonoscopy quality was high: the completion rate (defined as either caecal intubation, reaching an ileocolic anastomosis, or reaching an obstructing mass lesion) was 97.1% (community‐initiated, 1193 of 1233, 96.8%; NBCSP, 1104 of 1132, 97.5%), and the adenoma detection rate was 49%, exceeding international benchmarks for either symptomatic or screening patients (for screening: at least 25% in men and 15% in women;6 for populations enriched with patients with positive FIT results: 35%7). The rate of colorectal neoplasia (malignant or pre‐malignant) was similar in the two groups. Importantly, the difference in the rates of adenocarcinoma was not statistically significant (community‐initiated, 4.0%; NBCSP, 2.7%; difference, 1.3 percentage points [99% CI, –0.6 to 3.3 percentage points]; P = 0.09). The only statistically significant difference by type was that the incidence of high risk adenoma was slightly higher in the NBCSP group (22.9% v 17.2%; difference, 5.7 percentage points [99% CI, 1.4–10 percentage points]; P < 0.001) (Box 2). We found that the incidence and detection rates of colorectal neoplasia in people aged 50–74 years were similar for people with positive results for NBCSP or community‐initiated FITs. The large population in our study means that it provides colonoscopy providers strong evidence that evaluation should be performed equally promptly for patients with positive results from NBSCP and community‐initiated FITs. Box 1 – Demographic characteristics of the 2693 patients with positive faecal immunochemical test results and referred to the Newcastle Direct Access Colonoscopy Service for colonoscopy, 2014–18 Faecal immunochemical test Total Community‐initiated NBCSP Number of patients 1439 1254 2693 Sex Women 675 559 1234 Men 764 695 1459 Age (years), mean (SD) 62.9 (6.8) 63.2 (7.3) 63.1 (7.0) Numbers of patients 50–54 years 213 147 360 55–59 years 280 271 551 60–64 years 312 212 524 65–69 years 330 288 618 70–74 years 304 336 640 NBCSP = National Bowel Cancer Screening Program; SD = standard deviation. Box 2 – Differences in colonoscopy outcomes for people who had community‐initiated (1233 patients) or NBCSP (1132 patients) faecal immunochemical tests CI = confidence interval; NBCSP = National Bowel Cancer Screening Program. *Large sessile polyps (> 2 cm) or malignant polyps. † Between values for community‐initiated and NBCSP groups.

Simon Whitcher · Monique Magnusson · Jon Gani · Christopher Oldmeadow · Peter G Pockney

Patients with ruptured HCC should be treated with the aim of long term survival

Natassia P Tan · Ammar Majeed · Stuart K Roberts · Paul J Gow · Penny Hey · Xianjun Mah · Mark Goodwin · Siddharth Sood · John Lubel · Amanda Nicoll · Anouk Dev · Sally J Bell · William W Kemp

The long term benefits and risks of gluten avoidance for people without coeliac disease are unknown

Amanda Cartee · Joseph A Murray

Self-reported wheat sensitivity was reported by 14% of respondents in both 2015 and 2018

Michael DE Potter · Michael P Jones · Marjorie M Walker · Natasha A Koloski · Simon Keely · Gerald Holtmann · Nicholas J Talley AC

Infants with GORD should first be distinguished from those with physiological GOR and then be managed in a step-wise fashion, using non-pharmacological measures where possible and pharmacological measures where necessary

Robert N Lopez · Daniel A Lemberg

An 88-year-old woman presented with 2 months of right upper quadrant pain, weight loss, and 3 days of fevers

Sudharsan Venkatesan · Henrik Falhammar

FC testing of patients with lower gastrointestinal symptoms could reduce the number with functional disorders undergoing colonoscopy

Yoon‐Kyo An · David Prince · Fergus Gardiner · Teresa Neeman · Ecushla C Linedale · Jane M Andrews · Susan Connor · Jakob Begun

To the Editor: I thank Whitfield and colleagues for their article about hyperemesis gravidarum and abnormal liver function in pregnancy.1 In a 15‐month prospective study in South West Wales, abnormalities of liver function were present in 3% of pregnancies.2 In managing pregnant women with hepatic dysfunction, it is important to consider uncommon causes of liver disease that may be associated with serious maternal and fetal morbidity and mortality if untreated. Addison disease is a rare but potentially life‐threatening condition that may imitate hyperemesis gravidarum in presenting with vomiting, weight loss, postural hypotension and hyponatraemia.3,4 Addison disease has also been associated with elevated hepatic transaminases in 16 published cases, reversing with glucocorticoid replacement.5 In excluding Addison disease, the physiological rise in cortisol during pregnancy must be considered using trimester‐specific reference ranges for short synacthen testing.6 In the pregnant woman with unexplained liver disease and fever, acyclovir should be administered empirically, given the absence of cutaneous vesicles in up to 80% of affected patients and the extreme maternal and fetal mortality associated with untreated herpes simplex virus hepatitis.7 Budd–Chiari syndrome should be considered with abnormal liver function in pregnancy with abdominal pain, hepatomegaly and ascites. Additionally, the use of herbal and over‐the‐counter medications should be sought in pregnant women with abnormal liver function, given the high rates of complementary and alternative medicine use in pregnancy and their potential to cause liver injury.8 Investigations need to be interpreted with regard to gestational physiological changes, as copper, ceruloplasmin, α‐1 antitrypsin and alkaline phosphatase levels rise significantly in pregnancy. Serum lipase levels are commonly elevated in hyperemesis gravidarum — levels up to ten times normal have been reported in the absence of pancreatitis.9 Antithrombin III levels may be useful to distinguish acute fatty liver of pregnancy from pre‐eclampsia with haemolysis, elevated liver enzymes and low platelets.10 Bile acid levels are not specific for intrahepatic cholestasis of pregnancy, being elevated in many hepatic disorders including non‐alcoholic fatty liver disease. Twenty per cent of women with pruritus typical of intrahepatic cholestasis of pregnancy have normal bile acids and liver function at presentation, and symptoms may precede abnormal biochemistry by up to 6 weeks.11 In addition to ondansetron and glucocorticoids, mirtazapine has been effective in the management of hyperemesis gravidarum in case reports.12

Adam Morton

Universal tumour testing strategies for guiding germline genetic testing are likely to be cost-effective compared with no testing

Yoon‐Jung Kang · James Killen · Michael Caruana · Kate Simms · Natalie Taylor · Ian M Frayling · Tristan Snowsill · Nicola Huxley · Veerle MH Coupe · Suzanne Hughes · Victoria Freeman · Alex Boussioutas · Alison H Trainer · Robyn L Ward · Gillian Mitchell · Finlay A Macrae · Karen Canfell

The Chilaiditi sign refers to the interposition of intestine (usually transverse colon) between the liver and the diaphragm

Phillippa Gray

A 76- year- old man from rural Victoria presented with 4 months of difficulty swallowing due to a painful, large, non-healing tongue ulcer

Michael B MacIsaac · Sasha R Fehily · Stephen Muhi · Linda Yang · Penelope A McKelvie · Cameron J Jeremiah · Barbara Demediuk

The availability of paracetamol needs to be restricted to stem the increasing number of overdoses

Rose Cairns · Jared A Brown · Claire E Wylie · Andrew H Dawson · Geoffrey K Isbister · Nicholas A Buckley

Diverticular disease is a common gastrointestinal disorder with significant health burden; recent evidence is changing practice

Hayley You · Amy Sweeny · Michelle L Cooper · Michael Von Papen · James Innes

A 26- year- old man presented to the (ED) overnight with severe and disabling abdominal pain

David J Holland · Michael J Holland

Evidence suggests that appropriate hepatitis B virus (HBV) screening before B cell-depleting therapy is frequently not performed

Sanjivan Mudaliar · Ken Liu · Simone I Strasser